Clinical trial NCT03030183
Conditions: Paroxysmal Nocturnal Hemoglobinuria (PNH)
Keywords: PNH
Sponsor: Ra Pharmaceuticals
Start date: 2017-04-17; Completion date: 2018-03-28
Enrollment: 3 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of the study is to evaluate the safety and efficacy of RA101495 in patients with paroxysmal nocturnal hemoglobinuria (PNH) who have an inadequate response to eculizumab. Patients will be treated with RA101495 for 12 weeks.

Detailed description:

Arms: arm 1: Subjects will receive RA101495 at the dose of 0.3 mg/kg subcutaneously (SC) at Day 1 (loading dose) followed by a starting maintenance dose of 0.1 mg/kg daily SC
Interventions: intervention 1: Zilucoplan (RA101495)
Intervention descriptions: intervention 1: 0.3 mg/kg subcutaneously (SC) at Day 1 (loading dose) followed by a starting maintenance dose of 0.1 mg/kg daily SC

Protocol documents:
Prot_000.pdf: 
1
TITLE PAGE  
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RA PHARMACEUTICALS, INC. 
RA101495-01.203: 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 WHO HAVE AN INADEQUATE 
RESPONSE TO ECULIZUMAB 
Protocol Number: 
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Indication Studied:
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Company/Sponsor Signatory:
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Protocol Version:
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Release Date of Protocol:
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 +LVWRU\RIDQ\VLJQLILFDQWPHGLFDORUSV\FKLDWULFGLVRUGHUWKDWLQWKH
RSLQLRQRIWKHLQYHVWLJDWRUZRXOGPDNHWKHVXEMHFWXQVXLWDEOHIRU
SDUWLFLSDWLRQLQWKHVWXG\
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GHYLFHZLWKLQWKHGD\VSULRUWR6FUHHQLQJRUSDUWLFLSDWLRQLQDQRWKHU
FRQFXUUHQWFOLQLFDOWULDOLQYROYLQJDWKHUDSHXWLFLQWHUYHQWLRQ
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SHUPLWWHG
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Endpoints and 
Assessments
Safety and Tolerability
6DIHW\DVVHVVPHQWVZLOOLQFOXGHHYDOXDWLRQRI$(VDQG6$(VLQFOXGLQJ
PDMRUDGYHUVHYDVFXODUHYHQW0$9(FULWHULDFOLQLFDOODERUDWRU\WHVWV
(&*VYLWDOVLJQVDQGSK\VLFDOH[DPLQDWLRQV6DIHW\HYDOXDWLRQVZLOODOVR
LQFOXGHDGHWHUPLQDWLRQRIDQWLGUXJDQWLERGLHV$'$
Primary Efficacy:
x
7KHSULPDU\HYDOXDWLRQSHULRGLVIURP:HHNWR:HHN7KHSULPDU\
HIILFDF\HQGSRLQWLVWKHFKDQJHIURPEDVHOLQHLQVHUXP/'+OHYHOV
GXULQJWKLVSHULRGGHILQHGDVWKHPHDQ/'+YDOXHVRI:HHNV
DQGPLQXVWKHEDVHOLQHYDOXHRI/'+
Secondary Efficacy:
x
&KDQJHVIURPEDVHOLQHLQ/'+WRWDOELOLUXELQWRWDOKHPRJORELQIUHH
KHPRJORELQKDSWRJORELQUHWLFXORF\WHVDQGKHPRJORELQXULDDWHDFKRI
WKHVFKHGXOHGSRVWEDVHOLQHDVVHVVPHQWWLPHSRLQWV
Pharmacokinetic:
x
3ODVPDFRQFHQWUDWLRQVRI5$DQGLWVPDMRUPHWDEROLWHV
x
0D[LPXPSODVPDFRQFHQWUDWLRQ&PD[
x
7LPHFRUUHVSRQGLQJWR&PD[WPD[
x
$UHDXQGHUWKHGUXJFRQFHQWUDWLRQWLPHFXUYHV$8&W
x
3ODVPDFRQFHQWUDWLRQVRIHFXOL]XPDE
Pharmacodynamic:
x
&KDQJHVIURPEDVHOLQH&+
x
&KDQJHVIURPEDVHOLQHLQVKHHS5%&V5%&O\VLVIRUFODVVLFDO
FRPSOHPHQWSDWKZD\
x
&KDQJHVIURPEDVHOLQHLQ:LHVODEHQ]\PHOLQNHGLPPXQRVRUEHQWDVVD\
(/,6$IRUDOWHUQDWLYHFRPSOHPHQWSDWKZD\
x
&KDQJHVIURPEDVHOLQHLQ&OHYHOV
Exploratory:
x
&KDQJHVIURPEDVHOLQHLQTXDOLW\RIOLIH42/TXHVWLRQQDLUHVHJ
EORTC QLQ-C30, FACIT-Fatigue, and EQ-5D)
x
7UHDWPHQWVDWLVIDFWLRQTXHVWLRQQDLUH
x
0HFKDQLVWLFELRPDUNHUVHJFRPSOHPHQWIXQFWLRQFRPSOHPHQW


