A Phase 2, Open Label, Multicenter Study to Evaluate the Safety, Tolerability, Efficacy, and Pharmacokinetics of Sebelipase Alfa in Infants With Rapidly Progressive Lysosomal Acid Lipase Deficiency
Phase: PHASE2
Conditions: Lysosomal Acid Lipase Deficiency
Sponsor: Alexion Pharmaceuticals, Inc.

A PHASE 2, OPEN LABEL, MULTICENTER STUDY TO 
EVALUATE THE SAFETY, TOLERABILITY, 
EFFICACY, AND PHARMACOKINETICS OF 
SEBELIPASE ALFA IN INFANTS WITH RAPIDLY 
PROGRESSIVE LYSOSOMAL ACID LIPASE 
DEFICIENCY 
 
 
 
Unique Protocol ID: LAL-CL08 
NCT Number: 
NCT02193867 
EudraCT Number: 
2014-000533-22 
Date of Protocol: 
08 December 2015 
 
 
 

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A PHASE 2, OPEN LABEL, MULTICENTER STUDY TO 
EVALUATE THE SAFETY, TOLERABILITY, EFFICACY, AND 
PHARMACOKINETICS OF SEBELIPASE ALFA IN INFANTS 
WITH RAPIDLY PROGRESSIVE LYSOSOMAL ACID LIPASE 
DEFICIENCY 




Protocol Number:  
LAL-CL08 
Date of Protocol: 
08 December 2015 
Amendment: 
3.0 
Product: 
Sebelipase alfa (SBC-102) 
IND No.: 
108460 
EUDRACT No.: 
2014-000533-22 
Sponsor: 
Alexion Pharmaceuticals, Inc.  
 
352 Knotter Drive 
Cheshire, CT 06410 
USA 
 
Amendment History 
Protocol 
Date of Approval 
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Page 1 of 66 
 
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Protocol Synopsis 
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Summary of planned clinical study 
Protocol Number 
(study identifier) 
LAL-CL08 
Title 
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Page 4 of 66 
 
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Summary of planned clinical study 
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Page 7 of 66 
 
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Page 8 of 66 
 
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DO NOT COPY OR DISTRIBUTE WITHOUT PERMISSION

/$/&/3URWRFRO$PHQGPHQW
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Page 9 of 66 
 
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TXHVWLRQQDLUH LQ DFFRUGDQFH ZLWK WKH 7HFKQLFDO 0DQXDO DQG FRPSDUHG WR
DSSURSULDWHGHPRJUDSKLFQRUPV7KHWRWDOVFRUHDQGIXQFWLRQDODUHDVFRUHV
ZLOOEHVXPPDUL]HGDVFRQWLQXRXVGDWDDQGDFFRUGLQJWRWKHFODVVLILFDWLRQDV
WRZKHWKHUWKHVXEMHFWGLVSOD\VDEQRUPDOQRUPDOGHYHORSPHQW
6KLIW WDEOHV ZLOO EH XVHG WR WDEXODWH GLHWDU\ FKDQJHV LQFOXGLQJ
GLVFRQWLQXDWLRQ RI ORZIDWORZFKROHVWHURO GLHW DQGRU LQWURGXFWLRQ RI DQ
XQUHVWULFWHG DJHDSSURSULDWH GLHW  2EVHUYHG YDOXHV DQG FKDQJHV DQGRU
SHUFHQWFKDQJHVIURPEDVHOLQHLQRWKHUH[SORUDWRU\HIILFDF\HQGSRLQWVZLOOEH
WDEXODWHGIRUHDFKHYDOXDWLRQWLPHSRLQW
Exploratory Biomarkers 
([SORUDWRU\ ELRPDUNHUV ZLOO EH DQDO\]HG IRU WKH )$6  3RWHQWLDO GLVHDVH
UHODWHG ELRPDUNHUVZLOO EH OLVWHG DQG REVHUYHG YDOXHV DQG FKDQJHV DQGRU
SHUFHQWFKDQJHVIURPEDVHOLQHZLOOEHVXPPDUL]HGE\WLPHSRLQW
Subgroup Analyses 
7KH LPSDFW RI $'$V RQ VDIHW\ HIILFDF\ 3. DQG 3' HQGSRLQWV ZLOO EH
H[SORUHGGHVFULSWLYHO\$VVXEMHFWQXPEHUVSHUPLWRWKHUVXEJURXSDQDO\VHV
RILQWHUHVWPD\EHSHUIRUPHGLQFOXGLQJEXWDUHQRWOLPLWHGWRDJHJHQGHU
DQGUDFH 
Measures to minimize 
pain and distress (only 
if specific for this 
study) 
/RFDO DQDOJHVLF FUHDP HJ HXWHFWLF PL[WXUH RI ORFDO DQHVWKHWLFV ZLOO EH
DOORZHG DW OHDVW  PLQXWHV RU DFFRUGLQJ WR DSSOLFDEOH LQVWLWXWLRQDO
JXLGHOLQHVSULRUWR,9SODFHPHQWRUEORRGVDPSOLQJ
External safety review  
,QGHSHQGHQW6DIHW\5HYLHZ&RPPLWWHH
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Table of Contents 
PROTOCOL SYNOPSIS .............................................................................................................................. 4 
LIST OF ABBREVIATIONS........................................................................................................................ 14 
1 
INTRODUCTION ................................................................................................................................ 16 
 
