Conditions: Paroxysmal Nocturnal Hemoglobinuria
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 80
Healthy volunteers: no

Brief summary:
Evaluation of the Efficacy and Safety of APL-2 in Patients with Paroxysmal Nocturnal Hemoglobinuria

Detailed description:

Arms:
arm 1: 1080 mg pegcetacoplan administered subcutaneously twice-weekly or every three days. arm 2: Complement (C5) Inhibitor.

Interventions: intervention 1: Pegcetacoplan intervention 2: Soliris
Intervention descriptions: intervention 1: Complement (C3) Inhibitor intervention 2: Complement (C5) Inhibitor

Protocol document:
Prot_000.pdf: 









































































































































































SAP_001.pdf: 
Statistical Analysis Plan 2.0 
Protocol Number: APL2-302 
05 December 2019 
Apellis Pharmaceuticals, Inc. 
Page 1 of 65 
Confidential 
   
 
STATISTICAL ANALYSIS PLAN 
APL-2 
PHASE 3 
A Phase 3, Randomized, Multi-Center, Open-Label, Active-Comparator Controlled 
Study to Evaluate the Efficacy and Safety of APL-2 in Patients with Paroxysmal 
Nocturnal Hemoglobinuria (PNH) 
 
PROTOCOL IDENTIFIER: APL2-302 
 
Study Sponsor(s): 
Apellis Pharmaceuticals, Inc. 
6400 Westwind Way,  
Suite A 
Crestwood, KY 40014 
USA 
 
Author: 
 
 
Protocol: 
Version 1.0 (3rd October 2017) 
Version 2.0 (22nd November 2017) 
Version 3.0 (30th March 2018) 
Amendment 1, Version 2.0 (21st August 2018) 
Amendment 2, Version 1.0 (13th December 2018) 
Amendment 3, Version 1.0 (8th February 2019) 
Amendment 4, Version 1.0 (16 August 2019) 
 
SAP Version #: 
 
2.0 
 
 
SAP Date: 
12/05/2019 
 
Status 
Final 
 
 
 


Statistical Analysis Plan 2.0 
Protocol Number: APL2-302 
05 December 2019 
Apellis Pharmaceuticals, Inc. 
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APPROVAL SIGNATURES 
  
 
 
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Statistical Analysis Plan 2.0 
Protocol Number: APL2-302 
05 December 2019 
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TABLE OF CONTENTS 
APPROVAL SIGNATURES ............................................................................................2 
ABBREVIATIONS ............................................................................................................7 
1. 
INTRODUCTION..................................................................................................9 
2. 
OBJECTIVES, ESTIMAND(S), AND ENDPOINTS .........................................9 
2.1 
Objectives ............................................................................................................9 
2.2 
Endpoints ............................................................................................................9 
2.2.1 Primary Endpoint .........................................................................................9 
2.2.2 Key Secondary Endpoints ............................................................................9 
2.2.3 Secondary Endpoints ...................................................................................9 
2.2.4 Safety Endpoints ........................................................................................10 
2.2.5 Pharmacokinetic Endpoint .........................................................................10 
2.2.6 Pharmacodynamics Endpoint(s) ................................................................10 
3. 
STUDY DESIGN ..................................................................................................11 
3.1 
General Description ..........................................................................................11 
3.2 
Randomization ..................................................................................................13 
3.3 
Sample Size and Power Considerations ............................................................14 
4. 
STATISTICAL ANALYSIS SETS .....................................................................14 
4.1 
Screened Set ......................................................................................................14 
4.2 
Run-in Set .........................................................................................................14 
4.3 
Intent-to-Treat Set .............................................................................................14 
4.4 
Safety Set ..........................................................................................................14 
4.5 
Modified ITT Set...............................................................................................15 
4.6 
Per-protocol Set .................................................................................................15 
4.7 
Completers Set ..................................................................................................15 
4.8 
Pharmacokinetic Set ..........................................................................................15 
4.9 
Pharmacodynamic Set .......................................................................................15 
5. 
STUDY SUBJECTS .............................................................................................15 
5.1 
Disposition of Subjects .....................................................................................15 
5.2 
Demographic and Other Baseline Characteristics.............................................16 
5.3 
Medical and Thrombosis History ......................................................................17 


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5.4 
Prior Therapies, Procedures and Medication ....................................................18 
5.5 
Concomitant Medications .................................................................................18 
5.6 
Exposure to Investigational Product .................................................................19 
5.7 
Measurements of Treatment Compliance .........................................................20 
5.8 
Protocol Deviations ...........................................................................................20 
6. 
EFFICACY ANALYSES ....................................................................................21 
6.1 
Estimands ..........................................................................................................22 
6.2 
Analyses of Primary Efficacy Endpoint ............................................................26 
6.2.1 Primary Analysis of Primary Efficacy Endpoint .......................................26 
6.2.2 Sensitivity Analyses of Primary Efficacy Endpoint ..................................26 
6.2.3 Supportive Analyses of Primary Efficacy Endpoint ..................................27 
6.3 
Analyses of Key Secondary Efficacy Endpoints ..............................................28 
6.3.1 Transfusion Avoidance ..............................................................................28 
6.3.2 Continuous Key Secondary Endpoints ......................................................29 
6.3.3 Categorization of FACIT-Fatigue Scores ..................................................29 
6.3.4 Supportive Analyses of Key Secondary Efficacy Endpoints .....................30 
6.4 
Analyses of Secondary Efficacy Endpoints ......................................................30 
6.4.1 Randomized Control Period .......................................................................30 
6.4.1.1 Categorical Secondary Efficacy Endpoints ......................................30 
6.4.1.2 Continuous Secondary Efficacy Endpoints ......................................31 
6.4.2 Open-Label Period .....................................................................................32 
6.5 
Multiplicity Adjustment ....................................................................................33 
6.6 
Subgroup Analyses ...........................................................................................34 
7. 
SAFETY ANALYSIS...........................................................................................34 
7.1 
Adverse Events..................................................................................................34 
7.2 
Clinical Laboratory Data ...................................................................................36 
7.3 
Vital Signs .........................................................................................................37 
7.4 
Electrocardiogram (ECG) .................................................................................37 
7.5 
Other Safety Data ..............................................................................................39 


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Protocol Number: APL2-302 
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8. 
PHARMACOKINETIC ANALYSIS .................................................................39 
9. 
PHARMACODYNAMIC ANALYSIS...............................................................40 
10. 
OTHER ANALYSES ...........................................................................................41 
11. 
INTERIM ANALYSIS ........................................................................................41 
12. 
DATA MONITORING COMMITTEE/REVIEW COMMITTEE ................41 
13. 
DATA HANDLING CONVENTIONS ..............................................................41 
13.1 
General Data Reporting Conventions ...............................................................41 
13.2 
Definition of Baseline .......................................................................................42 
13.3 
Summary Table and Listing Presentations ........................................................42 
13.3.1 Efficacy Summary Tables, Figures and Listings .......................................42 
13.4 
Treatment Labels ...............................................................................................43 
13.5 
Definition of Visit Windows .............................................................................43 
13.6 
Derived Efficacy Endpoints ..............................................................................45 
13.7 
Repeated or Unscheduled Assessments of Safety Parameters ..........................47 
13.8 
Handling of Missing, Unused, and Spurious Data ............................................47 
13.8.1 Missing Data Imputation for Efficacy Endpoints ......................................47 
13.8.2 Missing Date of Investigational Product....................................................47 
13.8.2.1 Incomplete Start Date ..................................................................48 
13.8.2.2 Incomplete Stop Date ..................................................................49 
13.8.3 Missing Date Information for Adverse Events ..........................................49 
13.8.3.1 Incomplete Start Date ..................................................................50 
13.8.3.2 Incomplete Stop Date ..................................................................50 
13.8.4 Missing Severity Assessment for Adverse Events.....................................50 
13.8.5 Missing Relationship to Investigational Product for Adverse Events .......50 
13.8.6 Character Values of Clinical Laboratory Variables ...................................50 
14. 
ANALYSIS SOFTWARE ...................................................................................51 
15. 
CHANGES TO ANALYSES ...............................................................................51 
15.1 
Changes to Analyses Specified in the protocol .................................................51 
15.2 
Changes from Analyses Specified in the Previous Version of the SAP ...........51 


Statistical Analysis Plan 2.0 
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16. 
REFERENCES .....................................................................................................53 
17. 
APPENDICES ......................................................................................................54 
17.1 
Schedule of Assessments ..................................................................................54 
 
 
 
 
 
 
 
 
 
