Phase 2 Multicenter, Open-Label, Uncontrolled Study to Evaluate the Safety, Tolerability, Efficacy, Pharmacokinetics, and Pharmacodynamics of RA101495 in Subjects With Paroxysmal Nocturnal Hemoglobinuria
Phase: PHASE2
Conditions: Paroxysmal Nocturnal Hemoglobinuria (PNH)
Sponsor: Ra Pharmaceuticals

1 
TITLE PAGE  
 
RA PHARMACEUTICALS, INC. 
RA101495-01.201: A PHASE 2 MULTICENTER, OPEN-LABEL, UNCONTROLLED 
STUDY TO EVALUATE THE SAFETY, TOLERABILITY, EFFICACY, 
PHARMACOKINETICS, AND PHARMACODYNAMICS OF RA101495 IN SUBJECTS 
WITH PAROXYSMAL NOCTURNAL HEMOGLOBINURIA 
 
Protocol Number:  
RA101495-01.201 
Indication Studied: 
Paroxysmal Nocturnal Hemoglobinuria 
Developmental Phase of Study: 
2 
EudraCT Number: 
2016-003522-16 
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.  
 
 

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CENTER INVESTIGATOR SIGNATURE PAGE 
Protocol Title: A Phase 2 Multicenter, Open-Label, Uncontrolled Study to Evaluate the Safety, 
Tolerability, Efficacy, Pharmacokinetics, and Pharmacodynamics of RA101495 in Subjects with 
Paroxysmal Nocturnal Hemoglobinuria 
Protocol Version 1.1 
Protocol 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 Investigator 
 
 
 
 
 
Date 
 

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2 
SYNOPSIS 
 
Protocol title 
A Phase 2 Multicenter, Open-Label, Uncontrolled Study to Evaluate the 
Safety, Tolerability, Efficacy, Pharmacokinetics, and Pharmacodynamics of 
RA101495 in Subjects with Paroxysmal Nocturnal Hemoglobinuria 
Protocol number 
RA101495-01.201 
Phase of clinical 
development 
Phase 2 
Investigational 
medicinal product 
RA101495 administered by daily subcutaneous injection  
Study Population 
Adults with paroxysmal nocturnal hemoglobinuria (PNH) 
Investigative Sites 
Approximately 10 centers are planned in one or more of the following 
locations: Australia, Canada, Germany, New Zealand and United Kingdom 
Planned number of 
subjects  
Up to 20 subjects will be enrolled in the study in two cohorts: 
• 
Cohort A (Eculizumab Naïve): approximately 8-12 subjects 
• 
Cohort B (Eculizumab Switch): approximately 6-8 subjects 
Study objectives 
• 
To assess the safety and tolerability of RA101495 in subjects with PNH  
• 
To assess preliminary efficacy of RA101495 in subjects with PNH 
• 
To assess the pharmacokinetics (PK) and pharmacodynamics (PD) of 
RA101495 in subjects with PNH 
Study design 
Study RA101495-01.201 is a multicenter, open-label, uncontrolled study to 
evaluate the safety, tolerability, efficacy, pharmacokinetics and 
pharmacodynamics of RA101495 in subjects with PNH. 
The study will enroll two separate cohorts based on prior eculizumab 
treatment history.  
• 
Cohort A (Naïve) will include subjects who have not received 
eculizumab for treatment of PNH   
• 
Cohort B (Switch) will include subjects who have received treatment 
with eculizumab for at least 6 months prior to Screening.  
The planned enrollment is approximately 8-12 subjects in Cohort A and 
approximately 6-8 subjects in Cohort B, for a total of up to 20 subjects.  
Cohort A will commence enrollment prior to Cohort B.  Cohort B will not be 
opened until safety and efficacy data from at least 2 subjects completing the 
Week 2 Visit in Cohort A have been reviewed by the Sponsor and Study 
Investigators, and evidence of hemolysis suppression is demonstrated. 
The study includes an 8-week screening period and a 12-week Treatment 
Period. During the Treatment Period, subjects will return to the clinic weekly 
for the first 4 weeks followed by visits every 2 weeks to evaluate safety, 
tolerability, efficacy, PK and PD. Additional assessments will include 
immunogenicity, Quality of Life (QOL) questionnaires, biomarker samples, 
and optional pharmacogenomics. Safety assessments include physical exam, 
vital signs, electrocardiogram (ECG), clinical laboratory tests, and adverse 

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events (AEs).    
The risk of Neisseria meningitidis infection will be closely monitored during 
the study. During the screening period, prior to study entry, all subjects must 
have a documented negative result for Neisseria meningitidis colonization 
via a throat swab. All Cohort A (Naïve) subjects who have not been 
previously vaccinated against Neisseria meningitidis prior to study entry 
must be vaccinated and must receive ciprofloxacin for 14 days starting with 
the first dose of RA101495 at the Day 1 Visit. A booster vaccination should 
also be administered as clinically indicated according to the local standard of 
care.  All Cohort B (Switch) subjects must have documentation of prior 
Neisseria meningitidis vaccination (and booster if appropriate) prior to study 
entry. 
For Cohort A (Naïve) subjects, the Day 1 Visit may be scheduled at any time 
after Screening and confirmation of eligibility. For Cohort B (Switch) 
subjects, the Day 1 Visit should be scheduled to coincide with the next 
scheduled dose of eculizumab (i.e. 14 ± 2 days after from the last eculizumab 
dose). Eculizumab should NOT be administered at the Day 1 Visit or at 
anytime thereafter during the study 
During the Treatment Period, 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. 
At the conclusion of the Treatment Period subjects who complete the study 
and are demonstrating benefit will have the option to enroll in an extension 
study to continue receiving treatment with RA101495. Alternatively, they 
may opt to receive standard-of-care treatment off study, after consultation 
with their treating physician. If the subject withdraws early from the 
RA101495-01.201 study for any reason, he/she will not be eligible for the 
extension study.  
All subjects will receive a loading dose of 0.3 mg/kg to be administered 
subcutaneously (SC) at the Day 1 visit. Following in-clinic education and 
training, all subjects will self-administer daily SC doses of 0.1 mg/kg of 
RA101495 for 12 weeks. Except for Day 1, on study clinic days, the dose 
should be administered after the PK and PD collection has been completed.  
From the Week 2 Visit onwards, if a subject has not achieved an adequate 
response (defined as a lactate dehydrogenase [LDH] <1.5 x ULN), and 
following evaluation of safety and tolerability data by the investigator and 
the medical monitor, the dose should be escalated to 0.3 mg/kg daily. The 
dose may also be escalated to 0.3 mg/kg daily at any time in the event of an 
overt breakthrough hemolysis episode (e.g. hemoglobinuria). 
Duration of study 
participation 
The total duration of study participation for all subjects will include a 
Screening Period of up to 8 weeks and a 12-week Treatment Period for a 
total of up to 20 weeks.  
Study population 
To be eligible for this study, subjects must meet ALL of the following 

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inclusion criteria: 
1. Male or female ≥18 years 
2. Completed informed consent procedures, including signing and dating 
the informed consent form (ICF) 
3. Diagnosis of PNH by flow cytometry 
4. Cohort A (Naïve) subjects must not have received treatment with 
eculizumab prior to or during the Screening Period and must have a 
lactate dehydrogenase (LDH) level ≥2 times the upper limit of normal 
(xULN) during Screening 
5. Cohort B (Switch) subjects must have received treatment with 
eculizumab for at least 6 months prior to Screening  
6. Female subjects of child-bearing potential must have a negative 
pregnancy test at Screening and within 24-hours prior to the first dose of 
RA101495 
7. 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. 
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 

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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. Recent surgery requiring general anesthesia within the 2 weeks prior to 
Screening, or expected to have surgery requiring general anesthesia 
during the 12-week Treatment Period 
9. 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) 
10. 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  
11. Treatment 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)  
12. Unable or unwilling to comply with the requirements of the study 
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). 
 
Primary Efficacy:  
• 
The primary evaluation period is from Week 6 to Week 12. The primary 
efficacy endpoint is the change-from-baseline in serum LDH levels 
during this period, defined as the mean LDH values of Weeks 6, 8, 10, 
and 12 minus the baseline value of LDH.  
Secondary Efficacy: 
• 
Changes from baseline in LDH, total bilirubin, total hemoglobin, free 
hemoglobin, haptoglobin, reticulocytes, and hemoglobinuria, at each of 
the scheduled post-baseline 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) 
• 
Plasma concentrations of eculizumab (Cohort B only) 
Pharmacodynamic:  
• 
Changes from baseline CH50 
• 
Changes from baseline in sheep RBC (sRBC) lysis for classical 
complement pathway 
• 
Changes from baseline in Wieslab enzyme-linked immunosorbent assay 

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(ELISA) for alternative complement pathway 
• 
Changes from baseline in C5 levels 
Exploratory: 
• 
Changes from baseline in quality of life (QOL) questionnaires (e.g. 
EORTC QLQ-C30, FACIT-Fatigue, and EQ-5D) 
• 
Treatment satisfaction questionnaire  
• 
Mechanistic biomarkers (e.g. complement function, complement 
proteins, biomarkers of inflammation, biomarkers for thrombosis, 
biomarkers of liver function)  
• 
Pharmacogenomic analyses (optional)  
Statistical 
considerations 
Study Populations: The following study populations are defined: 
• 
Safety Population: All subjects who receive at least 1 dose of RA101495  
• 
Efficacy Evaluable Population: All subjects in the Safety Population 
who complete the 12-week Treatment Period  
• 
Per Protocol Population: All subjects in the Safety Population who 
complete the 12-week Treatment Period and 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 cohort 
separately. Where appropriate, data may be summarized for the overall 
study.  
A disposition of all consented subjects will be provided and will include a 
breakdown of subjects who consented, were treated, discontinued treatment, 
were lost to follow-up, or withdrew consent. 
Continuous 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 cohort and time 
point and also by pooling cohorts. 
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. 

