Conditions: Paroxysmal Nocturnal Hemoglobinuria (PNH)
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 19
Healthy volunteers: no

Brief summary:
The purpose of this study is to enable continued access to zilucoplan (RA101495) for patients with paroxysmal nocturnal hemoglobinuria (PNH) after they complete a zilucoplan clinical study.

Detailed description:

Arms:
arm 1: Subjects will continue to receive the final maintenance dose they were receiving in the qualifying study

Interventions: intervention 1: Zilucoplan (RA101495)
Intervention descriptions: intervention 1: Subjects will continue to receive the final maintenance dose they were receiving in the qualifying study.

Protocol document:
Prot_000.pdf: 
RA101495  
Protocol RA101495-01.202 
Version 1.1 
CONFIDENTIAL 
1 
1 
TITLE PAGE 
 
RA PHARMACEUTICALS, INC. 
RA101495-01.202: A MULTICENTER, OPEN-LABEL, UNCONTROLLED, 
EXTENSION STUDY OF RA101495 IN SUBJECTS WITH PAROXYSMAL NOCTURNAL 
HEMOGLOBINURIA WHO HAVE COMPLETED A RA101495 CLINICAL STUDY 
 
Protocol Number:  
RA101495-01.202 
Indication Studied: 
Paroxysmal Nocturnal Hemoglobinuria 
Developmental Phase of Study: 
2 
EudraCT Number: 
2016-003523-34 
Company/Sponsor Signatory: 
Ra Pharmaceuticals, Inc.  
Protocol Version: 
Version 1.1 
Release Date of Protocol: 
20 October  2016 
 
 
 
This study will be conducted by Ra Pharmaceuticals, Inc. and affiliates in compliance with the 
protocol, Good Clinical Practice, and all other applicable regulatory requirements, including the 
archiving of essential documents. 
CONFIDENTIAL 
This document contains confidential information. Any use, distribution, or disclosure without the 
prior written consent of Ra Pharmaceuticals, Inc. is strictly prohibited except to the extent 
required under applicable laws or regulations. Persons to whom the information is disclosed must 
be informed that the information is confidential and may not be further disclosed by them.
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


RA101495 
Protocol RA 101495-0 1.202 
Version 1.1 
SPONSOR SIGNATURE PAGE 
Protocol Title: A Multicenter, Open-label, Uncontrolled, Extension Study ofRA101495 in 
Subjects with Paroxysmal Nocturnal Hemoglobinuria Who Have Completed a RA101495 
Clinical Study 
Protocol Date: 20 October 2016 
Signature of Ra Pharmaceuticals, Inc. 
 
Name ofRa Pharmaceuticals, Inc. 
: 
 
 
Ra Pharmaceuticals, Inc. 
87 Cambridge Park Drive 
Cambridge, MA 02140 
 
 
CONFIDENTIAL 
2 
(Dito/16 
Date 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


RA101495  
Protocol RA101495-01.202 
Version 1.1 
CONFIDENTIAL 
3 
CENTER INVESTIGATOR SIGNATURE PAGE 
Protocol Title: A Multicenter, Open-label, Uncontrolled, Extension Study of RA101495 in 
Subjects with Paroxysmal Nocturnal Hemoglobinuria Who Have Completed a RA101495 
Clinical Study 
Protocol Version 1.1 
Date: 20 October  2016 
 
1. I have received and reviewed the Investigator's Brochure for RA101495. 
2. I have read this protocol and agree that the study is ethical. 
3. I agree to conduct the study as outlined in this protocol and in accordance with all applicable 
regulations and guidelines, including the current International Conference on Harmonisation 
Good Clinical Practice Guideline. 
4. I agree to maintain the confidentiality of all information received or developed in connection 
with this protocol. 
5. I agree that all electronic signatures will be considered the equivalent of a handwritten 
signature and will be legally binding. 
 
 
________________________________________________ 
_________________ 
Signature of Principal Investigator 
 
 
 
 
Date 
 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


RA101495  
Protocol RA101495-01.202 
Version 1.1 
CONFIDENTIAL 
4 
2 
SYNOPSIS 
Name of Sponsor 
Protocol number 
Investigational product 
Ra Pharmaceuticals, 
Inc. 
RA101495-01.202 
RA101495 
Protocol title 
A Multicenter, Open-label, Uncontrolled, Extension Study of 
RA101495 in Subjects with Paroxysmal Nocturnal Hemoglobinuria 
Who Have Completed a RA101495 Clinical Study 
Phase of clinical 
development 
2  
Rationale for the study The purpose of this study is to enable continued access to 
RA101495 for subjects with paroxysmal nocturnal hemoglobinuria 
(PNH) after they complete a Ra Pharmaceuticals sponsored clinical 
study with RA101495.  The study will evaluate long-term safety, 
tolerability, preliminary efficacy,  pharmacokinectics (PK), and 
pharmacodynamics (PD).  
Study objectives 
 To provide access to RA101495 for subjects with PNH who 
have completed a Ra Pharmaceuticals sponsored RA101495 
study, have demonstrated clinical benefit,and who wish to 
continue receiving RA101495 for treatment of PNH 
 To evaluate the long-term safety and tolerability of RA101495 
administered in subjects with PNH who have completed a Ra 
Pharmaceuticals sponsored RA101495 clinical study 
 To evaluate the long-term preliminary efficacy of RA101495 
administered to subjects with PNH who have completed a Ra 
Pharmaceuticals sponsored RA101495 clinical study 
 To obtain periodic PK and PD data to confirm long-term 
maintenance of steady-state RA101495 plasma levels and 
sustained inhibition of hemolysis and complement. 
Study design 
The design is a multicenter, open-label, extension study for subjects 
with PNH who have successfully completed a qualifying Ra 
Pharmaceuticals sponsored RA101495 clinical study. Subjects will 
continue to receive the final maintenance dose they were receiving 
in the qualifying study, as long as safety, tolerability, PK and PD 
data (from the qualifying study and this extension study) continue 
to demonstrate benefit. If additional data support a change in dose 
level for an individual subject in this extension study, investigators 
may increase or decrease the maintenance dose level, based on 
safety and PD findings, and in consultation with the medical 
monitor. All subjects will continue to be followed carefully for any 
evidence of meningococcal and/or other infection. 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


RA101495  
Protocol RA101495-01.202 
Version 1.1 
CONFIDENTIAL 
5 
Name of Sponsor 
Protocol number 
Investigational product 
Ra Pharmaceuticals, 
Inc. 
RA101495-01.202 
RA101495 
Duration of study 
participation 
The investigational medicinal product (IMP) (RA101495) will 
continue to be provided by the sponsor until RA101495 is approved 
and available in the territory, or the sponsor terminates 
development of RA101495 for PNH. In countries where RA101495 
is not approved or marketed, but in which sponsored clinical studies 
have been conducted, subjects may continue to receive RA101495 
through a compassionate use pathway. 
Study location and 
planned number of 
study centers 
All countries and centers participating in a RA101495 PNH clinical 
study. Planned locations include one or more of the following 
countries, Australia, Argentina, Canada, Germany, New Zealand, 
UK, and USA.  
Planned number of 
subjects 
Up to 28 subjects (i.e. all subjects participating in a RA101495 
PNH study). 
Study population 
To be eligible for this study, subjects must meet ALL of the 
following inclusion criteria: 
1. Completion of a qualifying Ra Pharmaceuticals sponsored 
RA101495 PNH study 
2. Evidence of ongoing clinical benefit in the opinion of the 
Investigator 
3. Completion of the informed consent procedure, including 
signing and dating the informed consent form (ICF)  
4. Female subjects of child bearing potential must have had a 
negative pregnancy test at the completion of the qualifying 
study prior to first dose of study drug in this extension study 
5. Sexually-active female subjects of child-bearing potential (i.e. 
women who are not post-menopausal or who have not had a 
bilateral oophorectomy, hysterectomy, or tubal ligation) and all 
male subjects (who have not been surgically sterilized by 
vasectomy) must agree to use effective contraception during the 
study. Effective contraception is defined as: 
o Hormonal contraception (e.g. oral contraceptive, 
transdermal contraceptive, contraceptive implant, or 
injectable hormonal contraceptive) for at least 3 months 
prior to study drug administration, throughout the study, and 
for 4 weeks after the last dose of study drug. 
o Double-barrier birth control (e.g. male condom, female 
condom, diaphragm sponge, or cervical cap together with 
spermicidal foam/gel/film/suppository) starting at the 
Screening Visit, throughout the study, and for 4 weeks after 
the last dose of study drug. 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


RA101495  
Protocol RA101495-01.202 
Version 1.1 
CONFIDENTIAL 
6 
Name of Sponsor 
Protocol number 
Investigational product 
Ra Pharmaceuticals, 
Inc. 
RA101495-01.202 
RA101495 
o Intrauterine contraception/device starting at the Screening 
Visit, throughout the study, and for 4 weeks after the last 
dose of study drug. 
o Total abstinence from sexual intercourse for at least one 
complete menstrual cycle prior to the Screening Visit, 
throughout the study, and for 4 weeks after the last dose of 
study drug  
o Maintenance of a monogamous relationship with a male 
partner who has been surgically sterilized by vasectomy. 
Subjects who meet ANY of the following exclusion criteria must be 
excluded from the study: 
1. Platelet count <30,000/µL or absolute neutrophil count (ANC) 
<500 cells/µL at Screening 
2. Calculated glomerular filtration rate of <30 mL/min/1.73m2 
based on modification of diet in renal disease (MDRD) equation 
at Screening 
3. Elevation of liver function tests: alanine aminotransferase 
(ALT) >2xULN or Direct Bilirubin and Alkaline Phosphatase 
both >2xULN 
4. Elevation of amylase or lipase >2xULN 
5. History of meningococcal disease 
6. Current systemic infection or suspicion of active bacterial 
infection 
7. Pregnant, planning to become pregnant, or nursing female 
subjects 
8. Active malignancy requiring surgery, chemotherapy, or 
radiation within the prior 12-months (subjects with a history of 
malignancy who have undergone curative resection or 
otherwise not requiring treatment for at least 12-months prior to 
Screening with no detectable recurrence are allowed) 
9. History of any significant medical or psychiatric disorder that in 
the opinion of the investigator would make the subject 
unsuitable for participation in the study  
10. With the exception of RA101495, other treatments with any 
investigational medicinal product or investigational device 
within the 30 days prior to Screening or participation in another 
concurrent clinical trial involving a therapeutic intervention 
(participation in observational studies and/or registry studies is 
permitted)  
11. Unable or unwilling to comply with the requirements of the 
study 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


RA101495  
Protocol RA101495-01.202 
Version 1.1 
CONFIDENTIAL 
7 
Name of Sponsor 
Protocol number 
Investigational product 
Ra Pharmaceuticals, 
Inc. 
RA101495-01.202 
RA101495 
Endpoints and 
Assessments 
Safety and Tolerability 
Safety assessments will include evaluation of AEs and SAEs 
(including major adverse vascular event (MAVE criteria), clinical 
laboratory tests, ECGs, vital signs, and physical examinations. 
Safety evaluations will also include a determination of anti-drug 
antibodies (ADA). 
Efficacy: 
Serum LDH levels, total bilirubin, total hemoglobin, free 
hemoglobin, haptoglobin, reticulocytes, and hemoglobinuria, at 
each of the scheduled assessment time-points.  
Pharmacokinetic:   
 Plasma concentrations of RA101495 and its major metabolites 
 Maximum plasma concentration (Cmax)  
 Time corresponding to Cmax (tmax) 
 Area under the drug concentration-time curves (AUC0-t) 
Pharmacodynamic:  
 CH50 
 sheep RBC (sRBC) lysis for classical complement pathway 
 Wieslab enzyme-linked immunosorbent assay (ELISA) for 
alternative complement pathway 
 C5 levels 
Exploratory endpoints 
 Quality of life (QOL) questionnaires (e.g. EORTC QLQ-C30 
and FACIT-Fatigue 
 Mechanistic biomarkers (e.g. complement function, 
complement proteins, biomarkers of inflammation, biomarkers 
for thrombosis, biomarkers of liver function) 
Statistical 
considerations 
Study Populations: The following study populations are defined: 
 Safety Population: All subjects who receive at least 1 injection 
of RA101495 on or after Day 1 of this extension study 
(RA101495-01.202) 
 Per Protocol Population: All subjects in the Safety Population 
who have no major protocol deviations 
 PK Population: All subjects in the Safety Population who have 
at least 1 plasma sample obtained for PK assessment 
 PD Population: All subjects in the Safety Population who have 
at least 1 plasma sample obtained for PD assessment 
General Considerations: Data will be summarized within each 
dose level separately. Where appropriate, data may be pooled 
across dose levels. 
A disposition of all consented subjects will be provided and will 
include a breakdown of subjects who consented, were treated, 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


RA101495  
Protocol RA101495-01.202 
Version 1.1 
CONFIDENTIAL 
8 
Name of Sponsor 
Protocol number 
Investigational product 
Ra Pharmaceuticals, 
Inc. 
RA101495-01.202 
RA101495 
discontinued treatment, and were lost to follow-up or withdrew 
consent. A summary of reasons for screen failures and treatment 
discontinuations will be provided. A summary of subjects included 
in each analysis population will be provided. 
Quantitative variables will be summarized with the mean, standard 
deviation (SD), median, and range. Categorical variables will be 
summarized using counts and proportions. 
Safety: Adverse events will be coded using the Medical Dictionary 
for Regulatory Activities (MedDRA) (version 18.0 or higher). 
Incidence rates for treatment-emergent AEs (TEAEs) by maximum 
severity and SAEs will be summarized. These summaries will be 
provided regardless of causality and for events that are considered 
related to treatment with RA101495. 
Quantitative laboratory endpoints will be summarized by dose level 
and time point and also by pooling dose levels. 
Descriptive statistics for ECG parameters (i.e. heart rate [HR], PR 
interval, RR interval, QRS interval, QT interval, QTcB interval, and 
QTcF interval) at each assessment time point will be presented. 
Descriptive statistics for vital signs (heart rate, body temperature, 
and blood pressure) will be presented. 
The complete set of physical examination findings will be provided 
in listings. Clinically significant physical examination 
abnormalities will be included and summarized as AEs if 
appropriate. 
Efficacy: Efficacy endpoints will be analyzed using descriptive 
statistics and graphical displays.  No formal statistical comparisons 
are specified. 
Pharmacokinetics: RA101495 and metabolite plasma 
concentrations will be summarized using descriptive statistics. No 
formal statistical comparisons are specified.  
Pharmacodynamics: Pharmacodynamics and efficacy endpoints 
will be summarized using descriptive statistics. No formal 
statistical comparisons are specified. 
Determination of Sample Size: Sample size will be determined by 
the number of eligible subjects completing a qualifying RA101495 
clinical study.  No formal statistical power calculations were 
performed. 
Interim Analysis: During the study, the Sponsor will conduct 
periodic interim analyses of the study data, which may include 
safety, tolerability, PK, PD and efficacy endpoints. 
 
 
 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


RA101495  
Protocol RA101495-01.202 
Version 1.1 
CONFIDENTIAL 
9 
 
3 
TABLE OF CONTENTS 
1 
TITLE PAGE ...............................................................................................................1 
2 
SYNOPSIS ....................................................................................................................4 
3 
TABLE OF CONTENTS ............................................................................................9 
4 
LIST OF ABBREVIATIONS AND DEFINITIONS ..............................................13 
5 
TIME AND EVENTS TABLE ..................................................................................15 
6 
INTRODUCTION......................................................................................................17 
6.1 
STUDY RATIONALE .......................................................................................................17 
7 
STUDY OBJECTIVES AND ENDPOINTS ............................................................18 
7.1 
OBJECTIVES ..................................................................................................................18 
7.1.1 
SAFETY ENDPOINTS ......................................................................................................18 
7.1.2 
EFFICACY ENDPOINTS ...................................................................................................18 
7.1.3 
PHARMACOKINETIC: .....................................................................................................18 
7.1.4 
PHARMACODYNAMIC ....................................................................................................18 
7.1.5 
EXPLORATORY ENDPOINTS ...........................................................................................19 
8 
STUDY DESIGN ........................................................................................................20 
8.1 
OVERVIEW OF STUDY DESIGN ......................................................................................20 
8.1.1 
SCREENING PERIOD .......................................................................................................20 
8.1.2 
TREATMENT PERIOD .....................................................................................................20 
8.2 
SUBJECT REGISTRATION PROCEDURES .........................................................................20 
8.2.1 
SCREENING AND ENROLLMENT .....................................................................................20 
8.2.2 
TREATMENT GROUP ASSIGNMENT ................................................................................21 
8.2.3 
BLINDING ......................................................................................................................21 
8.2.4 
DISCONTINUATION OF INVESTIGATIONAL MEDICINAL PRODUCT ..................................21 
8.2.5 
WITHDRAWAL FROM THE STUDY ..................................................................................22 
8.3 
EARLY STUDY TERMINATION .......................................................................................22 
8.4 
FINAL STUDY VISIT ......................................................................................................22 
9 
SELECTION OF STUDY POPULATION .............................................................23 
9.1 
INCLUSION CRITERIA ....................................................................................................23 
9.2 
EXCLUSION CRITERIA ...................................................................................................23 
9.3 
REMOVAL AND REPLACEMENT OF SUBJECTS IN THE STUDY .........................................24 
9.3.1 
PREMATURE DISCONTINUATION ...................................................................................24 
9.3.2 
REPLACEMENT OF SUBJECTS .........................................................................................25 
10 
INVESTIGATIONAL MEDICINAL PRODUCTS AND 
TREATMENTS..........................................................................................................26 
10.1 
STUDY TREATMENT ADMINISTRATION .........................................................................26 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


RA101495  
Protocol RA101495-01.202 
Version 1.1 
CONFIDENTIAL 
10 
10.1.1 
IDENTITY OF INVESTIGATIONAL PRODUCTS AND TREATMENT ......................................26 
10.1.2 
TREATMENT GROUPS ....................................................................................................26 
10.1.3 
DOSING SCHEDULE .......................................................................................................26 
10.1.4 
DOSE OR DOSING SCHEDULE MODIFICATIONS ..............................................................26 
10.1.4.1 
MISSED DOSE................................................................................................................27 
10.2 
STUDY TREATMENT MANAGEMENT ..............................................................................27 
10.2.1 
PREPARATION AND DISPENSING ....................................................................................27 
10.2.2 
STUDY DRUG SUPPLY, STORAGE, AND HANDLING .......................................................27 
10.2.3 
DISPOSAL, RETURN, OR RETENTION OF UNUSED DRUG ................................................28 
10.2.4 
DRUG ACCOUNTABILITY AND COMPLIANCE .................................................................28 
11 
STUDY ASSESSMENTS ..........................................................................................29 
11.1 
SUBJECT AND BASELINE DISEASE CHARACTERISTICS ...................................................29 
11.1.1 
DEMOGRAPHIC DATA....................................................................................................29 
11.1.2 
DISEASE AND PRIOR TREATMENT HISTORY .................................................................29 
11.1.3 
PRIOR AND CONCOMITANT MEDICATIONS ....................................................................29 
11.2 
SAFETY ASSESSMENTS ..................................................................................................29 
11.2.1 
MEDICAL AND SURGICAL HISTORY ................................................................................29 
11.2.2 
PHYSICAL EXAMINATION ..............................................................................................29 
11.2.3 
VITAL SIGNS .................................................................................................................30 
11.2.4 
ELECTROCARDIOGRAM .................................................................................................30 
11.2.5 
ADVERSE EVENT RECORDING .......................................................................................30 
11.2.6 
LABORATORY SAFETY ASSESSMENTS ...........................................................................30 
11.2.6.1 
BLOOD CHEMISTRY, HEMATOLOGY, AND COAGULATION .............................................30 
11.2.6.2 
URINALYSIS ..................................................................................................................31 
11.2.6.3 
PREGNANCY TEST .........................................................................................................32 
11.2.7 
PNH CLONE ..................................................................................................................32 
11.3 
IMMUNOGENICITY .........................................................................................................32 
11.4 
EFFICACY ASSESSMENTS ..............................................................................................32 
11.5 
PHARMACOKINETIC AND PHARMACODYNAMIC ASSESSMENTS .....................................32 
11.6 
EXPLORATORY ASSESSMENTS ......................................................................................33 
11.6.1 
QUALITY OF LIFE ASSESSMENT ....................................................................................33 
11.6.1.1 
EORTC-QLQ-C30 .......................................................................................................33 
11.6.1.2 
FACIT-FATIGUE ...........................................................................................................33 
11.6.2 
BIOMARKERS ................................................................................................................33 
12 
SAFETY REQUIREMENTS ....................................................................................35 
12.1 
DEFINITIONS .................................................................................................................35 
12.1.1 
ADVERSE EVENT ...........................................................................................................35 
12.1.2 
SERIOUS ADVERSE EVENT ............................................................................................35 
12.1.3 
ADVERSE EVENTS OF SPECIAL INTEREST ......................................................................36 
12.1.3.1 
THROMBOTIC ADVERSE EVENTS ...................................................................................36 
12.1.3.2 
HEPATIC ADVERSE EVENTS ..........................................................................................36 
12.1.3.3 
PANCREATIC ENZYME ELEVATIONS ..............................................................................36 
12.1.3.4 
INJECTION SITE REACTIONS ..........................................................................................36 
12.1.3.5 
INFECTION.....................................................................................................................37 
12.2 
EVALUATION AND CLASSIFICATIONS ............................................................................38 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