17.3 
Sensitivity Analyses for the Primary Efficacy Endpoint ..................................63 
 
CCI


Statistical Analysis Plan 2.0 
Protocol Number: APL2-302 
05 December 2019 
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ABBREVIATIONS 
AE 
Adverse Event  
AESI 
Adverse Event of Special Interest 
ANCOVA 
Analysis of Covariance 
ATC 
Anatomical Therapeutic Class 
BLQ 
Below Limit of Quantification 
BMI 
Body Mass Index 
CBER 
Center for Biologics Evaluation and Research 
CI 
Confidence Interval 
CMH 
Cochran-Mantel-Haenszel 
CRO 
Clinical Research Organization 
DMC 
Data Monitoring Committee 
DRC 
Data Review Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
FACIT 
Functional Assessment of Chronic Illness Therapy 
FDA 
Food and Drug Administration 
Hb 
Hemoglobin 
ICE 
Intercurrent Event 
ITT 
Intention-To-Treat 
IRT 
Interactive Response Technology 
LLN 
Lower Limit of Normal 
LASA 
Linear Analog Scale Assessment 
LDH 
lactate dehydrogenase 
LOV 
Last Observed Value 
LVOT 
Last Value on Treatment 
MAR 
Missing at Random 
MCMC 
Monte Carlo Markov Chain 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Multiple Imputation 
mITT 
Modified ITT set 
MMRM 
Mixed Model for Repeated Measures 
MNAR 
Missing not at Random 
PCS 
Potentially Clinically Significant  
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PP 
Per-Protocol 
PRBC 
Packed red blood cell 
PT 
Preferred Term (MedDRA) 
QOL 
Quality of Life 


Statistical Analysis Plan 2.0 
Protocol Number: APL2-302 
05 December 2019 
Apellis Pharmaceuticals, Inc. 
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QLQ-C30  
EORTC Quality of Life Questionnaire – Core 30 Scale 
QTcB 
QT Interval Corrected for Heart Rate Using Bazett’s Formula 
QTcF 
QT Interval Corrected for Heart Rate Using Fridericia’s Formula 
RBC 
Red Blood cell 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous 
SE 
Standard Error 
STD 
Standard Deviation 
SI 
Système International 
SOC 
System Organ Class 
TA 
Transfusion Avoidance 
TEAE   
Treatment-Emergent Adverse Event 
ULN 
Upper Limit of Normal 
WHO 
World Health Organization 
 
 
 


Statistical Analysis Plan 2.0 
Protocol Number: APL2-302 
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1. 
INTRODUCTION  
This statistical analysis plan (SAP) provides a technical and detailed elaboration of the 
statistical analyses of efficacy, safety and pharmacokinetic (PK)/pharmacodynamic (PD) 
data as described in the final study protocol version 1.0 dated 16 Aug 2019, incorporating 
the most recent amendment # 4. Specifications for tables, figures, and listings are 
contained in a separate document. Details in this SAP take precedence over those 
provided in the statistical section of the protocol. 
2. 
OBJECTIVES, ESTIMAND(S), AND ENDPOINTS 
2.1 
Objectives 
The primary objectives of this study are to establish the efficacy and safety of APL-2 
compared to eculizumab in subjects with paroxysmal nocturnal hemoglobinuria (PNH) 
who continue to have hemoglobin (Hb) levels <10.5 g/dL despite treatment with 
eculizumab. 
2.2 
Endpoints 
2.2.1 Primary Endpoint 
• 
Change from Baseline to Week 16, excluding data before the Randomized 
Controlled Period, in hemoglobin (Hb) level. 
2.2.2 Key Secondary Endpoints  
• 
Transfusion avoidance (TA) (Yes/No), defined as the proportion of subjects who do 
not require a transfusion during the Randomized Controlled Period.    
• 
Change from Baseline to Week 16, excluding data before the Randomized 
Controlled Period, in reticulocyte count. 
• 
Change from Baseline to Week 16, excluding data before the Randomized 
Controlled Period, in lactate dehydrogenase (LDH) level.  
• 
Change from Baseline to Week 16, excluding data before the Randomized 
Controlled Period, in FACIT-fatigue scale score, Version 4. 
2.2.3 Secondary Endpoints 
• 
Hemoglobin response in the absence of transfusions (Yes/No). Hemoglobin 
response is defined as an increase of at least ≥1 g/dL in hemoglobin from Baseline 
at Week 16, excluding data before the Randomized Controlled Period. 
• 
Reticulocyte normalization in the absence of transfusions (Yes/No).  Reticulocyte 
normalization is defined as the reticulocyte count being below the upper limit of the 
normal range at Week 16. 


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Protocol Number: APL2-302 
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Apellis Pharmaceuticals, Inc. 
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• 
Hemoglobin normalization in the absence of transfusions (Yes/No). Hemoglobin 
normalization is defined as the hemoglobin level being above the lower limit of the 
normal range at Week 16. 
• 
Change from Baseline to Week 16, excluding data before the Randomized 
Controlled Period, in indirect bilirubin level. 
• 
Change from Baseline to Week 16, excluding data before the Randomized 
Controlled Period, in haptoglobin level. 
• 
Change from Baseline to Week 16, excluding data before the Randomized 
Controlled Period, in LASA scores. 
• 
Change from Baseline to Week 16, excluding data before the Randomized 
Controlled Period, in QLQ-C30 scores.  
• 
Number of PRBC units transfused during the Randomized Controlled Period [> 
Day 1 to Week 16 and Week 4 to Week 16]. 
• 
Change from Baseline and change from Week 17 to Week 48 in hemoglobin level.  
• 
Change from Baseline and change from Week 17 to Week 48 in reticulocyte count.  
• 
Change from Baseline and change from Week 17 to Week 48 in lactate 
dehydrogenase (LDH) level. 
• 
Change from Baseline and change from Week 17 to Week 48 in FACIT-fatigue 
scale score. 
• 
Change from Baseline and change from Week 17 to Week 48 in LASA scores. 
• 
Change from Baseline and change from Week 17 to Week 48 in QLQ-C30 scores. 
• 
Number of PRBC units transfused during the Open-Label APL-2 Period [Week 17 
to Week 48 and Week 20 to Week 48]. 
 
2.2.4 Safety Endpoints 
• 
Incidence and severity of treatment-emergent adverse events (TEAEs) 
• 
Incidence of thromboembolic events 
• 
Changes from baseline in laboratory parameters 
• 
Changes from baseline in ECG parameters 
 
2.2.5 Pharmacokinetic Endpoint 
• 
APL-2 pharmacokinetic concentrations 
2.2.6 Pharmacodynamics Endpoint(s) 
• 
Change from Baseline to Week 16 and Week 48 in percentage of PNH Type II+III 
RBC cells opsonized with C3   


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• 
Change from Baseline to Week 16 and Week 48 in percentage of PNH Type II+III 
RBC cells   
• 
Change from Baseline to Week 16 and Week 48 in complement (e.g., CH50, 
AH50, and C3) levels 
 
The PD endpoints include changes from baseline and percentage changes from baseline 
for C3 deposition on RBC cells (percent C3d CD59 Type I, II and III), clonal distribution 
of PNH RBCs (percent CD59 Type I, II and III), PNH granulocytes (percent FLAER) 
and PNH monocytes (percent FLAER). 
In addition, the following endpoints will be derived: 
• 
Clonal distribution of PNH RBCs (percent Type II + III); this is simply the sum of 
the clonal distribution of PNH RBCs Type II and Type III. 
• 
C3d deposition on RBC cells (percent Type II + III); this is the number of events 
for C3d deposition on RBC cells (Type II) plus number of events for C3d 
deposition on RBC cells (Type III) divided by number of events for PNH CD59 
Type II and III expressed as a percent.   
3. 
STUDY DESIGN 
3.1 
General Description 
This is a prospective, Phase 3, randomized, multi-center, Open-label, active-comparator 
controlled study. A total of approximately 70 PNH subjects who are receiving 
eculizumab and who continue to have hemoglobin (Hb) levels <10.5 g/dL will be 
randomized to receive either APL-2 or eculizumab. The treatment Period of the study 
will consist of three parts:  
• 
4-week Run-in Period   
• 
16-week Randomized Controlled Period  
• 
32-week Open-label APL-2 only Period (although subjects who receive eculizumab 
during the 16-week Randomized Controlled Period will continue to receive 
eculizumab for the first 4 weeks in addition to APL-2) 


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During the 4-week Run-in Period (Day - 28 to ≤ Day 1) all subjects will receive self-
administered twice-weekly subcutaneous (SC) doses of APL-2 1,080 mg in addition to 
the subjects’ current dose of eculizumab treatment, which will continue as prescribed 
regardless of study visit scheduling or the APL-2 administration schedule (i.e. it is not 
required that eculizumab dosing aligns with APL-2 dosing or APL2-302 study visits). On 
Day 1, subjects will receive their dose of APL-2 and may receive eculizumab depending 
on their dosing schedules. Subjects will then be randomized to either Group 1 
(monotherapy APL-2) or Group 2 (monotherapy eculizumab). Subjects in Group 1 will 
receive APL-2, and subjects in Group 2 will receive eculizumab for the remainder of the 
16-week Randomized Controlled Period. During the Randomized Controlled Period, 
subjects will return to the clinical site at Weeks 1, 2, 4, 6, 8, 12 and 16 for efficacy and 
safety assessments. 
After completion of the Randomized Controlled Period (the end of Week 16), all subjects 
will continue into a 32-week Open-label APL-2 Period in which all subjects will receive 
twice-weekly doses of APL-2 1,080 mg. During this period, subjects will return to the 
clinical site on Weeks 17, 18, 20, 22 and 24 and every 4 weeks thereafter until Week 48 
for efficacy and safety assessments. Those subjects who received eculizumab in the 
Randomized Controlled Period will receive APL-2 in addition to eculizumab for 4 weeks 
(Weeks 17-20).  
After completion of the 52-week treatment Period (Week 48), subjects will be offered 
entry into an open-label extension study. Should the subject not enter the open label 
extension study they will exit the study and return to the site for 2 additional safety visits 
6 weeks apart. 
The study outline is displayed in the diagram below: 
  