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Efficacy: Efficacy endpoints will be summarized by cohort. No formal 
statistical comparisons between cohorts will be performed. Tests to assess 
change-from-baseline will be applied to endpoints as appropriate.  
For Cohort A (Naïve), the primary efficacy endpoint will be tested against a 
null hypothesis of a median change-from-baseline of 0 by a 2-sided 
Wilcoxon signed-rank test.  
For Cohort B (Switch) an inferential test of the change-from-baseline 
primary efficacy endpoint will not be performed.  Summary statistics for the 
primary endpoint will be provided including the mean, median, standard 
deviation, and standard error. 
Pharmacokinetics: Drug exposure in the different cohorts 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 
cohort and overall using descriptive statistics. 
Pharmacodynamics: Pharmacodynamics will be summarized by cohort. No 
formal statistical comparisons between cohorts will be performed. Tests to 
assess change-from-baseline will be applied to endpoints as appropriate. 
Determination of Sample Size: For Cohort A (Naïve) a sample size of 8 
subjects yields approximately 95% power to reject the null hypothesis that 
the median LDH change-from-baseline is 0 for the primary efficacy 
endpoint. This assumes a mean decrease in LDH from 2200 U/L at baseline 
to 327 U/L during the primary evaluation period (Weeks 6-12) with 
corresponding standard deviations of 1034 U/L and 443 U/L, respectively, 
and a within-subject correlation estimate of 0. This yields a change-from-
baseline mean of 1873 U/L and standard deviation of 1125 U/L. The power 
is based on a 2-sided Wilcoxon signed-rank test, at the 0.05 significance 
level.  
For Cohort B (Switch) a sample size of 6 subjects will yield a standard error 
of approximately 114 U/L for an LDH mean change-from-baseline estimate. 
This assumes a standard deviation of 443 U/L for the baseline and post-
baseline endpoints and a within-subject correlation estimate of 0.8, which 
yields change-from-baseline standard deviation of 280 U/L. 
Interim Analysis: During this open-label study, the Sponsor will review 
safety and efficacy data as it becomes available during the Treatment Period. 
Following completion of the 12-week Treatment Period, data will be cleaned 
and locked at the individual subject level, and will be available for final 
analysis by the Sponsor on a rolling basis. Completion and final data lock of 
Cohort A may occur before, and independent, of Cohort B, or vice versa.  

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TABLE OF CONTENTS 
1 
TITLE PAGE ...........................................................................................................................1 
2 
SYNOPSIS ................................................................................................................................4 
3 
TABLE OF CONTENTS ......................................................................................................10 
4 
LIST OF ABBREVIATIONS AND DEFINITIONS ..........................................................15 
5 
TIME AND EVENTS TABLE .............................................................................................18 
6 
INTRODUCTION .................................................................................................................22 
6.1 OVERVIEW OF PAROXYSMAL NOCTURNAL HEMOGLOBINURIA ..............................................22 
6.2 MECHANISM OF ACTION OF RA101495 .................................................................................22 
6.3 CLINICAL TRIAL EXPERIENCE WITH RA101495 ....................................................................24 
6.4 DEVELOPMENT RATIONALE ...................................................................................................28 
6.5 DOSE JUSTIFICATION FOR STUDY............................................................................................28 
6.5.1 RATIONALE FOR STARTING DOSE (0.1 MG/KG) ...................................................................28 
6.5.2 RATIONALE FOR USE OF LOADING DOSE ............................................................................30 
6.5.3 RATIONALE FOR DOSE ESCALATION TO 0.3MG/KG DAILY AFTER WK 2 .............................31 
7 
STUDY OBJECTIVES AND ENDPOINTS .......................................................................33 
7.1 OBJECTIVES ...........................................................................................................................33 
7.2 ENDPOINTS ............................................................................................................................33 
7.2.1 SAFETY AND TOLERABILITY ...............................................................................................33 
7.2.2 EFFICACY ............................................................................................................................33 
7.2.3 PHARMACOKINETIC ............................................................................................................33 
7.2.4 PHARMACODYNAMIC ..........................................................................................................33 
7.2.5 EXPLORATORY ....................................................................................................................34 
8 
STUDY DESIGN ...................................................................................................................35 
8.1 OVERVIEW OF STUDY DESIGN ...............................................................................................35 
8.1.1 RATIONALE FOR STUDY DESIGN .........................................................................................37 
8.2 STUDY PERIODS .....................................................................................................................37 
8.2.1 SCREENING PERIOD .............................................................................................................38 
8.2.2 TREATMENT ........................................................................................................................38 
8.3 SUBJECT REGISTRATION PROCEDURES ..................................................................................38 
8.3.1 SCREENING AND ENROLLMENT ...........................................................................................38 
8.3.2 TREATMENT GROUP ASSIGNMENT ......................................................................................39 
8.3.3 BLINDING ............................................................................................................................39 
8.4 DISCONTINUATION CRITERIA .................................................................................................39 
8.4.1 DISCONTINUATION OF INVESTIGATIONAL MEDICINAL PRODUCT ........................................39 
8.4.2 WITHDRAWAL FROM THE STUDY ........................................................................................40 
8.5 EARLY STUDY TERMINATION ................................................................................................40 
8.6 END OF STUDY .......................................................................................................................40 

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SELECTION OF STUDY POPULATION .........................................................................41 
9.1 INCLUSION CRITERIA .............................................................................................................41 
9.2 EXCLUSION CRITERIA ............................................................................................................42 
9.3 REMOVAL AND REPLACEMENT OF SUBJECTS IN THE STUDY ..................................................42 
9.3.1 PREMATURE DISCONTINUATION .........................................................................................42 
9.3.2 REPLACEMENT OF SUBJECTS ...............................................................................................43 
10 
INVESTIGATIONAL MEDICINAL PRODUCTS AND TREATMENTS ..................44 
10.1 STUDY TREATMENT ADMINISTRATION ................................................................................44 
10.1.1 IDENTITY OF INVESTIGATIONAL MEDICINAL PRODUCT AND TREATMENT ........................44 
10.1.2 TREATMENT GROUPS ........................................................................................................44 
10.1.2.1 DOSE ESCALATION ........................................................................................................44 
10.1.3 DOSING SCHEDULE ...........................................................................................................44 
10.1.4 DOSE PRESENTATION ........................................................................................................45 
10.1.4.1 MISSED DOSES ...............................................................................................................45 
10.2 STUDY TREATMENT MANAGEMENT .....................................................................................45 
10.2.1 PREPARATION AND DISPENSING ........................................................................................45 
10.2.2 STUDY DRUG SUPPLY, STORAGE, AND HANDLING ...........................................................45 
10.2.3 DISPOSAL, RETURN, OR RETENTION OF UNUSED DRUG ....................................................46 
10.2.4 DRUG ACCOUNTABILITY ...................................................................................................46 
10.3 COMPLIANCE .......................................................................................................................46 
11 
STUDY ASSESSMENTS ....................................................................................................47 
11.1 SUBJECT AND BASELINE DISEASE CHARACTERISTICS ..........................................................47 
11.1.1 DEMOGRAPHIC DATA........................................................................................................47 
11.1.2 DISEASE AND PRIOR TREATMENT HISTORY ......................................................................47 
11.1.3 PRIOR AND CONCOMITANT MEDICATIONS ........................................................................47 
11.2 SAFETY ASSESSMENTS .........................................................................................................47 
11.2.1 MEDICAL AND SURGICAL HISTORY ..................................................................................47 
11.2.2 PHYSICAL EXAMINATION ..................................................................................................47 
11.2.3 VITAL SIGNS .....................................................................................................................48 
11.2.4 ELECTROCARDIOGRAM .....................................................................................................48 
11.2.5 NEISSERIA MENINGITIDIS TESTING ......................................................................................48 
11.2.5.1 NEISSERIA MENINGITIDIS  PROPHYLACTIC TREATMENT ...................................................48 
11.2.6 ADVERSE EVENT RECORDING ...........................................................................................49 
11.2.7 LABORATORY SAFETY ASSESSMENTS ...............................................................................49 
11.2.7.1 BLOOD CHEMISTRY AND HEMATOLOGY ........................................................................49 
11.2.7.2 URINALYSIS ...................................................................................................................50 
11.2.7.3 PREGNANCY TEST ..........................................................................................................50 
11.2.8 PNH CLONE ......................................................................................................................51 
11.2.9 IMMUNOGENICITY .............................................................................................................51 
11.3 EFFICACY ASSESSMENTS .....................................................................................................51 
11.4 PHARMACOKINETIC AND PHARMACODYNAMIC ASSESSMENTS ............................................51 
11.5 ELECTRONIC DIARY CARD ...................................................................................................52 
11.6 EXPLORATORY ASSESSMENTS .............................................................................................52 
11.6.1 QUALITY OF LIFE ASSESSMENTS .......................................................................................52 
11.6.1.1 EORTC-QLQ-C30 ........................................................................................................52 

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11.6.1.2 FACIT-FATIGUE ............................................................................................................53 
11.6.1.3 EQ-5D ...........................................................................................................................53 
11.6.2 TREATMENT SATISFACTION QUESTIONNAIRE ...................................................................53 
11.6.3 BIOMARKERS ....................................................................................................................53 
11.6.4 PHARMACOGENOMIC ASSESSMENTS .................................................................................54 
12 
SAFETY REPORTING ......................................................................................................55 
12.1 DEFINITIONS ........................................................................................................................55 
12.1.1 ADVERSE EVENT ...............................................................................................................55 
12.1.2 SERIOUS ADVERSE EVENT ................................................................................................55 
12.1.3 ADVERSE EVENTS OF SPECIAL INTEREST ..........................................................................56 
12.1.3.1 THROMBOTIC ADVERSE EVENTS ....................................................................................56 
12.1.3.2 HEPATIC ADVERSE EVENTS ...........................................................................................56 
12.1.3.3 PANCREATIC ENZYME ELEVATIONS ...............................................................................56 
12.1.3.4 INJECTION SITE REACTIONS ...........................................................................................56 
12.1.3.5 INFECTION......................................................................................................................57 
12.2 EVALUATION AND CLASSIFICATIONS ...................................................................................58 
12.2.1 SEVERITY ..........................................................................................................................58 
12.2.2 CAUSALITY .......................................................................................................................58 
12.3 RECORDING, REPORTING, AND MONITORING .......................................................................59 
12.3.1 RECORDING AND REPORTING ............................................................................................59 
12.3.1.1 ADVERSE EVENTS ..........................................................................................................59 
12.3.1.2 SERIOUS ADVERSE EVENTS ...........................................................................................60 
12.3.1.3 DEATH ...........................................................................................................................60 
12.3.2 MONITORING ....................................................................................................................60 
12.3.2.1 POST-STUDY EVENTS .....................................................................................................61 
12.4 SPECIAL CIRCUMSTANCES ...................................................................................................61 
12.4.1 PREGNANCY ......................................................................................................................61 
12.4.2 OTHER ..............................................................................................................................61 
13 
STATISTICAL AND ANALYTICAL PLANS ................................................................62 
13.1 SAMPLE SIZE DETERMINATION ............................................................................................62 
13.2 ANALYSIS POPULATIONS .....................................................................................................62 
13.2.1 SAFETY POPULATION ........................................................................................................62 
13.2.2 EFFICACY EVALUABLE POPULATION ................................................................................62 
13.2.3 PER PROTOCOL POPULATION ............................................................................................62 
13.2.4 PHARMACOKINETIC POPULATION .....................................................................................62 
13.2.5 PHARMACODYNAMIC POPULATION ...................................................................................62 
13.3 STATISTICAL PLAN ..............................................................................................................63 
13.3.1 GENERAL CONSIDERATIONS ..............................................................................................63 
13.3.2 SUBJECT DISPOSITION .......................................................................................................63 
13.3.3 DEMOGRAPHY AND BASELINE DISEASE CHARACTERISTICS ..............................................63 
13.3.4 SAFETY ANALYSIS ............................................................................................................63 
13.3.4.1 ADVERSE EVENTS ..........................................................................................................63 
13.3.4.2 ADVERSE EVENTS OF SPECIAL INTEREST .......................................................................63 
13.3.4.3 CLINICAL LABORATORY EVALUATION ..........................................................................64 
13.3.4.4 ELECTROCARDIOGRAMS ................................................................................................64 