RA101495  
Protocol RA101495-01.202 
Version 1.1 
CONFIDENTIAL 
11 
12.2.1 
SEVERITY ......................................................................................................................38 
12.2.2 
CAUSALITY ...................................................................................................................38 
12.3 
RECORDING, REPORTING, AND MONITORING ................................................................39 
12.3.1 
RECORDING AND REPORTING ........................................................................................39 
12.3.1.1 
RECORDING AND REPORTING ADVERSE EVENT .............................................................39 
12.3.1.2 
RECORDING AND REPORTING SERIOUS ADVERSE EVENT ..............................................40 
12.3.1.3 
DEATH ..........................................................................................................................40 
12.3.2 
MONITORING ................................................................................................................40 
12.3.2.1 
POST-STUDY EVENTS ....................................................................................................40 
12.4 
SPECIAL CIRCUMSTANCES ............................................................................................41 
12.4.1 
PREGNANCY ..................................................................................................................41 
12.4.2 
OTHER ..........................................................................................................................41 
13 
STATISTICAL AND ANALYTICAL PLANS .......................................................42 
13.1 
SAMPLE SIZE DETERMINATION .....................................................................................42 
13.2 
ANALYSIS POPULATIONS ..............................................................................................42 
13.2.1 
SAFETY POPULATION ....................................................................................................42 
13.2.2 
PER PROTOCOL POPULATION ........................................................................................42 
13.2.3 
PHARMACOKINETIC POPULATION .................................................................................42 
13.2.4 
PHARMACODYNAMIC POPULATION ...............................................................................42 
13.3 
STATISTICAL PLAN .......................................................................................................42 
13.3.1 
GENERAL CONSIDERATIONS ..........................................................................................42 
13.3.2 
SUBJECT DISPOSITION ...................................................................................................42 
13.3.3 
DEMOGRAPHY AND BASELINE DISEASE CHARACTERISTICS ..........................................43 
13.3.4 
EXTENT OF EXPOSURE ..................................................................................................43 
13.3.5 
SAFETY ANALYSIS ........................................................................................................43 
13.3.5.1 
ADVERSE EVENTS .........................................................................................................43 
13.3.5.2 
ADVERSE EVENTS OF SPECIAL INTEREST ......................................................................43 
13.3.5.3 
CLINICAL LABORATORY EVALUATION .........................................................................44 
13.3.5.4 
ELECTROCARDIOGRAM .................................................................................................44 
13.3.5.5 
VITAL SIGNS .................................................................................................................45 
13.3.5.6 
PHYSICAL EXAMINATION ..............................................................................................45 
13.3.6 
EFFICACY ANLYSIS .......................................................................................................45 
13.3.6.1 
PHARMACOKINETIC ANALYSIS .....................................................................................45 
13.3.6.2 
PHARMACODYNAMIC ANALYSIS ...................................................................................45 
13.3.6.3 
EXPLORATORY ANALYSES ............................................................................................45 
13.3.7 
INTERIM ANALYSIS .......................................................................................................45 
14 
ETHICAL CONSIDERATIONS ..............................................................................46 
14.1 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE 
COMMUNICATIONS ........................................................................................................46 
14.1.1 
PROGRESS REPORTS ......................................................................................................46 
14.1.2 
FINAL INVESTIGATOR REPORT ......................................................................................46 
14.2 
INFORMED CONSENT OF STUDY SUBJECTS ....................................................................46 
14.3 
PROTOCOL COMPLIANCE ..............................................................................................47 
14.4 
PROTECTION OF CONFIDENTIALITY ...............................................................................47 
14.5 
DISCLOSURE OF STUDY RESULTS ..................................................................................48 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


RA101495  
Protocol RA101495-01.202 
Version 1.1 
CONFIDENTIAL 
12 
15 
REGULATORY AND ADMINISTRATIVE CONSIDERATIONS .....................49 
15.1 
QUALITY ASSURANCE ...................................................................................................49 
15.1.1 
MONITORING ................................................................................................................49 
15.1.2 
AUDIT ...........................................................................................................................49 
15.2 
CLINICAL RESEARCH ORGANIZATIONS .........................................................................49 
15.3 
DATA MANAGEMENT ....................................................................................................49 
15.3.1 
CASE REPORT FORMS ...................................................................................................49 
15.3.2 
SOURCE DOCUMENTS ...................................................................................................50 
15.4 
PREMATURE TERMINATION OR SUSPENSION OF THE STUDY .........................................50 
15.5 
CLINICAL STUDY REPORT .............................................................................................50 
15.6 
PUBLICATION POLICY ...................................................................................................51 
16 
REFERENCES ...........................................................................................................52 
 
LIST OF TABLES 
Table 1 
Table Time and Events ....................................................................................16 
Table 2  
Dose Presentations by Weight Brackets ..........................................................27 
Table 3 
Clinical Chemistry, Hematology, and Coagulation Analytes ..........................31 
Table 4 
Grading the Severity of Local Injection Site Reactions ...................................37 
Table 5 
Thrombotic Event Description (MAVE criteria) .............................................44 
 
 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


RA101495  
Protocol RA101495-01.202 
Version 1.1 
CONFIDENTIAL 
13 
4 
LIST OF ABBREVIATIONS AND DEFINITIONS 
Abbreviation 
Definitions 
ADA 
anti-drug antibody 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
aPTT/APTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
AUC 
area under the drug concentration-time curve 
BUN 
blood urea nitrogen 
C5 
complement component 5 
Cmax 
maximum plasma concentration 
CPK 
creatine phosphokinase  
CRO 
clinical research organization 
CRP 
C-reactive protein 
CT  
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
ELISA 
enzyme-linked immunosorbent assay 
EORTC-QLQ-C30 
European Organization for Research and Treatment of Cancer-Quality of Life 
Questionnaire 
FACIT-F 
Functional Assessment of Chronic Illness Therapy-Fatigue Scale 
GCP  
Good Clinical Practice  
GGT 
gamma-glutamyl transferase 
GPI 
glycosylphosphatidylinositol 
GPI-AP 
glycosylphosphatidylinositol-anchored proteins 
ICF 
informed consent form 
IEC 
Independent Ethics Committee 
IMP 
Investigational medicinal product 
INR 
international normalized ratio    
IP 
investigational product 
IRB 
Institutional Review Board 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


RA101495  
Protocol RA101495-01.202 
Version 1.1 
CONFIDENTIAL 
14 
Abbreviation 
Definitions 
ISR 
injection site reaction 
IV 
intravenous 
LDH 
lactate dehydrogenase 
LFT 
Liver function test 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MD 
multiple-dose 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
NA 
not applicable 
NCI 
National Cancer Institute 
PD 
pharmacodynamics 
PI 
Principal Investigator 
PK 
pharmacokinetics 
PNH 
paroxysmal nocturnal hemoglobinuria 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
QOL 
quality of life 
RBC 
red blood cell 
SAE 
serious adverse event 
SC 
subcutaneous 
SD 
standard deviation 
SOP 
Standard operating procedure 
TEAE 
treatment-emergent adverse event 
tmax 
time to corresponding Cmax 
ULN 
upper limit of normal 
URI 
upper respiratory infection 
VAS 
visual analogue scale 
WBC 
white blood cell 
 
 
 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


RA101495  
Protocol RA101495-01.202 
Version 1.1 
CONFIDENTIAL 
15 
5 
TIME AND EVENTS TABLE  
Assessments to be performed during the study are shown in Table 1.
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


RA101495  
Protocol RA101495-01.202 
 
 
 
 
Version 1.1 
CONFIDENTIAL 
16 
Table 1 
Table Time and Events   
Study Month 
Screening a 
/Day 1a,b 
1 
2 
3 
6 
9  
12  
Then Every 
3 Months  
Then Every 
12 Months 
only  
Final Study 
Visit 
Study Day→ 
1 
30 ± 7 
60 ± 7 
90 ± 7 
180 ± 7 
270 ± 7 
360 ± 7 
- (± 7) 
- (± 7) 
- 
Study Procedure ↓ 
 
 
 
 
 
 
 
 
 
 
Signature of ICF a 
X 
 
 
 
 
 
 
 
 
 
Review eligibility criteria 
X 
 
 
 
 
 
 
 
 
 
Prior and Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Physical examination 
X b 
X 
X 
X 
X 
X 
X 
X 
 
X 
Vital signs 
X b 
X 
X 
X 
X 
X 
X 
X 
 
X 
ECG 
X b 
 
 
 
 
 
X 
 
X 
X 
Blood chemistry  
X b 
X 
X 
X 
X 
X 
X 
X 
 
X 
Hematology 
X b 
X 
X 
X 
X 
X 
X 
X 
 
X 
Coagulationc 
X b 
X 
X 
X 
X 
X 
X 
X 
 
X 
Urinalysis  
X b 
X 
X 
X 
X 
X 
X 
X 
 
X 
PNH Clone size 
X b 
 
 
X 
X 
X 
X 
X 
 
X 
Pregnancy test  
X b 
X 
X 
X 
X 
X 
X 
X 
 
X 
Quality of life assessments   
X b 
X 
X 
X 
X 
X 
X 
X 
 
X 
Adverse event monitoring (including 
injection site reactions) 
Xb 
X 
X 
X 
X 
X 
X 
X 
 
X 
Pharmacokineticsd 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Pharmacodynamicsd 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Additional Biomarkersd 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Anti-drug antibodies 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
RA101495 dispensing and returne 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
RA101495 administrationf 
Xg 
X 
X 
X 
X 
X 
X 
X 
 
 
a. 
The Screening Visit should coincide with the qualifying study end of study visit and include signing of the informed consent. The informed consent should be provided to the subject prior to the 
qualifying study end of study visit to facilitate a proper informed consent process. 
b. 
All screening assessments are expected to be the same as those for the end of qualifying study visit and do not need to be repeated unless clinically indicated. Record AEs ongoing from qualifying 
study on Day 1 on the specific AE eCRF for ongoing AEs from the qualifying study. 
c. 
Coagulation tests should be performed as per standard practice on any subject taking anticoagulant therapy in addition to specified assessments in the study.  
d. 
PK/PD/Biomarkers sampling prior to dose on day of visit (dose held that morning and administered in clinic after blood samples are obtained).  
e. 
Study drug dispensing and return is monthly. Frequency of dispensing of IMP may be adjusted during the study. 
f. 
Study drug administration should be administered in clinic after PK and PD collection on clinic visit days for the first 12 months.  
g. 
On Day 1, the last dose administered on the last day of the qualifying study is considered the first dose on the extension study and should not be repeated. 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


RA101495  
Protocol RA101495-01.202 
Version 1.1 
CONFIDENTIAL 
17 
6 
INTRODUCTION 
Ra Pharmaceuticals, Inc. is developing RA101495, a subcutaneously–administered 15-amino 
acid cyclic peptide that inhibits the cleavage of complement component 5 (C5), for the treatment 
of paroxysmal nocturnal hemoglobinuria (PNH).  
6.1 
STUDY RATIONALE 
The RA101495-01.202 study is an extension study to Ra Pharmaceuticals’ sponsored qualifying 
studies evaluating RA101495 in subjects with PNH. Subjects who successfully complete 
participation in these qualifying studies, with evidence of continued clinical benefit in the 
opinion of the treating investigator, will have the option to continue to receive treatment with 
RA101495. While on this study, the subject will continue to be monitored for safety, tolerability, 
preliminary efficacy, PK, and PD. Subjects may continue to receive RA101495 provided by the 
sponsor until RA101495 is approved and available or the sponsor terminates the development of 
RA101495 for PNH. In countries where the study is conducted, but RA101495 is neither 
approved nor marketed, then study subjects may continue to receive RA101495 through a 
compassionate use pathway. 
Please refer to the Investigational Brochure for additional information on the chemistry, 
toxicology, pharmacology, and safety of RA101495, based on studies conducted in animals and 
the Phase 1 healthy volunteer study.    
 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


RA101495  
Protocol RA101495-01.202 
Version 1.1 
CONFIDENTIAL 
18 
7 
STUDY OBJECTIVES AND ENDPOINTS 
7.1 
OBJECTIVES 
The objectives of the study are: 
 To provide access to RA101495 for subjects with PNH who have who have completed a Ra 
Pharmaceuticals sponsored study, have demonstrated clinical benefit, and who wish to 
continue receiving RA101495 for treatment of PNH  
 To evaluate the long-term safety and tolerability of RA101495 administered to subjects with 
PNH who have completed a Ra Pharmaceuticals sponsored RA101495 clinical study 
 To evaluate the long-term preliminary efficacy of RA101495 administered to subjects with 
PNH who have completed a Ra Pharmaceuticals sponsored RA101495 clinical study 
 To obtain periodic PK and PD data to confirm long-term maintenance of steady-state 
RA101495 plasma levels and sustained inhibition of hemolysis and complement 
7.1.1 
SAFETY ENDPOINTS 
Safety assessments will include an evaluation of AEs and SAEs (including major adverse 
vascular event (MAVE criteria), clinical laboratory tests, ECGs, vital signs, and physical 
examinations. Safety evaluation will also include a determination of anti-drug antibodies (ADA).   
7.1.2 
EFFICACY ENDPOINTS 
Efficacy:  
Serum LDH levels, total bilirubin, total hemoglobin, free hemoglobin, haptoglobin, reticulocytes, 
and hemoglobinuria, at each of the scheduled assessment time-points. 
7.1.3 
PHARMACOKINETIC:   
 Plasma concentrations of RA101495 and its major metabolite(s) 
 Maximum plasma concentration (Cmax)  
 Time corresponding to Cmax (tmax) 
 Area under the drug concentration-time curves (AUC0-t) 
7.1.4 
PHARMACODYNAMIC  
 CH50 
 Sheep RBC (sRBC) lysis for the classical complement pathway  
 Wieslab ELISA for alternative complement pathway 
 C5 levels 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


RA101495  
Protocol RA101495-01.202 
Version 1.1 
CONFIDENTIAL 
19 
7.1.5 
EXPLORATORY ENDPOINTS 
 Quality of life (QOL) questionnaires (e.g. EORTC QLQ-C30 and FACIT-Fatigue) 
 Mechanistic biomarkers (e.g. complement function, complement proteins, biomarkers of 
inflammation, biomarkers for thrombosis, biomarkers of liver function) 
 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


RA101495  
Protocol RA101495-01.202 
Version 1.1 
CONFIDENTIAL 
20 
8 
STUDY DESIGN 
8.1 
OVERVIEW OF STUDY DESIGN 
The design is a multicenter, open-label, extension study for subjects with PNH who have 
successfully completed a qualifying Ra Pharmaceuticals sponsored RA101495 clinical study.  
Subjects will continue to receive the final maintenance dose they were receiving in the qualifying 
study, as long as safety, tolerability, PK and PD data (from the qualifying study or this extension 
study) continue to demonstrate benefit. If additional data support a change in dose level for an 
individual subject in this extension study, investigators may increase or decrease the maintenance 
dose level, based on safety and PD findings, and in consultation with the medical monitor. All 
subjects will continue to be followed carefully for any evidence of meningococcal and/or other 
infection. 
8.1.1 
SCREENING PERIOD 
The Screening Visit should coincide with the qualifying study end of visit and include signing of 
the informed consent. The informed consent should be provided to the subject prior to the 
qualifying study end of study visit to facilitate a proper informed consent process. Screening 
assessments are expected to be the same as those for the end of qualifying study visit and do not 
need to be repeated unless clinically indicated.  
8.1.2 
TREATMENT PERIOD 
All eligible subjects will receive open-label RA101495 daily by SC self-injection. The starting 
dose in the extension study will be the same as the final maintenance dose the subject was 
receiving in the qualifying study. The IMP (RA101495) will continue to be provided by the 
sponsor until RA101495 is approved and available in the territory or the sponsor terminates 
development of RA101495 for PNH. In countries where RA101495 is not approved or marketed, 
but in which sponsored clinical studies have been conducted, subjects may continue to receive 
RA101495 through a compassionate use pathway. 
8.2 
SUBJECT REGISTRATION PROCEDURES 
8.2.1 
SCREENING AND ENROLLMENT 
Written informed consent must be obtained before ANY study-related or enrollment procedures 
are performed.  
At the Screening Visit, subjects will be assigned a unique subject number that will also link to 
their qualifying study. Screening assessments are expected to be the same as the end of 
qualifying study visit and are listed below.  These tests would be repeated only if clinically 
indicated (note that it is expected that the end of qualifying study visit and the Screening Visit 
for the extension study occur on the same day and these assessments are performed only once to 
satisfy the requirements of both study protocols):  
 Documentation of successful completion of qualifying study 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


RA101495  
Protocol RA101495-01.202 
Version 1.1 
CONFIDENTIAL 
21 
 Review and record AEs ongoing at entry into this study (see Section 12.3) 
 Review and documentation of prior and concomitant medications   
 Physical examination, including height and weight 
 Vital signs (heart rate, body temperature, and blood pressure) in the sitting position after 
resting at least 5 minutes 
 12-lead electrocardiogram in a supine position (lying down) for at least 5 minutes prior to, 
and during, the recording (every 12 months or as clinically indicated) 
 Blood samples for clinical chemistry (including LDH), hematology, coagulation, and PNH 
clone size 
 Urine sample for urinalysis 
 Documentation of a negative pregnancy test for females of childbearing potential  
 Completion of quality of life questionnaires 
The inclusion and exclusion criteria will be reviewed to determine subject eligibility for study 
drug dosing on Day 1.  On Day 1, the last dose administered on the last day of the qualifying 
study is considered the first dose on the extension study and should not be repeated.   
8.2.2 
TREATMENT GROUP ASSIGNMENT 
All subjects will receive RA101495. 
8.2.3 
BLINDING 
This study is open-label.  
8.2.4 
DISCONTINUATION OF INVESTIGATIONAL MEDICINAL PRODUCT 
If a subject prematurely discontinues treatment with the investigational medicinal product (IMP), 
RA101495, at any time, the subject should return to clinic for a Final Study Visit. The following 
procedures will be completed at this visit: 
 Review and documentation of concomitant medications 
 Physical examination, including weight 
 Vital signs (heart rate, body temperature, blood pressure) in the sitting position after resting 
for at least 5 minutes 
 12-lead ECG in a supine position (lying down) for at least 5 minutes prior to, and during, the 
recording 
 Blood samples for clinical chemistry, hematology, coagulation, and PNH clone size 
 Urine sample for urinalysis 
 Urine pregnancy for females of childbearing potential only 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