 
Subjects who withdraw from treatment prior to the Week 48 visit will be encouraged to 
continue their participation in the study and return to the study site for their scheduled 
study procedures, except for APL-2 administration. Subjects who withdraw from the 


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Protocol Number: APL2-302 
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study prior to Week 48 and are currently being treated solely with APL-2 are 
recommended to receive at least one dose of eculizumab before discontinuing APL-2. 
The planned length of participation in the study for each subject is a maximum of 
approximately 72 weeks, including an 8-week screening Period, 52-week treatment 
period and 12-week follow-up Period. Those who enter the open label extension study 
will not require the 12-week follow-up Period.  
Subjects who fail the screening procedures should not be re-screened for the study unless 
this is agreed in advance and documented in writing with the sponsor.  
3.2 
Randomization 
Subject numbers will be assigned to subjects as they consent to take part in the study.  
Subjects who meet all the eligibility criteria will be eligible to enter the 4-week Run-in 
Period. Following completion of the Run-in Period, subjects will be randomly assigned 
(1:1) using interactive response technology (IRT) to receive either 1,080mg of APL-2 
twice-weekly or their current dose of eculizumab.  
Initially the randomization was stratified by the following:  
• 
Number of units of PRBC transfused within the 12 months prior to Day -28 (<3; ≥3) 
• 
Platelet count at screening (<100,000; ≥100,000) 
 
However, in Amendment 3 Version 1.0 of the protocol the stratification criteria were 
changed to: 
• 
Number of PRBC transfusions within the 12 months prior to Day -28 (<4; ≥4) 
 
(i.e., number of transfusion events regardless of PRBC units transfused) 
• 
Platelet count at screening (<100,000; ≥100,000) 
 
For analysis purposes subjects will be re-assigned to stratification groups based on their 
actual data; any misallocations at randomization will be identified in a listing. The 
stratification groups used for analyses will be based on the groups introduced in Protocol 
Amendment 3 Version 1.0. 


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Protocol Number: APL2-302 
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3.3 
Sample Size and Power Considerations 
A sample size of 64 randomized subjects (32 in each group) provides 90% power (using a 
2-sided t-test at the 5% level of significance) of obtaining a statistically significant 
difference between the groups with the primary endpoint, Week 16 change from baseline 
in hemoglobin level. This assumes a treatment difference between APL-2 and eculizumab 
of 1 g/dL and a standard deviation for the change from baseline of 1.2 g/dL (effect size = 
0.833). To account for loss of power due to discontinuations the study will attempt to 
randomize 70 subjects. 
If the standard deviation is as high as 1.4g/dL the power is reduced to 80%.  
Consequently, a blinded sample size re-assessment may be performed prior to the 
completion of study enrolment. A statistician blinded to treatment assignment will 
estimate the standard deviation for the primary endpoint and determine the sample size 
required to maintain the power for the study. This assessment will not lead to a reduction 
in the sample size. The sample size of the study may be increased to a maximum of 100. 
An increase beyond this maximum would require a protocol amendment. 
It is anticipated that more than 70 subjects will need to enter the Run-in Period to achieve 
70 randomized subjects. 
4. 
STATISTICAL ANALYSIS SETS 
4.1 
Screened Set  
The Screened set will include all subjects who signed the informed consent form. This set 
will only be used for the purposes of describing the subject disposition and for listing the 
data. 
4.2 
Run-in Set 
The Run-in set will include all subjects who receive at least one dose of APL-2. 
4.3 
Intent-to-Treat Set  
The Intent-to-Treat (ITT) set will include all subjects who were randomized. The 
analyses using this set will be based upon the randomized treatment group allocated. 
4.4 
Safety Set   
The Safety set will include all subjects who were randomized and received at least 1 dose 
of monotherapy study drug. This set will be used for safety analyses. The analyses using 
this set will be based upon the actual treatment received.  


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4.5 
Modified ITT Set  
The modified ITT (mITT) set will include all subjects in the ITT set who receive at least 
one dose of monotherapy beyond their Week 4 after randomization in the Randomized 
Controlled Period. The analyses using this set will be based upon the randomized 
treatment group allocated. 
4.6 
 Per-protocol Set  
The Per-protocol (PP) set will include all subjects in the ITT set who have not violated 
any inclusion or exclusion criteria and/or deviated from the protocol in a way that could 
influence their efficacy assessment. Decisions concerning the exclusion of subjects from 
this set will be made and documented prior to database lock. Subjects will be required to 
receive their randomized treatment to be included in the set and so analyses using this set 
will by default be based upon the actual treatment group allocated. 
4.7 
Completers Set 
The Completers set will consist of all subjects in the ITT set who have completed the 
Week 16 efficacy assessment for the study. The analyses using this set will be based upon 
the randomized treatment group allocated.  
4.8 
Pharmacokinetic Set  
The Pharmacokinetic (PK) set will include all subjects in the ITT analysis set who have 
at least 1 evaluable (i.e. not impacted by any important protocol deviations or other 
events) post- dose PK measurement (even if below the limit of quantification). The 
analyses using this set will be based upon the actual treatment received. 
4.9 
Pharmacodynamic Set  
The Pharmacodynamic (PD) set will include all subjects in the ITT analysis set who have 
at least 1 evaluable (i.e. not impacted by any important protocol deviations or other 
events) post-dose PD measurement. The analyses using this set will be based upon the 
actual treatment received. 
5. 
STUDY SUBJECTS 
5.1 
Disposition of Subjects 
For the Screened set, the number and percentage of subjects screened, who failed screening 
and the reason for screen failure will be summarized.   


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For the Run-in set, the following will be presented: 
• Number and percentage of subjects who receive at least 1 dose of APL-2 
• Number and percentage of subjects who completed the Run-in Period and were 
randomized 
• Number and percentage of subjects who completed the Run-in Period and were not 
randomized (identified as completing treatment until their Study Visit 5  
[Study Day 1]) 
• Number and percentage of subjects withdrawn from the study during the Run-in 
Period and reason for withdrawal 
For the Safety set, the following will be presented by treatment group and overall: 
• Number and percentage of subjects who received at least one dose of randomized 
treatment (APL-2 or eculizumab, and total) 
• Number and percentage of subjects who completed study treatment  
• Number and percentage of subjects who discontinued study treatment  
For those subjects who discontinue study treatment, the reason for discontinuation will be 
summarized for each of the following study periods:  
o Day -28 to ≤ Day 1 (Run-in Period) 
o > Day 1 to Week 16 (Randomized Controlled Period) 
o > Week 16 to Week 20 (Open-label Run-in Period) 
o > Week 20 to Week 48 (Open-label Period) 
• Number and percentage of subjects who completed the study  
• Number and percentage of subjects who enter the extension study 
• Number and percentage of subjects who withdrew from the study 
 
The number of subjects in each analysis set will be tabulated overall and by country or 
region (North America, Europe, Asia pacific) and will be presented in a listing.   
Subject data listings with disposition will be provided as well as a listing of subjects who 
did not satisfy the inclusion/exclusion criteria. 
5.2 
Demographic and Other Baseline Characteristics 
Demographics and baseline characteristics will be summarized by treatment group and 
overall using the ITT, mITT and Safety sets (if sets are different). 


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Demographic variables to be presented include age (years), age category (≤65 years and 
> 65 years), sex, race, ethnicity, country, weight (kg), height (m), BMI (kg/m2), and BMI 
category (<18.5, ≥18.5 - <25, ≥25 - <30, ≥30 - < 35, ≥ 35 kg/m2).   
As date of birth may not be recorded for all subjects, the age recorded on the eCRF will 
be used for analyses. 
Baseline characteristics to be present using Run-in set include the following: 
• Time since diagnosis of PNH (years) to Day -28 
• Duration of treatment with eculizumab to Day -28 
• Current eculizumab dose level and dosing regimen 
• Number of transfusions in the last 12 months prior to Day -28 
• Number of transfusions in the last 12 months prior to Day -28 (<4; ≥4)  
• Platelet count at screening (<100,000; ≥100,000) 
• Time since last transfusion to Day -28 
• Hemoglobin level (average of values recorded prior to dosing with APL-2) 
• Reticulocyte count (average of values recorded prior to dosing with APL-2) 
• LDH level (average of values recorded prior to dosing with APL-2) 
• Haptoglobin level (average of values recorded prior to dosing with APL-2) 
• Total bilirubin level (average of values recorded prior to dosing with APL-2) 
•  Indirect bilirubin level (average of values recorded prior to dosing with APL-2) 
• Total FACIT-fatigue score (nominally recorded on Day -28 prior to dosing with 
APL-2) 
The average baseline value for hemoglobin (Hb) will include local and central laboratory 
values for those subjects who have transfusions during the screening period. All other 
laboratory parameters, the average baseline values will be from central laboratory values 
only. 
  