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1.1.1 
Lysosomal Acid Lipase Deficiency ........................................................................................ 16 
1.1.2 
LAL Deficiency Presenting in Infancy .................................................................................... 16 
1.1.3 
Medical Plausibility of Enzyme Replacement Therapy for LAL Deficiency ........................... 17 
 
,19(67,*$7,21$/$*(17 
 
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 
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1.4.1 
Completed Study LAL-CL01 .................................................................................................. 20 
1.4.2 
Ongoing Study LAL-CL04 ..................................................................................................... 21 
1.4.3 
Ongoing Study LAL-CL02 ..................................................................................................... 21 
1.4.4 
Ongoing Study LAL-CL03 ..................................................................................................... 21 
 
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1.5.1 
Dose Rationale ...................................................................................................................... 22 
1.5.2 
Risk/Benefit Assessment ....................................................................................................... 22 
2 
STUDY OBJECTIVES ....................................................................................................................... 24 
 
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 
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 
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3 
STUDY DESIGN ................................................................................................................................. 25 
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3.1.1 
Dose Escalation..................................................................................................................... 26 
 
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3.2.1 
Dose Selection ...................................................................................................................... 27 
3.2.2 
Outcome Variable Selection .................................................................................................. 27 
3.2.3 
Study Duration ....................................................................................................................... 29 
4 
STUDY POPULATION ....................................................................................................................... 30 
 
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 
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4.6.1 
Premature Withdrawal from Study Participation ................................................................... 31 
4.6.2 
Procedures for Discontinuation ............................................................................................. 31 
 
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5 
SCHEDULE OF ASSESSMENTS AND STUDY PROCEDURES ..................................................... 33 
 
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5.1.1 
Informed Consent .................................................................................................................. 34 
5.1.2 
Subject Eligibility.................................................................................................................... 34 
5.1.3 
Medical History ...................................................................................................................... 34 
5.1.4 
Demographic Information ...................................................................................................... 34 
5.1.5 
Anthropometrics .................................................................................................................... 34 
5.1.6 
Physical Examination ............................................................................................................ 34 
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5.1.7 
Abdominal Ultrasound ........................................................................................................... 35 
5.1.8 
Abdominal MRI ...................................................................................................................... 35 
5.1.9 
Vital Signs .............................................................................................................................. 36 
5.1.10 
Electrocardiogram ............................................................................................................. 36 
5.1.11 
Laboratory Assessments .................................................................................................. 36 
5.1.12 
Denver II Developmental Screening Test ......................................................................... 38 
5.1.13 
Exploratory Biomarkers ..................................................................................................... 38 
5.1.14 
Pharmacokinetic Assessments ......................................................................................... 39 
5.1.15 
DNA Sample ..................................................................................................................... 40 
5.1.16 
LAL Enzyme Activity ......................................................................................................... 40 
5.1.17 
Liver Biopsy ....................................................................................................................... 41 
6 
INVESTIGATIONAL MEDICINAL PRODUCT ................................................................................... 42 
 
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6.3.1 
Receipt of IMP ....................................................................................................................... 42 
6.3.2 
Storage .................................................................................................................................. 42 
6.3.3 
Disposition ............................................................................................................................. 43 
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6.4.1 
Preparation of IMP ................................................................................................................ 43 
6.4.2 
Administration of IMP ............................................................................................................ 43 
 