5$
3URWRFRO5$$PHQGPHQW''-DQXDU\
&21),'(17,$/
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SURWHLQVELRPDUNHUVRILQIODPPDWLRQELRPDUNHUVIRUWKURPERVLV
ELRPDUNHUVRIOLYHUIXQFWLRQ
x
3KDUPDFRJHQRPLFDQDO\VHVRSWLRQDO
Statistical 
considerations
Study Populations7KHIROORZLQJVWXG\SRSXODWLRQVDUHGHILQHG
x
Safety Population$OOVXEMHFWVZKRUHFHLYHDWOHDVWGRVHRI5$
x
Efficacy Evaluable Population$OOVXEMHFWVLQWKH6DIHW\3RSXODWLRQ
ZKRFRPSOHWHWKHZHHN7UHDWPHQW3HULRG
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Per Protocol Population$OOVXEMHFWVLQWKH6DIHW\3RSXODWLRQZKR
FRPSOHWHWKHZHHN7UHDWPHQW3HULRGDQGKDYHQRPDMRUSURWRFRO
GHYLDWLRQV
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PK Population$OOVXEMHFWVLQWKH6DIHW\3RSXODWLRQZKRKDYHDWOHDVW
SODVPDVDPSOHREWDLQHGIRU3.DVVHVVPHQW
x
PD Population$OOVXEMHFWVLQWKH6DIHW\3RSXODWLRQZKRKDYHDWOHDVW
SODVPDVDPSOHREWDLQHGIRU3'DVVHVVPHQW
General Considerations
$GLVSRVLWLRQRIDOOFRQVHQWHGVXEMHFWVZLOOEHSURYLGHGDQGZLOOLQFOXGHD
EUHDNGRZQRIVXEMHFWVZKRFRQVHQWHGZHUHWUHDWHGGLVFRQWLQXHGWUHDWPHQW
ZHUHORVWWRIROORZXSRUZLWKGUHZFRQVHQW
&RQWLQXRXVYDULDEOHVZLOOEHVXPPDUL]HGZLWKWKHPHDQVWDQGDUGGHYLDWLRQ
6'PHGLDQDQGUDQJH&DWHJRULFDOYDULDEOHVZLOOEHVXPPDUL]HGXVLQJ
FRXQWVDQGSURSRUWLRQV
Safety:$GYHUVHHYHQWVZLOOEHFRGHGXVLQJWKH0HGLFDO'LFWLRQDU\IRU
5HJXODWRU\$FWLYLWLHV0HG'5$YHUVLRQRUKLJKHU,QFLGHQFHUDWHV
IRUWUHDWPHQWHPHUJHQW$(V7($(VE\PD[LPXPVHYHULW\DQG6$(VZLOO
EHVXPPDUL]HG7KHVHVXPPDULHVZLOOEHSURYLGHGUHJDUGOHVVRIFDXVDOLW\
DQGIRUHYHQWVWKDWDUHFRQVLGHUHGUHODWHGWRWUHDWPHQWZLWK5$
4XDQWLWDWLYHODERUDWRU\HQGSRLQWVZLOOEHVXPPDUL]HGE\WLPHSRLQW
'HVFULSWLYHVWDWLVWLFVIRU(&*SDUDPHWHUVLHKHDUWUDWH>+5@35LQWHUYDO
55LQWHUYDO456LQWHUYDO47LQWHUYDO47F%LQWHUYDODQG47F)LQWHUYDODW
HDFKDVVHVVPHQWWLPHSRLQWZLOOEHSUHVHQWHG
'HVFULSWLYHVWDWLVWLFVIRUYLWDOVLJQVKHDUWUDWHERG\WHPSHUDWXUHDQGEORRG
SUHVVXUHZLOOEHSUHVHQWHG
7KHFRPSOHWHVHWRISK\VLFDOH[DPLQDWLRQILQGLQJVZLOOEHSURYLGHGLQ
OLVWLQJV&OLQLFDOO\VLJQLILFDQWSK\VLFDOH[DPLQDWLRQDEQRUPDOLWLHVZLOOEH
LQFOXGHGDQGVXPPDUL]HGDV$(VLIDSSURSULDWH
Efficacy:1RIRUPDOVWDWLVWLFDOFRPSDULVRQVZLOOEHSHUIRUPHG6XPPDU\
VWDWLVWLFVIRUWKHSULPDU\DQGRWKHUHIILFDF\HQGSRLQWVZLOOEHSURYLGHG
LQFOXGLQJWKHPHDQPHGLDQVWDQGDUGGHYLDWLRQDQGVWDQGDUG
Pharmacokinetics:'UXJH[SRVXUHZLOOEHHYDOXDWHGXVLQJ3.SDUDPHWHUV
GHULYHGIURPQRQFRPSDUWPHQWDOPHWKRGV$OOFDOFXODWLRQVIRUWKHILQDO
DQDO\VLVZLOOEHEDVHGRQDFWXDOVDPSOLQJWLPHV,QGLYLGXDO3.SDUDPHWHUV
ZLOOEHSUHVHQWHGLQOLVWLQJVDQGVXPPDUL]HGXVLQJGHVFULSWLYHVWDWLVWLFV
Pharmacodynamics1RIRUPDOVWDWLVWLFDOFRPSDULVRQVZLOOEHSHUIRUPHG
6XPPDU\VWDWLVWLFVZLOOEHSURYLGHGLQFOXGLQJWKHPHDQPHGLDQVWDQGDUG
GHYLDWLRQDQGVWDQGDUGHUURU


5$
3URWRFRO5$$PHQGPHQW''-DQXDU\
&21),'(17,$/

Determination of Sample Size$VDPSOHVL]HRIVXEMHFWVZLOO\LHOGD
VWDQGDUGHUURURIDSSUR[LPDWHO\8/IRUDQ/'+PHDQFKDQJHIURP
EDVHOLQHHVWLPDWH7KLVDVVXPHVDVWDQGDUGGHYLDWLRQRI8/IRUWKH
EDVHOLQHDQGSRVWEDVHOLQHHQGSRLQWVDQGDZLWKLQVXEMHFWFRUUHODWLRQ
HVWLPDWHRI
Interim Analysis'XULQJWKLVRSHQODEHOVWXG\WKH6SRQVRUZLOOUHYLHZ
VDIHW\DQGHIILFDF\GDWDDVLWEHFRPHVDYDLODEOHGXULQJWKH7UHDWPHQW3HULRG
)ROORZLQJFRPSOHWLRQRIWKHZHHN7UHDWPHQW3HULRGGDWDZLOOEHFOHDQHG
DQGORFNHGDWWKHLQGLYLGXDOVXEMHFWOHYHODQGZLOOEHDYDLODEOHIRUILQDO
DQDO\VLVE\WKH6SRQVRURQDUROOLQJEDVLV


5$
3URWRFRO5$$PHQGPHQW''-DQXDU\
&21),'(17,$/

3
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 
 
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 
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 
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 
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 
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 
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 
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 
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7 
STUDY OBJECTIVES AND ENDPOINTS ............................................................33 
 
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 
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 
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8 
STUDY DESIGN ........................................................................................................35 
 
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9 
SELECTION OF STUDY POPULATION .............................................................43 
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10 
INVESTIGATIONAL MEDICINAL PRODUCTS AND 
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STATISTICAL AND ANALYTICAL PLANS .......................................................64 
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REGULATORY AND ADMINISTRATIVE CONSIDERATIONS .....................71 
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16 
REFERENCES ...........................................................................................................74 

LIST OF TABLES 
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RA101495  
Protocol RA101495-01.203                                                                                  Amendment 1 DD 17 January 2017
CONFIDENTIAL 
14
LIST OF FIGURES 
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 RA101495-01.203 Study Design .................................................................................35 
Figure 11 Kaplan-Meier survival of PNH patients stratified by LDH level (LDH 
dichotomized at 1.5xULN compared with age- and gender- matched 
controls) .......................................................................................................................38 
Figure 12 Patient-reported symptoms in the International PNH registry, stratified 
by LDH level (dichotomized at 1.5xULN). .................................................................39 
Figure 13 Inhibition of Hemolysis in vitro Lysis of PNH RBCs Without and With 
the Presence of RA101348 (identical peptide sequence to RA101495) ......................40 


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Abbreviation
Definitions
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5
TIME AND EVENTS TABLE 
$VVHVVPHQWVWREHSHUIRUPHGGXULQJWKHVWXG\DUHVKRZQLQ7DEOH


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Table 1 
Time and Events Table    
Phase 
Screening 
Period 
Treatment Period 
Study Week o 
-8 to 1 
0 
1 
2 
3 
4 
6 
8 
10 
12  
Study Daya o 
-56 to -1 
1 ± 2b 
8 ± 2 
15 ± 2 
22 ± 2 
29 ± 2 
43 ± 4 
57 ± 4 
71 ± 4 
84 ± 4 
(End of Study) 
Study Procedure p 
 
 
 
 
 
 
 
 
 
 
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 
 
 
 
 
 
 
 
 
 
Documentation of Neisseria vaccinationd 
X 
 
 
 
 
 
 
 
 
 
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 eventsh 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assessment of injection site reactionsi 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Phase 
Screening 
Period 
Treatment Period 
Study Week o 
-8 to 1 
0 
1 
2 
3 
4 
6 
8 
10 
12  
Study Daya o 
-56 to -1 
1 ± 2b 
8 ± 2 
15 ± 2 
22 ± 2 
29 ± 2 
43 ± 4 
57 ± 4 
71 ± 4 
84 ± 4 
(End of Study) 
Pharmacokinetics RA101495ij 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pharmacokinetics eculizumabk 
X 
X 
 