RA101495  
Protocol RA101495-01.202 
Version 1.1 
CONFIDENTIAL 
22 
 Completion of QOL questionnaires 
 Record AEs 
 Return of all used and unused study drug syringes to site 
Following discontinuation from the study, standard-of-care treatment may be initiated as 
recommended by the treating physician. 
8.2.5 
WITHDRAWAL FROM THE STUDY 
Subjects who are withdrawn from the study must promptly discontinue treatment with 
RA101495, and make every effort to return to the clinic to complete the Final Study Visit study, 
as described in Section 8.2.4. All unused study drug must be returned to the clinic as described in 
Section 10.2. 
In the event an investigator discontinues the study at his center, a subject may transfer to another 
investigator participating in this study. 
8.3 
EARLY STUDY TERMINATION 
The Sponsor may terminate this study early, either in its entirety, or at one or more study sites, 
for reasonable cause provided that written notice is submitted in advance of the intended 
termination. The investigator may also terminate the study at the site for reasonable cause, after 
providing written notice to the Sponsor in advance of the intended termination. Advance notice 
is not required by either party if the study is stopped due to safety concerns. If the Sponsor 
terminates the study for safety reasons, the Sponsor will immediately notify the investigator and 
subsequently provide written instructions for study termination. 
Nonclinical toxicology data supporting chronic dosing in this study is provided by an ongoing 
39-week study in primates. The duration of dosing in that study and review of in-life data is 
designed to exceed the duration of treatment of subjects enrolled into this extension study. If the 
chronic toxicology study is halted or terminated, a review of the available data will be conducted 
to assess risk to subjects on this extension study. As appropriate based on this review the 
Sponsor will notify the investigator and appropriate measures will be taken to ensure the safety 
of subjects.   
8.4 
FINAL STUDY VISIT 
The end-of-study is defined as the date of the last subject 's last visit. 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


RA101495  
Protocol RA101495-01.202 
Version 1.1 
CONFIDENTIAL 
23 
9 
SELECTION OF STUDY POPULATION 
9.1 
INCLUSION CRITERIA 
To be eligible for this study, subjects must meet all of the following inclusion criteria: 
1. Completion of a qualifying RaPharmaceuticals sponsored RA101495 PNH study 
2. Evidence of ongoing clinical benefit in the opinon of the investigator 
3. Completion of the informed consent procedure, including signing and dating the informed 
consent form (ICF)   
4. Female subjects of child bearing potential must have had a negative pregnancy test at the 
completion of the qualifying study prior to first dose of study drug in this extension study 
5. Sexually-active active female subjects of child-bearing potential (i.e. women who are not 
post-menopausal or who have not had a bilateral oophorectomy, hysterectomy, or tubal 
ligation) and all male subjects (who have not been surgically sterilized by vasectomy) must 
agree to use effective contraception during the study. Effective contraception is defined as:  
o Hormonal contraception (e.g. oral contraceptive, transdermal contraceptive, contraceptive 
implant, or injectable hormonal contraceptive) for at least 3 months prior to study drug 
administration, throughout the study, and for 4 weeks after the last dose of study drug. 
o Double-barrier birth control (e.g. male condom, female condom, diaphragm sponge, or 
cervical cap together with spermicidal foam/gel/film/suppository) starting at the 
Screening visit, throughout the study, and for 4 weeks after the last dose of study drug. 
o Intrauterine contraception/device starting at the Screening visit, throughout the study, and 
for 4 weeks after the last dose of study drug. 
o Total abstinence from sexual intercourse for at least one complete menstrual cycle prior 
to the Screening visit, throughout the study, and for 4 weeks after the last dose of study 
drug  
o Maintenance of a monogamous relationship with a male partner who has been surgically 
sterilized by vasectomy 
9.2 
EXCLUSION CRITERIA 
Subjects who meet any of the following exclusion criteria must be excluded from the study: 
1. Platelet count <30,000/µL or absolute neutrophil count (ANC) <500 cells/µL at Screening 
2. Caluculated glomerular filtration rate of <30 mL/min/1.73m2 based on modification of diet 
in renal disease (MDRD) equation at Screening 
3. Elevation of liver function tests (LFT): alanine aminotransferase (ALT) >2xULN or Direct 
Bilirubin and Alkaline Phosphatase (ALP) both >2xULN 
4. Elevation of amylase or lipase 2xULN 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


RA101495  
Protocol RA101495-01.202 
Version 1.1 
CONFIDENTIAL 
24 
5. History of meningococcal disease 
6. Current systemic infection or suspicion of active bacterial infection 
7. Pregnant, planning to become pregnant, or nursing female subjects 
8. Active malignancy requiring surgery, chemotherapy, or radiation within the prior 12-months 
(subjects with a history of malignancy who have undergone curative resection or otherwise 
not requiring treatment for at least 12-months prior to Screening with no detectable 
recurrence are allowed) 
9. History of any significant medical or psychiatric disorder that in the opinion of the 
investigator would make the subject unsuitable for participation in the study 
10. With the exception of RA101495, other treatments with with any investigational medicinal 
product or investigational device within the 30 days prior to Screening or participation in 
another concurrent clinical trial involving a therapeutic intervention (participation in 
observational studies and/or registry studies is permitted) 
11. Unable or unwilling to comply with the requirements of the study 
9.3 
REMOVAL AND REPLACEMENT OF SUBJECTS IN THE STUDY 
9.3.1 
PREMATURE DISCONTINUATION 
Every reasonable effort should be made to encourage retention of subjects in the study, 
maximize compliance with study drug, and facilitate attendance at all scheduled study visits.   
All subjects have the right to refuse further participation in the study at any time and for any 
reason. A subject’s participation must, therefore, be terminated immediately upon his/her 
request. 
The investigator will make every attempt to ascertain the reason(s) for discontinuation and to 
document this in detail in the source documentation and the appropriate sections of the electronic 
case report form (eCRF). Subjects may be withdrawn from the study due to any of the following 
reasons:  
 Subject withdraws consent 
 Subject is non-compliant, defined as refusal or inability to adhere to the study procedures 
 Unacceptable or intolerable treatment-related AEs 
 Use of any other investigational treatment 
 Any illness or circumstance (e.g. incarceration) that would substantially impact the study 
procedures or outcome measures 
 At the request of the Sponsor, regulatory agencies, or independent ethics committee 
(IEC)/institutional review board (IRB) 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


RA101495  
Protocol RA101495-01.202 
Version 1.1 
CONFIDENTIAL 
25 
 Loss to follow-up 
9.3.2 
REPLACEMENT OF SUBJECTS 
Subjects who discontinue their participation will not be replaced.  
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


RA101495  
Protocol RA101495-01.202 
Version 1.1 
CONFIDENTIAL 
26 
10 
INVESTIGATIONAL MEDICINAL PRODUCTS AND TREATMENTS 
10.1 
STUDY TREATMENT ADMINISTRATION 
10.1.1 
IDENTITY OF INVESTIGATIONAL PRODUCTS AND TREATMENT 
 
 
Subjects will be instructed to self-inject SC doses daily. The dose (dose volume) for each 
injection will depend on the dose at the end of the qualifying study and subject’s bodyweight 
(see Section 10.1.3 and Section 10.1.4).  
10.1.2 
TREATMENT GROUPS 
All subjects will receive RA101495 at the same dose level at the time they completed the 
qualifying study.  
10.1.3 
DOSING SCHEDULE 
Subjects will be required to self administer RA101495 as a SC injection once daily (every 24 
hours at approximately the same time each day.  On Day 1, the last dose administered on the last 
day of the qualifying study is considered the first dose on the extension study and should not be 
repeated. On days of the scheduled study visit at the investigator site, the dose must be 
administered after the blood work is completed at the investigator site. 
10.1.4 
DOSE OR DOSING SCHEDULE MODIFICATIONS  
Doses of RA101495 will be determined by a target dose and weight, accomplished using a fixed 
dose by weight brackets. These brackets are grouped by body weight category such that each 
subject will receive the no less than the target minimum dose to avoid sub-therapeutic dosing. 
For the 0.1 mg/kg dose, subjects will receive, at a minimum, a fixed dose of 0.1 mg/kg (range 
); for the 0.3 mg/kg dose, subjects will receive a minimum dose of 0.3 mg/kg 
(range 
). Table 2 summarizes dose presentations for RA101495 0.1 
mg/kg and 0.3 mg/kg doses. 
Dose adjustments are allowed throughout this extension study for reasons of safety and control 
of hemolysis and should be discussed with the medical monitor.  
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


RA101495  
Protocol RA101495-01.202 
Version 1.1 
CONFIDENTIAL 
27 
Table 2  
Dose Presentations by Weight Brackets 
Target 
Dose 
(mg/kg) 
Dose Presentation 
Weight Range 
(kg) 
Dose Range 
(mg/kg) 
Fill Volume 
Dose  
Number 
mL 
mg 
0.1 
1 
 
 
43 to ≤ 61 
 
0.1 
2 
 
 
>61 to ≤88 
 
0.1 
3 
 
 
>88 to ≤109 
 
0.3 
4 
 
 
43 to ≤56 
 
0.3 
5 
 
 
>56 to ≤77 
 
0.3 
6 
 
 
>77 to ≤109 
 
10.1.4.1 
MISSED DOSE 
If a subject misses one dose (i.e. 1 day) of RA101495, the subject should take the next planned 
dose as scheduled, and contact the investigator as soon as possible. If a subject misses 2 or more 
doses, the subject must notify the investigator immediately. 
10.2 
STUDY TREATMENT MANAGEMENT 
10.2.1 
PREPARATION AND DISPENSING 
Pre-filled syringes will be dispensed to each subject monthly. Frequency of dispensing of IMP 
may be adjusted during the study.   
Subjects will be provided training and detailed instructions regarding administration of 
RA101495 using the pre-filled syringes and the injection device in a separate manual.   
10.2.2 
STUDY DRUG SUPPLY, STORAGE, AND HANDLING 
 
 
 
   
The IMP should be stored at 2 °C to 8°C at the study site. Once dispensed to subjects, the IMP 
may be stored at controlled room temperature (20°C to 25°C [68°F to 77°F]) protected from 
sources of heat, light and damage. Storage of IMP outside of room temperatures should be 
avoided. 
Subjects will be instructed to self-inject SC doses daily every 24 hours at approximately the 
same time each day. 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


RA101495  
Protocol RA101495-01.202 
Version 1.1 
CONFIDENTIAL 
28 
All subjects will receive a study drug kit that will include RA101495 (prefilled syringes), a 
syringe disposal container, alcohol wipes, and adhesive dressings. 
10.2.3 
DISPOSAL, RETURN, OR RETENTION OF UNUSED DRUG 
At all visits, subjects will also receive a secure container to dispose of used syringes while at 
home. At each visit and the subject should bring the used container containing all used syringes 
to be returned to the site. The unused study drug (unused syringes) should be retained by the 
subject and be used first in the immediate weeks following each visit.   
10.2.4 
DRUG ACCOUNTABILITY AND COMPLIANCE 
All study drug (syringes) and disposal containers must be returned to the site at the last study 
visit.   
Compliance will be assessed at each study visit. 
 
 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


RA101495  
Protocol RA101495-01.202 
Version 1.1 
CONFIDENTIAL 
29 
11 
STUDY ASSESSMENTS 
Please refer to Table 1 Time and Events for the timing of assessments. 
11.1 
SUBJECT AND BASELINE DISEASE CHARACTERISTICS 
11.1.1 
DEMOGRAPHIC DATA 
The following demographic data collected from the qualitfying study will be linked to the 
extension sudy: date of birth, gender, ethnicity, and race.   
11.1.2 
DISEASE AND PRIOR TREATMENT HISTORY  
The data regarding the diagnosis of PNH will have been recorded in the qualifying study; these 
data will be linked to the extension protocol.  
11.1.3 
PRIOR AND CONCOMITANT MEDICATIONS 
All concomitant medications ongoing from the qualifying study will be documented.  
Concomitant medications include any prescription or over-the-counter medication that is 
ongoing on Day 1 or that is initiated following the first dose of study drug on Day 1.  
Findings will be recorded on the subject’s source documents and entered on the appropriate 
eCRF. Any changes to concomitant medications during the Treatment Period will be recorded in 
the eCRF. 
11.2 
SAFETY ASSESSMENTS 
11.2.1 
MEDICAL AND SURGICAL HISTORY  
Relevant medical history will be documented in the qualifying study. 
Adverse events ongoing from the qualifying study should be reviewed and recorded on the 
specific AE eCRF page for such ongoing events at the time of the last study visit of the 
qualifying study.  
If during the course of the study, a subject requires surgery with general anesthesia for any 
reason, continuation of study drug in the perioperative period is recommended, and should be 
discussed with the medical monitor. The event leading to surgery should be recorded as an AE 
per Section 12.3. 
11.2.2 
PHYSICAL EXAMINATION  
Physical examinations will include the following assessments: 
 General inspection 
 Weight (kilograms) 
 Examination of the injection site and draining nodes  
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


RA101495  
Protocol RA101495-01.202 
Version 1.1 
CONFIDENTIAL 
30 
 Head/ears/eyes/nose/throat examination 
 Mucosal examination for icterus 
 Cardiac examination 
 Auscultation of lungs 
 Abdominal examination (liver, spleen, and lower abdomen) 
 Assessment for neurological deficits 
 Musculoskeletal assessment 
Any abnormalities found will be recorded in the eCRF. 
11.2.3 
VITAL SIGNS 
Vital signs signs (heart rate, body temperature, and blood pressure) will be measured in the 
sitting position after resting for at least 5 minutes. If blood samples are scheduled at the same 
time, vital signs should be measured before the blood draw. Blood pressure may be measured 
manually or by automated device, preferably in the non-dominant arm. The same measurement 
technique should be used throughout the study for all subjects. Temperature will be measured 
with an electronic device.   
11.2.4 
ELECTROCARDIOGRAM  
Subjects should be in a supine position (lying down) for at least 5 minutes prior to and during the 
12-lead ECG recording. ECGs will be assessed as normal or abnormal by the investigator. Any 
abnormal findings will be recorded in the eCRF and clinical significance will be assessed by the 
investigator and if a finding is deemed clinically significant it should recorded as an adverse 
event. The ECG recording strip will be signed and dated by the investigator and stored in the 
medical records.   
ECGs should be performed prior to blood draws when both assessments are completed. 
Assessments should be completed once every 12 months, at the Final Study Visit, and as 
clinically indicated (Table 1).  
11.2.5 
ADVERSE EVENT RECORDING  
Guidance on the identification, monitoring, and reporting of AEs are provided in Section 12. 
11.2.6 
LABORATORY SAFETY ASSESSMENTS 
11.2.6.1 
BLOOD CHEMISTRY, HEMATOLOGY, AND COAGULATION  
Clinical chemistry and hematology analytes to be collected are identified in Table 3 and 
performed as specified in the Table 1. All coagulation tests should be performed as per standard 
practice on any subject taking anticoagulant therapy in addition to specified assessments in this 
schedule of events. 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


RA101495  
Protocol RA101495-01.202 
Version 1.1 
CONFIDENTIAL 
31 
Table 3 
Clinical Chemistry, Hematology, and Coagulation Analytes 
Clinical Chemistry 
Hematology 
alanine aminotransferase (ALT) 
free hemoglobin 
albumin 
haptoglobin 
alkaline phosphatase (ALP) 
hematocrit 
amylase 
hemoglobin 
aspartate aminotransferase (AST) 
mean corpuscular hemoglobin (MCH) 
bicarbonate 
mean corpuscular hemoglobin concentration  
bile acids 
(MCHC) 
bilirubin (total, direct, and indirect) 
mean corpuscular volume (MCV) 
blood urea nitrogen (BUN) 
platelet count 
calcium 
RBC count 
chloride 
reticulocyte count 
creatinine 
white blood cell (WBC) count and differential (%) 
gamma-glutamyl transferase (GGT) 
Coagulation 
glucose 
international normalized ratio (INR)/prothrombin  
time (PT) 
lactate dehydrogenase (LDH) 
lipase 
fibrinogen 
potassium 
partial thromboplastin time (PTT) or activated  
partial thromboplastin time (aPTT or APTT) 
sodium 
total protein 
Other 
uric acid 
C-reactive protein (CRP) 
 
creatine phosphokinase (CPK) 
11.2.6.2 
URINALYSIS 
A urinalysis will be performed to measure pH, specific gravity, protein (qualitative), glucose 
(qualitative), ketones (qualitative), bilirubin (qualitative), urobilinogen, occult blood, 
hemoglobin, and cells. A microscopic examination will be performed, if necessary, occult blood, 
and cells.  A microscopic examination will be performed, if necessary. Hemoglobinuria will be 
assessed using a urine colorimetric scoring system. 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


RA101495  
Protocol RA101495-01.202 
Version 1.1 
CONFIDENTIAL 
32 
11.2.6.3 
PREGNANCY TEST 
A urine dipstick pregnancy test (human chorionic gonadotropin) will be performed on female 
subjects of childbearing potential as per the Table 1,Time and Events.  
11.2.7 
PNH CLONE  
PNH clone size will be determined by peripheral blood flow cytometry analysis (RBCs and 
granulocytes) and is performed every 3 months as per Table 1, Time and Events. 
11.3 
IMMUNOGENICITY  
Blood samples for ADAs will be collected on all study visit days and the final study day. 
Samples will be sent to a central laboratory to determine the presence or absence of antibodies 
against RA101495 using a validated assay.  
Detailed instructions regarding sample collection, processing, and shipping will be provided in a 
separate laboratory manual.  
11.4 
EFFICACY ASSESSMENTS 
Efficacy assessments include the measurement of serum LDH levels as a measure of 
intravascular hemolysis. Additional assessments will include laboratory assessments of total 
bilirubin, total hemoglobin, free hemoglobin, haptoglobin, reticulocytes, and hemoglobinuria. 
11.5 
PHARMACOKINETIC AND PHARMACODYNAMIC ASSESSMENTS 
Blood samples for the measurement of plasma concentrations of RA101495 and metabolites will 
be collected on all subjects.  
Blood samples for pharmacodynamic assessments will be collected an all subjects and include 
measurements of: 
 CH50 
 sRBC lysis for classical complement pathway 
 Wieslab ELISA for alternative complement pathway 
 C5 levels 
Blood samples for PK and PD will be collected per the timepoints in Table 1 Time and Events.  
All samples will be sent to a central laboratory for analysis. Detailed instructions regarding PK 
and PD sample collection, processing, and shipping will be provided in a separate laboratory 
manual. 
 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