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7 
ASSESSMENT OF SAFETY ............................................................................................................. 44 
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7.1.1 
Clinical Adverse Events ......................................................................................................... 44 
7.1.2 
Laboratory Test Abnormality ................................................................................................. 46 
7.1.3 
Adverse Events of Special Interest (Infusion-Associated Reactions) ................................... 46 
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7.2.1 
Serious Adverse Events (Immediately Reportable to the Sponsor) ...................................... 47 
7.2.2 
Adverse Event Reporting Period ........................................................................................... 47 
7.2.3 
Treatment and Follow-up of Adverse Events ........................................................................ 47 
7.2.4 
Follow-up of Abnormal Laboratory Test Values .................................................................... 48 
7.2.5 
Pregnancy ............................................................................................................................. 48 
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7.4.1 
Investigator Reporting: Notifying the Study Sponsor ............................................................ 49 
7.4.2 
Investigator Reporting: Notifying the IRB/IEC ....................................................................... 49 
7.4.3 
Sponsor Reporting: Notifying the FDA and all Regulatory Authorities .................................. 49 
7.4.4 
Sponsor Reporting: Notifying Participating Investigators ...................................................... 50 
 
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8 
STATISTICAL PLAN ......................................................................................................................... 51 
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8.8.1 
Adverse Events ..................................................................................................................... 53 
8.8.2 
Clinical Laboratory Tests ....................................................................................................... 53 
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8.8.3 
Other Safety Data .................................................................................................................. 54 
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8.11.1 
Significance Levels ........................................................................................................... 54 
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ETHICAL CONSIDERATIONS .......................................................................................................... 57 
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CLINICAL STUDY REPORT AND PUBLICATION PLAN ................................................................ 58 
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REFERENCES ................................................................................................................................... 59 
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APPENDICES .................................................................................................................................... 62 
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1 Introduction 
7KLV GRFXPHQW LV D SURWRFRO IRU D KXPDQ UHVHDUFK VWXG\ 7KLV VWXG\ LV WR EH FRQGXFWHG
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1.1 Background 
1.1.1 Lysosomal Acid Lipase Deficiency 
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FRPSOHWH ORVV RI HQ]\PH IXQFWLRQ $VVPDQQ  The Metabolic and Molecular Basis of 
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WKH ILUVW  PRQWKV RI OLIH $VVPDQQ  The Metabolic and Molecular Basis of Inherited 
Disease7KLVIRUPRIWKHGLVHDVHQDPHGDIWHUWKHSK\VLFLDQZKRILUVWGHVFULEHGLW$EUDPRY
AMA J Dis ChildLVWKHPRVWUDSLGO\SURJUHVVLYHSUHVHQWDWLRQRI/$/'HILFLHQF\ZLWK