X 
 
X 
X 
 
 
 
Pharmacodynamics RA101495j 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Anti-drug antibodyl 
 
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 samplesj 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pharmacogenomic analysis (optional)m 
 
Xl 
 
 
 
 
 
 
 
 
Electronic diary training, dispensation, 
and collection 
 
X 
 
 
 
 
 
 
 
X 
RA101495 administrationn 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study drug dispensing and returno 
 
X 
 
X 
 
X 
X 
X 
X 
X 
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6
INTRODUCTION 
5D3KDUPDFHXWLFDOV,QFLVGHYHORSLQJ5$DVXEFXWDQHRXVO\±DGPLQLVWHUHGDPLQR
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6.1
OVERVIEW OF PAROXYSMAL NOCTURNAL HEMOGLOBINURIA 
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6.2
MECHANISM OF ACTION OF RA101495 
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Figure 1 
Mechanism of Action of RA101495 in Complement System 
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E\5$RI&EIRUPDWLRQDVPHDVXUHGE\&ERU0$&IRUPDWLRQXSRQDFWLYDWLRQRI
WKH&ODVVLFDODQG$OWHUQDWLYHFRPSOHPHQWSDWKZD\V,QWKHVHH[SHULPHQWVWKHUHODWLYHOHYHOVRI
ERWK&DDQG0$&ZHUHPHDVXUHGE\HQ]\PHOLQNHGLPPXQRVRUEHQWDVVD\V(/,6$VXVLQJ
DQWLERGLHVVSHFLILFIRU&DDQG&E
Figure 2 
Inhibition of C5a (left) and C5b-9 (MAC; right) Formation by RA101495 
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1RWH,QKLELWRULV5$
$EEUHYLDWLRQV& FRPSOHPHQWFRPSRQHQW0$& PHPEUDQHDWWDFNFRPSOH[
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Confiden al
Alterna vePathway
ClassicalPathway
MBLPathway
APC5Convertase
(C3bC3bBb)
C5
C5a
C5b
C6
C5b6
C7,C8,C9
MAC
CPC5Convertase
(C3bC4bC2a)
RA101495
Lysis
Log [Inhibitor] M
% Inhibition, C5a Production
-8
-6
-4
-2
0
2
4
0
50
100
Confi
Confiden
den alll


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6.3
CLINICAL TRIAL EXPERIENCE WITH RA101495 
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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) 
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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) 
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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 5 
Mean (SD) Red Blood Cell Lysis Over Time by Dose Group Following Single-Dose 
SC Administration in Healthy Volunteers (Study RA101495-1001) 
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0 .0 5  m g /kg
0 .1  m g /kg
0 .2  m g /kg
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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)
 
 
 
 
 
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P la c e b o
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Direct Hemolysis 
Direct Hemolysis 


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6.4
DEVELOPMENT RATIONALE 
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6.5
DOSE JUSTIFICATION FOR STUDY  
6.5.1
RATIONALE FOR STARTING DOSE (0.1 MG/KG)  
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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
1RPLQDO
0LQLPDO
PJNJ
4'
0D[LPXP
GRVH
PJNJ
4'
Cmax (μg/mL)
0HDQ




AUC0-24(h·μg/mL)
0HDQ




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
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Figure 7 
Predicted PK and PD Effects Resulting From Weight-Bracketed Dosing of 
RA101495 (0.1mg/kg daily) 
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6.5.2
RATIONALE FOR USE OF LOADING DOSE 
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Figure 8 
RA101495 Loading Dose (0.3mg/kg) and Predicted Control of Hemolysis After the 
First Dose 
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6.5.3
RATIONALE FOR DOSE ESCALATION TO 0.3MG/KG DAILY AFTER WEEK 2 
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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.  
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0
500
1000
1500
0
2
4
6
8
ss trough
0
50
100
90
Time (hours)
Plasma concentration (g/mL)
0.3 loading + 0.1 mpk QD
plasma level
%inh
% Inhibition of hemolysis


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7
STUDY OBJECTIVES AND ENDPOINTS 
7.1
OBJECTIVES 
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7.2
ENDPOINTS 
7.2.1
SAFETY AND TOLERABILITY 
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7.2.2
EFFICACY  
Primary efficacy
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Secondary efficacy:  
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7.2.3
PHARMACOKINETIC  
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7.2.4
PHARMACODYNAMIC  
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x
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x
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7.2.5
EXPLORATORY  
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8
STUDY DESIGN 
8.1
OVERVIEW OF STUDY DESIGN  
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Figure 10 
RA101495-01.203 Study Design 
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8.1.1
RATIONALE FOR STUDY DESIGN   
No Comparator 
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LVFRQVLGHUHGLQDSSURSULDWHWRDGPLQLVWHUDSODFHERWRVXEMHFWVZLWK31+
Dose Selection and Presentation 
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DSSURDFKDFFRPSOLVKHGXVLQJIL[HGGRVHE\ZHLJKWEUDFNHWVVXSSRUWLQJDZHLJKWUDQJHRIWR
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Primary Efficacy Endpoint 
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DVDFOLQLFDOO\DFFHSWHGPDUNHUIRUPRQLWRULQJWKHUHVSRQVHWRWKHUDS\DQGIRULGHQWLI\LQJ
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Rationale for the study population and the definition of inadequate response  
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Figure 11 
Kaplan-Meier survival of PNH patients stratified by LDH level (LDH dichotomized 
at 1.5xULN compared with age- and gender- matched controls) 
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Patient-reported symptoms in the International PNH registry, stratified by LDH 
level (dichotomized at 1.5xULN).
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Figure 13 
Inhibition of Hemolysis in vitro Lysis of PNH RBCs Without and With the Presence 
of RA101348 (identical peptide sequence to RA101495)
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8.2
STUDY PERIODS 
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SCREENING PERIOD 
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8.2.2
TREATMENT 
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8.3
SUBJECT REGISTRATION PROCEDURES 
8.3.1
SCREENING AND ENROLLMENT 
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8.3.2
TREATMENT GROUP ASSIGNMENT 
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8.3.3
BLINDING 
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8.4
DISCONTINUATION CRITERIA 
8.4.1
DISCONTINUATION OF INVESTIGATIONAL MEDICINAL PRODUCT 
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8.4.2
WITHDRAWAL FROM THE STUDY 
6XEMHFWVZKRDUHZLWKGUDZQIURPWKHVWXG\PXVWSURPSWO\GLVFRQWLQXHWUHDWPHQWZLWK
5$DQGPDNHHYHU\HIIRUWWRUHWXUQWRWKHFOLQLFWRFRPSOHWHDQ(QGRI6WXG\9LVLWDV
GHVFULEHGLQ6HFWLRQ$OOXQXVHGVWXG\GUXJV\ULQJHVPXVWEHUHWXUQHGWRWKHFOLQLFDV
GHVFULEHGLQ6HFWLRQ
8.5
EARLY STUDY TERMINATION  
7KH6SRQVRUPD\WHUPLQDWHWKLVVWXG\HDUO\HLWKHULQLWVHQWLUHW\RULQSDUWRUDWRQHRUPRUH
VWXG\VLWHVIRUUHDVRQDEOHFDXVHSURYLGHGWKDWZULWWHQQRWLFHLVVXEPLWWHGLQDGYDQFHRIWKH
LQWHQGHGWHUPLQDWLRQ7KHLQYHVWLJDWRUPD\DOVRWHUPLQDWHWKHVWXG\DWWKHVLWHIRUUHDVRQDEOH
FDXVHDIWHUSURYLGLQJZULWWHQQRWLFHWRWKH6SRQVRULQDGYDQFHRIWKHLQWHQGHGWHUPLQDWLRQ
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WKH6SRQVRUWHUPLQDWHVWKHVWXG\IRUVDIHW\UHDVRQVWKH6SRQVRUZLOOLPPHGLDWHO\QRWLI\WKH
LQYHVWLJDWRUDQGVXEVHTXHQWO\SURYLGHZULWWHQLQVWUXFWLRQVIRUVWXG\WHUPLQDWLRQ
8.6
END OF STUDY 
7KHHQGRIVWXG\LVGHILQHGDVWKHGDWHRIWKHODVWVXEMHFW¶VODVWYLVLW6XEMHFWVZKRFRPSOHWHWKH
7UHDWPHQW3HULRGDQGDUHGHULYLQJEHQHILWIURP5$ZLOOKDYHWKHRSWLRQWRHQWHUDORQJ
WHUPH[WHQVLRQVWXG\