RA101495  
Protocol RA101495-01.202 
Version 1.1 
CONFIDENTIAL 
33 
11.6 
EXPLORATORY ASSESSMENTS  
11.6.1 
QUALITY OF LIFE ASSESSMENT 
Quality of Life assessments will be performed according to the Time and Events Table, Table 1. 
These will include: 
 European Organization for the Research and Treatment of Cancer Quality of Life 
Questionnaire-C30 (EORTC-QLQ-C30) 
 Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Scale 
11.6.1.1 
EORTC-QLQ-C30 
The EORTC QLQ-C30 consists of 30 questions, which are incorporated into 5 functional 
domains (physical, role, cognitive, emotional, and social domains); a global health status/global 
QOL scale; 3 symptom scales (fatigue, pain, and nausea and vomiting scales); 6 single items that 
assess additional symptoms (e.g. dyspnea, appetite loss, sleep disturbance, constipation, and 
diarrhea); and the perceived financial burden of illness treatment [Aaronson, 1993; Aaronson, 
1996].  Subjects answer questions based on symptoms/status over the preceding week.  
11.6.1.2 
FACIT-FATIGUE 
The FACIT-Fatigue Scale is a 13-item, easy to administer tool that measures an individual’s 
level of fatigue during their usual daily activities over the past week. The level of fatigue is 
measured on a four point Likert scale (4 = not at all fatigued to 0 = very much fatigued) 
[Webster, 2003]. 
11.6.2 
BIOMARKERS  
Blood samples will be collected at designated time points in Table 1, Time and Events.  After the 
first year, blood samples for biomarker analysis should be collected whenever possible when 
there is an AE of thrombosis, pancreatic or hepatic event. All biomarkers will be analyzed by 
biological or biochemical assays at an accredited laboratory. Detailed instructions regarding 
sample collection, processing, and shipping will be provided in a separate laboratory manual. 
The study of biomarkers related to complement function, thrombosis, inflammation, and liver 
function will provide further insight in to the clinical efficacy and tolerability to RA101495 in 
PNH subject s. Complement protein levels and complement activity will be tested to evaluate 
response to RA101495 and understand subject characteristics related to variations in response to 
drug. Markers of thrombosis and inflammation will be tested to assess correlation with 
complement function and clinical response to RA101495 and to identify markers that may 
correlate with thrombotic risk in PNH subjects. Additionally, markers for liver function will be 
assessed to evaluate tolerability of RA101495. A list of analytes will be created through review 
of the literature, ongoing clinical studies, and ongoing exploratory work and may be finalized 
after completion of the study.  
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


RA101495  
Protocol RA101495-01.202 
Version 1.1 
CONFIDENTIAL 
34 
The completion of these investigations may be conditional based on the results of this or other 
clinical studies, and samples may be selected for analysis on the basis of clinical outcome. The 
results of the biomarker investigations will be reported separately from the main clinical study 
report. 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


RA101495  
Protocol RA101495-01.202 
Version 1.1 
CONFIDENTIAL 
35 
12 
SAFETY REQUIREMENTS 
12.1 
DEFINITIONS 
12.1.1 
ADVERSE EVENT 
An AE is any untoward medical occurrence in a subject administered a pharmaceutical product 
and which does not necessarily have a causal relationship with this treatment. An AE can 
therefore be any unfavorable and unintended sign (including a clinically significant abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the use of a 
medicinal product, whether or not considered related to the medicinal product. 
The following are not considered to be AEs despite requiring hospitalization: 
 Pre-existing conditions that, in the opinion of the investigator, did not worsen or progress 
during study participation 
 Routinely scheduled procedures or treatment 
 Elective procedures that had been scheduled prior to study participation (i.e. signing of the 
ICF) 
12.1.2 
SERIOUS ADVERSE EVENT 
An SAE is any untoward medical occurrence that: 
 results in death 
 is life-threatening threatening (note that this refers to an event in which the subject was at 
risk of death at the time of the event; it does not refer to an event that hypothetically might 
have caused death if it were more severe) 
 requires hospitalization or prolongation of existing hospitalization 
 results in persistent or significant disability/incapacity 
 results in a congenital anomaly/birth defect. 
An SAE may also be any other important medical event that may not be immediately 
life-threatening or result in death or hospitalization, but may jeopardize the subject or require 
intervention to prevent one of the other outcomes listed in the definition above. Examples of 
such events include intensive treatment in an emergency room or at home for bronchospasm, 
hyperkalemia, or convulsions that do not result in a formal hospitalization. 
Elective hospitalizations scheduled prior to study participation (i.e. signing of the ICF) should 
not be reported as an SAE. 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


RA101495  
Protocol RA101495-01.202 
Version 1.1 
CONFIDENTIAL 
36 
12.1.3 
ADVERSE EVENTS OF SPECIAL INTEREST 
12.1.3.1 
THROMBOTIC ADVERSE EVENTS  
All subjects should be monitored for signs and symptoms of thrombotic events at all study visits. 
The method of diagnosis (e.g. ultrasound, computed tomography [CT], magnetic resonance 
imaging [MRI], venogram, or other [specify]) for any reported event should be recorded in the 
eCRF. All AEs should be recorded and reported as AEs per Section 12.2 and Section 12.3. 
12.1.3.2 
HEPATIC ADVERSE EVENTS 
All subjects should be monitored for signs and symptoms of hepatic or biliary dysfunction. Liver 
function tests (LFTs) (ALP, ALT, AST, GGT, Direct Bilirubin and Indirect Bilirubin) are 
monitored at all study visits. The following guideline is provided: 
 In subjects with isolated ALT elevation >2xULN or direct bilirubin and ALP elevation 
>2xULN with no other explanation for the elevation(s), contact the medical monitor to 
review the case details and determine if the subject should continue or discontinue study 
treatment.  The subject should be monitored until the elevated enzymes return to Grade 1 
(NCI CTACE) or lower.  
 Subjects with isolated ALT elevations >3xULN concurrently with bilirubin elevation 
≥2xULN and a normal ALP with no other explanation for the elevation should be 
permanently discontinued. The medical monitor should be contacted as soon as possible to 
review the case.  The subject should be monitored until the elevated enzymes return to Grade 
1 (NCI CTACE) or lower.   
All AEs should be recorded and reported as AEs per Section 12.2 and Section 12.3. 
12.1.3.3 
PANCREATIC ENZYME ELEVATIONS  
Subjects should be monitored during the study for symptoms of pancreatitis or cholecystitis. 
Pancreatic enzymes (amylase and lipase) are monitored at all study visits.  
In subjects with elevations of amylase or lipase to National Cancer Institute Common 
terminology Criteria for Adverse Events (NCI CTCAE) Grade 3 (>2.5xULN) or Grade 4 
(>5xULN) contact the medical monitor to review the case details and determine if the subject 
should continue on study treatment. The subject should be monitored until amylase and/or lipase 
returns to Grade 1 or lower.  
All AEs should be recorded and reported as AEs per Section 12.2 and Section 12.3 
12.1.3.4 
INJECTION SITE REACTIONS  
The investigator should assess the injection site at each scheduled visit for: 
 Pain, tenderness, erythema, and induration severity (Table 4) 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


RA101495  
Protocol RA101495-01.202 
Version 1.1 
CONFIDENTIAL 
37 
 Erythema and induration: record the maximum linear diameter  
 Blisters, ulceration, necrosis: record the maximum linear diameter and severity 
 Lymphadenopathy 
In addition, the investigator will, whenever possible, take de-identified photos of the injection 
site reaction (ISR). 
Injection site reactions should be recorded as AEs per Section 12.1 and Section 12.3, and 
recorded on the ISR specific eCRF and AE eCRF as appropriate. 
Table 4 
Grading the Severity of Local Injection Site Reactions 
Local Reaction 
to Injectable 
Product 
Grade 1 
(Mild) 
Grade 2 
(Moderate) 
Grade 3 
(Severe) 
Grade 4 
(Potentially Life 
Threatening) 
Pain 
Does not interfere 
with activity 
Repeated use of 
non-narcotic pain 
reliever >24 hours or 
interferes with 
activity 
Any use of narcotic 
pain reliever or 
prevents daily 
activity 
Emergency room 
visit or 
hospitalization 
Tenderness 
Mild discomfort 
to touch 
Discomfort with 
movement 
Significant 
discomfort at rest 
Emergency room 
visit or 
hospitalization 
Erythema/ 
redness 
2.5 to 5.0 cm 
5.1 to 10.0 cm 
>10.0 cm 
Necrosis or 
exfoliative 
dermatitis 
Induration/ 
swelling 
2.5 to 5.0 cm and 
does not interfere 
with activity 
5.1 to 10.0 cm or 
interferes with 
activity 
>10.0 cm or 
prevents daily 
activity 
Necrosis 
12.1.3.5 
INFECTION  
All subjects should be monitored for signs and symptoms of Neisseria meningitidis infection. 
During the study, to mitigate the risk of infection, subjects will be counseled and reminded of 
early signs and symptoms of Neisseria meningitidis infection. A patient safety card detailing the 
signs and symptoms of infection with instructions to seek immediate medical attention will be 
provided to each subject. The card will also describe the subject’s participation in the study and 
the risks of infection associated with inhibition of the terminal complement system.  The patient 
safety card must be carried with the patient at all times while on treatment.   
All AEs should be recorded as AEs per Section 12.2 and Section 12.3. 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


RA101495  
Protocol RA101495-01.202 
Version 1.1 
CONFIDENTIAL 
38 
12.2 
EVALUATION AND CLASSIFICATIONS 
12.2.1 
SEVERITY 
The investigator should determine the severity of the reported AE by using the NCI- CTCAE 
(Version 4.0). These criteria will be provided in a separate manual.  
For any reported AE not described in the NCI-CTCAE, the following guidelines must be 
considered for severity evaluation: 
Adverse Event Severity 
Mild 
Symptom(s) barely noticeable to subject or does not make subject 
uncomfortable; does not influence performance or functioning; 
prescription drug not ordinarily needed for relief of symptom(s). 
Moderate 
Symptom(s) of a sufficient severity to make subject uncomfortable; 
performance of daily activity is influenced; subject is able to continue 
in study; treatment for symptom(s) may be needed. 
Severe 
Symptom(s) cause severe discomfort; symptoms cause incapacitation or 
significant impact on subject’s daily life; severity may cause cessation 
of treatment with study treatment; treatment for symptom(s) may be 
given and/or subject hospitalized. 
12.2.2 
CAUSALITY 
The causal relationship of the AE to study medication will be assessed by both the investigator 
and the Sponsor. The assessment of causal relationship to study drug should be evidence-based, 
and not based on the premise that all AEs are causally related to study drug until proven 
otherwise. Default categorization of ‘related’ without supportive evidence for a causal 
relationship to study drug is generally uninformative and does not contribute to understanding of 
the safety profile of the drug with respect to the intended population. 
Examples of evidence that would suggest a causal relationship between the drug and the AE 
include occurrence of an AE that is known to be strongly associated with drug exposure (e.g. 
injection site reaction), or an AE that is otherwise uncommon in the study population. Lack of 
efficacy of study drug, in isolation, leading to unmasking of underlying symptoms and signs of 
disease, should not be considered evidence of relatedness. 
The causal relationship of each AE is assessed using a binary system with all AEs classified as 
either ‘related’ or ‘unrelated’. 
Related: There is ‘reasonable possibility' that the drug caused the AE. The AE follows a 
reasonable temporal association from the time of study drug administration. There is supportive 
evidence to suggest a possible causal relationship, irrespective of the degree of certainty, 
between the observed AE and the study drug. There is no alternative more likely explanation for 
the AE. Lack of study drug efficacy is not considered, by itself, to be evidence of relatedness. 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


RA101495  
Protocol RA101495-01.202 
Version 1.1 
CONFIDENTIAL 
39 
Not Related: Lack of a reasonable temporal association from the administration of the study 
drug and the occurrence of the AE. There is evidence of an alternative explanation that is more 
likely as a cause of the AE. 
12.3 
RECORDING, REPORTING, AND MONITORING 
12.3.1 
RECORDING AND REPORTING 
The investigator must make every effort to properly evaluate all information relevant to the 
reported AE in such a way that a diagnosis can be confidently made and reported. For example, 
it is preferable to report “pneumonia” as the AE rather than its symptoms (e.g. “rales” or “fever”) 
as separate AEs. 
When recording and/or reporting AEs or SAEs, the following elements must be included: 
 the fulfilled criteria for seriousness as presented in Section 12.1.2 
 the severity of the event as defined in Section 12.2.1 
 the relationship of the event to study treatment as defined in Section 12.2.2 
Actions taken in relation to the AE will be recorded as drug withdrawn, drug interrupted, dose 
reduced, dose increased, concomitant medication, other action (e.g. diagnostic testing), or no 
action. Any medication given to treat the AE will be recorded separately in the concomitant 
medication list of the eCRF. 
The outcome of the AE will be recorded as date ended, ongoing, or resulting in death with date 
of death. 
12.3.1.1 
RECORDING AND REPORTING ADVERSE EVENT 
Pre-existing conditions that are detected prior to administration of the first dose of study drug in 
the qualifying study will have been recorded as part of medical history of the qualifying study. 
Any AE ongoing at the last visit of the qualifying study will be recorded on a specific eCRF page 
for such ongoing AEs from qualifying study. The AE reporting period will start with the first 
administration of study drug on Day 1 and will end with the final study visit, after which no new 
AEs are to be reported. In addition, SAEs will be collected from the time the subject signs the 
study specific informed consent until 30 days after the last dose of study drug. When possible, 
ongoing AEs assessed as related to the study drug will be followed until resolved or stabilized. 
The subjects will be monitored throughout the study for any AEs, including abnormal, clinically 
significant laboratory values, clinically significant findings at vital signs measurements, 
spontaneous reports by study subject s, and observations by the study personnel. Adverse events 
will be coded using Medical Dictionary for Regulatory Activities (MedDRA) after the eCRFs 
have been monitored and signed by the investigator.  
All AEs will be recorded in the eCRF. The investigator will assess and record any AE in detail 
including the date and time of onset, event diagnosis (if known) or sign/symptom, severity, time 
course (end date or ongoing), relationship of the AE to study drug, and any action(s) taken. All 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


RA101495  
Protocol RA101495-01.202 
Version 1.1 
CONFIDENTIAL 
40 
AEs should be reported separately (ie, 1 record per event). Reporting of AEs is event-based (ie, 
an ongoing event will not be closed until resolved or at the end of study). For the AE description, 
a diagnosis is preferred over symptoms. If no diagnosis can be made, each symptom will be 
reported as a separate AE. Abbreviations should be avoided. Descriptive words should be used 
for ongoing conditions as applicable (e.g. exacerbation of herpes genitalis or worsening of 
eczema).  
12.3.1.2 
RECORDING AND REPORTING SERIOUS ADVERSE EVENT 
Any SAE experienced by the subject from ICF signing up to 30 days after the last dose of study 
drug, regardless of severity or causality, must be recorded on the eCRF and SAE Form. 
The study site must formally notify the Sponsor of the SAE within 24 hours from the time the 
study site becomes aware of the SAE. A formal notification must be submitted to the Sponsor 
regardless of the following: 
 severity 
 causality 
 whether or not the subject received study treatment or undergone study related procedures  
The IEC/IRB will be notified as required by local regulations. The investigator will be 
responsible for submitting the required safety information to the appropriate IEC/IRB, including 
any safety reports received from the Sponsor as well as any SAEs occurring at his or her site.  
The Sponsor, or designee, will prepare any required safety reports for regulatory authorities and 
all active investigators. These reports will be provided as addenda to the Investigator’s Brochure, 
and the investigator will place these with the brochure. 
12.3.1.3 
DEATH 
Any event with an outcome of death should be appropriately recorded in the eCRF. All identified 
causes of death, including an assessment of the possible relationship of each to study treatment, 
must be reported as SAEs as outlined in Section 12.3.1.2. Any autopsy or other post-mortem 
findings (including a coroner’s report) should be provided when available. 
12.3.2 
MONITORING 
All AEs and SAEs should be monitored by the investigator until resolution or stabilization.  
12.3.2.1 
POST-STUDY EVENTS 
Any SAE that was continuing at the time of subject discontinuation or study completion should 
be monitored by the investigator until resolution or stabilization. 
SAEs that occur after the subject discontinues from or completes the study and are considered by 
the investigator to be related to study treatment or procedures should be reported using the same 
procedures outlined in Section 12.3.1.2. 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


RA101495  
Protocol RA101495-01.202 
Version 1.1 
CONFIDENTIAL 
41 
12.4 
SPECIAL CIRCUMSTANCES 
12.4.1 
PREGNANCY 
Subjects and their partners should avoid pregnancy throughout the course of the study. 
Pregnancy in a study subject or partner must be reported to the Sponsor within 1 working day of 
the site becoming aware of the pregnancy. Subjects with a positive pregnancy test before study 
drug dosing must not be dosed. 
Information regarding a pregnancy occurrence in a study subject or partner and the outcome of 
the pregnancy will be collected. 
Pregnancy in a study subject or partner is not, in itself, considered an AE. However, the medical 
outcome of an elective or spontaneous abortion, stillbirth, or congenital anomaly is considered an 
SAE and must be reported to the Sponsor within 24 hours of the site becoming aware of the 
event. The procedure of elective abortion should not be reported as an AE.  
12.4.2 
OTHER 
Certain safety events, called ‘Special Situations’, that occur in association with study 
medication(s) may require reporting. These Special Situations include, but are not limited to, the 
following: 
 Overdose of the medicinal product 
 Suspected abuse/misuse of the medicinal product 
 Inadvertent or accidental exposure to the medicinal product 
 Medication error involving medicinal product (with or without subject/subject exposure 
to the sponsor’s medicinal product, e.g. name confusion) 
Special situations should be reported on the Special Situations CRF whether they result in an 
AE/SAE or not. Special Situations associated with an AE/SAE should also be reported on the 
corresponding AE/SAE forms. 
 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


RA101495  
Protocol RA101495-01.202 
Version 1.1 
CONFIDENTIAL 
42 
13 
STATISTICAL AND ANALYTICAL PLANS   
13.1 
SAMPLE SIZE DETERMINATION 
Sample size will be determined by the number of eligible subjects completing a qualifying 
RA101495 clinical study. No formal statistical sample size estimates were performed. 
13.2 
ANALYSIS POPULATIONS 
Analysis populations defined in this study are described in the sections that follow.  
13.2.1 
SAFETY POPULATION 
The Safety Population will include all subjects who receive at least 1 injection of RA101495 on 
or after Day 1 of this extension study (RA101495-01.202). 
13.2.2 
PER PROTOCOL POPULATION 
The Per Protocol Population will include all subjects in the Safety Population who have no major 
protocol violations. 
13.2.3 
PHARMACOKINETIC POPULATION 
The PK Population will include all subjects in the Safety Population who have at least 1 plasma 
sample obtained for PK assessment.  
13.2.4 
PHARMACODYNAMIC POPULATION 
The PD Population will include all subjects in the Safety Population who have at least 1 plasma 
sample obtained for PD assessment. 
13.3 
STATISTICAL PLAN 
13.3.1 
GENERAL CONSIDERATIONS 
Data will be summarized within each dose level separately. Where appropriate, data will be 
pooled across dose levels. There will be no adjustments for multiple comparisons. Details of the 
statistical analysis methodology will be provided in a Statistical Analysis Plan. 
13.3.2 
SUBJECT DISPOSITION 
A disposition of all consented subjects will be provided. This will include a breakdown of 
subjects who consented, were treated, discontinued treatment, and were lost to follow-up, or 
withdrew consent. Additionally, a summary of subjects included in the analysis populations 
defined in Section 13.2 will be provided. 
 