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13.3.4.5 VITAL SIGNS ..................................................................................................................65 
13.3.4.6 PHYSICAL EXAMINATION ...............................................................................................65 
13.3.5 EFFICACY ANALYSIS .........................................................................................................65 
13.3.6 CLINICAL PHARMACOLOGY ANALYSIS .............................................................................65 
13.3.6.1 PHARMACOKINETIC ANALYSIS ......................................................................................65 
13.3.6.2 PHARMACODYNAMIC ANALYSIS ....................................................................................65 
13.3.7 INTERIM ANALYSIS ...........................................................................................................65 
14 
ETHICAL CONSIDERATIONS .......................................................................................67 
14.1 INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE 
COMMUNICATIONS ........................................................................................................67 
14.1.1 PROGRESS REPORTS ..........................................................................................................67 
14.1.2 FINAL INVESTIGATOR REPORT ..........................................................................................67 
14.2 INFORMED CONSENT OF STUDY SUBJECTS ...........................................................................67 
14.3 PROTOCOL COMPLIANCE .....................................................................................................68 
14.4 PROTECTION OF CONFIDENTIALITY ......................................................................................68 
14.5 DISCLOSURE OF STUDY RESULTS .........................................................................................69 
15 
REGULATORY AND ADMINISTRATIVE CONSIDERATIONS ..............................70 
15.1 QUALITY ASSURANCE ..........................................................................................................70 
15.1.1 MONITORING ....................................................................................................................70 
15.1.2 AUDIT ...............................................................................................................................70 
15.2 CLINICAL RESEARCH ORGANIZATIONS ................................................................................70 
15.3 DATA MANAGEMENT ...........................................................................................................70 
15.3.1 CASE REPORT FORMS .......................................................................................................70 
15.3.2 SOURCE DOCUMENTS .......................................................................................................71 
15.4 PREMATURE TERMINATION OR SUSPENSION OF THE STUDY ................................................71 
15.5 CLINICAL STUDY REPORT ....................................................................................................71 
15.6 PUBLICATION POLICY ..........................................................................................................72 
16 
REFERENCES ....................................................................................................................73 
 
LIST OF TABLES 
Table 1 Time and Events Table ..................................................................................................19 
Table 2 Experimental and Predicted PK Values for RA101495 in Humans ..............................29 
Table 3 Dose Presentations by Weight Brackets ........................................................................45 
Table 4 Clinical Chemistry, Hematology, and Coagulation Analytes ........................................50 
Table 5 Grading the Severity of Local Injection Site Reactions ................................................57 
Table 6 Thrombotic Event Description (MAVE Criteria) ..........................................................64 
 
 
LIST OF FIGURES 

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Figure 1 Mechanism of Action of RA101495 in Complement System ......................................23 
Figure 2 Inhibition of C5a (left) and C5b-9 (MAC; right) Formation by 
RA101495 ........................................................................................................23 
Figure 3 Mean (SD) Plasma RA101495 Concentrations Over Time by Dose 
Group Following Single-Dose SC Administration in Healthy 
Volunteers (Study RA101495-1001) ...............................................................25 
Figure 4 Mean (SD) Plasma RA101495 Concentrations Over Time by Dose 
Group Following Multiple-Dose SC Administration of 0.2 
mg/kg for 7 Days in Healthy Volunteers (Study RA101495-
1001) ................................................................................................................25 
Figure 5 Mean (SD) Red Blood Cell Lysis Over Time by Dose Group Following 
Single-Dose SC Administration in Healthy Volunteers (Study 
RA101495-1001) .............................................................................................26 
Figure 6 Mean (SD) Red Blood Cell Lysis Over Time by Dose Group in the 
Multiple-Dose Cohort Once Daily for 7-Days in Healthy 
Volunteers in (Study RA101495-1001) ...........................................................27 
Figure 7 Predicted PK and PD Effects Resulting From Weight-Bracketed Dosing 
of RA101495 (0.1mg/kg daily) ........................................................................30 
Figure 8 RA101495 Loading Dose (0.3mg/kg) and Predicted Control of 
Hemolysis After the First Dose........................................................................31 
Figure 9 Simulation of PK (blue) and PD (red) of RA101495 with a Loading 
Dose of 0.3mg/kg on Day 1 Followed by 0.1mg/kg Daily 
Thereafter. ........................................................................................................32 
Figure 10 RA101495-01.201 Study Design................................................................................35 

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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 
DNA 
deoxyribonucleic acid 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
e-diary 
Electronic diary 
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 
GCP  
Good Clinical Practice  
GGT 
gamma-glutamyl transferase 
GPI 
glycosylphosphatidylinositol 
GPI-AP 
glycosylphosphatidylinositol-anchored proteins 
HR 
heart rate 
ICF 
informed consent form 

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Abbreviation 
Definitions 
ICH 
International Conference on Harmonization  
IEC 
Independent Ethics Committee 
INR  
international normalized ratio 
IMP 
investigational medicinal product 
IRB 
Institutional Review Board 
ISR 
injection site reaction 
IV 
intravenous 
LDH 
lactate dehydrogenase 
LFT 
liver function tests 
MAC 
membrane attack complex 
MAVE 
major adverse vascular event 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MD 
multiple-dose 
MDRD 
modification of diet in renal disease  
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
NA 
not applicable 
NCI 
National Cancer Institute 
NHP 
non human primates 
NOEL 
no observed adverse effect level 
PD 
pharmacodynamics 
PI 
Principal Investigator 
PIG-A 
phosphatidylinositolglycan complementation class A 
PK 
pharmacokinetics 
PNH 
paroxysmal nocturnal hemoglobinuria 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
QD 
once daily 
QOL 
quality of life 
RBC 
red blood cell 

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Abbreviation 
Definitions 
RNA 
ribonucleic acid  
SAD 
single-ascending dose 
SAE 
serious adverse event 
SC 
subcutaneous 
SD 
standard deviation 
SF-12 
12-item short form health survey 
SOP 
standard operating procedure 
sRBC 
sheep Red Blood Cell  
SS 
steady state 
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 
 

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5 
TIME AND EVENTS TABLE 
Assessments to be performed during the study are shown in Table 1.  

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Table 1 
Time and Events Table    
Phase 
Screening 
Period 
Treatment Period 
Study Week → 
-8 to 1 
0 
1 
2 
3 
4 
6 
8 
10 
12 (End of 
Study) 
Study Daya → 
-56 to -1 
1 ± 2b 
8 ± 2 
15 ± 2 
22 ± 2 
29 ± 2 
43 ± 4 
57 ± 4 
71 ± 4 
84 ± 4 
Study Procedure ↓ 
 
 
 
 
 
 
 
 
 
 
ICF process and signed ICF 
X 
 
 
 
 
 
 
 
 
 
Review eligibility criteria 
X 
X 
 
 
 
 
 
 
 
 
Medical history and demographics 
X 
 
 
 
 
 
 
 
 
 
Prior and concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
X 
X 
 
 
 
X 
 
 
 
X 
Height and weightc 
X 
X 
 
 
 
X 
 
 
 
X 
Vital signs 
X 
X 
 
 
 
X 
 
 
 
X 
Electrocardiogram 
X 
X 
 
 
 
X 
 
 
 
X 
Neisseria throat swabd 
X 
 
 
 
 
 
 
 
 
 
Neisseria vaccinationd 
 
X 
 
 
 
X 
 
 
 
 
Ciprofloxacin treatmentd 
 
X 
X 
D14 
 
 
 
 
 
 
Blood chemistrye 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulationf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PNH clone size 
X 
 
 
 
 
X 
 
X 
 
X 
Pregnancy testg 
X 
X 
 
 
 
X 
 
X 
 
X 
Adverse events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 

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Phase 
Screening 
Period 
Treatment Period 
Study Week → 
-8 to 1 
0 
1 
2 
3 
4 
6 
8 
10 
12 (End of 
Study) 
Study Daya → 
-56 to -1 
1 ± 2b 
8 ± 2 
15 ± 2 
22 ± 2 
29 ± 2 
43 ± 4 
57 ± 4 
71 ± 4 
84 ± 4 
Assessment of injection site reactionsh 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pharmacokinetics RA101495i 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pharmacokinetics eculizumabj 
X 
X 
 
X 
 
X 
X 
 
 
 
Pharmacodynamics RA101495i 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Anti-drug antibodyk 
 
Xk 
 
 
 
X 
 
X 
 
X 
Quality of life questionnaires  
 
 
 
 
 
 
 
 
 
 
EORTC-QLQ-C30 
 
X 
 
 
 
X 
 
X 
 
X 
FACIT-Fatigue  
 
X 
 
 
 
X 
 
X 
 
X 
EQ-5D 
 
X 
 
 
 
X 
 
X 
 
X 
Treatment satisfaction assessment 
 
 
 
 
 
 
 
 
 
X 
Additional biomarker samplesi 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pharmacogenomic analysis (optional)l 
 
Xl 
 
 
 
 
 
 
 
 
Electronic diary training and dispensation, 
collection at End of Study 
 
X 
 
 
 
 
 
 
 
X 
RA101495 administrationm 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
RA101495 dispensing and returnn 
 
X 
 
X 
 
X 
X 
X 
X 
X 
 
Abbreviations: EORTC-QLQ-C30=European Organization for Research and Treatment of Cancer-Quality of Life Questionnaire; EQ-5D=EuroQol 5D 
questionnaire; FACIT-F=Functional Assessment of Chronic Illness Therapy-Fatigue Scale; ICF=informed consent form; LDH=lactate dehydrogenase; NA=not 
applicable; PD=pharmacodynamic; PK=pharmacokinetic. 