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2 Study Objectives 
2.1 Primary Objective  
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3 Study Design 
3.1 Overview of Study Design and Flow Chart 
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4 Study Population 
4.1 Target Population 
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4.2 Number of Subjects 
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4.3 Inclusion Criteria 
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4.4 Exclusion Criteria 
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4.5 Concomitant Medication and Treatment 
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4.6 Discontinuation of Subjects from Treatment or Assessment 
4.6.1 Premature Withdrawal from Study Participation  
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4.7 Subject Replacement Policy 
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4.8 Subject Recruitment and Screening 
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5 Schedule of Assessments and Study Procedures 
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Table 1: 
Mean Blood Volume, by Age 
Age
Mean blood volume per weight (mL/kg)
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5.1 Study Assessments 
5.1.1 Informed Consent 
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5.1.2 Subject Eligibility 
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5.1.3 Medical History 
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EHUHFRUGHGDW6FUHHQLQJ
5.1.4 Demographic Information 
7KHIROORZLQJGHPRJUDSKLFLQIRUPDWLRQZLOOEHFROOHFWHGDW6FUHHQLQJGDWHRIELUWKELUWKZHLJKW
JHQGHUUDFHDQGHWKQLFLW\
5.1.5 Anthropometrics 
$QWKURSRPHWULFVLQFOXGLQJZHLJKWUHFXPEHQWOHQJWKVXEMHFWVd\HDUVRIDJHDWWKHWLPHRI
H[DPLQDWLRQ RU KHLJKW VXEMHFWV ! \HDUV RI DJH DW WKH WLPH RI H[DPLQDWLRQ KHDG
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SURFHGXUHIRUHDFKDQWKURSRPHWULFPHDVXUHPHQW
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5.1.6 Physical Examination 
$SK\VLFDOH[DPLQDWLRQZLOOEHSHUIRUPHGE\WKH,QYHVWLJDWRURUTXDOLILHGGHVLJQHHDWWKH
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H[WUHPLWLHVMRLQWVDQGQHXURORJLFDOVWDWXV:KHQHYHUSRVVLEOHWKHVDPHSHUVRQVKRXOG
SHUIRUPWKHSK\VLFDOH[DPLQDWLRQDWHDFKVWXG\YLVLW$EQRUPDOILQGLQJVZLOOEHFDSWXUHGLQWKH
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5.1.7 Abdominal Ultrasound 
$EGRPLQDO XOWUDVRQRJUDSK\ ZLOO EH SHUIRUPHG DW WKH WLPHSRLQWV VSHFLILHG LQ $SSHQGL[ $ WR
PHDVXUHWKHOLYHUDQGVSOHHQVL]H
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LQWHUSUHWHGE\DUDGLRORJLVWWUDLQHGLQXOWUDVRQRJUDSK\
5.1.8 Abdominal MRI 
$EGRPLQDO05,VVKRXOGEHFRQVLGHUHGDWWKHWLPHSRLQWVVSHFLILHGLQ$SSHQGL[$WRSURYLGHD
PRUHDFFXUDWHTXDQWLILFDWLRQRIOLYHUDQGVSOHHQYROXPH
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5.1.9 Vital Signs 
9LWDOVLJQVZLOOLQFOXGHSXOVHUDWHUHVSLUDWRU\UDWHV\VWROLFDQGGLDVWROLFEORRGSUHVVXUHDQGFRUH
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VXFFHVVIXOO\FRPSOHWHGDWOHDVW\HDURIWUHDWPHQWZLWKQRRFFXUUHQFHRIPRGHUDWHWRVHYHUH
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5.1.10 Electrocardiogram 
$Q DJHDSSURSULDWH OHDG HOHFWURFDUGLRJUDP (&* ZLOO EH REWDLQHG DW 6FUHHQLQJ DQG
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EHVSHFLILHGDVFOLQLFDOO\VLJQLILFDQW&6RUQRWFOLQLFDOO\VLJQLILFDQW1&6
5.1.11 Laboratory Assessments 
5.1.11.1 Clinical Laboratory Tests 
%ORRGDQGXULQHVDPSOHVIRUODERUDWRU\WHVWVZLOOEHFROOHFWHGDWWKHWLPHSRLQWVVSHFLILHGLQ
$SSHQGL[$
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Table 2: 
Clinical Laboratory Tests, By Tier 
Tier 1 (Mandatory)
Complete Blood Count (CBC)/ 
Hematology:
:KLWHEORRGFHOOFRXQWUHGEORRGFHOOFRXQW
KHPRJORELQKHPDWRFULW0&90&+0&+&SODWHOHW
FRXQWQHXWURSKLOO\PSKRF\WHVPRQRF\WHV
HRVLQRSKLOVEDVRSKLOVSHULSKHUDOVPHDUIRU
H[DPLQDWLRQRIFHOOPRUSKRORJ\
Chemistry:
*OXFRVHXUHDQLWURJHQFUHDWLQLQHVRGLXP
SRWDVVLXPFKORULGHFDOFLXPPDJQHVLXPLQRUJDQLF
SKRVSKRUXVWRWDOSURWHLQODFWDWHGHK\GURJHQDVH
Liver Function Tests:
$676*27$/76*37DONDOLQHSKRVSKDWDVH**7
DOEXPLQELOLUXELQGLUHFWLQGLUHFWWRWDO
Anti-drug Antibody:
$QWLVHEHOLSDVHDOIDDQWLERG\
Urinalysis:
S+JOXFRVHNHWRQHVEORRGSURWHLQQLWULWHDQG
OHXNRF\WHVPLFURVFRSLFH[DPLQDWLRQZLOORQO\EHGRQH
LIEORRGQLWULWHDQGRUOHXNRF\WHVDUHDEQRUPDO
Coagulation Studies: 