 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


RA101495  
Protocol RA101495-01.202 
Version 1.1 
CONFIDENTIAL 
43 
13.3.3 
DEMOGRAPHY AND BASELINE DISEASE CHARACTERISTICS 
Quantitative variables will be summarized with the mean, median, and range. Categorical 
variables will be summarized using counts and proportions.  
13.3.4 
EXTENT OF EXPOSURE 
The number of injections and dose-levels will be summarized from the start of this study. The 
number of subjects with an increase in dose and decrease in dose (relative to the dose at the start 
of the study) will be summarized. Additionally the number of subject -years on drug will be 
summarized by dose and overall. 
13.3.5 
SAFETY ANALYSIS 
Safety analysies will be performed by the dose level as well as pooled across dose levels. 
13.3.5.1 
ADVERSE EVENTS 
Adverse events will be coded using MedDRA (version 18.0 or higher). 
Incidence rates for treatment-emergent adverse events (TEAEs) by maximum severity and SAEs 
will be summarized. These summaries will be provided regardless of causality and for events 
that are considered possibly related to treatment with RA101495. TEAEs are defined as follows: 
 An AE that occurs after a subject’s initial treatment RA101495 start for this study 
(RA101495-01.202) that was not present at the time of treatment start; or 
 An AE that increases in severity after treatment start at this study, if the event was present at 
the time of treatment start. 
TEAEs will be summarized for each dose level separately. Pooled summaries will also be 
provided for eculizumab-naïve, eculizumab-switch, and inadequate responder populations 
separately.  
AEs occurring before the first dose of study drug in this study will be summarized separately and 
included in the overall AE analysis as appropriate.  
13.3.5.2 
ADVERSE EVENTS OF SPECIAL INTEREST 
Thrombotic AEs will be summarized separately by system organ class, preferred term, and dose. 
The events in Table 5 will be evaluated in the assessment of thrombotic AEs: MAVE criteria 
[Hillmen, 2007]) will be evaluated in the assessment of thrombotic AEs: 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


RA101495  
Protocol RA101495-01.202 
Version 1.1 
CONFIDENTIAL 
44 
Table 5 
Thrombotic Event Description (MAVE criteria)  
Thrombophlebitis/Deep vein thrombosis 
Mesenteric/Visceral arterial thrombosis 
Pulmonary embolus 
Hepatic/Portal vein thrombosis 
Myocardial infarction 
Dermal thrombosis 
Transient ischemic attack 
Gangrene (non-traumatic, non-diabetic) 
Renal vein thrombosis 
Cerebral arterial occlusion/ cerebrovascular 
accident 
Acute peripheral vascular occlusion 
Cerebral venous occlusion 
Amputation (non-traumatic, non-diabetic) 
Renal arterial thrombosis 
Mesenteric/Visceral vein thrombosis 
Other 
Unstable angina 
 
13.3.5.2.1 
HEPATIC ADVERSE EVENTS 
Hepatic and biliary AEs and will be summarized separately by system organ class, preferred 
term, and dose level. Liver function tests will be summarized by changes from baseline and 
graded in severity using the NCI CTCAE criteria.  
13.3.5.2.2 
PANCREATIC ENZYME ELEVATIONS 
Pancreatic AEs and will be summarized separately by system organ class, preferred term, and 
dose level.  Pancreatic elevations will be summarized by changes from baseline and graded in 
severity using the NCI CTCAE criteria.  
13.3.5.2.3 
INJECTION SITE REACTIONS 
ISRs will be summarized separately by system organ class, preferred term, and dose level. The 
summary will include additional details on these events as described in Section 11.2.3 and 
Section 12.1.3.  
13.3.5.2.4 
INFECTION  
AEs related to infection with Neisseria meningitidis will be summarized separately by system 
organ class, preferred term, and dose level. 
13.3.5.3 
CLINICAL LABORATORY EVALUATION 
Quantitative laboratory endpoints will be summarized by time point using descriptive statistics. 
13.3.5.4 
ELECTROCARDIOGRAM 
Descriptive statistics for ECG parameters (i.e. heart rate (HR), PR interval, RR interval, QRS 
interval, QT interval, and QTcB intervals, and QTc F intervals ) at each assessment timepoint 
will be presented.  
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


RA101495  
Protocol RA101495-01.202 
Version 1.1 
CONFIDENTIAL 
45 
13.3.5.5 
VITAL SIGNS 
Descriptive statistics for vital signs (heart rate, body temperature, and blood pressure) at each 
assessment timepoint will be presented. 
13.3.5.6 
PHYSICAL EXAMINATION 
The complete set physical examination findings will be provided in listings. Clinically 
significant physical examination abnormalities will included and summarized as AEs if 
appropriate. 
13.3.6 
EFFICACY ANLYSIS 
Efficacy endpoints will be summarized using descriptive statistics. Tests to assess change-from-
baseline will be performed as appropriate. 
13.3.6.1 
PHARMACOKINETIC ANALYSIS 
Drug exposure will be evaluated using PK parameters derived from non-compartmental methods. 
All calculations for the final analysis will be based on actual sampling times. Individual PK 
parameters will be presented in listings and summarized by doses using descriptive statistics. 
13.3.6.2 
PHARMACODYNAMIC ANALYSIS 
Pharmacodynamic endpoints will be summarized. No formal statistical comparison between 
doses will be performed. Tests to assess change-from-baseline will be performed as appropriate. 
13.3.6.3 
EXPLORATORY ANALYSES 
The quality of life endpoints will be summarized descriptively.  
13.3.6.3.1 
BIOMARKER ANALYSIS 
The completion of analyses will be conditional based on the results of this or other clinical 
studies, and samples may be selected for analysis on the basis of clinical outcome (see 
Section 11.6.2). The results of the biomarker investigations will be reported separately from the 
main clinical study report. 
13.3.7 
INTERIM ANALYSIS 
During the study, the Sponsor will conduct periodic interim analyses of the study data which 
may include safety, tolerability, PK, PD and efficacy endpoints. 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


RA101495  
Protocol RA101495-01.202 
Version 1.1 
CONFIDENTIAL 
46 
14 
ETHICAL CONSIDERATIONS 
This study shall be conducted in accordance with the ethical principles that have their origin in 
the Declaration of Helsinki and that are consistent with Good Clinical Practice (GCP) and 
applicable regulatory requirement(s).  
14.1 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE 
COMMUNICATIONS 
Prior to study initiation, the investigator/institution should have written and dated 
approval/favorable opinion from the IEC/IRB for the study protocol, written ICF, consent form 
updates, subject recruitment procedures (e.g. advertisements), and any other written information 
to be provided to subjects. A current copy of the Investigator’s Brochure must be provided to the 
IEC/IRB as part of the written application. During the study, the investigator/institution should 
provide to the IEC/IRB all documents subject for review. 
14.1.1 
PROGRESS REPORTS 
The investigator should submit written summaries of the study status to the IEC/IRB annually, or 
more frequently, if requested by the IRB/IEC. 
14.1.2 
FINAL INVESTIGATOR REPORT 
Upon completion of the study, the investigator/institution should provide a summary of the 
study’s outcome to the IEC/IRB and the regulatory authorities with any required reports. 
14.2 
INFORMED CONSENT OF STUDY SUBJECTS 
In obtaining and documenting informed consent, the investigator should comply with the 
applicable regulatory requirement(s) and should adhere to GCP and to the ethical principles that 
have their origin in the Declaration of Helsinki.  
The written ICF and any other written information to be provided to subjects should be revised 
whenever important new information becomes available that may be relevant to the subject’s 
consent. Any revised written ICF and written information should receive the IEC/IRB’s 
approval/favorable opinion in advance of use. The subject or the subject’s legally acceptable 
representative should be informed in a timely manner if new information becomes available that 
may be relevant to the subject’s willingness to continue participation in the study. The 
communication of this information should be documented. 
The investigator should fully inform the subject or the subject’s legally acceptable representative 
of all pertinent aspects of the study, including the written information and the approval/ 
favorable opinion by the IEC/IRB. Before informed consent may be obtained, the investigator 
should provide the subject or the subject’s legally acceptable representative ample time and 
opportunity to inquire about details of the study and to decide whether or not to participate in the 
study. All questions about the study should be answered to the satisfaction of the subject or the 
subject’s legally acceptable representative.  
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


RA101495  
Protocol RA101495-01.202 
Version 1.1 
CONFIDENTIAL 
47 
Prior to a subject’s participation in the study, the written ICF should be signed and personally 
dated by the subject or by the subject’s legally acceptable representative and by the person who 
conducted the informed consent discussion. If a subject is unable to read or if a legally 
acceptable representative is unable to read, an impartial witness should be present during the 
entire informed consent discussion. 
Prior to participation in the study, the subject or the subject’s legally acceptable representative 
should receive a copy of the signed and dated written ICF and any other written information 
provided to the subjects. During a subject’s participation in the study, the subject or the subject’s 
legally acceptable representative should receive a copy of the signed and dated consent form 
updates and a copy of any amendments to the written information provided to subjects. 
14.3 
PROTOCOL COMPLIANCE 
The investigator/institution should conduct the study in compliance with the protocol agreed to 
by the Sponsor and regulatory authorities (if required) and which was given approval/favorable 
opinion by the IRB/IEC. The investigator/institution and the sponsor should sign the protocol, or 
an alternative contract, to confirm agreement. 
The investigator should not implement any deviation from, or changes to, the protocol without 
agreement by the Sponsor and prior review and documented approval/favorable opinion from the 
IEC/IRB of an amendment, except where necessary to eliminate immediate hazard(s) to study 
subjects or when the change involves only logistical or administrative aspects of the study (eg, 
change in monitor, change of telephone number). When an important deviation from the protocol 
is deemed necessary for an individual subject, the investigator must contact the Medical Monitor 
for the study. 
Such contact must be made as soon as possible to permit a review by the Sponsor to determine 
the impact of the deviation on the subject’s participation and/or the assessment of safety or 
efficacy in the study. Any significant protocol deviations affecting subject eligibility and/or 
safety must be reviewed and/or approved by the IEC/IRB and regulatory authorities, as 
applicable, prior to implementation. 
The investigator should document and explain any deviation from the approved protocol. 
14.4 
PROTECTION OF CONFIDENTIALITY 
Prior to study participation, the investigator shall inform the subject or the subject’s legally 
acceptable representative that the monitor(s), auditor(s), IEC/IRB, and the regulatory authorities 
will be granted direct access to the subject’s original medical records for verification of clinical 
study procedures and/or data, without violating the confidentiality of the subject, to the extent 
permitted by the applicable laws and regulations and that, by signing a written ICF, the subject or 
the subject’s legally acceptable representative is authorizing such access.  
In addition, prior to study participation, the subject must be informed that the records identifying 
the subject will be kept confidential and, to the extent permitted by the applicable laws and/or 
regulations, will not be made publicly available; if the results of the study are published, the 
subject’s identity will remain confidential. 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


RA101495  
Protocol RA101495-01.202 
Version 1.1 
CONFIDENTIAL 
48 
14.5 
DISCLOSURE OF STUDY RESULTS 
The Sponsor will post the results of the study in a publicly accessible database in accordance 
with the applicable laws and regulations. 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


RA101495  
Protocol RA101495-01.202 
Version 1.1 
CONFIDENTIAL 
49 
15 
REGULATORY AND ADMINISTRATIVE CONSIDERATIONS 
15.1 
QUALITY ASSURANCE 
Quality assurance and quality control systems shall be implemented and maintained with written 
standard operating procedures (SOPs) to ensure that the study is conducted and data are 
generated, documented (recorded), and reported in compliance with the protocol, GCP, and the 
applicable regulatory requirement(s). Quality control shall be applied to each stage of data 
handling to ensure that all data are reliable and have been processed correctly. 
An agreement must be secured from all involved parties to ensure direct access to all study 
related sites, source documents, and reports for the purpose of monitoring and auditing by the 
Sponsor, and of inspection by regulatory authorities. 
15.1.1 
MONITORING 
On-site monitoring visits will be conducted before, at regular intervals during, and after the 
study, as appropriate, by Sponsor-approved monitors. At a minimum, the accuracy and 
completeness of the eCRF entries, source documents, and other study-related records will be 
checked against one another during these visits. After each monitoring visit, a report of any 
significant findings/facts, deviations, and deficiencies will be communicated to the investigator. 
The actions taken to address the findings and secure compliance should be documented.  
15.1.2 
AUDIT 
An audit may be performed independently of, and separately from, routine monitoring to 
evaluate clinical study conduct and compliance with the protocol, SOPs, GCP, and the applicable 
regulatory requirements.  
15.2 
CLINICAL RESEARCH ORGANIZATIONS 
A Clinial Research Organization will be utilized to assist in the conduct of this study. Accredited 
central laboratories will be used for the analysis of safety laboratory samples and for the 
bioanalytical testing of PK and PD blood samples. 
15.3 
DATA MANAGEMENT 
15.3.1 
CASE REPORT FORMS 
Case report forms must be completed for each subject screened/enrolled in this study. These 
forms will be used to transmit information collected during the study to the Sponsor and 
regulatory authorities, as applicable. The case report form data for this study are being collected 
with an eCRF. The documentation related to the validation of the eCRFs will be maintained in 
the Trial Master File. The Trial Master File will be maintained by the CRO and the Sponsor. 
The investigator will document subject data in his/her own subject files. These subject files will 
serve as source data for the study. All eCRF data required by this protocol will be recorded by 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


RA101495  
Protocol RA101495-01.202 
Version 1.1 
CONFIDENTIAL 
50 
investigative site personnel. All data entered into the eCRF will be supported by source 
documentation. 
The investigator or an authorized member of the investigator’s staff will make any necessary 
corrections to the eCRF. All change information, including the date and person performing the 
corrections, will be available via the audit trail, which will be part of the electronic data capture 
system. For any correction, a reason for the alteration will be provided. The eCRFs will be 
reviewed periodically for completeness and acceptability by Sponsor personnel (or their 
representatives). The Sponsor (or their representatives) will also be allowed access to all source 
documents pertinent to the study in order to verify eCRF entries. The investigator will review the 
eCRFs for completeness and accuracy and provide his or her electronic signature and date to 
eCRFs as evidence thereof. 
Access to the electronic data capture system will be password-protected and will be removed 
from the investigator site at the end of the site’s participation in the study. Data from the eCRF 
will be archived on appropriate data media and provided to the investigator at that time as a 
durable record of the site’s eCRF data. It will be possible for the investigator to make paper 
printouts that media. 
15.3.2 
SOURCE DOCUMENTS 
Source documents are defined as original documents, data, and records. These may include 
hospital records, clinical and office charts, laboratory data/information, subjects' diaries or 
evaluation checklists, pharmacy dispensing and other records, recorded data from automated 
instruments, microfiches, photographic negatives, microfilm or magnetic media, ECGs, X-rays, 
ultrasounds, angiograms, venograms, CT scans, and/or MRI scans. Data collected during this 
study must be recorded on the appropriate source documents. 
The investigator(s)/institution(s) will permit study-related monitoring, audits, IEC/IRB review, 
and regulatory inspection(s), providing direct access to source data documents. 
15.4 
PREMATURE TERMINATION OR SUSPENSION OF THE STUDY 
If the Sponsor terminates or suspends the study, the investigator/institution should promptly 
inform the IEC/IRB and provide the IEC/IRB a detailed written explanation of the termination or 
suspension. If the IEC/IRB terminates or suspends its approval/favorable opinion of the study, 
the investigator/institution should promptly notify the Sponsor and provide the Sponsor with a 
detailed written explanation of the termination or suspension. 
15.5 
CLINICAL STUDY REPORT 
Whether the study is completed or prematurely terminated, the clinical study report will be 
prepared and provided to the regulatory agencies as required by the applicable regulatory 
requirement(s). 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


RA101495  
Protocol RA101495-01.202 
Version 1.1 
CONFIDENTIAL 
51 
15.6 
PUBLICATION POLICY 
The Sponsor recognizes the importance of communicating the results of scientific studies, 
including clinical trials, and therefore, strongly supports their publication of trial findings in 
peer-reviewed scientific journals and presentation of data at professional society seminars or 
conferences. The Sponsor also has legitimate corporate and investor responsibilities, including, 
but not limited to, protecting confidential information about its proprietary products and 
obtaining patent protection for its intellectual property. 
Therefore, the following procedures apply to any communication (including written, oral, or 
electronic; manuscript, abstract, other publication, or presentation) of results or information 
arising from this study (including any ancillary studies involving trial subjects) to any third 
parties: 
 The proposed communication will be prepared in collaboration with the Sponsor. The first 
publication from this study is expected to be a summary of partial or complete data, jointly 
produced by the Sponsor and the participating investigators. The participating investigators 
will be invited to contribute as co-authors in the joint communication. If a joint 
communication with a summary of all protocol results has not been submitted for publication 
within eighteen (18) months of completion or termination of the study at all participating 
sites and final locking of the study database, the participating investigators will be free to 
publish separately, subject to the procedures set forth in this section. 
 The final proposed version must be submitted to the Sponsor for review and comment at least 
30 days prior to presentation, submission for publication, or other dissemination.  
 In the event the Sponsor reasonably determines that a proposed communication contains 
confidential or patentable material, they may require either of the following:  
o The material be removed from the communication  
o The communication may be delayed to permit filing the appropriate intellectual property 
protection. These procedures apply regardless of whether the study is completed as 
planned or is terminated prematurely for any reason.   
All publications will give Ra Pharmaceuticals, Inc. and/or its research personnel appropriate 
credit (ie, authorship or acknowledgement) for any direct contribution made by them. 
Authorship will be decided jointly by the investigators and the Sponsor. Manuscripts will 
conform to the Uniform Requirements for Manuscripts Submitted to Biomedical Journals, 
including, but not limited to, the standards for authorship contained therein. 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


RA101495  
Protocol RA101495-01.202 
Version 1.1 
CONFIDENTIAL 
52 
16 
REFERENCES 
Aaronson NK, Ahmedzai S, Bergman B, et al. The European Organization for Research and 
Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials 
in oncology. J Natl Cancer Inst 1993;85(5):365-376. 
Aaronson NK, Cull A, Kaasa S, et al. The European Organization for Research and Treatment of 
Cancer (EORTC) modular approach to quality of life assessment in oncology: an update.  In: 
Spilker B, ed. Quality of Life and Pharmacoeconomics in Clinical Trials. 2nd Ed. New York, 
NY: Lippincott Williams & Wilkins. 1996; 179-189. 
Hillmen P, Muss P, Duhrsen, U, et al. Effect of the complement inhibitor eculizumab on 
thromboembolism in patients with paroxysmal nocturnal hemoglobinuria. Blood; 2007: 
110:4123-4128. 
Webster, K, Cella D, and Yost K. The functional assessment of chronic illness therapy (FACIT) 
measurement system: properties, applications, and interpretation. Health Qual Life Outcomes 
2003;1:79-85. 
 
 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.