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9
SELECTION OF STUDY POPULATION 
9.1
INCLUSION CRITERIA  
7REHHOLJLEOHIRUWKLVVWXG\VXEMHFWVPXVWPHHWALL RIWKHIROORZLQJLQFOXVLRQFULWHULD

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
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IRUP,&)

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PRQWKVSOXVRQHRUPRUHRIWKHIROORZLQJFULWHULD
o
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WR6FUHHQLQJ
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DQGZLWKLQKRXUVSULRUWRWKHILUVWGRVHRI5$
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6H[XDOO\DFWLYHIHPDOHVXEMHFWVRIFKLOGEHDULQJSRWHQWLDOLHZRPHQZKRDUHQRWSRVW
PHQRSDXVDORUZKRKDYHQRWKDGDELODWHUDORRSKRUHFWRP\K\VWHUHFWRP\RUWXEDOOLJDWLRQ
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7RWDODEVWLQHQFHIURPVH[XDOLQWHUFRXUVHIRUDWOHDVWRQHFRPSOHWHPHQVWUXDOF\FOHSULRU
WRWKH6FUHHQLQJ9LVLWWKURXJKRXWWKHVWXG\DQGIRUZHHNVDIWHUWKHODVWGRVHRIVWXG\
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9.2
EXCLUSION CRITERIA 
6XEMHFWVZKRPHHWANY RIWKHIROORZLQJH[FOXVLRQFULWHULDPXVWEHH[FOXGHGIURPWKHVWXG\


5$
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UHFXUUHQFHDUHDOORZHG
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9.3
REMOVAL AND REPLACEMENT OF SUBJECTS IN THE STUDY 
9.3.1
PREMATURE DISCONTINUATION 
(YHU\UHDVRQDEOHHIIRUWVKRXOGEHPDGHWRHQFRXUDJHUHWHQWLRQRIVXEMHFWVLQWKHVWXG\
PD[LPL]HFRPSOLDQFHZLWKVWXG\GUXJDQGIDFLOLWDWHDWWHQGDQFHDWDOOVFKHGXOHGVWXG\YLVLWV
$OOVXEMHFWVKDYHWKHULJKWWRUHIXVHIXUWKHUSDUWLFLSDWLRQLQWKHVWXG\DWDQ\WLPHDQGIRUDQ\
UHDVRQ$VXEMHFW¶VSDUWLFLSDWLRQPXVWWKHUHIRUHEHWHUPLQDWHGLPPHGLDWHO\XSRQKLVKHU
UHTXHVW
7KHLQYHVWLJDWRUZLOOPDNHHYHU\DWWHPSWWRDVFHUWDLQWKHUHDVRQVIRUGLVFRQWLQXDWLRQDQGWR
GRFXPHQWWKLVLQGHWDLOLQWKHVRXUFHGRFXPHQWDWLRQDQGWKHDSSURSULDWHVHFWLRQVRIWKHHOHFWURQLF
FDVHUHSRUWIRUPH&5)6XEMHFWVPD\EHZLWKGUDZQIURPWKHVWXG\GXHWRDQ\RIWKHIROORZLQJ
UHDVRQV


5$
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9.3.2
REPLACEMENT OF SUBJECTS 
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10
INVESTIGATIONAL MEDICINAL PRODUCTS AND TREATMENTS 
10.1
STUDY TREATMENT ADMINISTRATION 
10.1.1
IDENTITY OF INVESTIGATIONAL MEDICINAL PRODUCT AND TREATMENT 
7KHLQYHVWLJDWLRQDOPHGLFLQDOSURGXFW,035$ZLOOEHVXSSOLHGDVDVWHULOH
SUHVHUYDWLYHIUHHDTXHRXVVROXWLRQSUHILOOHGLQWRP/JODVVV\ULQJHVZLWKDJDXJHòLQFK
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10.1.2
TREATMENT GROUPS  
$OOHOLJLEOHVXEMHFWVZLOOUHFHLYHDVLQJOHORDGLQJGRVHRIPJNJ5$6&IROORZHGE\
VWXG\GUXJDWPJNJ6&RQFHGDLO\
10.1.2.1
DOSE ESCALATION  
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GDLO\'RVHHVFDODWLRQPD\SURFHHGRQO\LIQRVHYHUHLH*UDGHRUVHULRXVWUHDWPHQW
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)RUVXEMHFWVZKRKDYHDGRVHLQFUHDVHWRPJNJVDPSOHVIRU3.DQG3'VKRXOGEHFROOHFWHG
DWSUHGRVHRIWKHILUVWGD\RIWKHQHZGRVHWKHQDWVFKHGXOHGYLVLWVSHUWKH7LPHDQG(YHQWV
7DEOH7DEOH
10.1.3
DOSING SCHEDULE 
7KH'D\9LVLWVKRXOGEHVFKHGXOHGWRFRLQFLGHZLWKWKHQH[WVFKHGXOHGGRVHRIHFXOL]XPDELH
rGD\VDIWHUIURPWKHODVWHFXOL]XPDEGRVH(FXOL]XPDEVKRXOG127EHDGPLQLVWHUHGRQ
WKH'D\9LVLWRUDWDQ\WLPHWKHUHDIWHUGXULQJWKHVWXG\
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DGPLQLVWHUHGGXULQJWKHVWXG\YLVLWE\WKHVLWHVWDII'XULQJWKHUHPDLQGHURIWKH7UHDWPHQW
3HULRGVXEMHFWVZLOOVHOIDGPLQLVWHUWKHGDLO\GRVHPJNJRUPJNJHYHU\KRXUVDW
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VLWHWKHGRVHPXVWEHDGPLQLVWHUHGDIWHUWKHEORRGZRUNLVFRPSOHWHGDWWKHLQYHVWLJDWRUVLWH
10.1.4
DOSE PRESENTATION  
'RVHVRI5$ZLOOEHGHWHUPLQHGE\DWDUJHWGRVHDQGZHLJKWDFFRPSOLVKHGXVLQJDIL[HG
GRVHE\ZHLJKWEUDFNHWV7KHVHEUDFNHWVDUHJURXSHGE\ERG\ZHLJKWFDWHJRU\VXFKWKDWHDFK
VXEMHFWZLOOUHFHLYHWKHQROHVVWKDQWKHWDUJHWPLQLPXPGRVHWRDYRLGVXEWKHUDSHXWLFGRVLQJ
)RUWKHPJNJGRVHVXEMHFWVZLOOUHFHLYHDWDPLQLPXPDIL[HGGRVHRIPJNJUDQJH