5.3 
Medical and Thrombosis History 
Medical history will be coded using the latest Medical Dictionary for Regulatory 
Activities (MedDRA) Version available. Summaries will be presented for the Run-in set 
by System Organ Class (SOC) and Preferred Term (PT) with numbers and percentages 


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by treatment group and overall. Each subject will be counted only once in each SOC or 
SOC/PT summary. 
In the summary table, medical history will be presented by decreasing frequency of 
subjects overall within each SOC and then similarly by decreasing frequency of subjects 
overall within each PT. In cases of SOCs or PTs with equal frequencies, medical history 
will be sorted alphabetically. 
A summary of thrombosis history will also be presented for the Run-in set with numbers 
and percentages for each type of thrombosis by treatment group and overall. 
5.4 
Prior Therapies, Procedures and Medication  
Prior and concomitant medications will be coded using the latest WHO Drug Dictionary 
version available. Medication will be presented by ATC level 2 (therapeutic main group) 
and ATC level 5 (standardized medication name) with numbers and percentages by 
treatment group and overall.  A subject who takes more than one medication will be 
counted only once if these medications belong to the same extended ATC classification.   
In the summary tables, prior medication and concomitant medications will be presented by 
decreasing frequency of subjects overall within each ATC level 2 class and then similarly 
by decreasing frequency of subjects overall within each ATC level 5 class. In cases of ATC 
level 2 classes or ATC level 5 classes with equal frequencies, medications will be sorted 
alphabetically. 
Prior medications will be defined as those medications started prior to the administration 
of APL-2 on Day -28. Concomitant medications will be defined as those medications taken 
following administration of APL-2 on Day -28. Hence medications started before receiving 
APL-2 but continuing after will be considered as both prior and concomitant medications.  
The listing of medications will identify prior and concomitant medications. 
Prior procedure and intervention will be presented similar to those of prior medications 
detailed above. 
Prior medications will be summarized using the Run-in set and be presented by treatment 
group (APL-2/ eculizumab and non-randomized (if any)) and overall.  
5.5 
Concomitant Medications  
Concomitant medications will be summarized for different periods of the study: 


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Study Period 
Analysis 
Set 
Treatment Groups 
Run-in  
Run-in 
APL-2 (up to Day 1 (≤ Day 1) / 
Eculizumab (up to Day 1 (≤ Day 1)) 
Non-randomized (up to the end of 
study [if any]) 
Overall 
Randomized  
Safety 
APL-2 (up to Week 16*) 
Eculizumab (up to Week 16*) 
Overall  
Randomized and Open- 
label 
Safety 
APL-2 
Eculizumab 
Overall 
* or end of study for those who do not complete Week 16 
 
5.6 
Exposure to Investigational Product 
The following parameters will be calculated and presented by treatment group for the Run-
in Period (Day -28 to ≤ Day 1), Randomized controlled Period (> Day 1 to Week 16) and 
Open-label Period (Week 17 to Week 48) periods using the safety set: 
• Total Dose administered (mg) 
• Duration of Treatment (days) 
• Number and percentage of subjects received infusions  
o Number and percentage of subjects with all infusions completed 
o Number and percentage of subjects with any infusions interrupted  
o Number and percentage of subjects received only1, only 2, etc infusion 
• Total number of infusions  
• Number and percentage of infusions completed  
• Number and percentage of infusions interrupted 
 
Total time on study treatment (Days) calculated as the time in days from first study drug 
infusion date until the last study drug infusion date for the Randomized Controlled Period 
(i.e., treatment duration = last study drug infusion in the Randomized Controlled Period – 
first study drug infusion + 1 . The data will be summarized by treatment group. 


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The treatment duration for the Open-label Period will also be calculated and summarized 
separately. 
Number of infusions for each subject will summarized using descriptive statistics.  
5.7 
Measurements of Treatment Compliance 
Percent compliance will be calculated for the Randomized Controlled Period using the 
safety set as follow: 
Percent compliance = total number of study infusions taken from Day 2 to end of 
Randomization Controlled Period (Week 16) / total number of expected infusions to end 
of Randomization Controlled Period.   
The number and percentage of subjects who had a percentage of drug compliance range by 
increment of 10% (≥ 80% - 90% and ≥ 90 - ≤100%) will then be presented in a table by 
treatment group. 
The number of expected doses will be different between the two groups in the Randomized 
Controlled Period as it will be 32 to 37 doses for APL-2 twice weekly or every 3 days and 
8 doses for eculizumab q2w. 
 
Compliance will also be calculated and summarized by treatment group for the Run-in and 
the Open-label Periods using the calculation shown above. 
By-subjects listing will be produced for treatment compliance and exposure. 
5.8 
Protocol Deviations 
All protocol deviations will be reviewed and documented before database lock. Protocol 
deviations are being captured in the clinical database by the site staff.  They may also be 
identified through programmable checks of the data. 
Key protocol deviations include any violations of inclusion and exclusion criteria. This 
includes unknown violations at enrolment and on-study violations, such as taking a 
prohibited medication. 
The CRO/Apellis will classify major and minor protocol deviations per the agreed 
protocol deviation management plan. The Apellis study team will review the protocol 
deviations and their classification throughout the study and before database lock.  


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6. 
 EFFICACY ANALYSES 
Unless otherwise specified, baseline for all efficacy analyses is defined as the average of 
measurements recorded prior to taking the first dose of investigational product (i.e. prior 
to the start of the Run-in Period (Day -28)).  
All confidence intervals (CI) will be 2-sided 95% confidence intervals. All statistical 
superiority tests will be 2-sided hypothesis tests performed at the 5% level of significance 
for main effects.   
For non-inferiority tests, non-inferiority will be concluded if the appropriate limit of the 
95% confidence interval indicates APL-2 is no inferior than eculizumab by the defined 
non-inferiority margin for each applicable efficacy parameter as detailed below in the 
section of key secondary endpoints.  This is equivalent to a 1-sided hypothesis test at the 
2.5% significance level. 
Summary Tables 
Absolute values and changes from baseline will be summarized by treatment group and 
visit within each of the periods of the study.   
For categorical data, the number and percentage will be summarized by treatment group 
and visit within each of the periods of the study. 
If a subject has a transfusion during the Randomized Controlled Period, their data 
collected after the transfusion will be excluded from the calculation of descriptive 
statistics for all efficacy endpoints. 
Hemoglobin (Hb) level will also be categorized as increase from baseline (< 1.0 g/dL, 
≥1.0 - < 2.0 g/dL and ≥ 2 g/dL) and the number and percentages will be presented and 
summarized in a table. 
Additional summary tables will be generated whereby data collected after the transfusion 
will be included in the calculation of descriptive statistics for all efficacy endpoints other 
than hemoglobin. 
For the Run-in Period, Open-label Period and overall, observed data will be summarized 
by three treatment group (APL-2, eculizumab, and non-randomized [if any]) and for 
Randomized Controlled Period by two treatment group (APL-2 and eculizumab). 


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Listings 
Absolute values and changes from baseline will be included in the listings.  Flags will 
also be included to identify values that meet the responder/normalization criteria. 
6.1 
Estimands 
• The primary objective is to compare APL-2 and Eculizumab at week 16 
assuming that the subjects continue the assigned treatment as directed. 
• The intercurrent events (ICE) that will be considered are: 
1. Transfusions 
2. Discontinuation of Study Treatment 
3. Withdrawal from the study 
Transfusions 
With this study population it is likely that some subjects who are not having their 
hemolysis suitably controlled by study medication will have a drop in Hb during the 16 
weeks of Randomized Controlled Period and require a red blood cell transfusion.   
However, it would be scientifically unsound to use data collected after the transfusion in 
efficacy analyses for the study.  Consequently, for any subject who receives a transfusion 
(per the transfusion criteria listed in Section 12.7.1 of the protocol), all subsequent values 
will be set to missing for the following measurements (While on-Treatment Strategy): 
• Hemoglobin count 
• Reticulocyte count 
• LDH level 
• Bilirubin level 
• Haptoglobin level 
• FACIT-fatigue scale score 
• LASA scores 
• QLQ-C30 scores 
Discontinuation of Study Treatment 
If a subject discontinues study treatment, any values collected after discontinuation will 
continue to be used in analyses (Treatment Policy).  