SAP_001.pdf: 
Ra Pharmaceuticals, Inc. (part of UCB) 
Clinical Study Report 
FINAL 
RA101495-01.202 (UCB PNH001) 
 
 
16.1.9 Documentation of Statistical Methods 
 
CONFIDENTIAL 
16.1.9 
Documentation of Statistical Methods 
Statistical Analysis Plan (v2.0) 15 October 2021 
 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


Sign-off page
Statistical Analysis Plan
FINAL
Document title:
Sign-off status:
Digitally signed by:
Electronic Signature Page
Automatically generated on 19-OCT-2021 15:45 (GMT +03:00) for document ID: 0900000b81159328
This signoff page has been automatically generated to capture the digital signatures of authorized signatories.
Each record has been time-stamped and verified as authentic by certified software, providing evidence that the
signed document has not been altered or tampered with post-signature.
NAME, POSITION
ROLE
DATE TIME STAMP
originator
15-OCT-2021
22:39 (GMT +03:00)
reviewer
15-OCT-2021
22:41 (GMT +03:00)
reviewer
16-OCT-2021
10:56 (GMT +03:00)
reviewer
18-OCT-2021
10:28 (GMT +03:00)
approver
18-OCT-2021
20:22 (GMT +03:00)
approver
19-OCT-2021
15:45 (GMT +03:00)
Certified
by PSI CRO AG
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


Statistical Analysis Plan: RA101495-01.202 / PNH001 
Review Status: Final 
Version: 2.0 
 
Version Date: 15OCT2021 
 
 
 
CONFIDENTAL 
Page 1 of 37 
 
Ra Pharmaceuticals Inc (now part of UCB) 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
PROTOCOL RA101495-01.202 (UCB study PNH001) 
 
A MULTICENTER, OPEN-LABEL, UNCONTROLLED, 
EXTENSION STUDY OF RA101495 IN SUBJECTS WITH PAROXYSMAL NOCTURNAL 
HEMOGLOBINURIA WHO HAVE COMPLETED A RA101495 CLINICAL STUDY 
 
 
Protocol code:  
RA101495-01.202 (UCB study PNH001) 
SAP Version:  
Final 2.0 
SAP Date:  
15OCT2021 
Author:  
 
 
 
 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


Statistical Analysis Plan: RA101495-01.202 / PNH001 
Review Status: Final 
Version: 2.0 
 
Version Date: 15OCT2021 
 
 
 
CONFIDENTAL 
Page 2 of 37 
 
DOCUMENT HISTORY 
VERSION HISTORY 
Version # 
Version Date 
Final 1.0 
09 April 2021 
Final 2.0 
15OCT2021 
REVISION HISTORY 
Version # 
Chapter 
Revision Summary 
Reason(s) for Revision 
1.0 
N/A 
Initial release 
N/A 
2.0 
2 
CRF version updated 
New CRF version 
 
9.4 
Reason for treatment 
discontinuation removed from 
disposition summary 
No separate treatment 
discontinuation reason was 
collected in addition to study 
discontinuation reason 
 
9.6.4 
WHODrug version updated 
Newer version used 
 
9.8.3 
AE summary extended 
Due to reporting requirements 
 
9.11 
Clarification that no interim 
analysis was performed 
No interim analysis was 
performed 
 
10 
No analysis of CH50 
No data available 
 
 
 
 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


Statistical Analysis Plan: RA101495-01.202 / PNH001 
Review Status: Final 
 
Version: 2.0 
 
Version Date: 15OCT2021 
 
 
 
CONFIDENTAL 
Page 3 of 37 
 
 
 
APPROVAL SIGNATURES 
STUDY TITLE: A MULTICENTER, OPEN-LABEL, UNCONTROLLED, 
EXTENSION STUDY OF RA101495 IN SUBJECTS WITH PAROXYSMAL 
NOCTURNAL HEMOGLOBINURIA WHO HAVE COMPLETED A RA101495 CLINICAL 
STUDY 
PROTOCOL NUMBER: RA101495-01.202 (UCB study PNH001) 
SAP Final 2.015OCT2021 
 
PSI 
Author: 
 
Signature: 
................................................................ 
Date: ...................... 
 
: 
 
Signature: 
........... .................................................... 
Date: ...................... 
 
:
 
Signature: 
................................................................ 
Date: ...................... 
 
: 
 
Signature: 
........... .................................................... 
Date: ...................... 
 
UCB 
: 
 
Signature: 
................................................................ 
Date: ...................... 
 
: 
 
Signature: 
................................................................ 
Date: ...................... 
 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


Statistical Analysis Plan: RA101495-01.202 / PNH001 
Review Status: Final 
 
Version: 2.0 
 
Version Date: 15OCT2021 
 
 
 
CONFIDENTAL 
Page 4 of 37 
 
 
 
TABLE OF CONTENTS 
1. 
LIST OF ABBREVIATIONS ............................................................................................................................. 6 
2. 
INTRODUCTION ............................................................................................................................................ 8 
3. 
STUDY OBJECTIVES ...................................................................................................................................... 8 
3.1 
Objectives .................................................................................................................................................... 8 
4. 
STUDY DESCRIPTION ................................................................................................................................... 8 
4.1 
Study Design ................................................................................................................................................ 8 
4.2 
Study Treatment .......................................................................................................................................... 8 
4.3 
Data and Safety Monitoring Board (DSMB) ..................................................................................................... 9 
5. 
SAMPLE SIZE AND POWER CALCULATION .................................................................................................... 9 
6. 
ANALYSIS ENDPOINTS ................................................................................................................................. 9 
6.1 
Efficacy Endpoints ........................................................................................................................................ 9 
6.2 
Safety Endpoints .......................................................................................................................................... 9 
6.3 
Exploratory Endpoints ................................................................................................................................... 9 
6.4 
Pharmacokinetic Endpoints ........................................................................................................................... 9 
6.5 
Pharmacodynamic Endpoints ......................................................................................................................... 9 
7. 
ANALYSIS POPULATIONS ........................................................................................................................... 10 
8. 
COHORTS .................................................................................................................................................... 10 
9. 
ANALYTICAL PLAN AND STATISTICAL METHODS ....................................................................................... 10 
9.1 
General Conventions and Statistical Considerations....................................................................................... 10 
9.2 
Definition of Baseline, Study Visits, and Visit Windows .................................................................................. 11 
9.3 
Handling of Missing Data ............................................................................................................................ 12 
9.4 
Subject Disposition ..................................................................................................................................... 12 
9.5 
Protocol Deviations ..................................................................................................................................... 12 
9.6 
Subject Characteristics ................................................................................................................................ 13 
9.6.1 
Baseline and Demographic Characteristics .................................................................................. 13 
9.6.2 
Medical History ......................................................................................................................... 13 
9.6.3 
PNH Disease And Treatment History .......................................................................................... 13 
9.6.4 
Prior and Concomitant Medications ............................................................................................ 13 
9.7 
Efficacy Endpoints and Analysis ................................................................................................................... 14 
9.7.1 
Analysis of Efficacy Endpoints .................................................................................................... 14 
9.8 
Safety Endpoints and Analysis ..................................................................................................................... 14 
9.8.1 
Exposure to Study Treatment .................................................................................................... 14 
9.8.2 
Clinical Laboratory Evaluation .................................................................................................... 14 
9.8.3 
Adverse Events ......................................................................................................................... 16 
9.8.4 
Immunogenicity........................................................................................................................ 21 
9.8.5 
Electrocardiogram ..................................................................................................................... 21 
9.8.6 
Vital Signs and Other Safety Parameters .................................................................................... 22 
9.9 
Exploratory Endpoints ................................................................................................................................. 22 
9.9.1 
EORTC QLQ-C30 ....................................................................................................................... 22 
9.9.2 
FACIT-Fatigue .......................................................................................................................... 25 
9.9.3 
Mechanistic Biomarkers ............................................................................................................. 26 
9.10 
Other Endpoints and Analysis ...................................................................................................................... 26 
9.10.1 
Pharmacokinetics ...................................................................................................................... 26 
9.10.2 
Pharmacodynamic .................................................................................................................... 26 
9.11 
Interim Analysis ......................................................................................................................................... 27 
10. 
DEVIATIONS FROM ANALYSIS AS DESCRIBED IN THE PROTOCOL ............................................................ 28 
11. 
PROGRAMMING SPECIFICATIONS ............................................................................................................. 29 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


Statistical Analysis Plan: RA101495-01.202 / PNH001 
Review Status: Final 
 
Version: 2.0 
 
Version Date: 15OCT2021 
 
 
 
CONFIDENTAL 
Page 5 of 37 
 
 
 
12. 
REFERENCES ............................................................................................................................................... 30 
13. 
APPENDIX I: LIST OF TABLES, LISTINGS, AND FIGURES ........................................................................... 31 
14. 
APPENDIX II. SCHEDULE OF ASSESSMENTS .............................................................................................. 37 
 
 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


Statistical Analysis Plan: RA101495-01.202 / PNH001 
Review Status: Final 
 
Version: 2.0 
 
Version Date: 15OCT2021 
 
 
 
CONFIDENTAL 
Page 6 of 37 
 
 
 
1. 
LIST OF ABBREVIATIONS 
 
Abbreviation 
Full Term 
ADA 
Anti-drug Antibody 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
aPTT/APTT 
Activated Partial Thromboplastin Time 
AST 
Aspartate Aminotransferase 
AUC 
Area Under the Drug Concentration-time Curve 
BMI  
Body Mass Index 
BUN 
Blood Urea Nitrogen 
C5 
Complement Component 5 
CH50 
Complement Total 
cm 
Centimeter 
Cmax 
Maximum Plasma Concentration 
CPK 
Creatine Phosphokinase  
CRP 
C-reactive Protein 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
ELISA 
Enzyme-linked Immunosorbent Assay 
EQ-5D 
EuroQol 5D Questionnaire 
EORTC-QLQ-C30 
European Organization for Research and Treatment 
of Cancer-Quality of Life Questionnaire 
FACIT-F 
Functional Assessment of Chronic Illness Therapy-
Fatigue Scale 
GGT 
Gamma-glutamyl Transferase 
HR 
Heart Rate 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization  
INR  
International Normalized Ratio 
ISR 
Injection Site Reaction 
kg 
Kilogram 
LDH 
Lactate Dehydrogenase 
MAVE 
Major Adverse Vascular event 
MCH 
Mean Corpuscular Hemoglobin 
MCHC 
Mean Corpuscular Hemoglobin Concentration 
MCV 
Mean Corpuscular Volume 
MDRD 
Modification of Diet in Renal Disease 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
NCI 
National Cancer Institute 
PD 
Pharmacodynamics 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


Statistical Analysis Plan: RA101495-01.202 / PNH001 
Review Status: Final 
 
Version: 2.0 
 
Version Date: 15OCT2021 
 
 
 
CONFIDENTAL 
Page 7 of 37 
 
 
 
PK 
Pharmacokinetics 
PNH 
Paroxysmal Nocturnal Hemoglobinuria 
PT 
Prothrombin Time 
PT 
Preferred Term 
PTT 
Partial Thromboplastin Time 
QOL 
Quality of Life 
RBC 
Red Blood Cell 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SOC 
System Organ Class 
sRBC 
Sheep Red Blood Cell  
TEAE 
Treatment-emergent Adverse Event 
tmax 
Time to Corresponding Cmax 
ULN 
Upper Limit of Normal 
VAS 
Visual Analogue Scale 
WBC 
White Blood Cell 
<LLOQ 
Below the Lower Limit of Quantification 
 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


Statistical Analysis Plan: RA101495-01.202 / PNH001 
Review Status: Final 
 
Version: 2.0 
 
Version Date: 15OCT2021 
 
 
 
CONFIDENTAL 
Page 8 of 37 
 
 
 
2. 
INTRODUCTION 
This statistical analysis plan (SAP) covers the analysis and reporting for protocol RA101495-
01.202 dated 20 October 2016 and electronic case report form (eCRF) version 44 dated 22 
March 2021. The following country-specific amendments are also reflected: 
USA: Study Protocol amendment (version 03-FEB-2017)  
Germany: Study Protocol amendment (version 03-MAY-2017) 
Finland: Study Protocol amendment (version 24-FEB-2017) 
UK: Study Protocol amendment (version 07-FEB-2017) 
Denmark: Study Protocol amendment (version 11-APR-2017) 
 
3. 
STUDY OBJECTIVES 
3.1 
OBJECTIVES 
x 
To provide access to RA101495 for subjects with PNH who have completed a Ra 
Pharmaceuticals sponsored study, have demonstrated clinical benefit, and who wish to 
continue receiving RA101495 for treatment of PNH 
x 
To evaluate the long-term safety and tolerability of RA101495 administered to subjects 
with PNH who have completed a Ra Pharmaceuticals sponsored RA101495 clinical 
study 
x 
To evaluate the long-term preliminary efficacy of RA101495 administered to subjects 
with PNH who have completed a Ra Pharmaceuticals sponsored RA101495 clinical 
study 
x 
To obtain periodic PK and PD data to confirm long-term maintenance of steady-state 
RA101495 plasma levels and sustained inhibition of hemolysis and complement 
4. 
STUDY DESCRIPTION 
4.1 
STUDY DESIGN 
The design is a multicenter, open-label, extension study for subjects with PNH who have 
successfully completed a qualifying Ra Pharmaceuticals sponsored RA101495 (zilucoplan) 
clinical study (RA101495-01.201 or RA101495-01.203). Subjects will continue to receive the 
final maintenance dose they were receiving in the qualifying study, as long as safety, 
tolerability, PK and PD data (from the qualifying study or this extension study) continue to 
demonstrate benefit. If additional data support a change in dose level for an individual subject in 
this extension study, investigators may increase or decrease the maintenance dose level, 
based on safety and PD findings, and in consultation with the medical monitor. All subjects will 
continue to be followed carefully for any evidence of meningococcal and/or other infection. 
4.2 
STUDY TREATMENT 
All eligible subjects will receive open-label RA101495 daily by SC self-injection. The starting 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


Statistical Analysis Plan: RA101495-01.202 / PNH001 
Review Status: Final 
 
Version: 2.0 
 
Version Date: 15OCT2021 
 
 
 
CONFIDENTAL 
Page 9 of 37 
 
 
 
dose in the extension study will be the same as the final maintenance dose the subject was 
receiving in the qualifying study. The IMP (RA101495) will continue to be provided by the 
sponsor until RA101495 is approved and available in the territory or the sponsor terminates 
development of RA101495 for PNH. 
4.3 
DATA AND SAFETY MONITORING BOARD (DSMB) 
No DSMBs are scheduled for this study.  
5. 
SAMPLE SIZE AND POWER CALCULATION 
Sample size will be determined by the number of eligible subjects completing a qualifying 
RA101495 clinical study. No formal statistical sample size estimates were performed.  
6. 
ANALYSIS ENDPOINTS 
6.1 
EFFICACY ENDPOINTS 
Serum LDH levels, total bilirubin, total hemoglobin, free hemoglobin, haptoglobin, reticulocytes, 
and hemoglobinuria, at each of the scheduled assessment time-points. 
6.2 
SAFETY ENDPOINTS 
Safety assessments will include an evaluation of AEs and SAEs (including major adverse 
vascular event (MAVE criteria)), clinical laboratory tests, ECGs, vital signs, and physical 
examinations.  
6.3 
EXPLORATORY ENDPOINTS 
x 
Quality of life (QOL) questionnaires (e.g. EORTC QLQ-C30 and FACIT-Fatigue) 
x 
Mechanistic biomarkers (e.g. complement function, complement proteins, biomarkers of 
inflammation, biomarkers for thrombosis, biomarkers of liver function) to be summarized 
in a separate report. 
6.4 
PHARMACOKINETIC ENDPOINTS 
x 
Plasma concentrations of RA101495 and its major metabolite(s) 
6.5 
PHARMACODYNAMIC ENDPOINTS 
 
x 
CH50 
x 
Sheep RBC (sRBC) lysis for the classical complement pathway 
x 
Wieslab ELISA for alternative complement pathway 
x 
C5 levels 
Note: CH50 is not analyzed as it is not collected. 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


Statistical Analysis Plan: RA101495-01.202 / PNH001 
Review Status: Final 
 
Version: 2.0 
 
Version Date: 15OCT2021 
 
 
 
CONFIDENTAL 
Page 10 of 37 
 
 
 
7. 
ANALYSIS POPULATIONS 
SAFETY POPULATION 
The Safety Population will include all subjects who receive at least 1 injection of RA101495 on 
or after Day 1 of this extension study (RA101495-01.202). 
PHARMACOKINETIC POPULATION 
The PK population will include all subjects in the safety Population who have at least 1 plasma 
sample obtained for PK assessment. 
PHARMACODYNAMIC POPULATION 
The PD population will include all subjects in the safety Population who have at least 1 plasma 
sample obtained for PD assessment. 
8. 
COHORTS 
The following cohorts of the study populations will be used for analyses.   
Eculizumab Naïve Subjects  
This will include all subjects who have not received eculizumab for treatment of PNH (i.e., 
subjects from study RA101495-01.201 Cohort A (Naïve)).  
Eculizumab Switch Subjects  
This will include all subjects who have received treatment with eculizumab for at least 6 months 
prior to Screening. (i.e., subjects from study RA101495-01.201 Cohort B (Switch)).  
Inadequate Response to Eculizumab Subjects  
This will be a subset of the Eculizumab Switch Subjects coming from the RA101495-01.203 
study, including all subjects who had an inadequate response to eculizumab defined as having 
received eculizumab for at least 6 months plus meeting one or both of the following criteria: 
x 
A documented lactate dehydrogenase (LDH) level ≥ 1.5 x the upper limit of normal 
(ULN) within 90 days prior to Screening 
x 
Presence of a known C5 mutation conferring resistance to eculizumab. 
9. 
ANALYTICAL PLAN AND STATISTICAL METHODS 
9.1 
GENERAL CONVENTIONS AND STATISTICAL CONSIDERATIONS 
Data will be summarized by eculizumab-naïve, eculizumab switch, and inadequate responder 
groups with all doses within these groups being pooled. 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


Statistical Analysis Plan: RA101495-01.202 / PNH001 
Review Status: Final 
 
Version: 2.0 
 
Version Date: 15OCT2021 
 
 
 
CONFIDENTAL 
Page 11 of 37 
 
 
 
All clinical study data will be presented in Subject data listings. Descriptive statistics (n, mean, 
standard error of the mean, standard deviation, median, minimum, and maximum) will be 
calculated by cohort for continuous variables.   
Counts and proportions will be presented by cohort for categorical and ordinal variables.  If 
there are missing values, the number of missing values will be presented, but without a 
percentage and the number of non-missing values used as the denominator.  
Means, medians, standard deviations, standard error of the mean, and confidence intervals will 
be reported to one decimal place more than the data reported on the CRF or by the 
laboratory/vendor. Minimum and maximum will be reported to the same number of decimal 
places displayed on the CRF or by the laboratory/vendor.  
Assuming that an endpoint is expected to be in a numeric format, all non-numeric values 
entered as “< X.XX” or “> Y.YY” will be analyzed as X.XX or Y.YY, respectively.  
9.2 
DEFINITION OF BASELINE, STUDY VISITS, AND VISIT WINDOWS 
Unless otherwise specified, a subject’s baseline will be the value from the Screening/Day 1 
value of this study. The Screening Visit will generally coincide with the qualifying study end of 
study visit. Should the last qualifying study visit be missing, the last available observation in the 
qualifying study will be used. All screening assessments are expected to be the same as those 
for the end of qualifying study visit and do not need to be repeated unless clinically indicated. 
Change from baseline will be calculated by subtracting the baseline value from the post-dose 
assessment for each subject (i.e. post-dose – baseline). Percent change from baseline will be 
calculated as 100×change score/ baseline score. 
There will be no windowing of study visits in this study. However, the following rules will be used 
to assign display values of study visits: 
Visit in SDTM 
Display in Analysis 
Comment 
  
Baseline 
Assigned per SAP above 
Day 30 
Month 1 
  
Day 60 
Month 2 
  
Day 90 
Month 3 
  
Day 120 
Month 4 
  
Day 150  
Month 5 
  
Day 180  
Month 6 
  
Day 210 
Month 7 
  
Day 240 
Month 8 
  
Day 270 
Month 9 
  
Day 300 
Month 10 
  
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


Statistical Analysis Plan: RA101495-01.202 / PNH001 
Review Status: Final 
 
Version: 2.0 
 
Version Date: 15OCT2021 
 
 
 
CONFIDENTAL 
Page 12 of 37 
 
 
 
Day 330 
Month 11 
  
Day 360 
Month 12 
  
Day 390 
Month 13 
  
Day 420 
Month 14 
  
3 Month Visit 1 
Month 15 
  
3 Month Visit 1-1 
Month 16 
  
3 Month Visit 1-2 
Month 17 
  
3 Month Visit 2 
Month 18 
  
3 Month Visit 2-1 
Month 19 
  
3 Month Visit 2-2 
Month 20 
  
… 
  
  
3 Month Visit x 
Add one month from previous 
  
3 Month Visit x-1 
Add one month from previous 
  
3 Month Visit x-2 
Add one month from previous 
  
… 
  
  
3 Month Visit 12 
Month 50 
  
3 Month Visit 12-1 
Month 51 
  
3 Month Visit 12-2 
Month 52 
  
Final Study Visit 
Final Study Visit 
Combine all subjects' last visit as reported in CRF 
regardless of study duration.  
 