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WRPJNJ)RUWKHPJNJGRVHOHYHOVXEMHFWVZLOOUHFHLYHDPLQLPXPGRVHRI
PJNJUDQJHPJNJWRPJNJ7DEOHVXPPDUL]HVGRVHSUHVHQWDWLRQVIRU5$
PJNJDQGPJNJGRVHV6XEMHFWVZKRSUHVHQWZLWKDKLJKHUERG\ZHLJKW!NJZLOO
EHDFFRPPRGDWHGRQDFDVHE\FDVHEDVLVLQFRQVXOWDWLRQZLWKWKHPHGLFDOPRQLWRU
Table 3 
Dose Presentations by Weight Brackets 
Target 
Dose 
(mg/kg) 
Dose Presentation 
Weight Range 
(kg) 
Dose Range 
(mg/kg) 
Fill Volume 
Dose  
Number 
mL 
mg 
0.1 
1 
0.150 
6 
43 to <61 
0.10 to 0.14 
0.1 
2 
0.220 
8.8 
61 to <88 
0.10 to 0.14 
0.1 
3 
0.310 
12.4 
88 to <109
0.11 to 0.14 
0.3 
4 
0.416 
16.6 
43 to <56
0.30 to 0.39 
0.3 
5 
0.574 
23 
56 to <77
0.30 to 0.41 
0.3 
6 
0.810 
32.4 
77 to <109
0.30 to 0.42 

10.1.4.1
MISSED DOSES 
,IDVXEMHFWPLVVHVRQHGRVHLHGD\RI5$WKHVXEMHFWVKRXOGGRFXPHQWWKHPLVVHG
GRVHLQKLVKHUVXEMHFWHGLDU\DQGWDNHWKHQH[WSODQQHGGRVHDVVFKHGXOHG7KHVXEMHFWVKRXOG
FRQWDFWWKHLQYHVWLJDWRUDVVRRQDVSRVVLEOH,IDVXEMHFWPLVVHVRUPRUHGRVHVWKHVXEMHFWPXVW
QRWLI\WKHLQYHVWLJDWRULPPHGLDWHO\
10.2
STUDY TREATMENT MANAGEMENT 
10.2.1
PREPARATION AND DISPENSING 
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10.2.2
STUDY DRUG SUPPLY, STORAGE, AND HANDLING 
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10.2.3
DISPOSAL, RETURN, OR RETENTION OF UNUSED DRUG 
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10.2.4
DRUG ACCOUNTABILITY 
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10.3
COMPLIANCE 
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GLDU\7KHHGLDU\HQWULHVZLOOEHHYDOXDWHGWRGHWHUPLQHFRPSOLDQFHZLWKVWXG\GUXJ
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11
STUDY ASSESSMENTS 
3OHDVHUHIHUWR7DEOHIRUWKHWLPLQJRIVWXG\DVVHVVPHQWV
11.1
SUBJECT AND BASELINE DISEASE CHARACTERISTICS 
11.1.1
DEMOGRAPHIC DATA 
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11.1.2
DISEASE AND PRIOR TREATMENT HISTORY  
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11.1.3
PRIOR AND CONCOMITANT MEDICATIONS 
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11.2
SAFETY ASSESSMENTS 
11.2.1
MEDICAL AND SURGICAL HISTORY  
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11.2.2
PHYSICAL EXAMINATION  
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11.2.3
VITAL SIGNS 
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11.2.4
ELECTROCARDIOGRAM  
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11.2.5
NEISSERIA MENINGITIDIS TESTING 
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11.2.6
ADVERSE EVENT RECORDING  
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11.2.7
LABORATORY SAFETY ASSESSMENTS 
11.2.7.1
BLOOD CHEMISTRY AND HEMATOLOGY  
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Table 4 
Clinical Chemistry, Hematology, and Coagulation Analytes 
Clinical Chemistry
Hematology
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11.2.7.2
URINALYSIS 
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11.2.7.3
PREGNANCY TEST 
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11.2.8
PNH CLONE  
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11.2.9
IMMUNOGENICITY 
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11.3
EFFICACY ASSESSMENTS  
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11.4
PHARMACOKINETIC AND PHARMACODYNAMIC ASSESSMENTS 
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ELECTRONIC DIARY CARD 
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11.6
EXPLORATORY ASSESSMENTS  
11.6.1
QUALITY OF LIFE ASSESSMENTS 
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11.6.1.1
EORTC-QLQ-C30 
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11.6.1.2
FACIT-FATIGUE 
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11.6.1.3
EQ-5D 
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11.6.2
TREATMENT SATISFACTION QUESTIONNAIRE 
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11.6.3
BIOMARKERS 
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11.6.4
PHARMACOGENOMIC ASSESSMENTS 
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SAFETY REPORTING 
12.1
DEFINITIONS 
12.1.1
ADVERSE EVENT 
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12.1.2
SERIOUS ADVERSE EVENT 
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12.1.3
ADVERSE EVENTS OF SPECIAL INTEREST 
12.1.3.1
THROMBOTIC ADVERSE EVENTS  
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12.1.3.2
HEPATIC ADVERSE EVENTS 
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VXEMHFWVKRXOGFRQWLQXHVWXG\WUHDWPHQWUHGXFHGRVHRUGLVFRQWLQXHVWXG\WUHDWPHQW7KH
VXEMHFWVKRXOGEHPRQLWRUHGXQWLOWKHGLUHFWELOLUXELQUHWXUQWROHVVWKDQRUHTXDOWR[8/1
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6XEMHFWVZLWKLVRODWHG$/7RU$67HOHYDWLRQV![8/1FRQFXUUHQWO\ZLWKGLUHFWELOLUXELQ
HOHYDWLRQ![8/1DQGDQRUPDO$/3ZLWKQRRWKHUH[SODQDWLRQIRUWKHHOHYDWLRQVKRXOGEH
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12.1.3.3
PANCREATIC ENZYME ELEVATIONS  
6XEMHFWVVKRXOGEHPRQLWRUHGGXULQJWKHVWXG\IRUV\PSWRPVRISDQFUHDWLWLVRUFKROHF\VWLWLV
3DQFUHDWLFHQ]\PHVDP\ODVHDQGOLSDVHDUHPRQLWRUHGZHHNO\IRUWKHILUVWZHHNVIROORZHGE\
HYHU\ZHHNVGXULQJWKHVWXG\
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,QVXEMHFWVZLWKHOHYDWLRQVRIDP\ODVHRUOLSDVHWR1&,&7&$(9HUVLRQ*UDGH
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GLVFRQWLQXHGLIDWWKHPJNJGDLO\GRVH7KHVXEMHFWVKRXOGEHPRQLWRUHGXQWLODP\ODVH
DQGRUOLSDVHUHWXUQVWR*UDGHRUORZHU7KHPHGLFDOPRQLWRUVKRXOGEHFRQWDFWHGWR
UHYLHZWKHFDVH