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Withdrawal from the Study 
This situation will be handled in the same way as described for transfusions above (While 
on Treatment Strategy). 
The following table shows the primary Estimands and the sensitivity and the supportive 
analyses for the primary efficacy endpoint: 


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Definition 
Attributes 
The effect APL-2 
compared to 
eculizumab on Hb 
levels after 16 weeks of 
monotherapy treatment 
to PNH subjects 
 
A: Population 
B: Variable (or endpoint) 
C: Strategy for addressing intercurrent 
event (ICE) 
D: Population-level 
summary 
ITT 
Week 16 Hb change from baseline  
• 
For transfusion and withdrawal from 
the study: all measurements after the 
ICE events will be set to missing 
(while on-treatment strategy) 
• 
For discontinuation of treatment: all 
measurements after discontinuation 
will be used in the analyses 
(treatment strategy)  
Difference between 
treatment means with 95% 
confidence interval 
Sensitivity Analyses 
ITT 
Week 16 Hb change from baseline 
Controlled-Based Pattern Imputation 
 
Difference between 
treatment means with 95% 
confidence interval 
ITT 
Week 16 Hb change from baseline 
Imputation based on the delta-adjusted stress 
testing method (Tipping Point)  
 
Difference between 
treatment means with 95% 
confidence interval 
Supportive Analyses 
PP 
Week 16 Hb change from baseline 
Same as primary endpoint ICE criteria. 
Difference between 
treatment means with 95% 
confidence interval 
mITT 
Week 16 Hb change from baseline 
Same as primary endpoint ICE criteria. 
Difference between 
treatment means with 95% 
confidence interval 
ITT 
Week 16 Hb change from baseline 
Use all available data. i.e. not setting values to 
missing after transfusions 
Difference between 
treatment means with 95% 
confidence interval 


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ITT subjects 
who complete 
the study  
Week 16 Hb change from baseline 
Use all available data. 
Difference between 
treatment means with 95% 
confidence interval 
ITT 
Hb Change from baseline 
• 
Last Hb Level before ICE for subject 
with ICE. 
• 
Last available Hb level for subject 
without ICE.  
Difference between 
treatment means with 95% 
confidence interval based 
on nonparametric 
randomization-based 
ANCOVA 


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6.2 
Analyses of Primary Efficacy Endpoint 
6.2.1 
Primary Analysis of Primary Efficacy Endpoint 
The primary efficacy endpoint is the change from baseline in Hb level at Week 16 of the 
Randomized Controlled Period.  If a subject receives a transfusion during the randomized 
Controlled Period or withdraws from the study, the Hb levels up to the transfusion or 
time of withdrawal will be included in the model.  If subject receives transfusion, the pre 
transfusion Hb value from the local laboratory will be used, however, if it is not collected 
or missing, then the pre transfusion central laboratory Hb value will be used. 
The between-treatment group comparison for the primary efficacy endpoint will be 
performed using a mixed effect model for repeated measures (MMRM); (Mallinckrodt 
CH, 2008). The model will include fixed categorical effects for treatment group, study 
visit, stratification variables (based on transfusion history and platelet count) and the 
study visit-by-treatment group interaction, as well as the continuous, fixed covariate of 
baseline Hb level. Initially an unstructured covariance matrix will be investigated. If this 
analysis fails to converge, other structure will be tested, and the final covariance structure 
will be determined using the Akaike’s information criteria. The Kenward Roger’s 
approximation will be used to estimate denominator degrees of freedom.  
The difference between APL-2 and eculizumab mean Hb changes from baseline at Week 
16 will be calculated along with its 2-sided 95% CI and associated P-value from the 
MMRM model. 
6.2.2 
Sensitivity Analyses of Primary Efficacy Endpoint 
The primary analysis model relies on the assumption of Missingness At Random (MAR).  
According to this assumption, the unobserved outcome values for subjects who 
discontinue study treatment early are considered to be similar to the observed outcome 
values in subjects with similar history assigned to the same treatment group. In other 
words, the distribution of the unobserved future outcomes for subjects who discontinue 
study treatment is the same as the distribution of the observed outcomes for those who 
continue treatment, conditional on the available data prior to discontinuation. 
Additional analyses that reflect possible lack of treatment benefits following a subject’s 
discontinuation from study treatment will be performed using the following methods:  
1- Control-based pattern imputation method using the data up to ICE.  


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2- Imputation based on the delta-adjusted stress testing (Tipping Point) method using 
the data up to ICE.  
These methods can be considered as sensitivity analyses for the primary MAR based 
analysis where deterioration of the future unobserved outcomes constitutes specific types 
of departure from the MAR assumption towards the Missingness Not At Random 
(MNAR) assumption.  
The control-based multiple imputation sensitivity analysis will consider a certain type of 
the MNAR mechanism for the missing data within the pattern-mixture framework, where 
it will be assumed that subjects who discontinue early from the APL-2 group will follow 
the trajectory of outcomes similar to the one in the Eculizumab group after their 
discontinuation, taking into account the observed values prior to discontinuation (Ratitch 
et al., 2013). Subjects who discontinue early from the Eculizumab group will be assumed 
to have unobserved outcomes similar to other Eculizumab subjects who remain in the 
Eculizumab group (see Appendix 17.3).  
The second imputation approach will be based on the delta-adjusted stress testing 
method, also known as the tipping point analysis (O’Kelly and Ratitch, 2014, Chapter 7). 
This method assumes that subjects who discontinue from the APL-2 group experience 
worsening defined by a pre-specified adjustment in the primary efficacy endpoint (mean 
Hb change from baseline at Week 16). After the initial imputation, a range of shifts will 
be added to the imputed missing data in both APL-2 and Eculizumab groups. 
The details are provided in the Appendix 17.3. 
6.2.3 
Supportive Analyses of Primary Efficacy Endpoint 
The following supportive analyses will be provided for the primary endpoints: 
• an MMRM analysis using the PP set using data up to ICE 
• an MMRM analysis using the mITT set using all available data after Week 4. 
• an MMRM analysis using all available data from the ITT set, regardless of 
whether the Hb measurement was following a transfusion. 
• an MMRM analysis using the completers set using data up to ICE.  
• Nonparametric Randomization-Based ANCOVA using ITT set using the data 
specified below. 


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The difference between APL-2 and Eculizumab in mean Hb changes from baseline at 
Week 16 will be calculated along with its 2-sided 95% CI. 
For the nonparametric randomization-based ANCOVA analysis, the endpoint will be the 
rank of the change from baseline in Hb level. The Hb level is defined as follow: 
• Last Hb Level before ICE for subject with ICE. 
• Last available Hb level for subject without ICE.  
The between-treatment group comparison for the rank-based primary efficacy endpoint 
will be performed using an Analysis of Covariance (ANCOVA).  The model will include 
fixed categorical effects for treatment group, and stratification variables (based on 
transfusion history and platelet count).  
6.3 
Analyses of Key Secondary Efficacy Endpoints  
The analyses of key secondary efficacy endpoints are based on non-inferiority tests. Non-
inferiority will be concluded if the appropriate limit of the 95% 2-sided confidence 
interval indicates APL-2 is not inferior to eculizumab by the defined non-inferiority 
margin for each key secondary efficacy endpoints as detailed below (section 6.3.2). 
Once the non-inferiority is established for the key secondary endpoints, then superiority 
will be assessed for transfusion avoidance, change from Baseline to Week 16 in 
reticulocyte count and change from Baseline to Week 16 in FACIT-fatigue score using a 
closed-testing procedure at a significance level of 0.05. 
6.3.1 
Transfusion Avoidance 
The number and percentage of subjects in the following categories will be presented by 
treatment group: 
• no transfusions over the Randomized Controlled Period (> Day 1 to Week 16) 
• receive a transfusion during the Randomized Controlled Period 
• withdrew from the study without having had a transfusion during the 
Randomized Controlled Period  
Subjects who have not had a transfusion but withdraw before Week 16 will be considered 
as having a transfusion in the analysis of transfusion avoidance. 
The number and percentage of subjects with transfusion avoidance will be tabulated by 
treatment group and compared between treatment groups using a stratified Cochran-


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Mantel Haenszel (CMH) chi-square test. The treatment difference in percentages and 
95% confidence interval for the difference will be presented using the stratified 
(Miettinen, 1985) method. 
 
If the lower bound of the 95% CI for the difference between APL-2 and eculizumab 
treatment groups is greater than the non-inferiority margin of -20%, then APL-2 will be 
considered non-inferior to eculizumab. 
 
6.3.2 
Continuous Key Secondary Endpoints 
 
Change from Baseline Endpoints 
 
The absolute values and changes from baseline in reticulocyte count, LDH level and 
FACIT-fatigues scale score will be summarized by treatment group at Baseline and each 
study visit. 
The change from baseline at Week 16 in reticulocyte count, LDH level and FACIT-
fatigue scale score will be analyzed using the same methods described for the primary 
analysis of the primary efficacy endpoint except using their own baseline as a covariate, 
using the ITT and mITT sets. 
For reticulocyte count, if the upper bound of the 95% CI for the treatment difference is 
less than the non-inferiority margin of 10, then APL-2 will be considered non-inferior to 
eculizumab. 
 
For LDH, if the upper bound of the 95% CI for the treatment difference is less than the 
non-inferiority margin of 20, then APL-2 will be considered non-inferior to eculizumab. 
 
For FACIT-fatigue score, if the lower bound of the 95% CI for the treatment difference is 
greater than the non-inferiority margin of -3 then APL-2 will be considered non-inferior 
to eculizumab.  
6.3.3 
Categorization of FACIT-Fatigue Scores 
 
The FACIT-fatigue scores will be categorized and the proportion of subjects with an 
improvement of at least 3 points for the FACIT-fatigue scores from baseline will be 
summarized by treatment group and by visit using the ITT and mITT sets. 
 