9.3 
HANDLING OF MISSING DATA 
Unless otherwise stated, missing data will not be imputed; observed cases will be used in the 
analyses. 
9.4 
SUBJECT DISPOSITION 
A disposition of all consented subjects will be provided. This will include a breakdown of 
subjects who consented, were treated, and were discontinued from the study. The primary 
reason for discontinuation from the study will be summarized. Additionally, a summary of 
subjects included in the analysis populations outlined in Section 7 will be included.  
Listings of all the disposition data, including date of IC signed, date and reason of 
discontinuation, and protocol version will be created. 
9.5 
PROTOCOL DEVIATIONS 
Major Protocol deviations will be summarized. Protocol deviations will be presented in a listing 
that will include all deviations that lead to a subject being withdrawn from the per-protocol 
population. 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


Statistical Analysis Plan: RA101495-01.202 / PNH001 
Review Status: Final 
 
Version: 2.0 
 
Version Date: 15OCT2021 
 
 
 
CONFIDENTAL 
Page 13 of 37 
 
 
 
9.6 
SUBJECT CHARACTERISTICS 
9.6.1 
BASELINE AND DEMOGRAPHIC CHARACTERISTICS 
Subject demographics and baseline characteristics will be summarized for the safety 
population.  
Descriptive statistics will be provided for age, height, weight, and body mass index (BMI, 
calculated as weight in kilograms divided by height in meters squared). Frequencies and 
percentages will be tabulated for sex, race, ethnicity, and country.  
Age will be calculated as (informed consent date in the RA10495-01.202 study – date of birth + 
1)/365.25, truncated and displayed as years. Should either or both the month and day of birth 
be missing, the date will be set to June 1st.  
BMI will be calculated as weight (kg)/height2 (m2), using the weight and height measurements 
obtained at screening. 
Inches will be converted to centimeters with 2.54 cm being equal to 1 in.  
9.6.2 
MEDICAL HISTORY  
Medical history will be summarized with data that was collected at the screening visit of the 
subject’s qualifying study will be coded using MedDRA version 19.1 or higher. The summary in 
this section will be run for the safety Population. The number of Subjects with prior and 
concurrent conditions by preferred term will be output. 
9.6.3 
PNH DISEASE AND TREATMENT HISTORY 
Separate listings for PNH disease history and PNH treatment will be created. 
 
9.6.4 
PRIOR AND CONCOMITANT MEDICATIONS 
All concomitant medications ongoing from the qualifying study will be documented. All 
medications will be documented using WHODrug Global Format B3 September 2020 or higher. 
Concomitant medications include any prescription or over-the-counter medication that is 
ongoing on Day 1 or that is initiated following the first dose of study drug on Day 1. A 
medication will be classified as a prior medication if its start date is earlier than the date of first 
study drug administration and is not ongoing at the first dose.  
Incidence of prior and concomitant medications will be presented by therapeutic area, and 
preferred (generic) drug name for the safety population 
 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


Statistical Analysis Plan: RA101495-01.202 / PNH001 
Review Status: Final 
 
Version: 2.0 
 
Version Date: 15OCT2021 
 
 
 
CONFIDENTAL 
Page 14 of 37 
 
 
 
9.7 
EFFICACY ENDPOINTS AND ANALYSIS 
9.7.1 ANALYSIS OF EFFICACY ENDPOINTS 
Efficacy endpoints will be summarized at each scheduled assessment time point using 
descriptive statistics for the observed and change from baseline values for safety population.  
 Efficacy assessments include: 
x 
LDH levels 
x 
Total bilirubin 
x 
Total hemoglobin 
x 
Free hemoglobin 
x 
Haptoglobin 
x 
Reticulocytes 
x 
Hemoglobinuria using a urine colorimetric system. 
9.8 
SAFETY ENDPOINTS AND ANALYSIS 
Safety analysis results will be presented using the safety Population. 
9.8.1 
EXPOSURE TO STUDY TREATMENT 
Subjects were required to self administer RA101495 as a SC injection once daily (every 24 
hours at approximately the same time each day). On Day 1, the last dose administered on the 
final day of the qualifying study was considered the first dose on the extension study and was 
not be repeated. On days of the scheduled study visit at the investigator site, the dose was to 
be administered after the blood work was completed at the investigator site 
Dose-levels will be summarized from the start of this study. The number of subjects with an 
increase in dose and decrease in dose (relative to the dose at the start of the study) will be 
summarized. 
9.8.2 CLINICAL LABORATORY EVALUATION 
Data listings will be produced for all collected laboratory data including hematology, chemistry, 
and coagulation and urinalysis. Laboratory values outside laboratory’s normal ranges will be 
flagged as H (high, above normal) or L (low, below normal) in laboratory data listings. 
(A) CLINICAL CHEMISTRY, HEMATOLOGY, AND COAGULATION ANALYTES 
Hematology, Serum Chemistry, Coagulation, C-reactive protein, and Creatine phosphokinase 
analyte, and Liver Function Test (see Table 3) values and change from baseline will be 
tabulated using descriptive statistics at each planned visit. The data will be presented in 
separate listings. 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


Statistical Analysis Plan: RA101495-01.202 / PNH001 
Review Status: Final 
 
Version: 2.0 
 
Version Date: 15OCT2021 
 
 
 
CONFIDENTAL 
Page 15 of 37 
 
 
 
Table 3: Clinical Chemistry, Hematology, and Coagulation Analytes 
Clinical Chemistry 
Hematology 
alanine aminotransferase (ALT) 
albumin 
alkaline phosphatase (ALP) 
amylase 
aspartate aminotransferase (AST) 
bicarbonate 
bile acids 
bilirubin (direct, and indirect) 
blood urea nitrogen (BUN) 
calcium 
chloride 
creatinine 
gamma-glutamyl transferase (GGT) 
glucose 
lipase 
potassium 
sodium 
total protein 
uric acid 
 
 
hematocrit 
hemoglobin 
mean corpuscular hemoglobin (MCH) 
mean corpuscular hemoglobin concentration  
(MCHC) 
mean corpuscular volume (MCV) 
platelet count 
RBC count 
 
white blood cell (WBC) count and differential (%) 
Coagulation 
international normalized ratio (INR)/prothrombin time 
(PT) 
fibrinogen 
partial thromboplastin time (PTT) or activated  
partial thromboplastin time (aPTT or APTT) 
Other 
C-reactive protein (CRP) 
creatine phosphokinase (CPK) 
(B) URINALYSIS 
Urinalysis will be performed for measurement of pH, specific gravity, protein (qualitative), 
glucose (qualitative), ketones (qualitative), bilirubin (qualitative), urobilinogen, occult blood, 
hemoglobin, and cells. 
Urinalysis values will be tabulated using descriptive statistics at each planned visit. 
(C) PREGNANCY TEST 
A urine dipstick pregnancy test (human chorionic gonadotropin) will be performed on female 
subjects of childbearing potential. These results will be listed. 
(D) PNH CLONE 
PNH clone size will be determined by peripheral blood flow cytometry analysis (RBCs and 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


Statistical Analysis Plan: RA101495-01.202 / PNH001 
Review Status: Final 
 
Version: 2.0 
 
Version Date: 15OCT2021 
 
 
 
CONFIDENTAL 
Page 16 of 37 
 
 
 
granulocytes) and is performed every 3 months. These results will be summarized and listed.  
 
9.8.3 
ADVERSE EVENTS 
Adverse events will be coded using MedDRA (version 19.1 or higher). All events will be 
summarized and presented by Incidence rates for treatment-emergent adverse events (TEAEs) 
by maximum severity and SAEs will be summarized. These summaries will be provided 
regardless of causality and for events that are considered possibly related to treatment with 
RA101495. 
 TEAEs are defined as follows: 
x 
An AE that occurs after a subject’s initial treatment RA101495 start for this study 
(RA101495-01.202) that was not present at the time of treatment start; or 
 
x 
An AE that increases in severity after treatment start in this study, if the event was 
present at the time of treatment start. 
TEAEs will be summarized for each cohort. 
AEs occurring before the first dose of study drug in this study will be summarized separately 
and included in the overall AE analysis as appropriate. 
The following TEAE summaries will be provided and, where applicable, summarized by 
system organ class, and preferred term: 
x 
Overall summary of Treatment Emergent Adverse Events  
x 
Incidence of Treatment Emergent Adverse Events  
x 
Incidence of Non-serious Treatment Emergent Adverse Events  
x 
Incidence of Treatment Emergent Adverse Events by Maximum Severity 
x 
Incidence of Treatment Emergent Adverse Events by Relationship to Study Drug  
x 
Incidence of Treatment Emergent Adverse Events Leading to Study Discontinuation  
x 
Incidence of Serious Treatment Emergent Adverse Events.  
x 
Incidence of Treatment Emergent Adverse Events above Reporting Frequency 
Threshold of 5% 
x 
Incidence of Non-Serious Treatment Emergent Adverse Events above Reporting 
Frequency Threshold of 5% 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


Statistical Analysis Plan: RA101495-01.202 / PNH001 
Review Status: Final 
 
Version: 2.0 
 
Version Date: 15OCT2021 
 
 
 
CONFIDENTAL 
Page 17 of 37 
 
 
 
x 
Incidence of TEAEs Leading to Death 
x 
Incidence of treatment-related TEAEs Leading to Death* 
x 
Incidence of treatment-related serious TEAEs * 
x 
Incidence of treatment-related TEAEs leading to study drug discontinuation* 
x 
Incidence of Grade 3 or greater TEAEs*  
x 
Incidence of treatment-related Grade 3 or greater TEAEs* 
(*: only in overall summary) 
For these summaries, the number and percentage of subjects who experienced at least one of 
the TEAE as well as (where applicable) the number and percentage of subjects who 
experienced each specific SOC and PT will be presented.  The corresponding number of 
TEAEs will also be presented, where applicable.  
For the presentation of TEAE incidences, the SOCs will be sorted alphabetically, and within 
SOC, the preferred term (PT) will be used and presented by decreasing total frequency. 
(A) DETERMINING TREATMENT EMERGENT WITH ADVERSE EVENT DATES 
The following rules apply when determining if an AE is treatment-emergent in the scenario 
where the start date is missing or partially missing. These rules provide an algorithm to “impute” 
a complete AE start date which will then be used to determine if the AE is treatment emergent.  
AE start date missing day and month: 
x 
If the year is the same as the year of the treatment start date, the day and month of the 
date of treatment start date will be assigned to the missing fields.   
x 
If the year is prior to the year of the treatment start date, December 31 will be assigned 
to the missing fields.  
x 
If the year is after the year of the date of the treatment start date, January 1 will be 
assigned to the missing fields.  
AE start date missing month only: 
x 
The day will be treated as missing, and both month and day will be replaced according 
to the above procedure.  
AE start date missing day only: 
x 
If the month and year are the same as the month and year of the treatment start date, 
the day of the treatment start date will be assigned to the missing day.  
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


Statistical Analysis Plan: RA101495-01.202 / PNH001 
Review Status: Final 
 
Version: 2.0 
 
Version Date: 15OCT2021 
 
 
 
CONFIDENTAL 
Page 18 of 37 
 
 
 
x 
If either the year is before the year of the date of the treatment start date or if both years 
are the same but the month is before the month of the treatment start date, the last day 
of the month will be assigned to the missing day.  
x 
If either the year is after the year of the treatment start date or if both years are the same 
but the month is after the month of the treatment start date, the first day of the month will 
be assigned to the missing day.  
AE start date completely missing: 
x 
If the AE end date is complete and after the treatment start date, the treatment start date 
will be assigned to the missing start date.  
x 
If the end date is complete and before the treatment start date, the end date will be 
assigned to the missing start date  
x 
Otherwise the AE start date will be assigned the treatment start date.  
If the end date is complete and the imputed start date as above is after the end date, the start 
date will be imputed by the end date.  
(B) 
ADVERSE EVENTS OF SPECIAL INTEREST 
(I) THROMBOTIC ADVERSE EVENTS 
A separate table for thrombotic TEAEs will be presented, summarizing TEAEs by SOC and PT. 
The events in Table 1 (Hillmen, 2007]) will be evaluated in the assessment of thrombotic 
TEAEs. 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


Statistical Analysis Plan: RA101495-01.202 / PNH001 
Review Status: Final 
 
Version: 2.0 
 
Version Date: 15OCT2021 
 
 
 
CONFIDENTAL 
Page 19 of 37 
 
 
 
Table 1: Thrombotic Event Description (MAVE Criteria) 
MAVE Criteria 
AE Preferred Term Mapping 
Thrombophlebitis/Deep vein 
thrombosis 
 
Preferred Term: 10051055 Deep vein thrombosis 
Preferred Term: 10043570 Thrombophlebitis 
Pulmonary embolus 
Preferred Term: 10037377 Pulmonary embolism 
Myocardial infarction 
Preferred Term: 10028596 Myocardial infarction 
Transient ischemic attack 
Preferred Term: 10044390 Transient ischaemic attack 
Renal vein thrombosis 
Preferred Term: 10038548 Renal vein thrombosis 
Acute peripheral vascular occlusion 
Preferred Term: 10053648 Vascular occlusion 
Amputation (non-traumatic, non-
diabetic) 
Preferred Term: 10061627 Amputation 
Mesenteric/Visceral vein thrombosis 
Preferred Term: 10027402 Mesenteric vein thrombosis 
Preferred Term: 10077829 Visceral venous thrombosis 
Unstable angina 
Preferred Term: 10002388 Angina unstable 
Mesenteric/Visceral arterial 
thrombosis 
Preferred Term: 10027397 Mesenteric artery thrombosis 
Lower level term: 10043611 Thrombosis arterial 
Hepatic/Portal vein thrombosis 
Preferred Term: 10019713 Hepatic vein thrombosis 
Preferred Term: 10036206 Portal vein thrombosis 
Dermal thrombosis 
Lower level term: 10042545 Superficial phlebothrombosis 
Gangrene (non-traumatic, non-
diabetic) 
Preferred Term: 10017711 Gangrene 
Preferred Term: 10009971 Colon gangrene 
Preferred Term: 10017954 Gastrointestinal gangrene 
Cerebral arterial 
occlusion/cerebrovascular accident 
Preferred Term: 10008190 Cerebrovascular accident 
Preferred Term: 10008089 Cerebral artery occlusion 
Cerebral venous occlusion 
Preferred Term: 10076895 Cerebral vascular occlusion 
Renal arterial thrombosis 
Preferred Term: 10038380 Renal artery thrombosis 
Abbreviation: MAVE=major adverse vascular event. 
 
(II) HEPATIC ADVERSE EVENTS 
Hepatic TEAEs and will be summarized separately by SOC, PT, and cohort. Liver function tests 
will be summarized by changes from baseline and graded in severity using the NCI CTCAE 
(Version 4.03) criteria. 
These AEs will defined using MedDRA SMQs as: 
Drug related hepatic disorders – comprehensive search (SMQ)(20000006) excluding liver 
neoplasms, malignant and unspecified (SMQ)(20000011) and liver neoplasms, benign 
(SMQ)(20000012). 
(III) PANCREATIC ENZYME ELEVATION 
Pancreatic enzyme elevation will be reported as incidence of baseline and post baseline grades 
per NCI CTCAE (Version 4.03) criteria for increased amylase (Preferred Term “Amylase 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


Statistical Analysis Plan: RA101495-01.202 / PNH001 
Review Status: Final 
 
Version: 2.0 
 
Version Date: 15OCT2021 
 
 
 
CONFIDENTAL 
Page 20 of 37 
 
 
 
increased”) and increased lipase (Preferred Term “Lipase increased”). 
(IV) INJECTION SITE REACTION ADVERSE EVENTS 
The investigator will assess the injection sites at each scheduled visit for: 
• 
Pain, tenderness, erythema, and induration severity (Table 2) 
• 
Erythema and induration: maximum linear diameter  
• 
Blisters, ulceration, necrosis: maximum linear diameter and severity 
• 
Lymphadenopathy (absent, mild, moderate, or severe) 
 
 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


Statistical Analysis Plan: RA101495-01.202 / PNH001 
Review Status: Final 
 
Version: 2.0 
 
Version Date: 15OCT2021 
 
 
 
CONFIDENTAL 
Page 21 of 37 
 
 
 
Table 2: Grading the Severity of Local Injection Site Reactions 
Local Reaction 
to Injectable 
Product 
Grade 1 
(Mild) 
Grade 2 
(Moderate) 
Grade 3 
(Severe) 
Grade 4 
(Potentially Life 
Threatening) 
Pain 
Does not interfere 
with activity 
Repeated use of 
non-narcotic pain 
reliever >24 hours or 
interferes with 
activity 
Any use of narcotic 
pain reliever or 
prevents daily 
activity 
Emergency room 
visit or 
hospitalization 
Tenderness 
Mild discomfort 
to touch 
Discomfort with 
movement 
Significant 
discomfort at rest 
Emergency room 
visit or 
hospitalization 
Erythema/ 
redness 
2.5 to 5.0 cm 
5.1 to 10.0 cm 
>10.0 cm 
Necrosis or 
exfoliative 
dermatitis 
Induration/ 
swelling 
2.5 to 5.0 cm and 
does not interfere 
with activity 
5.1 to 10.0 cm or 
interferes with 
activity 
>10.0 cm or 
prevents daily 
activity 
Necrosis 
 
The Injection site reactions CRF page has the date of assessment but is not specifically 
connected to a study visit (even though the assessment is planned to be done in conjunction 
with visits). Study visit will be assigned algorithmically based on the visit start and end dates 
and the actual ISR assessment date.  
 
ISRs will be further analysed by SOC and PT for high level terms “injection site reactions”, and 
“administration site reactions”.  
 
(C) TEAE WITH SOC "INFECTIONS AND INFESTATIONS" 
TEAEs related to infection will be summarized separately by system organ class, preferred 
term, and cohort. These are defined as those with “infections and infestations” as their system 
organ class.  
 