5$
3URWRFRO5$$PHQGPHQW''-DQXDU\
&21),'(17,$/

x
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XQWLODP\ODVHDQGRUOLSDVHUHWXUQVWR*UDGHRUORZHU7KHPHGLFDOPRQLWRUVKRXOGEH
FRQWDFWHGWRUHYLHZWKHFDVH
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12.1.3.4
INJECTION SITE REACTIONS  
7KHLQYHVWLJDWRUVKRXOGDVVHVVWKHLQMHFWLRQVLWHDWHDFKVFKHGXOHGYLVLWIRU
x
3DLQWHQGHUQHVVHU\WKHPDDQGLQGXUDWLRQVHYHULW\7DEOH
x
(U\WKHPDDQGLQGXUDWLRQUHFRUGWKHPD[LPXPOLQHDUGLDPHWHU
x
%OLVWHUVXOFHUDWLRQQHFURVLVUHFRUGWKHPD[LPXPOLQHDUGLDPHWHUDQGVHYHULW\
x
/\PSKDGHQRSDWK\
,QDGGLWLRQWKHLQYHVWLJDWRUZLOOZKHQHYHUSRVVLEOHWDNHGHLGHQWLILHGSKRWRVRIWKHLQMHFWLRQ
VLWHUHDFWLRQ,65
,QMHFWLRQVLWHUHDFWLRQVVKRXOGEHUHFRUGHGDV$(VSHU6HFWLRQDQG6HFWLRQDQG
UHFRUGHGRQWKH,65VSHFLILFH&5)DQG$(H&5)DVDSSURSULDWH
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)
3DLQ
'RHVQRWLQWHUIHUH
ZLWKDFWLYLW\
5HSHDWHGXVHRI
QRQQDUFRWLFSDLQ
UHOLHYHU!KRXUVRU
LQWHUIHUHVZLWK
DFWLYLW\
$Q\XVHRIQDUFRWLF
SDLQUHOLHYHURU
SUHYHQWVGDLO\
DFWLYLW\
(PHUJHQF\URRP
YLVLWRU
KRVSLWDOL]DWLRQ
7HQGHUQHVV
0LOGGLVFRPIRUW
WRWRXFK
'LVFRPIRUWZLWK
PRYHPHQW
6LJQLILFDQW
GLVFRPIRUWDWUHVW
(PHUJHQF\URRP
YLVLWRU
KRVSLWDOL]DWLRQ
(U\WKHPD
UHGQHVV
WRFP
WRFP
!FP
1HFURVLVRU
H[IROLDWLYH
GHUPDWLWLV
,QGXUDWLRQ
VZHOOLQJ
WRFPDQG
GRHVQRWLQWHUIHUH
ZLWKDFWLYLW\
WRFPRU
LQWHUIHUHVZLWK
DFWLYLW\
!FPRU
SUHYHQWVGDLO\
DFWLYLW\
1HFURVLV
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3URWRFRO5$$PHQGPHQW''-DQXDU\
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12.1.3.5
INFECTION 
$OOVXEMHFWVVKRXOGEHPRQLWRUHGIRUVLJQVDQGV\PSWRPVRI1HLVVHULDPHQLQJLWLGLVLQIHFWLRQ
6XEMHFWVDUHPRQLWRUHGHYHU\ZHHNVIRUDGYHUVHHYHQWV
7RUHGXFHWKHULVNRILQIHFWLRQGXULQJWKHVFUHHQLQJSHULRGDOOVXEMHFWVPXVWKDYHDQHJDWLYH
UHVXOWIRU1HLVVHULDPHQLQJLWLGLVFRORQL]DWLRQYLDWKURDWVZDESULRUWRVWXG\HQWU\$OOVXEMHFWV
PXVWKDYHGRFXPHQWDWLRQRISULRU1HLVVHULDPHQLQJLWLGLVYDFFLQDWLRQDQGERRVWHULIDSSURSULDWH
SULRUWRVWXG\HQWU\
'XULQJWKH7UHDWPHQW3HULRGWRPLWLJDWHWKHULVNRILQIHFWLRQVXEMHFWVZLOOEHFRXQVHOHGDQG
UHPLQGHGRIHDUO\VLJQVDQGV\PSWRPVRI1HLVVHULDPHQLQJLWLGLVLQIHFWLRQ$SDWLHQWVDIHW\FDUG
GHWDLOLQJWKHVLJQVDQGV\PSWRPVRILQIHFWLRQZLWKLQVWUXFWLRQVWRVHHNLPPHGLDWHPHGLFDO
DWWHQWLRQZLOOEHSURYLGHGWRHDFKVXEMHFW7KHFDUGZLOODOVRGHVFULEHWKHVXEMHFW¶VSDUWLFLSDWLRQ
LQWKHVWXG\DQGWKHULVNVRILQIHFWLRQDVVRFLDWHGZLWKLQKLELWLRQRIWKHWHUPLQDOFRPSOHPHQW
V\VWHP7KHSDWLHQWVDIHW\FDUGPXVWEHFDUULHGZLWKWKHSDWLHQWDWDOOWLPHVZKLOHRQWUHDWPHQW
$OO$(VVKRXOGEHUHFRUGHGDV$(VSHU6HFWLRQDQG6HFWLRQ
12.1.3.6
DOSE MODIFICATION FOR OTHER ADVERSE EVENTS   
)RUDOO*UDGHWUHDWPHQWHPHUJHQW$(VRWKHUWKDQWKHKHSDWLFDQGSDQFUHDWLF$(VGHVFULEHG
LQVHFWLRQVDQGVWXG\GUXJVKRXOGEHGRVHUHGXFHGLIDWWKHPJNJGDLO\
GRVHRUSHUPDQHQWO\GLVFRQWLQXHGLIDWWKHPJNJGDLO\GRVH
$OO$(VVKRXOGEHUHFRUGHGDV$(VSHU6HFWLRQDQG6HFWLRQ
12.2
EVALUATION AND CLASSIFICATIONS 
12.2.1
SEVERITY 
7KHLQYHVWLJDWRUVKRXOGGHWHUPLQHWKHVHYHULW\RIWKHUHSRUWHG$(E\XVLQJWKH1&,&7&$(
9HUVLRQ7KHVHFULWHULDZLOOEHSURYLGHGLQDVHSDUDWHPDQXDO
)RUDQ\UHSRUWHG$(QRWGHVFULEHGLQWKH1&,&7&$(WKHIROORZLQJJXLGHOLQHVPXVWEH
FRQVLGHUHGIRUVHYHULW\HYDOXDWLRQ
Adverse Event Severity
0LOG
6\PSWRPVEDUHO\QRWLFHDEOHWRVXEMHFWRUGRHVQRWPDNHVXEMHFW
XQFRPIRUWDEOHGRHVQRWLQIOXHQFHSHUIRUPDQFHRUIXQFWLRQLQJ
SUHVFULSWLRQGUXJQRWRUGLQDULO\QHHGHGIRUUHOLHIRIV\PSWRPV
0RGHUDWH
6\PSWRPVRIDVXIILFLHQWVHYHULW\WRPDNHVXEMHFWXQFRPIRUWDEOH
SHUIRUPDQFHRIGDLO\DFWLYLW\LVLQIOXHQFHGVXEMHFWLVDEOHWRFRQWLQXHLQ
VWXG\WUHDWPHQWIRUV\PSWRPVPD\EHQHHGHG
6HYHUH
6\PSWRPVFDXVHVHYHUHGLVFRPIRUWV\PSWRPVFDXVHLQFDSDFLWDWLRQRU
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WUHDWPHQWZLWKVWXG\WUHDWPHQWWUHDWPHQWIRUV\PSWRPVPD\EHJLYHQ