37,15D377
)HFDORFFXOWEORRG(screening; thereafter only if the 
preceding assessment was abnormal or if clinically 
indicated)
DNA Sample VFUHHQLQJ
6HH6HFWLRQ
LAL Enzyme Activity VFUHHQLQJ:
6HH6HFWLRQ
Tier 2 (Optional, based on blood volume thresholds)
Lipid Panel:
7RWDOFKROHVWHUROWULJO\FHULGH+'//'/
Other Chemistry: 
)HUULWLQKLJKVHQVLWLYLW\&UHDFWLYHSURWHLQKV&5)
Tier 3 (Optional, based on blood volume thresholds)
Pharmacokinetic Assessments
6HH6HFWLRQ
Exploratory Biomarkers
6HH6HFWLRQ
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5.1.11.2 Clinical Laboratory Collection for Changes in Dose or Lipid Lowering 
Medications 
6XEMHFWVZKRXQGHUJRDGRVHPRGLILFDWLRQRUFKDQJHVLQOLSLGORZHULQJPHGLFDWLRQVZLOOKDYH
WKHIROORZLQJDGGLWLRQDOODERUDWRU\PRQLWRULQJVFKHGXOHRIVHOHFWHGDQDO\WHV
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3ULRUWRWKHILUVWLQIXVLRQRIQHZGRVHVFKHGXOHRUFKDQJHLQOLSLGORZHULQJPHGLFDWLRQ
VHUXPOLSLGSDQHOOLYHUSDQHOKHPDWRORJ\VHUXPFKHPLVWU\IHUULWLQKV&53
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5.1.11.3 Clinical Laboratory Collection and Analysis 
5HIHU WR WKH 620 DQGRU ODERUDWRU\ PDQXDO IRU IXUWKHU GHWDLOV UHJDUGLQJ WKH FROOHFWLRQ
SURFHVVLQJDQGVWRUDJHRIWKHVHVDPSOHV
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XQH[SODLQHGFOLQLFDOO\VLJQLILFDQWDEQRUPDOODERUDWRU\WHVWYDOXHVWKHWHVWVVKRXOGEHUHSHDWHG
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ZLWKLQWKHQRUPDOUDQJHDQGRUDQDGHTXDWHH[SODQDWLRQKDVEHHQLGHQWLILHG
5.1.12 Denver II Developmental Screening Test 
7KH'HQYHU,,ZLOOEHDGPLQLVWHUHGDWWKHWLPHSRLQWVVSHFLILHGLQ$SSHQGL[$
7KH'HQYHU,,LVDVWDQGDUGL]HGPHDVXUHWRDVVHVVGHYHORSPHQWLQFKLOGUHQIURPPRQWKWR
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SDUHQWUHSRUWHGLWHPVLQIXQFWLRQDODUHDVILQHPRWRUDGDSWLYHJURVVPRWRUSHUVRQDOVRFLDO
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DQGKDGQRREYLRXVGHYHORSPHQWDOGLVDELOLWLHVWKHQRUPVLQGLFDWHZKHQDQG
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'HQYHU,,LVEDVHGXSRQWKHFKLOG
VDJH1RWHWKDWIRUSUHPDWXUHLQIDQWVWKHQXPEHURIPRQWKV
SUHPDWXUHLVVXEWUDFWHGIURPWKHLQIDQW
VFKURQRORJLFDODJH)RUHDFKWHVWLWHPDGPLQLVWHUHG
WKH FOLQLFLDQ GHWHUPLQHV LIWKH FKLOG
V UHVSRQVHIDOOV ZLWKLQ RU RXWVLGH RI WKH QRUPDO H[SHFWHG
UDQJHRIVXFFHVVRQWKDWLWHPIRUWKHFKLOG
VDJH7KHLQWHUSUHWDWLRQRIWKHLQGLYLGXDOWHVWLWHPV
LVWKHQXVHGWRFODVVLI\WKHFKLOG
VGHYHORSPHQWLQHDFKIXQFWLRQDODUHDDQGIRUWKHRYHUDOOWHVW
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5.1.13 Exploratory Biomarkers 
:KHQHYHU IHDVLEOH EDVHG RQ WKH EORRG YROXPH WKUHVKROG IRU WKH VXEMHFW¶V ZHLJKW D EORRG
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5.1.14 Pharmacokinetic Assessments 
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5.1.15 DNA Sample 
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5.1.16 LAL Enzyme Activity 
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5.1.17 Liver Biopsy 
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6 Investigational Medicinal Product 
6.1  Description of IMP 
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6.2 Method for Assigning Subjects to Treatment Groups 
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6.3 Storage and Disposition of IMP 
6.3.1 Receipt of IMP 
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6.3.2 Storage 
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6.3.3 Disposition 
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6.4 Preparation and Administration of IMP  
6.4.1 Preparation of IMP 
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6.4.2 Administration of IMP 
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6.5 Blinding of IMP 