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a. 
Study visits have a Visit window of ±2 days after the actual planned Visit day for the first 4 weeks, and ±4 days from week 6 to week 12. 
b. For Cohort A (Naïve) subjects, the Day 1 Visit may be scheduled at any time after Screening and confirmation of eligibility.  For Cohort B (Switch) 
subjects, the Day 1 Visit should be scheduled to coincide with the next scheduled dose of eculizumab (i.e. 14 ±2 after from the last eculizumab dose). 
Eculizumab should NOT be administered at the Day 1 Visit or at any time thereafter during the study. 
c. 
Height will be measured only at the Screening Visit. 
d. All subjects must have a negative throat swab for Neisseria meningitidis infection for eligibility. All subjects in Cohort A must be vaccinated against 
Neisseria meningitidis and should have a booster as indicated by standard of care.  All subjects in Cohort A must receive ciprofloxacin to be taken orally 
on Days 1 to 14. All Cohort B subjects must have documentation of prior Neisseria meningitidis vaccination (and booster if appropriate) prior to study 
entry. 
e. 
Including LDH for primary efficacy endpoint 
f. 
Coagulation tests should be performed, according to standard practice, on all subjects taking anticoagulant therapy. 
g. For all female subjects of childbearing potential, a negative serum pregnancy test must be documented at the Screening Visit and a negative urine 
pregnancy test must be documented at the Day 1 Visit prior to dosing. All other pregnancy tests will be urine.  
h. The injection site should be assessed at each clinic visit through Day 84 (End of Study).  
i. 
Blood samples for PK and PD and additional biomarker sampling at the following time points in relationship to the first dose of RA101495: pre-dose 
(within 1 hour before first dose administration) and at 1, 3, and 6 hours post-dose on Day 1. For subjects who have a dose increase to 0.3 mg/kg, 
samples for PK and PD should be collected at pre-dose Day 1 of the new dose, see footnote j.  On clinic visit days, PK and PD samples should be 
collected prior to administration of RA101495. 
j. 
For subjects in Cohort B only, blood samples for PK of eculizumab should be collected at screening, Day 1, Day 15, Day 29, and Day 43. (at 2-week, 4-
week, and 6-week) Visits. The sample should be collected prior to administration of RA101495.  
k. Blood sample for ADA on Day 1 must be obtained prior to dosing of RA101495.  
l. 
Blood sample for optional pharmacogenomic testing must be obtained on Day 1.   
m. On clinic visit days, the study drug RA101495 should be administered after blood samples for PK and PD are collected. 
n. Prefilled syringes containing RA101495 will be dispensed every 2 weeks. Subjects will also receive a secure container to dispose of used syringes at 
each visit and should return the used container containing all used syringes to each study visit. All study drug (syringes) and disposal containers must be 
returned to the site at the last study visit. Dosing on study visit days will be held until the completion of the PK and PD sample blood collection has been 
completed. 

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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).  
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.    
6.1 
OVERVIEW OF PAROXYSMAL NOCTURNAL HEMOGLOBINURIA 
Paroxysmal nocturnal hemoglobinuria is a rare, acquired, clonal hematopoietic stem cell 
disorder caused by a deficiency in glycosylphosphatidylinositol (GPI) linked proteins on 
cell surfaces and characterized by intravascular hemolysis and venous thrombosis. Due to 
its rarity, accurate estimates of its prevalence are limited. The most detailed 
epidemiological study was performed in the United Kingdom, which estimated the 
incidence at 1.3 cases per 1,000,000 population/year with a prevalence of 15.9 cases per 
1,000,000 population [Hill, 2006]. A subsequent study in Finland estimated prevalence to 
be approximately 10 per 1,000,000 population [Kairemo, 2010]. PNH is usually 
diagnosed in patients in their early 30s with a slight female predominance. The condition 
affects individuals of all races and ethnicities [Socie, 1996; Nishimura, 2004; Rosse, 
2004; Schrezenmeier, 2014]. 
Patients with PNH may initially present with hemoglobinuria, abdominal pain, smooth 
muscle dystonias, and fatigue. The disease is characterized by intravascular hemolysis 
and thrombotic complications involving unusual sites such as hepatic, mesenteric, 
cerebral, and the dermal veins [Parker, 2005]. PNH is a consequence of a nonmalignant 
clonal expansion of one or more hematopoietic stem cells that have acquired a somatic 
mutation of the X-linked phosphatidylinositolglycan complementation class A (PIG-A) 
gene, which is required for the biosynthesis of a lipid moiety, GPI, responsible for 
attaching a variety of proteins to the cell surface. As a consequence of mutant PIG-A, all 
GPI-anchored proteins (GPI-AP) are deficient on affected stem cells and their progeny. 
Two GPI-APs, CD55 (decay accelerating factor) and CD59 (membrane inhibitor of 
reactive lysis), normally expressed on hematopoietic cells, are responsible for protecting 
blood cells from the lytic activity of the terminal complement membrane attack complex 
(MAC). Patients with PNH are unable to synthesize functional versions of these proteins 
on hematopoietic stem cells, resulting in the accumulation of alternative pathway 
complement proteins on the surface of red blood cells (RBC), C5 cleavage, formation of 
the MAC, and subsequent lysis. This intravascular hemolysis is the characteristic clinical 
manifestation of the disease [Parker, 2007]. 
6.2 
MECHANISM OF ACTION OF RA101495 
RA101495 inhibits complement activation at the level of C5 (See Figure 1), a clinically 
validated target for the treatment of PNH. RA101495 binds with high affinity to 
complement C5 and prevents its cleavage by C5 convertase into the cleavage products 
C5a and C5b. Inhibition of C5 cleavage therefore prevents the assembly and cytolytic 

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activity of MAC on GPI-AP-deficient erythrocytes. RA101495 can also bind to C5b to 
block binding of C6, which further prevents the assembly of the C5b-9 MAC. Using 
surface plasmon resonance and analysis of a high-resolution co-crystal structure, 
RA101495 has been shown to bind to a specific site on C5 distinct from the eculizumab-
binding site and exhibits a strong and rapid association with C5 coupled with a slow 
dissociation rate. 
Figure 1 
Mechanism of Action of RA101495 in Complement System 
 
 
The dose-dependent inhibition by RA101495 of C5a formation upon activation of the 
Classical Pathway is depicted in the left panel of Figure 2. The right panel of Figure 2 
shows the inhibition by RA101495 of C5b formation (as measured by C5b-9 or MAC 
formation) upon activation of the Classical and Alternative complement pathways. In 
these experiments, the relative levels of both C5a and MAC were measured by enzyme-
linked immunosorbent assays (ELISAs) using antibodies specific for C5a and C5b-9.  
Figure 2 
Inhibition of C5a (left) and C5b-9 (MAC; right) Formation by RA101495 
 
 
Note: Inhibitor is RA101495  

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Abbreviations: C5=complement component 5; MAC=membrane attack complex. 
 
6.3 
CLINICAL TRIAL EXPERIENCE WITH RA101495 
Clinical trial experience with RA101495 to date includes a single Phase 1 study 
(RA10145-1001) in healthy volunteers. The study RA101495-1001 was a randomized, 
double-blind, placebo-controlled, single-ascending-dose (SAD) and multiple-dose (MD) 
study designed to evaluate the safety, pharmacokinetics (PK), and pharmacodynamics 
(PD) of RA101495.    
The first part of the study (SAD) evaluated a single dose of RA101495 versus placebo at 
4 dose levels (0.05, 0.1, 0.2 and 0.4 mg/kg) in separate cohorts. The SAD enrolled 
22 subjects; 14 received RA101495 (0.05 mg/kg in two subjects; 0.1, 0.2 and 0.4 mg/kg 
in four subjects each) and eight subjects received placebo, two per each dose level. 
The second part of the study (MD) evaluated 7 daily doses of RA101495 versus placebo 
at a single dose level (0.2 mg/kg). The MD enrolled six subjects; four received 
RA101495 and two received placebo. 
RA101495 when administered as a single dose and with 7-day repeat dosing displayed 
consistent and predictable PK that tightly correlated with the PD effect (inhibition of 
hemolysis and suppression of complement activity).   
The plasma concentrations of RA101495 following single-dose SC administration (SAD) 
showed dose-dependent increases across all dose levels examined (0.05, 0.1, 0.2, and 0.4 
mg/kg) (Figure 3). The mean Cmax ranged from 1010 to 5873 ng/mL across doses.  The 
mean AUC0-24 ranged from 21,440 to 112,300 ng* h/mL across doses. The mean half-life 
(t1/2) was consistent across dose levels and ranged from 155.6 to 185.4 hours. 
In the multiple dose (MD) portion of the study, the day 1 mean Cmax and AUCtau were 
2533 ng/mL and 50,010 ng*h/mL respectively, which were consistent with results from 
the 0.2 mg/kg single-dose cohort over the same post-dose period.  Following daily sc 
administration for 7 days, the Cmax and AUCtau increased by approximately 2.9 and 3.0-
fold respectively (Figure 4). Day 7 time to maximum plasma concentration (median Tmax 
= 3.0 hours), total body clearance (mean CL/F = 1.3 mL/h/kg)), elimination rate constant 
(Kel = 0.0043h-1 ) and half-life (t1/2 = 161.9 h) were all similar to single dose 
administration indicating that the absorption and elimination of RA101495 does not 
change significantly with repeat daily sc administration. The apparent volume of 
RA101495 distribution (Vz/F) showed some increase with administration of multiple 
doses of RA101495 (0.2 mg/kg SAD mean Vz/F = 71.4 mL/kg; 0.2 mg/kg MD mean day 
7 Vz/F = 311.6 mL/kg). However, the day 7 Vz/F for RA101495 was still less than total 
body water suggesting that RA101495 does not distribute into the extravascular space 
upon repeat SC administration. 
. 

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Figure 3 
Mean (SD) Plasma RA101495 Concentrations Over Time by Dose Group 
Following Single-Dose SC Administration in Healthy Volunteers (Study 
RA101495-1001) 
 
 
 
 
 
Figure 4 
Mean (SD) Plasma RA101495 Concentrations Over Time by Dose Group 
Following Multiple-Dose SC Administration of 0.2 mg/kg for 7 Days in 
Healthy Volunteers (Study RA101495-1001) 
 
 
 
 
 
0 .0 5  m g /kg
0 .1  m g /kg
0 .2  m g /kg
0 .4  m g /kg

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RA101495 demonstrated strong pharmacodynamic effects on terminal complement. 
RA101495 administered as a single dose achieved rapid dose-dependent inhibition of ex-
vivo hemolysis as measured by a sheep red blood cell (sRBC) lysis assay (Figure 5).  The 
maximum PD effect was apparent approximately 3 hours after a single dose. The 
maximal percent inhibition of hemolysis compared to baseline reached ≥90% for the 0.1, 
0.2, and 0.4 mg/kg single-dose cohorts and 60% for the lowest dose (0.05 mg/kg) cohort. 
Mean hemolysis levels remained below baseline for up to 2 days in the 0.05 mg/kg 
cohort, up to 4 days in the 0.1 mg/kg cohort, and for up to 7 days in the 0.2 and 0.4 mg/kg 
cohorts. 
RA10495 administered for 7-days achieved inhibition of hemolysis that was rapid and 
sustained at ≥95% across the dosing period in all subjects, (Figure 6). The mean percent 
inhibition of hemolysis compared to baseline reached >95% beginning at the first time 
point, 3 hours after dosing on Day 1, and continued throughout 7 days of dosing; all 
individual subjects showed ≥90% inhibition of hemolysis at all time points. At 24 hours 
after the last dose, inhibition of hemolysis was observed to be ≥97% in all subjects. Eight 
days after the last dose of RA10495, the mean inhibition of hemolysis remained ≥56%. 
Two subjects had inhibition of hemolysis >70% through 8 days after the last day of 
dosing. Hemolysis returned to pre-dose levels in all subjects within two weeks following 
the last dose. 
Figure 5 
Mean (SD) Red Blood Cell Lysis Over Time by Dose Group Following 
Single-Dose SC Administration in Healthy Volunteers (Study RA101495-
1001) 
 
 
 