5$
3URWRFRO5$$PHQGPHQW''-DQXDU\
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Adverse Event Severity
0LOG
6\PSWRPVEDUHO\QRWLFHDEOHWRVXEMHFWRUGRHVQRWPDNHVXEMHFW
XQFRPIRUWDEOHGRHVQRWLQIOXHQFHSHUIRUPDQFHRUIXQFWLRQLQJ
SUHVFULSWLRQGUXJQRWRUGLQDULO\QHHGHGIRUUHOLHIRIV\PSWRPV
DQGRUVXEMHFWKRVSLWDOL]HG
12.2.2
CAUSALITY 
7KHFDXVDOUHODWLRQVKLSRIWKH$(WRVWXG\PHGLFDWLRQZLOOEHDVVHVVHGE\ERWKWKHLQYHVWLJDWRU
DQGWKH6SRQVRU7KHDVVHVVPHQWRIFDXVDOUHODWLRQVKLSWRVWXG\GUXJVKRXOGEHHYLGHQFHEDVHG
DQGQRWEDVHGRQWKHSUHPLVHWKDWDOO$(VDUHFDXVDOO\UHODWHGWRVWXG\GUXJXQWLOSURYHQ
RWKHUZLVH'HIDXOWFDWHJRUL]DWLRQRIµUHODWHG¶ZLWKRXWVXSSRUWLYHHYLGHQFHIRUDFDXVDO
UHODWLRQVKLSWRVWXG\GUXJLVJHQHUDOO\XQLQIRUPDWLYHDQGGRHVQRWFRQWULEXWHWRXQGHUVWDQGLQJRI
WKHVDIHW\SURILOHRIWKHGUXJZLWKUHVSHFWWRWKHLQWHQGHGSRSXODWLRQ
([DPSOHVRIHYLGHQFHWKDWZRXOGVXJJHVWDFDXVDOUHODWLRQVKLSEHWZHHQWKHGUXJDQGWKH$(
LQFOXGHRFFXUUHQFHRIDQ$(WKDWLVNQRZQWREHVWURQJO\DVVRFLDWHGZLWKGUXJH[SRVXUHHJ
LQMHFWLRQVLWHUHDFWLRQRUDQ$(WKDWLVRWKHUZLVHXQFRPPRQLQWKHVWXG\SRSXODWLRQ/DFNRI
HIILFDF\RIVWXG\GUXJLQLVRODWLRQOHDGLQJWRXQPDVNLQJRIXQGHUO\LQJV\PSWRPVDQGVLJQVRI
GLVHDVHVKRXOGQRWEHFRQVLGHUHGHYLGHQFHRIUHODWHGQHVV
7KHFDXVDOUHODWLRQVKLSRIHDFK$(LVDVVHVVHGXVLQJDELQDU\V\VWHPZLWKDOO$(VFODVVLILHGDV
HLWKHUµUHODWHG¶RUµQRWUHODWHG¶
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UHDVRQDEOHWHPSRUDODVVRFLDWLRQIURPWKHWLPHRIVWXG\GUXJDGPLQLVWUDWLRQ7KHUHLVVXSSRUWLYH
HYLGHQFHWRVXJJHVWDSRVVLEOHFDXVDOUHODWLRQVKLSLUUHVSHFWLYHRIWKHGHJUHHRIFHUWDLQW\
EHWZHHQWKHREVHUYHG$(DQGWKHVWXG\GUXJ7KHUHLVQRDOWHUQDWLYHPRUHOLNHO\H[SODQDWLRQIRU
WKH$(/DFNRIVWXG\GUXJHIILFDF\LVQRWFRQVLGHUHGE\LWVHOIWREHHYLGHQFHRIUHODWHGQHVV
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GUXJDQGWKHRFFXUUHQFHRIWKH$(7KHUHLVHYLGHQFHRIDQDOWHUQDWLYHH[SODQDWLRQWKDWLVPRUH
OLNHO\DVDFDXVHRIWKH$(
12.3
RECORDING, REPORTING, AND MONITORING 
12.3.1
RECORDING AND REPORTING 
7KHLQYHVWLJDWRUPXVWPDNHHYHU\HIIRUWWRSURSHUO\HYDOXDWHDOOLQIRUPDWLRQUHOHYDQWWRWKH
UHSRUWHG$(LQVXFKDZD\WKDWDGLDJQRVLVFDQEHFRQILGHQWO\PDGHDQGUHSRUWHG)RUH[DPSOH
LWLVSUHIHUDEOHWRUHSRUW³SQHXPRQLD´DVWKH$(UDWKHUWKDQLWVV\PSWRPVHJ³UDOHV´RU³IHYHU´
DVVHSDUDWH$(V
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WKHIXOILOOHGFULWHULDIRUVHULRXVQHVVDVSUHVHQWHGLQ6HFWLRQ