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6.3.4 
Supportive Analyses of Key Secondary Efficacy Endpoints 
The key secondary endpoints will also be analyzed using the PP set.  
The analyses for the key continuous secondary endpoints will be repeated using all 
available data. 
6.4 
Analyses of Secondary Efficacy Endpoints  
6.4.1 
Randomized Control Period 
6.4.1.1 
Categorical Secondary Efficacy Endpoints 
The number and percentage of subjects meeting the following criteria will be tabulated 
by treatment group at Week 16 and the superiority test will be used to compare the 2 
 treatment group: 
• Hemoglobin response (≥ 1 g/dL increase from baseline in the absence of 
transfusion) 
• Reticulocyte normalization (≤ ULN) 
• Hemoglobin normalization (≥ LLN) 
Also, the number and percentage of subjects in the following categories will be presented 
by treatment group: 
• receive a transfusion during the Randomized Controlled Period 
• withdrew from the study before Week 16  
 
The hemoglobin response, reticulocyte normalization and hemoglobin normalization 
responder endpoints are binary responses (i.e., Yes vs. No); each endpoint will be 
analyzed using the Cochran-Mantel-Haenszel (CMH) test adjusting for stratification 
factors at randomization. The odds ratio of being a responder (Yes) on each of the 
endpoints for the APL-2 vs. eculizumab and associated 95% confidence interval (CI) will 
be provided. Subjects who received a transfusion between Day 2 and Week 16 or 
withdraw without providing efficacy data at Week 16 will be classified as non-responders 
in these endpoint’s primary analysis. 
 
Additionally, the proportion of responders based on each of the key secondary endpoints 
(Hemoglobin response, Reticulocyte normalization, Hemoglobin normalization , and 
absence  of transfusion) for each treatment group will be summarized, and their 
respective 95% CI using the stratified (Miettinen, 1985)method will be reported. The 


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difference in the proportion of responders between the 2 treatment groups and the 
corresponding 95% CI will also be summarized. 
 
6.4.1.2 
Continuous Secondary Efficacy Endpoints 
Change from Baseline Endpoints 
 
Superiority will be assessed for the change from baseline to week 16 for the continuous 
secondary endpoints 
The absolute values and changes from baseline in indirect and total bilirubin level, 
haptoglobin level, LASA scores and QLQ-C30 will be summarized by treatment group at 
Baseline and each study visit. 
The indirect bilirubin is not reported in the database and it will be derived from the total 
and direct bilirubin as follow: 
indirect bilirubin = total bilirubin – direct bilirubin 
The Change from baseline at Week 16 in indirect bilirubin level, haptoglobin level, 
LASA scores and QLQ-C30 scores will be analyzed using the same methods described 
for the primary analysis of the primary endpoint, except using their own baseline as a 
covariate. The ITT and mITT sets will be used. 
Number of PRBC units and Number of Transfusions 
The number of PRBC is reported in units and mL in the database, therefore, the mL will 
be converted to units using the following formula: 
 Number of PRBC units = Round (PRBC (mL) / 300),1). 
The total number of units of PRBCs transfused and number of transfusions during the 
Randomized Controlled Period will be compared between the treatment groups using 
Wilcoxon rank-sum test. The difference between the medians will be estimated along 
with its 95% confidence interval (stratified).  
The following supporting analyses for the number of PRBC units and number of 
transfusions to account for subjects who withdraw during the Randomized Controlled 
Period before Week 16 will be provided:  


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• The number of units of PRBCs transfused and the number of transfusions will be 
analyzed using log-incidence density ratios (non-parametric) adjusting for 
treatment (Dmitrienko & Koch). For each treatment, the incidence density will be 
the number units of PRBCs transfused or number of transfusions that a subject 
experienced, normalized by the number of days during the Randomized 
Controlled Period. 
• The number of units of PRBC and the number of transfusions will be estimated 
based the duration they were in the Randomized Controlled Period (i.e. number 
per week x duration of endpoint). Hence the analysis of this endpoint will equate 
to an analysis of the frequency of transfusions. 
Normalized LDH to ULN (i.e. LDH Value/ ULN) will be computed and summarized by 
treatment group and by visit. 
6.4.2 
Open-Label Period 
Absolute values and changes from baseline from Week 17 up to Week 48 will only 
summarized using ITT set in the following parameters by treatment group at each study 
visit.   Missing scores during the Open-label Period will not be imputed. 
• hemoglobin level  
• reticulocyte count  
• lactate dehydrogenase (LDH) level  
• Total and indirect Bilirubin 
• haptoglobin 
• FACIT-fatigue scale score  
• LASA scores  
• QLQ-C30 scores  
Number of PRBC units transfused during the Open-Label APL-2 Period will be 
summarized.  
In addition, Week 48 shift from Week 16 tables will also be produced for hemoglobin 
count, reticulocyte level and LDH.  The number and percentage of subjects will be 
tabulated by treatment group using the following categories for normalization (≤ ULN for 
reticulocytes and LDH, and ≥ LLN for hemoglobin) of each parameter: 
Week 16 categories 
• Normalized at Week 16 
• Not normalized at Week 16 


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• Transfusion during the Randomized Controlled Period  
• Withdrew prior to Week 16 
Week 48 categories 
• Normalized at Week 48 
• Not normalized at Week 48 
• Transfusion during the Open-label Period  
• Withdrew prior to Week 48 
A similar table will be produced for hemoglobin response (≥ 1 g/dL increase from 
baseline). Marginal totals and percentages will be included. 
6.5 
Multiplicity Adjustment 
To preserve the Type 1 error rate, the key secondary endpoints will be tested in a 
hierarchical manner after statistical significance is reached for the primary endpoint. Once 
one hypothesis is tested not significant, all subsequent tests will not be assessed. Estimates 
will be computed for all key secondary and secondary endpoints regardless of whether a 
hypothesis is tested not significant preventing assessment of subsequent tests.  
1) Transfusion avoidance (TA) – non-inferiority (NI) test (2.5% level) using a NI 
margin of -20% for the difference between proportions. 
2) Change from Baseline to Week 16 in reticulocyte count – NI test (2.5% level) using 
a NI margin of +10  
3) Change from Baseline to Week 16 in LDH – NI test (2.5% level) using a NI margin 
of +20  
4) Change from Baseline to Week 16 in FACIT-fatigue score – NI test (2.5% level) 
using a NI margin of -3  
Once the non-inferiority is established for the key secondary endpoints, superiority will be 
assessed in a hierarchical manner using a two-sided test at significance level of 0.05 for the 
following key secondary endpoints: 
5. Transfusion avoidance  
6. Change from Baseline to Week 16 in reticulocyte count. 
7. Change from Baseline to Week 16 in FACIT-fatigue score.  


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6.6 
Subgroup Analyses 
The primary and key secondary endpoints will be summarized and analyzed by the 
following subgroups: 
1- Number of PRBC transfusions within the 12 months prior to Day -28 (<4; ≥4) 
 
(i.e., number of transfusion events regardless of PRBC units transfused) 
 
2- Platelet count at screening (<100,000; ≥100,000) 
 
Summary statistics of the primary and key secondary endpoints will also be provided for 
subgroups based on sex, race, and age (≤65 years and > 65 years). 
 
7. 
SAFETY ANALYSIS  
The safety analysis will be performed using the Run-in and Safety Sets.  For each safety 
variable, the last value collected before the first dose of investigational product will be 
used as baseline for all analyses of that safety variable. Last Observed Value on 
Treatment (LVOT) will be defined as the last valid assessment obtained after Baseline 
and whilst on investigational product. Last Observed Value (LOV) will be defined as the 
last valid assessment obtained after Baseline. 
All safety data available at the time of database lock for Week 16 will be provided. 
Safety analyses will be conducted according to the treatment the subject received. 
7.1 
Adverse Events  
Adverse events will be coded using the latest Version of MedDRA. 
An AE (classified by preferred term) that occurs during the study will be considered a 
TEAE if it has a start date on or after the first dose of investigational product or if it has a 
start date before the date of the first dose, but increases in severity on or after the date of 
the first dose.  If more than 1 AE with the same preferred term is reported before the date 
of the first dose, then the AE with the greatest severity will be in summaries.  An AE that 
occurs more than 30 days after the date of the last dose will not be counted as a TEAE. 
Only TEAEs will be included in the summary tables.  
An overall summary will be provided for each Period of the study. 