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6.6 Destruction of IMP 
)ROORZLQJ ,03 DFFRXQWDELOLW\ DQG ZULWWHQ SHUPLVVLRQ IURP WKH 6SRQVRU WR GHVWUR\ ,03
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7 Assessment of Safety  
7KHPHWKRGVIRUFROOHFWLQJVDIHW\GDWDDUHGHVFULEHGEHORZ $OOSHUVRQQHOLQYROYHG ZLWKWKH
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7.1 Adverse Events and Laboratory Abnormalities 
7.1.1 Clinical Adverse Events 
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EXWSRVHVQRVLJQLILFDQWRUSHUPDQHQWULVNRIKDUPWRWKHUHVHDUFKSDUWLFLSDQW 
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Table 3: 
Assessment of Causality 
Relationship to IMP  
Criteria for Judgment 
5HODWHG
5HDVRQDEOHWHPSRUDOUHODWLRQVKLSRIWKHFOLQLFDOHYHQW
WRVWXG\GUXJDGPLQLVWUDWLRQ$1'FDQQRWEH
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SRVVLEOHEXWQRWXQOLNHO\$1'RWKHUGUXJVWKHUDSHXWLF
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8QOLNHO\5HODWHG
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SODXVLEOHH[SODQDWLRQIRUWKHREVHUYHGHYHQW
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FDXVHIRUWKHUHDFWLRQ
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SURYLGHGEHORZ
$serious adverse eventLVDQ\$(WKDWUHVXOWVLQDQ\RIWKHIROORZLQJRXWFRPHV
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$QLPSRUWDQWPHGLFDOHYHQWWKDWPD\QRWUHVXOWLQGHDWKEHOLIHWKUHDWHQLQJRUUHTXLUH
KRVSLWDOL]DWLRQPD\EHFRQVLGHUHGDQ6$(ZKHQEDVHGXSRQDSSURSULDWHPHGLFDO
MXGJPHQWWKHHYHQWPD\MHRSDUGL]HWKHVXEMHFWDQGPD\UHTXLUHPHGLFDORUVXUJLFDO
LQWHUYHQWLRQWRSUHYHQWRQHRIWKHRXWFRPHVOLVWHG
$OO$(VWKDWGRQRWPHHWDQ\RIWKHFULWHULDIRUVHULRXVVKRXOGEHUHJDUGHGDVnon-serious 
adverse events*LYHQWKHVHYHULW\DQGOLIHWKUHDWHQLQJQDWXUHRI/$/'HILFLHQF\LQLQIDQWVLWLV
SODXVLEOH WKDW VRPH SHGLDWULF VXEMHFWV ZLOO EH KRVSLWDOL]HG GXULQJ WKH ILUVW VHYHUDO ZHHNV RQ
VWXG\&RQWLQXDWLRQRIWKLVLQLWLDOKRVSLWDOL]DWLRQIRUSDUWLFLSDWLRQLQWKHWULDOLVQRWFRQVLGHUHGDQ
6$(  $OVR D KRVSLWDOL]DWLRQ WR DFFRPPRGDWH D VWXG\ SURFHGXUH LV QRW FRQVLGHUHG DQ 6$(
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7.1.2 Laboratory Test Abnormality 
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IURPWKHFHQWUDOODERUDWRU\2XWRIUDQJHODERUDWRU\WHVWYDOXHVVKRXOGQRWEHUHSRUWHGDV$(V
81/(66WKH\DUHFRQVLGHUHGWREHFOLQLFDOO\VLJQLILFDQWDEQRUPDOLWLHVE\WKH,QYHVWLJDWRU
7.1.3 Adverse Events of Special Interest (Infusion-Associated Reactions) 
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7.2 Handling of Safety Parameters 
7.2.1 Serious Adverse Events (Immediately Reportable to the Sponsor) 
$OO6$(VandDOO,$5VVHULRXVDQGQRQVHULRXVLUUHVSHFWLYHRIWKHWUHDWPHQWUHFHLYHGE\WKH
VXEMHFWPXVWEHUHSRUWHGWRWKH6SRQVRURUGHVLJQHHLPPHGLDWHO\DQGQRODWHUWKDQKRXUVRI
WKH,QYHVWLJDWRU¶VILUVWNQRZOHGJHRIWKHHYHQWH[SHGLWHGUHSRUWLQJ
7.2.2 Adverse Event Reporting Period 
7KHVWXG\SHULRGGXULQJZKLFK$(VPXVWEHUHSRUWHGLVGHILQHGDVWKHSHULRGIURPVLJQDWXUHRI
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7.2.3 Treatment and Follow-up of Adverse Events 
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7.2.4 Follow-up of Abnormal Laboratory Test Values  
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7.2.5 Pregnancy 
6XEMHFWVLQWKLVVWXG\ZLOOEHRIQRQUHSURGXFWLYHSRWHQWLDO
7.3 Recording of Adverse Events 
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7.4 Reporting of Serious Adverse Events and Unanticipated Problems  
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7.4.1 Investigator Reporting: Notifying the Study Sponsor 
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7.4.3 Sponsor Reporting: Notifying the FDA and all Regulatory Authorities  