 
0 .0 5  m g /kg
0 .1  m g /kg
0 .2  m g /kg
0 .4  m g /kg

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Figure 6 
Mean (SD) Red Blood Cell Lysis Over Time by Dose Group in the Multiple-
Dose Cohort Once Daily for 7-Days in Healthy Volunteers in (Study 
RA101495-1001) 
 
 
 
 
 
Note: Figure on the right is a duplicate of the figure on the left with an expanded y-axis. 
Safety: Across all the SAD cohorts, 7 of the 14 of the subjects treated with RA101495, 
had adverse events (AEs), which occurred more frequently in the highest dose cohort (0.4 
mg/kg). All subjects in the MD (0.2 mg/kg) had at least 1 AE. All AEs resolved. In all 
cohorts of the SAD and MD, there were no AEs that led to study drug discontinuation. 
No serious AEs (SAE) or deaths occurred during the study. 
In the SAD the most common AEs regardless of causality in subjects who received 
single-doses of RA101495 were injection site erythema (3 subjects, cohort 4), upper 
respiratory tract infection (URI) (1 subject, cohort 1; 2 subjects, cohort 4), and headache 
(2 subjects, cohort 4). Other AEs that occurred in 1 subject each were bronchitis (cohort 
1); catheter site phlebitis (cohort 3); fatigue (cohort 4); and back pain (cohort 4). AEs in 
subjects who received placebo were diarrhea, myalgia, headache, and rash, all in 1 
subject each.   
All AEs of injection site erythema events were reported in subjects who received the 
highest single-dose of RA101495 (0.4 mg/kg). All were reported as Grade 1 in severity 
with no pain, tenderness, swelling, or induration. No treatment was required and all 
events resolved spontaneously and rapidly following dosing. All these AEs were 
considered related to study drug by the investigator. 
In the MD cohort, the most common AE in subjects who received multiple-doses of 
RA101495 regardless of causality was injection site erythema (3 subjects) and headache 
(2 subjects).  Other AEs were dyspepsia, URI, back pain, dizziness, contact dermatitis, 
miliaria, and rash; all in 1 subject each. One subject had injection site pain due to a 
booster vaccination. AEs in subjects who received placebo were URI (2 subjects) and 
injection site reaction, injection site pain, back pain, and headache; all in 1 subject each.  
P la c e b o
R A 1 0 1 4 9 5
Direct Hemolysis 
Direct Hemolysis 

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Three subjects who received RA101495 had Grade 1 injection site erythema. One of 
these 3 subjects reported 4 separate AEs of injection site erythema (on Day 1, Day 2, Day 
5, and Day 6). The other 2 subjects had 1 event each (1 on Day 1 and 1 on Day 5). All 
AEs of injection site erythema were reported at a severity of Grade 1 with no pain, 
tenderness, swelling, or induration. No treatment was required and all events resolved 
spontaneously prior to the next dose. All were considered related to study drug by the 
investigator. One subject on placebo had a Grade 1 injection site reaction (stinging and 
numbness) and Grade 1 injection site pain (stinging). Both events were assessed as mild, 
of Grade 1 severity and resolved spontaneously.   
In all cohorts, laboratory and electrocardiogram (ECG) changes from baseline were 
considered not clinically significant, and none were reported as adverse events.  
6.4 
DEVELOPMENT RATIONALE 
RA101495 is being developed to treat patients with PNH. Based on PK and PD data 
generated to date, RA101495 has the potential to provide several advantages over the 
only currently approved therapy for PNH, eculizumab.  
Daily administration of RA101495 is expected to result in near complete and sustained 
suppression of C5 for improved control of hemolysis. Continuous inhibition of hemolysis 
is important in the prevention of breakthrough hemolysis. Eculizumab at the approved 
dose of 900 mg biweekly has been associated with breakthrough hemolysis in some 
patients requiring dose increases beyond the approved dose described in the current 
product label [Hill 2005]. Breakthrough hemolysis with eculizumab treatment typically 
occurs towards the end the biweekly infusion cycle and has been shown to be associated 
with sub-therapeutic eculizumab levels at those time points [Nakayama, 2016; Brodsky, 
2014]. Daily dosing with RA101495 is designed to ensure that C5 is continuously 
inhibited and is therefore expected to eliminate end-of-cycle breakthrough episodes. 
As a self-administered SC product, RA101495 has the potential to improve treatment 
satisfaction and improve dosing convenience for patients with PNH, and may enable a 
reduction in the cost of providing care. The current standard-of-care requires health 
professionals to administer eculizumab via a biweekly intravenous (IV) infusion. 
Published studies of patient preferences for SC versus IV therapy show a clear preference 
for SC administration, and SC administration has been shown to increase compliance, 
patient satisfaction and QOL, as well as reduce treatment costs, drug requirements, and 
the complications of intravenous access [Stoner, 2015; Besarab, 2002]. Phase 2 studies of 
RA101495 will include quantitative instruments for evaluating QOL. 
6.5 
DOSE JUSTIFICATION FOR STUDY  
6.5.1 
RATIONALE FOR STARTING DOSE (0.1 MG/KG)  
The 0.1 mg/kg/day dose was selected to satisfy the following criteria: 
 Predicted steady state drug levels for the nominal as well as the maximum dose 
(based on weight bracketing) are below the no observed adverse effect level 
(NOAEL) values for Cmax and AUC0-24 observed in toxicology studies (Table 2) 

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 Predicted steady state Cmax and AUC0-24 are not expected to exceed the values 
observed during the Phase 1 RA101495-1001 MD study in healthy volunteers 
(Table 2) 
 Inhibition of hemolysis is expected to be maintained at ≥90% at all times 
(following a loading dose of 0.3 mg/kg; see Section 6.5.2). This prediction is 
supported by overlaying the expected RA101495 plasma concentrations at steady 
state, with the PK/PD relationship obtained from Phase 1 studies in healthy 
volunteers  (Figure 7). Adequate and sustained control of hemolysis is a key 
component of both efficacy and safety in PNH. In this disease, even a modest 
transient decrease in complement blockade can lead to immediate “breakthrough” 
intravascular hemolysis and recrudescence of severe PNH symptoms. This 
consideration is particularly important with respect to the potential for missed 
doses. 
 
Table 2 
Experimental and Predicted PK Values for RA101495 in Humans 
Pharmacokinetic 
Parameter 
Statistic 
RA101495 
(2 mg/kg) 
NOAEL 
NHP 
RA101495 
(0.2 mg/kg) 
QDx7; Day 
7 Human 
(SD) 
RA101495 (0.1 mg/kg) 
Steady State Prediction in 
Human 
Nominal 
(Minimal) 
0.1 mg/kg 
QD 
Maximum 
dose* 
0.14 mg/kg 
QD 
Cmax (μg/mL) 
Mean 
33.8 
7.29 (0.66) 
6.57 
7.12 
AUC0-24(h·µg/mL) 
Mean 
573 
151.3 (12) 
141.5 
152.8 
*Indicates the potential maximum dose received by patients due to weight bracketed dosing  
 
 

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Figure 7 
Predicted PK and PD Effects Resulting From Weight-Bracketed Dosing of 
RA101495 (0.1mg/kg daily) 
 
Note:  Predicted plasma concentration range (blue lines) resulting from weight-bracketed dosing of 
RA101495 at 0.1mg/kg daily and expected PD effect (% hemolysis). 
 
6.5.2 
RATIONALE FOR USE OF LOADING DOSE 
In order to achieve and maintain hemolysis control efficiently, the Sponsor proposes the 
use of a single loading dose of 0.3 mg/kg to adequately suppress hemolysis after the first 
dose. Single doses of up to 0.4mg/kg SC were studied and were well-tolerated in the 
phase 1 SAD study in human volunteers. The rationale for the use of a 0.3mg/kg loading 
dose is supported by overlaying the expected RA101495 plasma trough concentrations 
after the first dose, with the PK/PD relationship obtained from Phase 1 studies in healthy 
volunteers (Figure 8). Based on the PK/PD model described in the supplementary report, 
the loading dose does not impact expected exposures at steady state (Figure 9). 

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Figure 8 
RA101495 Loading Dose (0.3mg/kg) and Predicted Control of Hemolysis 
After the First Dose 
 
Note: A loading dose of 0.3mg/kg is predicted to achieve the target PD effect (>90% hemolysis inhibition) 
at trough levels, to facilitate immediate control of hemolysis after the first dose. 
6.5.3 
RATIONALE FOR DOSE ESCALATION TO 0.3MG/KG DAILY AFTER WK 2 
As illustrated in Figure 9, RA101495 drug levels corresponding to 90% of the expected 
steady state values are estimated to be achieved by day 10.  The corresponding inhibition 
of hemolysis is estimated to be greater than 95% at both peak and trough drug levels.  
From the Week 2 Visit onwards, if a subject has not achieved an adequate response 
(defined as an LDH <1.5 x ULN), and following evaluation of safety and tolerability data 
by the investigator and the medical monitor, the dose should be escalated to 0.3 mg/kg 
daily. The dose may also be escalated to 0.3 mg/kg daily at any time in the event of an 
overt breakthrough hemolysis episode (e.g. hemoglobinuria).  

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Figure 9 
Simulation of PK (blue) and PD (red) of RA101495 with a Loading Dose of 
0.3mg/kg on Day 1 Followed by 0.1mg/kg Daily Thereafter.  
 
Note: Loading Dose of 0.3 mg/kg SC does not impact steady state PK of RA101495 

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7 
STUDY OBJECTIVES AND ENDPOINTS 
7.1 
OBJECTIVES 
• To assess the safety and tolerability of RA101495 in subjects with PNH  
• To assess preliminary efficacy of RA101495 in subjects with PNH 
• To assess PK and PD of RA101495 in subjects with PNH 
7.2 
ENDPOINTS 
7.2.1 
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 evaluation will also include a determination of anti-drug antibodies 
(ADA).  Laboratory assessments will include PNH clone size.  
7.2.2 
EFFICACY  
Primary efficacy:  
• The primary evaluation period is from Week 6 to Week 12. The primary efficacy 
endpoint is the change-from-baseline in serum LDH levels during this period, defined 
as the mean LDH values of Weeks 6, 8, 10, and 12 minus the baseline value of LDH. 
Secondary efficacy:  
• Changes from baseline in LDH, total bilirubin, total hemoglobin, free hemoglobin, 
haptoglobin, reticulocytes, and hemoglobinuria, at each of the scheduled post-
baseline assessment time-points.  
7.2.3 
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) 
• Plasma concentrations of eculizumab (Cohort B only)  
7.2.4 
PHARMACODYNAMIC  
• Changes from baseline CH50 
• Changes from baseline in sRBC lysis for the classical complement pathway  
• Changes from baseline in Wieslab ELISA for alternative complement pathway 
• Changes from baseline in C5 levels 

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7.2.5 
EXPLORATORY  
• Changes from baseline in QOL questionnaires (e.g. EORTC QLQ-C30, FACIT-
Fatigue, and EQ-5D) 
• Treatment satisfaction questionnaire 
• Mechanistic biomarkers (e.g. complement function, complement proteins, biomarkers 
of inflammation, biomarkers for thrombosis, biomarkers of liver function)  
• Pharmacogenomic analyses (optional) (See Section 11.6.4) 

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8 
STUDY DESIGN 
8.1 
OVERVIEW OF STUDY DESIGN  
Study RA101495-01.201 is a multicenter, open-label, uncontrolled study to evaluate 
safety, efficacy, pharmacokinetics and pharmacodynamics of RA101495 in subjects with 
PNH. A schematic of the RA101495-01.201 study design is provided Figure 10.  
Figure 10 
RA101495-01.201 Study Design 
 
 
The study will enroll two separate cohorts where subjects are assigned based on prior 
eculizumab treatment history.  
• Cohort A (Naïve) will enroll subjects who have not received eculizumab for treatment 
of PNH prior to or during the Screening Period 
• Cohort B (Switch) will enroll subject who have received eculizumab treatment for at 
least 6 months prior to Screening 
The planned enrollment is approximately 8-12 subjects in Cohort A and approximately 6-
8 subjects in Cohort B, for a total of up to 20 subjects.  
Cohort A will commence enrollment prior to Cohort B. Cohort B will not be opened until 
safety and efficacy data from at least 2 subjects completing the Week 2 Visit in Cohort A 
have been reviewed by the Sponsor and Study Investigators, and evidence of hemolysis 
suppression is demonstrated. 
The study includes an 8-week screening period and a 12-week Treatment Period. During 
the Treatment Period, subjects will return to the clinic weekly during the first 4 weeks 
followed by visits every 2 weeks to evaluate of safety, tolerability, efficacy, PK and PD. 