5$
3URWRFRO5$$PHQGPHQW''-DQXDU\
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x
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UHGXFHGGRVHLQFUHDVHGFRQFRPLWDQWPHGLFDWLRQRWKHUDFWLRQHJGLDJQRVWLFWHVWLQJRUQR
DFWLRQ$Q\PHGLFDWLRQJLYHQWRWUHDWWKH$(ZLOOEHUHFRUGHGVHSDUDWHO\LQWKHFRQFRPLWDQW
PHGLFDWLRQOLVWRIWKHH&5)
7KHRXWFRPHRIWKH$(ZLOOEHUHFRUGHGDVGDWHHQGHGRQJRLQJRUUHVXOWLQJLQGHDWKZLWKGDWH
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12.3.1.1
ADVERSE EVENTS 
3UHH[LVWLQJFRQGLWLRQVWKDWDUHGHWHFWHGSULRUWRDGPLQLVWUDWLRQRIWKHILUVWGRVHRIVWXG\GUXJ
ZLOOEHUHFRUGHGDVSDUWRIPHGLFDOKLVWRU\)RUDOOVXEMHFWVWKH$(UHSRUWLQJSHULRGZLOOVWDUW
ZLWKWKHILUVWDGPLQLVWUDWLRQRIVWXG\GUXJRQ'D\DQGZLOOHQGZLWKWKHILQDOVWXG\YLVLWDIWHU
ZKLFKQRQHZ$(VDUHWREHUHSRUWHG:KHQSRVVLEOHRQJRLQJ$(VDVVHVVHGDVUHODWHGWRWKH
VWXG\GUXJZLOOEHIROORZHGXQWLOUHVROYHGRUVWDELOL]HG
7KHVXEMHFWVZLOOEHPRQLWRUHGWKURXJKRXWWKHVWXG\IRUDQ\$(VLQFOXGLQJDEQRUPDOFOLQLFDOO\
VLJQLILFDQWODERUDWRU\YDOXHVFOLQLFDOO\VLJQLILFDQWILQGLQJVDWYLWDOVLJQVPHDVXUHPHQWV
VSRQWDQHRXVUHSRUWVE\VWXG\VXEMHFWVDQGREVHUYDWLRQVE\WKHVWXG\SHUVRQQHO$GYHUVHHYHQWV
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LQYHVWLJDWRU
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LQFOXGLQJWKHGDWHDQGWLPHRIRQVHWHYHQWGLDJQRVLVLINQRZQRUVLJQV\PSWRPVHYHULW\WLPH
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$(VVKRXOGEHUHSRUWHGVHSDUDWHO\LHUHFRUGSHUHYHQW5HSRUWLQJRI$(VLVHYHQWEDVHGLH
DQRQJRLQJHYHQWZLOOQRWEHFORVHGXQWLOUHVROYHGRUDWWKHHQGRIVWXG\)RUWKH$(GHVFULSWLRQ
DGLDJQRVLVLVSUHIHUUHGRYHUV\PSWRPV,IQRGLDJQRVLVFDQEHPDGHHDFKV\PSWRPZLOOEH
UHSRUWHGDVDVHSDUDWH$($EEUHYLDWLRQVVKRXOGEHDYRLGHG'HVFULSWLYHZRUGVVKRXOGEHXVHG
IRURQJRLQJFRQGLWLRQVDVDSSOLFDEOHHJH[DFHUEDWLRQRIKHUSHVJHQLWDOLVRUZRUVHQLQJRI
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12.3.1.2
SERIOUS ADVERSE EVENTS 
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12.3.1.3
DEATH 
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12.3.2
MONITORING 
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12.3.2.1
POST-STUDY EVENTS 
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12.4
SPECIAL CIRCUMSTANCES 
12.4.1
PREGNANCY 
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12.4.2
OTHER 
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13
STATISTICAL AND ANALYTICAL PLANS 
13.1
SAMPLE SIZE DETERMINATION 
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13.2
ANALYSIS POPULATIONS 
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13.2.1
SAFETY POPULATION 
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13.2.2
EFFICACY EVALUABLE POPULATION 
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13.2.3
PER PROTOCOL POPULATION 
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13.2.4
PHARMACOKINETIC POPULATION 
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13.2.5
PHARMACODYNAMIC POPULATION 
7KH3'3RSXODWLRQZLOOLQFOXGHDOOVXEMHFWVLQWKH6DIHW\3RSXODWLRQZKRKDYHDWOHDVWSODVPD
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13.3
STATISTICAL PLAN 
13.3.1
GENERAL CONSIDERATIONS 
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13.3.2
SUBJECT DISPOSITION 
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5$
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13.3.3
DEMOGRAPHY AND BASELINE DISEASE CHARACTERISTICS 
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13.3.4
SAFETY ANALYSIS 
6DIHW\DQDO\VHVZLOOEHSHUIRUPHGRQWKH6DIHW\3RSXODWLRQ
13.3.4.1
ADVERSE EVENTS 
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13.3.4.2
ADVERSE EVENTS OF SPECIAL INTEREST 
13.3.4.2.1
THROMBOTIC ADVERSE EVENTS 
7KURPERWLF$(VZLOOEHVXPPDUL]HGVHSDUDWHO\E\V\VWHPRUJDQFODVVDQGSUHIHUUHGWHUP7KH
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Table 6 
Thrombotic Event Description (MAVE Criteria) 
7KURPERSKOHELWLV'HHSYHLQWKURPERVLV
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13.3.4.2.2
HEPATIC ADVERSE EVENTS 
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WHUP/LYHUIXQFWLRQWHVWVZLOOEHVXPPDUL]HGE\FKDQJHVIURPEDVHOLQHDQGJUDGHGLQVHYHULW\
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13.3.4.2.3
PANCREATIC ENZYME ELEVATIONS 
3DQFUHDWLF$(VDQGZLOOEHVXPPDUL]HGVHSDUDWHO\E\V\VWHPRUJDQFODVVDQGSUHIHUUHGWHUP
3DQFUHDWLFHOHYDWLRQVZLOOEHVXPPDUL]HGE\FKDQJHVIURPEDVHOLQHDQGJUDGHGLQVHYHULW\XVLQJ
WKH1&,&7&$(FULWHULD
13.3.4.2.4
INJECTION SITE REACTIONS 
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13.3.4.2.5
INFECTION  
$(VUHODWHGWRLQIHFWLRQZLWKNeisseria meningitidisZLOOEHVXPPDUL]HGVHSDUDWHO\E\V\VWHP
RUJDQFODVVDQGSUHIHUUHGWHUP
13.3.4.3
CLINICAL LABORATORY EVALUATION 
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13.3.4.4
ELECTROCARDIOGRAMS 
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13.3.4.5
VITAL SIGNS 
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13.3.4.6
PHYSICAL EXAMINATION 
7KHFRPSOHWHVHWSK\VLFDOH[DPLQDWLRQILQGLQJVZLOOEHSURYLGHGLQOLVWLQJV&OLQLFDOO\
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13.3.5
EFFICACY ANALYSIS 
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VWDQGDUGHUURU
13.3.6
CLINICAL PHARMACOLOGY ANALYSIS 
13.3.6.1
PHARMACOKINETIC ANALYSIS 
'UXJH[SRVXUHZLOOEHHYDOXDWHGXVLQJ3.SDUDPHWHUVGHULYHGIURPQRQFRPSDUWPHQWDOPHWKRGV
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SDUDPHWHUVZLOOEHSUHVHQWHGLQOLVWLQJVDQGVXPPDUL]HGXVLQJGHVFULSWLYHVWDWLVWLFV
13.3.6.2
PHARMACODYNAMIC ANALYSIS 
1RIRUPDOVWDWLVWLFDOFRPSDULVRQVZLOOEHSHUIRUPHG6XPPDU\VWDWLVWLFVZLOOEHSURYLGHG
LQFOXGLQJWKHPHDQPHGLDQVWDQGDUGGHYLDWLRQDQGVWDQGDUGHUURU
13.3.7
INTERIM ANALYSIS 
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DYDLODEOHGXULQJWKH7UHDWPHQW3HULRG)ROORZLQJFRPSOHWLRQRIWKHZHHN7UHDWPHQW3HULRG
GDWDZLOOEHFOHDQHGDQGORFNHGDWWKHLQGLYLGXDOVXEMHFWOHYHODQGZLOOEHDYDLODEOHIRUILQDO
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14
ETHICAL CONSIDERATIONS 
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14.1
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE 
COMMUNICATIONS 
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14.1.1
PROGRESS REPORTS 
7KHLQYHVWLJDWRUVKRXOGVXEPLWZULWWHQVXPPDULHVRIWKHVWXG\VWDWXVWRWKH,(&,5%DQQXDOO\RU
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14.1.2
FINAL INVESTIGATOR REPORT 
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14.2
INFORMED CONSENT OF STUDY SUBJECTS 
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14.3
PROTOCOL COMPLIANCE 
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14.4
PROTECTION OF CONFIDENTIALITY 
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14.5
DISCLOSURE OF STUDY RESULTS 
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15
REGULATORY AND ADMINISTRATIVE CONSIDERATIONS 
15.1
QUALITY ASSURANCE 
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DSSOLFDEOHUHJXODWRU\UHTXLUHPHQWV4XDOLW\FRQWUROVKDOOEHDSSOLHGWRHDFKVWDJHRIGDWD
KDQGOLQJWRHQVXUHWKDWDOOGDWDDUHUHOLDEOHDQGKDYHEHHQSURFHVVHGFRUUHFWO\
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15.1.1
MONITORING 
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15.1.2
AUDIT 
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15.2
CLINICAL RESEARCH ORGANIZATIONS 
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15.3
DATA MANAGEMENT 
15.3.1
CASE REPORT FORMS 
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15.3.2
SOURCE DOCUMENTS 
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15.4
PREMATURE TERMINATION OR SUSPENSION OF THE STUDY 
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