9.8.4 
IMMUNOGENICITY 
No analysis of immunogenicity will be performed. 
 
9.8.5 
ELECTROCARDIOGRAM 
Descriptive statistics for ECG parameters (i.e. heart rate (HR), PR interval, RR interval, QRS 
interval, QT interval, and QTcB intervals, and QTcF intervals) at each assessment timepoint will 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


Statistical Analysis Plan: RA101495-01.202 / PNH001 
Review Status: Final 
 
Version: 2.0 
 
Version Date: 15OCT2021 
 
 
 
CONFIDENTAL 
Page 22 of 37 
 
 
 
be presented. The interpretation of ECG will be summarized at each visit. 
QTc intervals will be calculated using both Fridericia’s and Bazett’s corrections, with the 
formulae: 
Fridericia’s correction:  QTc = QT/RR0.33  
Bazett’s correction:  QTc =QT/RR0.5. 
9.8.6 
VITAL SIGNS AND OTHER SAFETY PARAMETERS 
Descriptive statistics for the actual value at each timepoint and the change from baseline to 
each post baseline timepoint in systolic and diastolic BP, heart rate, and body temperature will 
be tabulated by cohort and overall. 
The complete set of physical examination findings will be provided in listings. Clinically 
significant physical examination abnormalities will be included and summarized as AEs if 
appropriate. 
Grade 3 and 4 of increased lipase and amylase levels over baseline levels will be tabulated.  
9.9 
EXPLORATORY ENDPOINTS 
All exploratory analyses will be done for the safety population.  
9.9.1 
EORTC QLQ-C30 
Summary statistics for each scales/items scores will be presented as well as the corresponding 
change from baseline scores for each scheduled assessment time-point.  
Global health status 
x 
Global health status/QoL 
Functional scales 
x 
Physical functioning 
x 
Role functioning  
x 
Emotional functioning 
x 
Cognitive functioning 
x 
Social functioning 
Symptom scales/items 
x 
Fatigue 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


Statistical Analysis Plan: RA101495-01.202 / PNH001 
Review Status: Final 
 
Version: 2.0 
 
Version Date: 15OCT2021 
 
 
 
CONFIDENTAL 
Page 23 of 37 
 
 
 
x 
Nausea and vomiting 
x 
Pain 
x 
Dyspnoea 
x 
Insomnia 
x 
Appetite loss 
x 
Constipation 
x 
Diarrhoea 
x 
Financial difficulties. 
The EORTC QLQ-C30 consists of 30 questions, which are incorporated into 5 functional 
domains (physical, role, cognitive, emotional, and social domains; see Table 4); a global health 
status/global QOL scale; 3 symptom scales (fatigue, pain, and nausea and vomiting scales); 6 
single items that assess additional symptoms (e.g. dyspnea, appetite loss, sleep disturbance, 
constipation, and diarrhea); and the perceived financial burden of illness treatment (Aaronson, 
1993; Aaronson, 1996). Subjects answer questions based on symptoms/status over the 
preceding week.  
The QLQ-C30 is composed of both multi-item scales and single-item measures. These include 
five functional scales, three symptom scales, a global health status / QoL scale, and six single 
items. 
Each of the multi-item scales includes a different set of items - no item occurs in more than one 
scale. 
All of the scales and single-item measures range in score from 0 to 100. A high scale score 
represents a higher response level. 
x 
a high score for a functional scale represents a high / healthy level of functioning 
x 
a high score for the global health status / QoL represents a high QoL, 
x 
a high score for a symptom scale / item represents a high level of symptomatology / 
problems. 
The principle for scoring these scales is the same in all cases: 
1. Estimate the average of the items that contribute to the scale; this is the raw score. 
2. Use a linear transformation to standardize the raw score, so that scores range from 0 to 
100; a higher score represents a higher ("better") level of functioning, or a higher 
("worse") level of symptoms. 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


Statistical Analysis Plan: RA101495-01.202 / PNH001 
Review Status: Final 
 
Version: 2.0 
 
Version Date: 15OCT2021 
 
 
 
CONFIDENTAL 
Page 24 of 37 
 
 
 
Table 4: Scoring the EORTC QLQ-C30 
 
Scale 
Number 
of Items 
Item 
Range* 
Item 
Numbers 
Functional 
scales 
Global health status / QoL 
 
 
 
 
 
  Global health status/QoL 
QL2 
2 
6 
29, 30 
 
Functional scales 
 
 
 
 
 
  Physical functioning 
PF2 
5 
3 
1 to 5 
F 
  Role functioning  
RF2 
2 
3 
6, 7 
F 
  Emotional functioning 
EF 
4 
3 
21 to 24 
F 
  Cognitive functioning 
CF 
2 
3 
20, 25 
F 
  Social functioning 
SF 
2 
3 
26, 27 
F 
Symptom scales / items 
 
 
 
 
 
  Fatigue 
FA 
3 
3 
10, 12, 18 
 
  Nausea and vomiting 
NV 
2 
3 
14, 15 
 
  Pain 
PA 
2 
3 
9, 19 
 
  Dyspnoea 
DY 
1 
3 
8 
 
  Insomnia 
SL 
1 
3 
11 
 
  Appetite loss 
AP 
1 
3 
13 
 
  Constipation 
CO 
1 
3 
16 
 
  Diarrhoea 
DI 
1 
3 
17 
 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


Statistical Analysis Plan: RA101495-01.202 / PNH001 
Review Status: Final 
 
Version: 2.0 
 
Version Date: 15OCT2021 
 
 
 
CONFIDENTAL 
Page 25 of 37 
 
 
 
  Financial difficulties 
FI 
1 
3 
28 
 
* Item range is the difference between the possible maximum and the minimum response to 
individual items; most items take values from 1 to 4, giving range = 3. The exceptions are 
the items contributing to the global health status/QoL, which are 7-point questions with 
range = 6, 
For all scales, the Raw Score is the mean of the component items.  
For functional scales the score is: 
Score = {1  (Raw score  1)/(range)}×100 
and for Symptom scales/items and Global health status/QoL: 
Score = {(Raw score  1)/(range)}×100. 
Due to the potential for non-normal data, the change from baseline for the EORTC QLQ-C30 
scales will be assessed by a two-sided Wilcoxon signed-rank test. 
9.9.2 
FACIT-FATIGUE 
The overall FACIT-Fatigue score and the individual 13 item scores will be summarized as well 
as the corresponding change from baseline scores for each scheduled assessment time-point. 
Shift tables displaying the individual item values from baseline to each post-baseline visit will 
also be presented. 
The FACIT-Fatigue Scale is a 13-item, easy to administer tool that measures an individual’s 
level of fatigue during their usual daily activities over the preceding week. The level of fatigue is 
measured on a five point ordinal scale (4 = not at all fatigued to 0 = very much fatigued) 
[Webster, 2003]. 
The items and scoring algorithm are given in Table 5. 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


Statistical Analysis Plan: RA101495-01.202 / PNH001 
Review Status: Final 
 
Version: 2.0 
 
Version Date: 15OCT2021 
 
 
CONFIDENTAL 
Page 26 of 37 
 
 
 
9.9.3 
MECHANISTIC BIOMARKERS  
 A separate analysis plan will be prepared for mechanistic biomarkers.  
9.10 OTHER ENDPOINTS AND ANALYSIS 
9.10.1 
PHARMACOKINETICS 
All following pharmacokinetic endpoints will be summarized using descriptive statistics. 
x Plasma concentrations of RA101495 and its major metabolites 
 
9.10.2 
PHARMACODYNAMIC  
Pharmacodynamic endpoints will be summarized at each scheduled assessment time point 
using descriptive statistics for the observed and change from baseline values. 
Note: CH50 is not analyzed as it is not collected. 
 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


Statistical Analysis Plan: RA101495-01.202 / PNH001 
Review Status: Final 
 
Version: 2.0 
 
Version Date: 15OCT2021 
 
 
 
CONFIDENTAL 
Page 27 of 37 
 
 
 
9.11 
INTERIM ANALYSIS 
A formal interim analysis was not performed.  
 
 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


Statistical Analysis Plan: RA101495-01.202 / PNH001 
Review Status: Final 
 
Version: 2.0 
 
Version Date: 15OCT2021 
 
 
 
CONFIDENTAL 
Page 28 of 37 
 
 
 
10. 
DEVIATIONS FROM ANALYSIS AS DESCRIBED IN THE 
PROTOCOL 
1. Due to the small number of subjects increasing doses, all analysis is done on the pooled 
cohorts instead of by dose level.  
 
2. Due to some injections being done away from the clinic, total number of injections will 
not be summarized.  
 
3. No analyses will be done on maximum plasma concentration, time to maximum 
concentration, or area under the drug-concentration time curves. 
 
4. Due to the small number of subjects in the study, no analysis will be done on the per-
protocol population. Similarly no hypothesis testing will be done on study endpoints.  
 
5. Pancreatic enzyme elevation will not be summarized as AEs, but using the incidence of 
NCI CTCAE grades for amylase and lipase.  
 
6. TEAEs for infections will not be restricted to Neisseria meningitidis. 
 
7. No analysis will be done on subject-years of exposure.  
 
8. No analysis of immunogenicity (ADA) will be performed. 
 
9. No analysis of CH50 will be performed. 
 
10. No interim analysis was performed. 
. 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


Statistical Analysis Plan: RA101495-01.202 / PNH001 
Review Status: Final 
 
Version: 2.0 
 
Version Date: 15OCT2021 
 
 
 
CONFIDENTAL 
Page 29 of 37 
 
 
 
                                                                                                                                                                                          
11. 
PROGRAMMING SPECIFICATIONS 
All outputs will be produced using SAS version 9.4 or a later version. 
The margins should be at least 1.50 inches for the binding edge and 1.0 inches for all others.  
In the top left portion of each table/listing, the protocol number will be presented. On the next 
line a table/listing number followed by the title of the table/listing and population information will 
be displayed. Horizontal lines will appear after the column heading of the table/listing. Footnotes 
will be put under the main body of text at the bottom of the page. The SAS program name will 
appear bottom left in a string and the page number will appear on the bottom right corner of 
each table/listing. The date and time of creation of table/listing will appear bottom left under to 
the SAS program name line.  
Courier New 8-point bold font will be used for all tables and listings. Usually, a landscape layout 
is suggested for both tables and listings, but it is not mandatory. Any date information in the 
listing will use the date9. format, for example, 07MAY2002 or other appropriate formats. 
The list of tables, listings, and figures is given in section below. Shells for unique tables and 
listings are provided in a separate Mock-Up TFLs document. 
 
 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


Statistical Analysis Plan: RA101495-01.202 / PNH001 
Review Status: Final 
 
Version: 2.0 
 
Version Date: 15OCT2021 
 
 
 
CONFIDENTAL 
Page 30 of 37 
 
 
 
12. 
REFERENCES 
Aaronson NK, Ahmedzai S, Bergman B, et al. The European Organization for Research and 
Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials 
in oncology. J Natl Cancer Inst 1993;85:365-376. 
Aaronson NK, Cull A, Kaasa S, et al. The European Organization for Research and Treatment of 
Cancer (EORTC) modular approach to quality of life assessment in oncology: an update. In: 
Spilker B, ed. Quality of Life and Pharmacoeconomics in Clinical Trials. 2nd Ed. New York, 
NY: Lippincott Williams & Wilkins. 1996:179-189. 
Webster K, Cella D, and Yost K. The functional assessment of chronic illness therapy (FACIT) 
measurement system: properties, applications, and interpretation. Health Qual Life Outcomes 
2003; 1:79-85. 
 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


Statistical Analysis Plan: RA101495-01.202 / PNH001 
Review Status: Final 
Version: 2.0 
 
Version Date: 15OCT2021 
 
 
 
CONFIDENTAL 
Page 31 of 37 
 
 
13. 
APPENDIX I: LIST OF TABLES, LISTINGS, AND FIGURES 
 
 
Table 14.1.1.1 Subject Disposition All Enrolled Subjects 
Table 14.1.1.2 Major Protocol Deviations Safety Population  
Table 14.1.2 Subject Demographics and Baseline Characteristics Safety Population 
Table 14.1.3 Exposure to Study Treatment Safety Population 
Table 14.1.4 Medical History and Concurrent Conditions Safety Population 
Table 14.1.5.1 Concomitant Medication Safety Population 
Table 14.1.5.2 Prior Medication Safety Population 
Table 14.2.1 Summary of Serum LDH Levels (U/L) Safety Population 
Table 14.2.2 Summary of Total Bilirubin Values (umol/L) Safety Population 
Table 14.2.3 Summary of Total Hemoglobin Values (g/L) Safety Population 
Table 14.2.4 Summary of Free Hemoglobin Values (mg/dL) Safety Population 
Table 14.2.5 Summary of Haptoglobin Values (g/L) Safety Population 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


Statistical Analysis Plan: RA101495-01.202 / PNH001 
Review Status: Final 
 
Version: 2.0 
 
Version Date: 15OCT2021 
 
 
 
CONFIDENTAL 
Page 32 of 37 
 
 
 
Table 14.2.6 Summary of Reticulocytes Values (10^12/L) Safety Population 
Table 14.2.7 Summary of Hemoglobinuria Values Safety Population 
Table 14.2.8 Summary of EORTC QLQ-C30 Safety Population 
Table 14.2.9.1 Summary of FACIT-Fatigue: Overall Score Safety Population 
Table 14.2.9.2 Summary of FACIT-Fatigue: Individual Items Safety Population 
Table 14.2.9.3 Summary of FACIT-Fatigue: Items Shift Table Safety Population 
Table 14.2.10 Summary of CH50 Values Pharmacodynamic Population 
Table 14.2.11 Summary of sRBC Values Pharmacodynamic Population 
Table 14.2.12 Summary of Wieslab ELISA Values Pharmacodynamic Population 
Table 14.2.13 Summary of C5 Values Pharmacodynamic Population 
Table 14.2.14 Summary of Plasma RA101495 Concentrations Pharmacokinetic Population 
Table 14.3.1 Overall Summary of Treatment Emergent Adverse Events Safety Population 
Table 14.3.2.1 Treatment Emergent Adverse Events by System Organ Class, and Preferred Term Safety Population 
Table 14.3.2.2 Non-Serious Treatment Emergent Adverse Events by System Organ Class, and Preferred Term Safety Population 
Table 14.3.2.3 Treatment Emergent Adverse Events by System Organ Class, Preferred Term, and Maximum Severity Safety Population 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


Statistical Analysis Plan: RA101495-01.202 / PNH001 
Review Status: Final 
 
Version: 2.0 
 
Version Date: 15OCT2021 
 
 
 
CONFIDENTAL 
Page 33 of 37 
 
 
 
Table 14.3.2.4 Treatment Emergent Adverse Events by System Organ Class, Preferred Term, and Relationship to Study Drug Safety Population 
Table 14.3.2.5 Treatment Emergent Adverse Events Leading to Study Discontinuation by System Organ Class, and Preferred Term Safety Population 
Table 14.3.2.6 Serious Treatment Emergent Adverse Events by System Organ Class, and Preferred Term Safety Population 
Table 14.3.2.7 Incidence of Treatment Emergent Adverse Events  by System Organ Class, Preferred Term above Reporting Frequency Threshold of 5% 
Safety Population 
Table 14.3.2.8 Incidence of Non-Serious Treatment Emergent Adverse Events  by System Organ Class, Preferred Term above Reporting Frequency 
Threshold of 5% Safety Population 
Table 14.3.2.9 Incidence of Treatment-related Treatment Emergent Adverse Events by System Organ Class and Preferred Term Safety Population 
Incidence of Treatment-related Grade 3 or greater Treatment Emergent Adverse Events by System Organ Class and Preferred Term Safety Population 
Table 14.3.3.1 Thrombotic Treatment Emergent Adverse Events by System Organ Class, and Preferred Term Safety Population 
Table 14.3.3.2 Hepatic Treatment Emergent Adverse Events by System Organ Class, and Preferred Term Safety Population 
Table 14.3.3.3.1 Injection Site Reaction Treatment Emergent Adverse Events by System Organ Class, and Preferred Term Safety Population 
Table 14.3.3.3.2 Injection Site Reactions – Details Safety Population 
Table 14.3.3.4 Infection Treatment Emergent Adverse Events by System Organ Class, and Preferred Term Safety Population 
Table 14.3.4.1 Summary of Clinical Chemistry Laboratory Values Safety Population 
Table 14.3.4.2 Summary of Hematology Laboratory Values Safety Population 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


Statistical Analysis Plan: RA101495-01.202 / PNH001 
Review Status: Final 
 
Version: 2.0 
 
Version Date: 15OCT2021 
 
 
 
CONFIDENTAL 
Page 34 of 37 
 
 
 
Table 14.3.4.3 Summary of Coagulation Laboratory Values Safety Population 
Table 14.3.4.4 Summary of C-Reactive Protein and Creatine Phosphokinase Values Laboratory Values Safety Population 
Table 14.3.4.5 Summary of Urinalysis Laboratory Values Safety Population 
Table 14.3.4.6 Summary of Liver Function Test Values Safety Population 
Table 14.3.4.7 Increased Amylase and Lipase Test Values Safety Population 
Table 14.3.4.8 Summary of PNH Clone Size Values Safety Population 
Table 14.3.5 Summary of Vital Signs by Visit Safety Population 
Table 14.3.6.1 Summary of ECG Values by Visit Safety Population 
Table 14.3.6.2 ECG Interpretation by Visit Safety Population 
Listing 16.2.1.1 Subject Disposition Safety Population 
Listing 16.2.1.2 Protocol Deviations Safety Population 
Listing 16.2.2.1 Medical history Safety Population 
Listing 16.2.2.2 PNH Disease History Safety Population 
Listing 16.2.2.3 PNH Treatment history Safety Population 
Listing 16.2.3.1 Prior Medications Safety Population 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


Statistical Analysis Plan: RA101495-01.202 / PNH001 
Review Status: Final 
 
Version: 2.0 
 
Version Date: 15OCT2021 
 
 
 
CONFIDENTAL 
Page 35 of 37 
 
 
 
Listing 16.2.3.2 Concomitant Medications Safety Population 
Listing 16.2.4 Exposure to Study Treatment Safety Population 
Listing 16.2.5 Demographics Safety Population 
Listing 16.2.6 Efficacy Endpoints Safety Population 
Listing 16.2.7 EORTC QLQ-C30 Scores Safety Population 
Listing 16.2.8  FACIT Fatigue Scores Safety Population 
Listing 16.2.9.1 Adverse Events Safety Population 
Listing 16.2.9.2 Serious Adverse Events Safety Population 
Listing 16.2.9.3 Thrombotic Adverse Events Safety Population 
Listing 16.2.9.4 Hepatic Adverse Events Safety Population 
Listing 16.2.9.5 Pancreatic Adverse Events Safety Population 
Listing 16.2.9.6 Injection Site Reaction Adverse Events Safety Population 
Listing 16.2.9.7 Infection Adverse Events Safety Population 
Listing 16.2.10 Injection Site Reactions Safety Population 
Listing 16.2.11.1 Hematology Safety Population 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


Statistical Analysis Plan: RA101495-01.202 / PNH001 
Review Status: Final 
 
Version: 2.0 
 
Version Date: 15OCT2021 
 
 
 
CONFIDENTAL 
Page 36 of 37 
 
 
 
Listing 16.2.11.2 Clinical Chemistry Safety Population 
Listing 16.2.11.3 Coagulation, C-Reactive Protein, and Creatine Phosphokinase Safety Population 
Listing 16.2.11.4 Urinalysis Safety Population 
Listing 16.2.11.5 Liver Function Safety Population 
Listing 16.2.11.6 Pancreatic Enzyme Tests Safety Population 
Listing 16.2.11.7 PNH Clone Size Safety Population 
Listing 16.2.12 Vital Signs Safety Population 
Listing 16.2.13 ECG Safety Population 
Listing 16.2.14 Physical Examination Safety Population 
Listing 16.2.15 Pregnancy Test Safety Population 
Listing 16.2.16 Pharmacodynamic Endpoints Pharmacodynamic Population 
Listing 16.2.17 Plasma RA101495, RA102758 and RA103488 PK Concentrations Pharmacokinetic Population 
Listing 16.2.18 Deaths Safety Population 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


Statistical Analysis Plan: RA101495-01.202 / PNH001 
Review Status: Final 
Version: 2.0 
 
Version Date: 15OCT2021 
 
 
 
CONFIDENTAL 
Page 37 of 37 
 
 
14. 
APPENDIX II. SCHEDULE OF ASSESSMENTS 
 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.