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For the Run-in Period of the study the number and percentage of subjects, Total events, 
and Total unique events (Run-in set) who have the following will be tabulated by 2 
treatment groups (APL-2/eculizumab and non-randomized (if any)) and overall: 
• any TEAE 
• any TEAE considered as related to APL-2 (evaluated by the investigator as 
definitely related, possibly related)  
• any TEAE considered as related to eculizumab (evaluated by the investigator as 
definitely related, possibly related)  
• any TEAE considered as related to infusion procedure (evaluated by the 
investigator as definitely related, possibly related) 
• maximum severity TEAE of mild, moderate or severe; i.e. a subject with TEAEs 
at different intensities will be summarized at the most severe intensity 
• any injection site reaction 
• any serious TEAE  
• any serious TEAE considered related (definitely, probably, possibly) to either 
study drug 
• any TEAE leading to death 
• Any treatment emergent infections, serious infections, and related infections 
 
The number and percentage of subjects reporting TEAEs in each treatment group and 
overall will be tabulated by system organ class (SOC) and preferred term; by SOC, 
preferred term, and maximum severity. TEAEs considered related to investigational 
product will also be summarized by SOC and preferred term. If more than 1 AE occurs 
with the same preferred term for the same subject, then the subject will be counted only 
once for that preferred term using the most severe and most related occurrence for the 
summarization by severity and by relationship to investigational product.  Any TEAEs with 
missing severity information will be taken as severe for these summaries and be footnoted 
and any TEAEs with missing causality information will be taken as related for these 
summaries and be footnoted. 
Similar tabulations will be presented for TEAEs in the Randomized Controlled and Open-
label Periods, except that: 
• the Safety set will be used, and 
• tabulations will be by the 2 treatment groups (APL-2 and eculizumab) 


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In addition to having the tabulations by study Period, data will also be summarized over 
the whole study for APL-2 and eculizumab up to 30 days beyond the last dose of study 
medication.  
For the Run-in Period (Day1 to Week 4) and the post-Run-in Period (Week 4 to Week 16) 
within the Randomized Controlled Period, an additional table will be created as supportive 
analyses to present and compare the TEAEs by treatment group (ALP-2 and eculizumab) 
using the Safety set. 
All summaries will be ordered by descending frequency of subjects within each SOC and 
then similarly by decreasing frequency of subjects within each PT, in the overall column. 
In cases of SOCs or PTs with equal frequencies, TEAEs will be sorted alphabetically. 
All TEAEs will be listed by study Period, treatment group, subject and AE onset date. 
Onset time since dose (start date/time – dose date/time) and AE duration (stop date/time – 
start date/time) will be included in the listing; where applicable imputed data will be used 
for the calculation of onset time and AE duration, but the original dates/time information 
will be presented in the listing. 
A separate listing of serious AEs will also be generated.   
If there are any deaths a listing will include the date of death and primary cause of death. 
7.2 
Clinical Laboratory Data 
Descriptive statistics for clinical laboratory values (in SI units) and changes from baseline 
for each Period at each assessment time point, as well as shift tables from baseline to 
each visit for quantitative variables will be presented by treatment group. The laboratory 
values will be compared to its normal range at every visit and the following categories 
will be derived for the shift tables (below N-R, Normal, Above N-R, and undetermined). 
In case of using local laboratory with different normal ranges for Hb levels pre 
transfusion, the method developed by (Stein, 1992) may be utilized to normalize the Hb 
data for the purpose of analyses.  If, however, the Hb normal ranges for all laboratories 
are close to each other, a global Hb normal range may be created to be used for analyses. 
Clinical laboratory test values are potentially clinically significant () if they meet either 
the low or high PCS criteria listed in Table 2. The number and percentage of subjects 
with post-baseline PCS values will be tabulated by treatment group and overall. The 


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percentages will be calculated relative to the number of subjects with available baseline 
values and at least 1 post-baseline assessment. The numerator is the total number of 
subjects by-visit with at least 1 post-baseline PCS value. A supportive listing of subjects 
with post-baseline PCS values will be provided including the subject number, site, 
baseline, and post-baseline values.  
Table 2: Criteria for Potentially Clinically Significant Laboratory Tests 
Parameter 
SI Unit 
Lower Limit 
Higher Limit 
Hematology 
Hemoglobin 
       Mild 
       Moderate 
       Severe 
g/dL 
 
10 
7 
< 7 
 
12 
10 
Neutrophils Levels 
       Mild 
       Moderate 
       Severe 
109 cell/L 
  
 
1,5 
1 
< 0.5 
 
1 
0.5 
Platelets levels 
       Mild 
       Moderate 
       Severe 
109/L 
 
150 
100 
< 50 
 
100 
50 
 
All laboratory data will be listed for the Run-in and Safety Sets. The listing will include 
change from baseline values and values outside the laboratory reference range will be 
flagged. 
Any urine microscopy data collected will be listed. 
7.3 
Vital Signs 
Descriptive statistics for vital signs (e.g., body temperature, respiratory rate, blood pressure, 
and heart rate) and their changes from baseline will be presented by study Period, 
treatment group, visit (day) and scheduled time. 
All vital signs data will be listed for the Run-in and Safety Sets. The listing will include 
change from baseline values 
7.4 
Electrocardiogram (ECG) 
QT Analyses will be performed by ERT and the results will be delivered to Apellis in a 
separate data. Descriptive statistics for ECG variables (e.g., heart rate, PR interval, QRS 
interval, QT interval, and QTc interval) and their changes from baseline will be presented 


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by study Period, treatment group, visit (day) and scheduled time. The mean of the 
triplicate measurements will be derived prior to summarizing the data.  QTc interval will 
be calculated using both Bazett (QTcB=QT/(RR)1/2) and Fridericia (QTcF=QT/(RR)1/3) 
corrections; and if RR is not available, it will be replaced with 60/hr in the correction 
formula.   
ECG interpretation will be summarized by visit.  The “worst” clinical assessment of the 
triplicate ECGs (order of abnormal clinically significant, abnormal not clinically 
significant and normal) will be used 
A shift table from baseline to each visit for qualitative ECG results will be presented.  
The number of subjects with at least one value post baseline satisfying the PCS criteria, 
will be tabulated. All replicates (i.e. individual values for triplicates) and all scheduled and 
unscheduled values will be assessed. The following categories will be used: 
Parameter 
Criteria 
Heart Rate 
All values within 50 -100 bpm 
At least one value ≤ 50 bpm* and no values ≥ 100 bpm 
At least one value ≥ 100 bpm* and no values ≤ 50 bpm  
At least one value ≥ 100 bpm* and one value ≤ 50 bpm* 
PR Interval 
< 200 msec 
≥ 200 msec* 
QT Interval 
< 480 msec 
≥ 480 msec* 
QRS Interval 
< 120 msec 
≥ 120 msec* 
QTcB, QTcF 
<450 msec 
≥ 450 msec and <480 msec 
≥ 480 msec and <500 msec* 
≥ 500 msec* 
QT, QTcF increase from 
baseline 
< 30 msec 
≥ 30 msec and < 60 msec* 
≥ 60 msec* 
* Values of PCS. 
 
All ECG data will be listed for the Run-in set for Run-in Period and Safety Set for 
Randomized Controlled Period. Separate listings will be provided for the replicate data and 


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the means of triplicate measurements.  Changes from baseline values will be included in 
the listings and in both listings PCS values will be flagged.  
7.5 
Other Safety Data 
Immunogenicity, physical examination and pregnancy test data will be listed for the 
Safety Set.  For Immunogenicity data, the number and percentage of subjects developing 
antidrug antibodies (ADA), where applicable, will be summarized by treatment group. 
8. 
PHARMACOKINETIC ANALYSIS  
All summaries and analyses of the pharmacokinetic data will be based on the 
Pharmacokinetic Set. 
APL-2 concentrations reported as below the limit of quantification (BLQ) will be taken 
as zero for linear plots, and equal to the lower limit of quantification (LLOQ) for semi-
logarithmic plots.  For the computation of descriptive statistics, BLQ will be taken as 
zero, except for the calculation of the geometric mean where the LLOQ will be used. 
The APL-2 concentrations will be evaluated using the PK analysis set. APL-2 
concentrations will be summarized by treatment group (relevant as eculizumab 
Randomized subjects will receive APL-2 during the Run-in and Open-label Periods) at 
each scheduled time point using descriptive statistics. The 6-hour post dose 
concentrations will only be included in the calculation of summary statistics if within a 
±30 minute window of 6 hours after dosing. All other samples, except follow-up samples, 
are to be taken pre-dose.  If a subject discontinues APL-2 dosing, then concentrations 
from samples collected more than 1 day after the last dose will be excluded from 
calculations.  Follow-up samples will only be included if within 10% of the scheduled 
time after the last APL-2 dose. 
The number of subjects with a value > BLQ will also be tabulated.   
Linear and log-linear mean (± SE) concentration profile plots against time will be 
produced for each treatment group. The actual sampling time will be used on the x-axis. 
Plots will be presented for the full profile (Day -28 to Day 420). 
A listing of all concentration data will be presented by dose.  The actual time, deviation 
and percent deviation from nominal time will also be listed.   


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Population pharmacokinetic and exposure-response modelling of the safety and efficacy 
data will be described in an APL-2 Population Pharmacokinetic/Pharmacodynamic 
Analysis Plan which will be performed by consultant or CRO. The methods will be based 
on the FDA Guidance for both Exposure-Response and Population Pharmacokinetics 
(FDA Guidance for Industry Population Pharmacokinetics, FDA Guidance for Exposure-
Response Relationships). 
9. 
PHARMACODYNAMIC ANALYSIS
All summaries and analyses of the pharmacodynamic data will be based on the 
Pharmacodynamic set.
Observed values, changes from baseline and percentage changes from baseline will be 
summarized by treatment group at each visit using descriptive statistics for the following 
parameters: 
•
Change from Baseline to Week 16 and Week 48 in percentage of PNH Type
II+III RBC cells opsonized with C3
•
Change from Baseline to Week 16 and Week 48 in percentage of PNH Type
II+III RBC cells
•
Change from Baseline to Week 16 and Week 48 in complement (e.g., CH50,
AH50, and C3) levels
•
Changes from baseline and percentage changes from baseline for C3 deposition
on RBC cells (percent C3d CD59 Type I, II and III), clonal distribution of PNH
RBCs (percent CD59 Type I, II and III), PNH granulocytes (percent FLAER) and
PNH monocytes (percent FLAER).
In addition, the following endpoints will be derived and Changes from baseline and 
percentage changes from baseline will be summarized: 
•
Clonal distribution of PNH RBCs (percent Type II + III); this is simply the sum
of the clonal distribution of PNH RBCs Type II and Type III.
•
C3d deposition on RBC cells (percent Type II + III); this is the number of events
for C3d deposition on RBC cells (Type II) plus number of events for C3d
deposition on RBC cells (Type III) divided by number of events for PNH CD59
Type II and III expressed as a percent.
Mean profile plots will also be presented graphically by treatment group for the observed 
values and percentage changes from baseline. The nominal sampling time will be used on 
the x-axis. Plots will be presented for the full profile (Day -28 to Day 420). 