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Additional assessments will include immunogenicity, QOL questionnaires, biomarker 
samples and optional pharmacogenomics.  
Safety assessments will include reporting of AEs and SAEs (including MAVE criteria), 
clinical laboratory tests, ECGs, vital signs, and physical examinations. Safety evaluations 
will also include a determination of anti-drug antibodies (ADA).  
All subjects must have a negative result for Neisseria meningitidis colonization via a 
throat swab prior to study entry. All Cohort A (Naïve) subjects who have not been 
previously vaccinated must be vaccinated against Neisseria meningitidis and receive 
ciprofloxacin for 14 days of starting with the first dose of RA101495 at the Day 1 Visit. 
A booster vaccination should be administered as clinically indicated consistent with local 
standard of care. All Cohort B (Switch) subjects must have documentation of prior 
Neisseria meningitidis vaccination (and booster if appropriate) prior to study entry.  
For Cohort A (Naïve) subjects, the Day 1 Visit may be scheduled at any time after 
Screening and confirmation of eligibility.  
For Cohort B (Switch) subjects, the Day 1 Visit should be scheduled to coincide with the 
next scheduled dose of eculizumab (i.e. 14 ±2 days after from the last eculizumab dose). 
Eculizumab should NOT be administered at the Day 1 Visit or at anytime thereafter 
during the study. 
During the Treatment Period 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. 
At the conclusion of the Treatment Period subjects who complete the study and are 
demonstrating benefit will have the option to enroll in an open-label extension study to 
continue receiving treatment with RA101495 or they may receive standard-of-care 
treatment off study, after consultation with their treating physician. If the subject 
withdraws early from the study for any reason, he/she will not be eligible for the 
extension study.  
All subjects will receive a loading dose of 0.3 mg/kg to be administered SC at the Day 1 
visit. Following in-clinic education and training, all subjects will self-inject daily SC 
doses of 0.1mg/kg of study drug every 24 hours at approximately the same time each day 
for the subsequent 12 weeks. On study clinic days, the dose should be administered after 
the PK and PD collection has been completed. 
From the Week 2 Visit onwards, if a subject has not achieved an adequate response 
(defined as an LDH <1.5 x ULN), and following evaluation of safety and tolerability data 
by the investigator and the medical monitor, the dose should be escalated to 0.3 mg/kg 
daily. The dose may also be escalated to 0.3 mg/kg daily at any time in the event of an 
overt breakthrough hemolysis episode (e.g. hemoglobinuria).   

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8.1.1 
RATIONALE FOR STUDY DESIGN   
The current study in PNH subjects is designed as an open-label study and does not 
include a placebo group. Given the severity of the disease, and the availability of an 
approved treatment, it is considered inappropriate to administer a placebo to subjects with 
PNH. 
The starting dose selected for the study is 0.1 mg/kg (following a loading dose of 0.3 
mg/kg). This dose level of RA101495 is anticipated to achieve and maintain ≥90% 
sustained inhibition of hemolysis based on the Phase 1 healthy volunteer study and 
pharmacokinetics and pharmacokinetic modeling (see Section 6.5 Dose Justification). A 
second, higher dose level (0.3 mg/kg) will be available for those subjects who do not 
adequately respond to the starting dose (i.e. with LDH ≥1.5xULN) or who experience 
overt breakthrough hemolysis (e.g. hemoglobinuria).  
Dose presentation and administration of RA101495 will be determined by a target 
weight-based approach, accomplished using fixed-dose-by-weight brackets supporting a 
weight range of 43 to 109 kg. This method of dosing will insure that no subject receives a 
sub-therapeutic dose (Section 10.1.3). Avoidance of sub-therapeutic doses is critically 
important in PNH to minimize the risk of breakthrough hemolysis.  
The primary endpoint for the study is the change in LDH from baseline to the primary 
evaluation period (mean of values at the Week 6, Week 8, Week 10, and Week 12 visits).  
LDH, an enzyme that catalyzes the conversion of lactate to pyruvic acid and vice versa, is 
highly abundant in erythrocytes and is a well-established marker of intravascular 
hemolysis in PNH.  In a Phase 3 clinical study, eculizumab reduced hemolysis as 
assessed by the reduction of mean (± SD) serum LDH levels from 2200 ± 1034 U/L at 
baseline to 700 ± 388 U/L after one week, and maintained this effect through week 26 
(327 ± 433 U/L) [Hillmen 2006].   
Since the approval of eculizumab, LDH has emerged as a clinically accepted marker for 
monitoring the response to therapy, and for identifying subjects experiencing 
breakthrough hemolysis [Soliris® 2016, Soliris® 2015].  In subjects approaching the end 
of the 14-day eculizumab dosing interval, there is a close correlation between the return 
of complement activity, clinical manifestations of breakthrough intravascular hemolysis, 
and elevations in LDH [Hill 2005].   
It is expected that, based on daily subcutaneous administration, RA101495 will provide 
more consistent pharmacodynamic coverage of complement inhibition, and may have the 
potential to reduce the risk of breakthrough hemolysis seen with eculizumab. 
8.2 
STUDY PERIODS 
The total duration of study participation for all subjects will be will be up to 20 weeks, 
including a Screening Period of up to 8 weeks and a 12-week Treatment Period. 

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8.2.1 
SCREENING PERIOD 
The Screening Visit will occur at least 2 days, but no more than 56 days, before the first 
dose of RA101495 on Day 1.  
8.2.2 
TREATMENT 
All subjects will receive treatment with RA101495 from Day 1 to Day 84 during the 
Treatment Period. Subjects completing the 12-week Visit and are demonstrating benefit, 
in consultation with the treating physician, will have the option to enroll in a long-term 
open-label extension study to continue receiving treatment with RA101495. If a subject 
chooses not to participate in the extension study, the subject will receive standard-of-care 
treatment off–study as recommended by the treating physician.  
8.3 
SUBJECT REGISTRATION PROCEDURES 
8.3.1 
SCREENING AND ENROLLMENT 
Written informed consent must be obtained before ANY study-related procedures are 
performed.  
At the Screening Visit, subjects will be assigned a unique subject number. The following 
assessments will be performed during screening. 
• Demographic and baseline characteristics 
• Medical history, including a detailed history of PNH diagnosis information, 
symptoms, complications, and treatment over the 6 months prior to Screening 
• Review and documentation of prior (within the previous 30 days) and concomitant 
medications 
• Physical examination, including height and 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 (including LDH), hematology, and coagulation 
• Urine sample for urinalysis 
• Serum pregnancy for females of childbearing potential only 
• Throat swab for Neisseria meningitidis  
The inclusion and exclusion criteria will be reviewed to determine subject eligibility for 
study participation at the Screening Visit and prior to drug dosing on Day 1.  

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8.3.2 
TREATMENT GROUP ASSIGNMENT 
Eligible subjects will be assigned to one of two cohorts based on their prior treatment 
history for PNH. The two cohorts are: 
• Cohort A (Naïve) subjects who have not have received treatment with eculizumab 
prior to or during the Screening Period 
• Cohort B (Switch) subjects who have received treatment with eculizumab for at least 
6 months prior to Screening  
8.3.3 
BLINDING 
This is an open-label study.  
8.4 
DISCONTINUATION CRITERIA 
8.4.1 
DISCONTINUATION OF INVESTIGATIONAL MEDICINAL PRODUCT 
If a subject prematurely discontinues the investigational medicinal product (IMP), 
RA101495, at any time prior to completion of the Day 84 Visit during the Treatment 
Period, the subject should return to clinic for an End-of-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, PNH clone size 
• Urine sample for urinalysis 
• Serum pregnancy for females of childbearing potential only 
• Return of electronic diary (e-diary) to site 
• Completion of QOL questionnaires 
• Completion of treatment satisfaction questionnaire 
• Record AEs 
• Blood samples for: 
 PK analysis 
 PD analysis 
 ADA determination  
 Additional biomarkers 

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• Return of all used and unused study drug syringes and injection device to site  
8.4.2 
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 an End-of-Study 
Visit, as described in Section 8.4.1. All unused study drug syringes must be returned to 
the clinic as described in Section 10.2.  
8.5 
EARLY STUDY TERMINATION  
The Sponsor may terminate this study early, either in its entirety, in one or other cohort, 
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. 
8.6 
END OF STUDY 
The end-of-study is defined as the date of the last subject’s last visit. Subjects who 
complete the Treatment Period, and are deriving benefit from RA101495, will have the 
option to enter a long-term extension study. 

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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. Male or female ≥18 years 
2. Completed informed consent procedures, including signing and dating the informed 
consent form (ICF). 
3. Diagnosis of PNH by flow cytometry 
4. Cohort A (Naïve) subjects must not have received treatment with eculizumab prior to 
or during the Screening Period and must have a lactate dehydrogenase (LDH) level 
≥2 times the upper limit of normal (xULN) during Screening 
5. Cohort B (Switch) subjects must have received treatment with eculizumab for at least 
6 months prior to Screening   
6. Female subjects of child bearing potential must have a negative pregnancy test at 
Screening and within 24-hours prior to the first dose of RA101495 
7. 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. 
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. 

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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. 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 (ALP) 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. Recent surgery requiring general anesthesia within the 2 weeks prior to Screening, or 
expected to have surgery requiring general anesthesia during the 12-week Treatment 
Period 
9. 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)  
10. 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  
11. Treatment 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) 
12. 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.   

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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) 
• Loss to follow-up 
9.3.2 
REPLACEMENT OF SUBJECTS 
Enrolled subjects who prematurely discontinue study treatment for any reason prior to the 
Day 84 Visit may be replaced, at the discretion of the Sponsor, in order to obtain an 
adequate number of evaluable subjects (see Section 13.2).  