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7.4.4 Sponsor Reporting: Notifying Participating Investigators 
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7.5 Independent Safety Review Committee (SRC) 
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8 Statistical Plan 
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8.1 General Considerations 
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8.3 Analysis Sets 
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Full Analysis Set 
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8.4 Demographics and Baseline Characteristics 
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8.5 Subject Disposition  
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8.7 Efficacy Analysis 
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8.8 Safety Analysis 
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8.8.1 Adverse Events 
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7KH IUHTXHQF\ RI VXEMHFWV ZLWK WUHDWPHQWHPHUJHQW $(V 6$(V DQG ,$5V E\ V\VWHP RUJDQ
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8.8.2 Clinical Laboratory Tests 
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8.8.3 Other Safety Data 
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8.9 Pharmacokinetics  
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8.10 Exploratory Biomarker Analysis 
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8.11 Other Statistical Issues 
8.11.1 Significance Levels 
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8.12 Subgroup Analyses 
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8.13 Missing or Invalid Data 
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8.14 Interim Analysis 
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9 
 Data Handling and Record Keeping 
9.1 Confidentiality 
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9.2 Source Documents 
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ILOHV DQG UHFRUGV NHSW DW WKH SKDUPDF\ DW WKH ODERUDWRULHV DQG DW PHGLFRWHFKQLFDO
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9.3 Case Report Forms 
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9.4 Records Retention 
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10 Study Monitoring, Auditing, and Inspecting 
10.1 Study Monitoring Plan 
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11 Ethical Considerations 
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12 Clinical Study Report and Publication Plan 
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13 References 
$VVPDQQ*6HHGRUI8$FLGOLSDVHGHILFLHQF\:ROPDQGLVHDVHDQGFKROHVWHU\OHVWHUVWRUDJH
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$EUDPRY$6FKRUU6:ROPDQ0*HQHUDOL]HG[DQWKRPDWRVLVZLWKFDOFLILHGDGUHQDOVAm J Dis 
Childr
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SKHQRW\SHLQ:ROPDQDQGFKROHVWHUROHVWHUVWRUDJHGLVHDVHMol Genet Metab
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O\VRVRPDODFLGOLSDVHLQSDWLHQWVZLWKFKROHVWHU\OHVWHUVWRUDJHGLVHDVHHepatology
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GHILFLHQF\PDFURSKDJHWDUJHWHG JOXFRFHUHEURVLGDVH IRU *DXFKHU
V GLVHDVH N Engl J Med
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LQIXVLRQV RI JOXFRFHUHEURVLGDVH LQ D SDWLHQW ZLWK *DXFKHU GLVHDVH Proc Natl Acad Sci
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Appendix A: Schedule of Assessments 
 
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Page 63 of 66 
 
ALEXION PHARMACEUTICALS, INC. PROPRIETARY AND CONFIDENTIAL:  
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Page 64 of 66 
 
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