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10 
INVESTIGATIONAL MEDICINAL PRODUCTS AND 
TREATMENTS 
10.1 
STUDY TREATMENT ADMINISTRATION 
10.1.1 
IDENTITY OF INVESTIGATIONAL MEDICINAL PRODUCT AND TREATMENT 
The investigational medicinal product (IMP) RA101495 will be supplied as a sterile, 
preservative-free, aqueous solution pre-filled into 1 mL glass syringes with a 29 gauge ½ 
inch staked needle placed within a self-administration device. 
Subjects will be instructed to self-administer SC doses daily. The dose (dose volume) for 
each injection will depend on the dose requirement and subject’s bodyweight (see Section 
10.1.3 and Section 10.1.4). 
10.1.2 
TREATMENT GROUPS  
All eligible subjects in Cohort A and Cohort B will receive a single loading dose of 
0.3mg/kg RA101495 SC followed by study drug at 0.1 mg/kg SC once daily.   
10.1.2.1 
DOSE ESCALATION  
From the Week 2 Visit onwards, if a subject has not achieved an adequate response 
(defined as an LDH <1.5 x ULN), and following evaluation of safety and tolerability data 
by the treating investigator and the medical monitor, the dose should be escalated to 0.3 
mg/kg daily. The dose may also be escalated to 0.3 mg/kg daily at any time in the event 
of an overt breakthrough hemolysis event (e.g. hemoglobinuria).  
For subjects who have a dose increase to 0.3 mg/kg, samples for PK and PD should be 
collected at pre-dose of the first day of the new dose, then at scheduled visits per the 
Time and Events Table (Table 1). 
10.1.3 
DOSING SCHEDULE 
For Cohort A (Naïve) subjects, the Day 1 Visit may be scheduled at any time after 
Screening and confirmation of eligibility.  
For Cohort B (Switch) subjects, the Day 1 Visit should be scheduled to coincide with the 
next scheduled dose of eculizumab (i.e. 14 ± 2 days after from the last eculizumab dose). 
Eculizumab should NOT be administered on the Day1 Visit or at anytime thereafter 
during the study. 
Subjects in Cohort A (Naïve) and Cohort B (Switch) will receive a loading dose of 0.3 
mg/kg dose of RA101495 on Day 1, which will be administered during the study Visit by 
the site staff. During the remainder of the Treatment Period, subjects will self-administer 
the daily dose (0.1 mg/kg or 0.3 mg/kg) every 24 hours at approximately the same time 
each day. 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. 

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10.1.4 
DOSE PRESENTATION  
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 bodyweight 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 0.10 to 0.14 mg/kg); in the 0.3 mg/kg dose, subjects will 
receive a minimum dose of 0.3 mg/kg (range 0.3 mg/kg to 0.41 mg/kg). Table 3 
summarizes dose presentations for RA101495 0.1 mg/kg and 0.3 mg/kg doses. Subjects 
who present with a higher body weight (>109 kg) will be accommodated on a case-by- 
case basis, in consultation with the medical monitor.  
Table 3 
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 
0.150 
6 
≥43 to <61 
0.10 to 0.14 
0.1 
2 
0.220 
8.8 
≥61 to <88 
0.10 to 0.14 
0.1 
3 
0.310 
12.4 
≥88 to <109 
0.11 to 0.14 
0.3 
4 
0.416 
16.6 
≥43 to <56 
0.30 to 0.39 
0.3 
5 
0.574 
23 
≥56 to <77 
0.30 to 0.41 
0.3 
6 
0.810 
32.4 
≥77 to <109 
0.30 to 0.42 
 
10.1.4.1 
MISSED DOSES 
If a subject misses one dose (i.e. 1 day) of RA101495, the subject should document the 
missed dose in his/her subject e-diary and take the next planned dose as scheduled. The 
subject should 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 every 2 weeks, beginning on Day 1 
of the Treatment Period.   
Subjects will be trained and provided 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 
RA101495 will be provided as a sterile, preservative-free, aqueous solution for injection 
containing 40 mg/mL of active ingredient, RA101495, in a formulation of 50 mM sodium 

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phosphate and 76 mM sodium chloride at a pH of 7.0 pre-filled into a 1 mL glass syringe 
with a ½ inch, 29 gauge staked needle. Six dosage strengths will be supplied as shown in 
Table 3.  
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 room temperature (20°C to 25°C [68°F to 77°F]) for up to 30 days 
protected from sources of heat, light and damage. Storage of IMP outside of room 
temperature should be avoided.  
Subjects will be instructed to self-inject SC doses daily every 24 hours at approximately 
the same time each day. The subject will be provided with an injection device for use 
during the study.  Subject may inject in the abdomen (preferred site), thigh or upper arm. 
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 the subject should return the used container containing all 
used syringes to the site. The unused study drug (unused syringes) should be retained by 
the subject and be used first in the immediate two weeks.   
All study drug (syringes) and disposal containers must be returned to the site at the last 
study visit.  
10.2.4 
DRUG ACCOUNTABILITY 
An e-diary where the subject documents study drug administration will be used to 
reconcile accountability during the study. The number of study drug syringes dispensed 
used, and returned will be documented.  
10.3 
COMPLIANCE 
Subjects will be required to record the date, time, and location of injections each day in 
an e-diary. The e-diary entries will be evaluated to determine compliance with study drug 
administration. If a subject does not confirm daily dosing using the e-diary, the 
investigator will receive an automated notification to contact the subject. 

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11 
STUDY ASSESSMENTS 
Please refer to Table 1 for the timing of study assessments. 
11.1 
SUBJECT AND BASELINE DISEASE CHARACTERISTICS 
11.1.1 
DEMOGRAPHIC DATA 
The following demographic data will be collected: date of birth, gender, ethnicity, and 
race.  
11.1.2 
DISEASE AND PRIOR TREATMENT HISTORY  
A detailed history of PNH for a minimum of 6 months prior to Screening will be 
obtained, including (but not limited to) the following data: date of diagnosis, PNH clone 
size at diagnosis (if available), history of thrombotic events, history of transfusions, and 
history of PNH-specific prior therapy (e.g. immunosuppressives, anticoagulants, 
associated bone-marrow disorders).  
For Cohort B (Switch) subjects, the date eculizumab treatment was initiated and dose 
received will be documented. A dosing history for each subject (including dates and all 
dosage changes for a minimum of 6 months prior to Screening) will also be recorded.  
11.1.3 
PRIOR AND CONCOMITANT MEDICATIONS 
In addition to PNH-specific prior therapy (Section 11.1.2), all prescriptions and over-the-
counter medications taken during the 30 days prior to the screening visit 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 to assess subject eligibility. 
Detailed medical history regarding the occurrence of specific events or conditions (e.g. 
underlying bone marrow pathology, major vascular events, pulmonary hypertension, 
impaired renal or hepatic function, infections, malignancies) for a minimum of 6 months 
prior to Screening will also be collected.  
11.2.2 
PHYSICAL EXAMINATION  
Physical examinations will include the following assessments: 

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• General inspection 
• Weight (kg) and height (height in cm to be collected at Screening  
• Visit only) 
• Examination of the injection site and draining nodes  
• 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 (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 described in the eCRF and the investigator 
will assess clinical significance. 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 
(see Table 1).  
11.2.5 
NEISSERIA MENINGITIDIS TESTING 
All subjects must have a negative result for Neisseria meningitidis colonization via a 
throat swab prior to study entry. The throat swabs for Neisseria meningitidis will be 
obtained at Screening and sent to a certified laboratory for analysis to confirm absence of 
colonization.   
11.2.5.1 
NEISSERIA MENINGITIDIS  PROPHYLACTIC TREATMENT 

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All subjects who have not been previously vaccinated will receive prophylactic treatment 
with Neisseria meningitidis vaccine and ciprofloxacin. These subjects must be vaccinated 
against Neisseria meningitidis prior to starting their first dose of RA101495. A booster 
vaccination should be administered as clinically indicated, consistent with local standard 
of care. All previously unvaccinated subjects will be treated with oral ciprofloxacin from 
Day 1 to Day 14. All Cohort B (Switch) subjects must have documentation of prior 
Neisseria meningitidis vaccination (and booster if appropriate) prior to study entry. 
11.2.6 
ADVERSE EVENT RECORDING  
Guidance on the identification, monitoring, and reporting of AEs is provided in 
Section 12.   
11.2.7 
LABORATORY SAFETY ASSESSMENTS 
11.2.7.1 
BLOOD CHEMISTRY AND HEMATOLOGY  
Clinical chemistry and hematology analytes to be collected are identified in Table 4 and 
should be performed as specified in the Time and Events 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.   

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Table 4 
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) 
 
11.2.7.2 
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.  Hemoglobinuria will be assessed using a urine colorimetric scoring system.  
11.2.7.3 
PREGNANCY TEST 
A serum pregnancy test for human chorionic gonadotropin will be performed on female 
subjects of childbearing potential at Screening.  

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A urine dipstick pregnancy test (human chorionic gonadotropin) will be performed on 
female subjects of childbearing potential at Day 1 pre-dose and Day 29, Day 57, and Day 
84 (End of Study). 
11.2.8 
PNH CLONE  
Blood sample for measurement of PNH clone size will be collected at Screening and Day 
29, Day 57, and Day 84 (or End-of-Study Visit).  PNH clone size will be determined by 
peripheral blood flow cytometry analysis (RBCs and granulocytes).    
11.2.9 
IMMUNOGENICITY 
Blood samples for ADAs will be collected prior to dosing on Day 1 and on Day 29, Day 
57, and Day 84 (or at the End-of-Study Visit) in all enrolled subjects. 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. 
11.3 
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. 
11.4 
PHARMACOKINETIC AND PHARMACODYNAMIC ASSESSMENTS 
Blood samples for the measurement of plasma concentrations of RA101495 and 
metabolites will be collected on all subjects. Subjects in Cohort B will also have a blood 
sample for measurement of eculizumab plasma concentrations.  
Blood samples for pharmacodynamic assessments will be collected from 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 at the following time points in 
relationship to the first dose of RA101495: pre-dose (within 1 hour before first dose 
administration) and at 1, 3, and 6 hours post-dose on Day 1. For subjects who have a dose 
increase to 0.3 mg/kg, samples for PK and PD should be collected at pre-dose Day 1 of 
the new dose.  

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For subjects in Cohort B only, blood samples for PK of eculizumab should be collected at 
screening, Day 1, Day 15, Day 29, and Day 43. The sample should be collected prior to 
administration of RA101495. 
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. 
11.5 
ELECTRONIC DIARY CARD 
Subjects will be required to record the following information each day in a subject e-
diary during study participation: 
• Confirmation of administration of daily (every 24 hours) dose of RA101495 that 
includes date, time, and location of injection of RA101495  
Subject e-diaries will be collected/dispensed at the time points shown in the Time and 
Events Table (Table 1). Subjects will be given detailed instructions on how to complete 
entries in subject diaries throughout study participation.  
11.6 
EXPLORATORY ASSESSMENTS  
11.6.1 
QUALITY OF LIFE ASSESSMENTS 
Quality of life assessments will be performed according to the Time and Events Table 
(Table 1). The following QOL questionnaires will be used during this study: 
• 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-Fatigue) Scale 
• EuroQol-5D (EQ-5D) 
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.  

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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 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]. 
11.6.1.3 
EQ-5D 
The EQ-5D is a standardized instrument for measuring generic health status. The EQ-5D 
consists of the EQ-5D descriptive system and the EQ visual analogue scale (VAS). The 
EQ-5D descriptive system comprises the following 5 dimensions: mobility, self-care, 
usual activities, pain/discomfort and anxiety/depression; each dimension has 3 levels: no 
problems, some problems, extreme problems [EuroQol, 1990]. Subjects answer questions 
based on symptoms and health status on the day the questionnaire is completed.  
11.6.2 
TREATMENT SATISFACTION QUESTIONNAIRE 
A treatment satisfaction questionnaire using a 5-point Likert response scale will be 
administered to all subjects to assess overall satisfaction with SC administration of the 
study medication at the end of the 12-week Treatment Period.  
A more targeted questionnaire using a 5-point Likert response scale will be administered 
to the Cohort B (Switch) subjects only to assess their preference for daily SC self-
injection at home compared with biweekly infusions given by a health-care professional 
in the clinic. 
11.6.3 
BIOMARKERS 
Blood samples will be collected at designated time points, concomitant with PK and PD 
sampling (see Table 1). 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 safety of 
RA101495 in PNH subjects. 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.  
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 may be reported separately from the 
main clinical study report. 

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11.6.4 
PHARMACOGENOMIC ASSESSMENTS 
Participation in the pharmacogenomic assessment is optional and subjects must consent 
to the pharmacogenomic analysis using a separate consent form. 
For subjects who opt to participate in pharmacogenomics studies, a blood sample will be 
obtained on Day 1. All genomic analyses will be performed at an accredited laboratory. 
Detailed instructions regarding sample collection, processing, and shipping will be 
provided in a separate laboratory manual. 
Genomic studies will be performed (e.g. deoxyribonucleic acid [DNA] sequencing, DNA 
copy number analysis, ribonucleic acid [RNA] expression profiling) to explore whether 
specific genomic features correlate with response or resistance to study drug. 
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 genomic investigations may be reported separately from the 
main clinical study report. 

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12 
SAFETY REPORTING 
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 (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 SAEs.  

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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 (weekly for the first 4 weeks followed by every 2 weeks). 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 as AEs per Section 12.1 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 weekly for the first 4 weeks followed by every 2 weeks 
during the study. 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 as AEs per Section 12.1 and 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 weekly for the first 
4 weeks followed by every 2 weeks during the study.  
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 as AEs per Section 12.1 and Section 12.3 
12.1.3.4 
INJECTION SITE REACTIONS  
The investigator should assess the injection sites at each scheduled visit for: 

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• Pain, tenderness, erythema, and induration severity (Table 5) 
• 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 5 
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. Subjects are monitored every 2 weeks for adverse events.  
To reduce the risk of infection, during the screening period, all subjects must have a 
negative result for Neisseria meningitidis colonization via throat swab prior to study 
entry. All Cohort A (Naïve) subjects who have not been previously vaccinated must be 
vaccinated against Neisseria meningitidis and receive ciprofloxacin for 14 days of 
starting with the first dose of RA101495 at the Day 1 Visit. A booster vaccination should 
be administered as clinically indicated, consistent with local standard of care. All cohort 
B (Switch) subjects must have documentation of prior Neisseria meningitidis vaccination 
(and booster if appropriate) prior to study entry. 

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During the Treatment Period, 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 12.1 and Section 12.3. 
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 
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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.  
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 discontinued, 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 
ADVERSE EVENTS 
Pre-existing conditions that are detected prior to administration of the first dose of study 
drug will be recorded as part of medical history. For all subjects, 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. 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 subjects, and observations by the study 

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personnel. Adverse events will be coded using 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 AEs should be reported separately (i.e. 1 record per event). Reporting 
of AEs is event-based (i.e. 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 
SERIOUS ADVERSE EVENTS 
Any SAE experienced by the subject from signing the ICF through 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 underwent 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 should be monitored by the investigator until resolution or stabilization.  

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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. 
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/patient 
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. 

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13 
STATISTICAL AND ANALYTICAL PLANS 
13.1 
SAMPLE SIZE DETERMINATION 
For Cohort A (Naïve) a sample size of 8 subjects yields approximately 95% power to 
reject the null hypothesis that the median LDH change-from-baseline is 0 for the primary 
efficacy endpoint. This assumes a mean decrease in LDH from 2200 U/L at baseline to 
327 U/L during the primary evaluation period (Weeks 6 -12) with corresponding standard 
deviations of 1034 U/L and 443 U/L, and a within-subject correlation estimate of 0. This 
yields a change-from-baseline mean of 1873 U/L and standard deviation of 1125 U/L. 
The power is based on a 2-sided Wilcoxon signed-rank test at the 0.05 significance level.  
For Cohort B (Switch) a sample size of 6 subjects will yield a standard error of 
approximately 114 for an LDH mean change-from-baseline estimate. This assumes a 
standard deviation of 443 for the baseline and post-baseline endpoints and a within-
subject correlation estimate of 0.8, which yields change-from-baseline standard deviation 
of 280 U/L. 
The LDH mean and standard deviation estimates are based on the results summarized by 
Hillmen [Hillmen, 2006]. 
13.2 
ANALYSIS POPULATIONS 
Analysis populations in this study are defined in the sections that follow.  
13.2.1 
SAFETY POPULATION 
The Safety Population will include all subjects who receive at least one injection of 
RA101495.  
13.2.2 
EFFICACY EVALUABLE POPULATION 
The Efficacy Evaluable Population will include all subjects in the Safety Population who 
complete the 12-week Treatment Period.  
13.2.3 
PER PROTOCOL POPULATION 
The Per Protocol Population will include all subjects in the Safety Population who 
complete the 12-week Treatment Period and have no major protocol violations. 
13.2.4 
PHARMACOKINETIC POPULATION 
The PK Population will include all subjects in the Safety Population who have at least 1 
plasma sample obtained for PK assessment.  
13.2.5 
PHARMACODYNAMIC POPULATION 
The PD Population will include all subjects in the Safety Population who have at least 1 
plasma sample obtained for PD assessment. 

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13.3 
STATISTICAL PLAN 
13.3.1 
GENERAL CONSIDERATIONS 
Data will be summarized within each cohort separately. Where appropriate, data may be 
summarized for the overall study. 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. 
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 
SAFETY ANALYSIS 
Safety analyses will be performed on the individual cohorts.  
13.3.4.1 
ADVERSE EVENTS 
Adverse events (AE) will be coded using MedDRA (version 18.0 or higher). 
Incidence rates for treatment emergent adverse events (TEAE) 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 treatment start that was not present at the time of treatment 
start; or 
• An AE that increases in severity after treatment start, if the event was present at the 
time of treatment start. 
AEs occurring before the first dose of study drug will be summarized separately.  
13.3.4.2 
ADVERSE EVENTS OF SPECIAL INTEREST 
13.3.4.2.1 
THROMBOTIC ADVERSE EVENTS 
Thrombotic AEs will be summarized separately by system organ class, preferred term, 
and cohort. The events in  Table 6 (MAVE criteria [Hillmen 2007]) will be evaluated in 
the assessment of thrombotic AEs: 

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Table 6 
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 
 
Abbreviation: MAVE=major adverse vascular event. 
 
13.3.4.2.2 
HEPATIC ADVERSE EVENTS 
Hepatic and biliary AEs and will be summarized separately by system organ class, 
preferred term, and cohort.  Liver function tests will be summarized by changes from 
baseline and graded in severity using the NCI CTCAE criteria.  
13.3.4.2.3 
PANCREATIC ENZYME ELEVATIONS 
Pancreatic AEs and will be summarized separately by system organ class, preferred term, 
and cohort.  Pancreatic elevations will be summarized by changes from baseline and 
graded in severity using the NCI CTCAE criteria.  
13.3.4.2.4 
INJECTION SITE REACTIONS 
ISRs will be summarized separately by system organ class, preferred term, and cohort. 
The summary will include additional details on these events as described in Section 
12.1.3.  
13.3.4.2.5 
INFECTION  
AEs related to infection with Neisseria meningitidis will be summarized separately by 
system organ class, preferred term, and cohort.   
13.3.4.3 
CLINICAL LABORATORY EVALUATION 
Quantitative laboratory endpoints will be summarized by time point using descriptive 
statistics. 
13.3.4.4 
ELECTROCARDIOGRAMS 

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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.  
13.3.4.5 
VITAL SIGNS 
Descriptive statistics for vital signs (i.e. heart rate, body temperature, and blood pressure) 
will be presented. 
13.3.4.6 
PHYSICAL EXAMINATION 
The complete set physical examination findings will be provided in listings. Clinically 
significant physical examination abnormalities will be included and summarized as AEs 
if appropriate.  
13.3.5 
EFFICACY ANALYSIS 
Efficacy endpoints will be summarized by cohort. No formal statistical comparisons 
between cohorts will be performed. Tests to assess change-from-baseline will be applied 
to endpoints as appropriate. 
For Cohort A (Naïve), the primary efficacy endpoint will be tested against a null 
hypothesis of a median change-from-baseline of 0 by a 2-sided Wilcoxon signed-rank 
test.  
For Cohort B (Switch) an inferential test of the change-from-baseline primary efficacy 
endpoint will not be performed. Summary statistics for the primary endpoint will be 
provided including the mean, median, standard deviation, and standard error. 
13.3.6 
CLINICAL PHARMACOLOGY ANALYSIS 
13.3.6.1 
PHARMACOKINETIC ANALYSIS 
Drug exposure in the different cohorts 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 cohort using descriptive statistics. 
13.3.6.2 
PHARMACODYNAMIC ANALYSIS 
Pharmacodynamics endpoints will be summarized by cohort. No formal statistical 
comparisons between cohorts will be performed. Tests to assess change-from-baseline 
will be applied to endpoints as appropriate. 
13.3.7 
INTERIM ANALYSIS 
During this open-label study, the Sponsor will review safety and efficacy data as it 
becomes available during the Treatment Period. Following completion of the 12-week 
Visit , data will be cleaned and locked at the individual subject level, and will be 

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available for final analysis by the Sponsor on a rolling basis. Completion and final data 
lock of Cohort A may occur before, and independent of, Cohort B, or vice versa. 

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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 IEC/IRB. 
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 

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answered to the satisfaction of the subject or the subject’s legally acceptable 
representative.  
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. 
A separate consent form will be provided for sample collection for pharmacogenomic 
testing.  
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 (e.g. 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 

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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. 
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. 

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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 Clinical 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. 

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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 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 from 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). 

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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 from one or both cohorts, 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. 

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16 
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