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Changes from baseline and percentage changes from baseline will be included in listings.  
10. 
OTHER ANALYSES 
No other analyses are planned for this study. 
11. 
INTERIM ANALYSIS  
No formal interim analyses are planned for the primary endpoint, however data from the 
first 16 weeks will be reported once all subjects have completed their Week 16 visit or 
discontinued prior to Week 16 and the database has been cleaned for all visits up to and 
including Week 16. 
12. 
DATA MONITORING COMMITTEE/REVIEW COMMITTEE  
A DMC will be set up to review only the safety and tolerability data during the trial, and 
no formal reviews for efficacy will be performed.  The DMC charter will be prepared in a 
separate document. The first DMC meeting will be scheduled 3 months after the first 
subject is randomized, and approximately at 6-month intervals, thereafter. 
13. 
 DATA HANDLING CONVENTIONS  
13.1 
General Data Reporting Conventions  
Continuous variables will be summarized using the following descriptive statistics:  n, 
mean, median, standard deviation, minimum, maximum. Categorical and count variables 
will be summarized by the number of subjects (n) and the percentage of subjects in each 
category.  
All subjects in the analysis set being used will be accounted for in summaries tables.   
Unless otherwise specified, the mean, median should be printed out to 1 more decimal 
place than the original values, and standard deviations should be printed out to 2 more 
decimal places than the original values. The minimum and maximum should report the 
same number of decimal places as the original values. Percentages will be displayed with 
1 decimal place; except percentages will not be presented when the count is zero and 100% 
will be presented as an integer. Unless stated otherwise, for all percentages, the number of 
subjects in the analysis population for the treatment group will be the denominator. 


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13.2 
Definition of Baseline  
Unless stated otherwise, baseline will be taken as the average of measurements prior to 
the start of APL-2 treatment (nominally Day -28) for efficacy endpoints, but as the last 
measurement before the first dose of APL-2 for other endpoints. 
The average baseline value for hemoglobin (Hb) will include local laboratory and central 
values for those subjects who have transfusions during the screening Period. All other 
Laboratory parameters, the average baseline values will be from central laboratory values 
only. 
13.3 
Summary Table and Listing Presentations 
In by-visit summary tables, the baseline will be summarized using all available data, but 
also for each visit using only the baseline data from subjects with available data at the 
visit; hence the mean change from baseline will equal the mean visit value – mean 
baseline value. 
Throughout this document ‘change from baseline’ refers to the actual change from 
baseline (i.e. visit value – baseline value).   
All data will be listed, and data listings will be presented by study Period and treatment 
group. Data listings will present study days in addition to dates, where study day is 
derived as (assessment date – randomization date) +1. Therefore, the date of 
randomization will be identified as Study Day 2. The date of randomization has been 
chosen as Day 2 as subjects in the eculizumab group may not have their first Randomized 
eculizumab dose until a few days after randomization. 
13.3.1 
Efficacy Summary Tables, Figures and Listings 
Absolute values and changes from baseline will be summarized by treatment group and 
visit within each of the Periods of the study.   
If a subject has a transfusion their data collected after the transfusion will be excluded 
from the calculation of descriptive statistics for all efficacy endpoints. 
The number and percentage of subjects meeting the following criteria will also be 
tabulated by treatment group, for each visit: 
• Hemoglobin response (≥ 1 g/dL increase from baseline) 
• Hemoglobin normalization (≥ LLN) 
• Reticulocyte normalization (≤ ULN) 


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• LDH normalization (≤ ULN)  
For the Run-in and Open-label Periods observed data will be summarized by treatment 
group (2 groups for the Run-in Period (APL-2/ Eculizumab, and non-Randomized (if 
any)) and 2 groups (APL-2 and Eculizumab) for the Open-label Period) and overall.   
Plots of Continuous Variables 
Mean (± SE) plots will be displayed for each Period of the study separately. 
The plots will be presented by treatment group using the means derived from the 
summaries mentioned above.   
Listings 
Changes from baseline will be included in the listings.  Flags will also be included to 
identify values that meet the responder/normalization criteria. 
13.4 
 Treatment Labels 
Summary tables covering visits during the 16-week Randomized Controlled Period will be 
presented by treatment group. The labels to be used in TFLs will be: 
 
• APL-2  
• Eculizumab 
Summaries covering visits during the Screening, 4-week Run-in and 32-week Open-label 
Periods will be presented by treatment group and overall subjects.  Some subjects may not 
progress into the Randomized Controlled Period from the Run-in Period; for summaries 
these will be assigned to a group with the label “Non-randomized”. 
13.5 
Definition of Visit Windows  
Data will be summarized and analyzed based on the list of visits specified in table below. 
The relative day of each assessment [(date of assessment) – (date for randomization +1] 
will be calculated for post randomization while the relative day of each assessment will 
be calculated as  [(date of assessment) – (date for randomization)] for prior to 
randomization The relative day will be used to assign analysis visit following the table 
below. All the records post-baseline will be assigned to an appropriate analysis visit using 
the following:  
For the post-baseline visits, the lower and the upper bound for the analysis visit windows 
are defined as the midpoints of the target date of the scheduled visits. If the date of 
assessment falls in between the lower bound and the upper bound for a visit as specified in 


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the schedule of assessments of the protocol, then it will be assigned to that visit. If the 
interval separating 2 scheduled visits is an even number of days, the middle day will be 
included in the lower bound of the next visit. If more that 1 record is within the same 
analysis visit window, the record closest to the midpoint of the interval will be used in the 
analysis. If 2 records are tied before and after the middle of the interval, the earlier record 
will be used in the analysis. If more than one assessment (including the early termination 
or unscheduled assessments) falls within the same defined window, the assessment closest 
to the target day with non-missing data will be considered for analysis.  
All assessments that occur on > Day 1 will be assigned to the Randomization Controlled 
Period, whilst any assessment that occurs prior or equal to Day 1 (≤ Day 1) will be assigned 
to the Run-in Period. See the table below for details on visit windows: 
 
 
Part 
Study Visit 
Target 
Day 
Analysis Window 
Interval 
S + Run-in 
 
 
1 
Up to -84 
< -28 
NA 
2 
-28 
≥-28 – ≤ -25 
3 
3 
-21 
>-25 - ≤ -17 
8 
4 
-14 
>-17 – 0 
18 
Asymmetric 
5 Day1 / 
Week 1 
1 
1 
1 
RCP 
 
 
 
 
6 Week 2 
14 
>=2- ≤ 21 
14 
7 
28 
21 – ≤ 35 
14 
8 
42 
35 - ≤ 49 
14 
9 
56 
49 - ≤ 69 
20 
10 
84 
70 - ≤ 98 
28 
11 
112 
98 - ≤ 116 
8 
O-L 
12 
119 
116 - ≤ 123 
6  
13 
126 
123 - ≤ 132 
10 
14 
140 
133 - ≤ 147 
14 
15 
154 
147 - ≤ 161 
14 
16 
168 
161 – ≤ 175 
14 


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Part 
Study Visit 
Target 
Day 
Analysis Window 
Interval 
17 
196 
175 –≤ 209 
14 
18 
224 
210 - ≤ 238 
28 
19 
252 
238 - ≤ 252 
28 
20 
280 
252 - ≤ 280 
28 
21 
308 
280 - ≤ 308 
28 
22 
336 
308 - ≤ 336 
28 
23 
378 
336 - ≤ 378 
28 
FU 
24 
420 
378 - ≤ 420 
28 
 
 
 
 
 
 
 
13.6 
Derived Efficacy Endpoints  
FACIT-fatigue scale score 
The FACIT Fatigue Scale is a 13 item Likert scaled instrument which is self-
administered by the subjects during clinic visits. Subject are presented with 13 statements 
and asked to indicate their responses as it applies to the past 7 days. The 5 possible 
responses are ‘Not at all’ (0), ‘A little bit’ (1), ‘Somewhat’ (2), ‘Quite a bit’ (3) and ‘Very 
much’ (4). With 13 statements the total score has a range of 0 to 52. Before calculating 
the total score, most responses (all except Answers 5 and 7) are reversed to ensure that 
the higher score corresponds to a higher quality of life.  
Linear Analog Scale Assessment (LASA) 
The Linear Analog Scale assessment (LASA) consists of three items asking respondents 
to rate their perceived level of functioning. Specific domains include activity level, ability 
to carry out daily activities, and an item for overall QOL. Their level of functioning is 
reported on a 0-100 scale with 0 representing “As low as could be” and 100 representing 


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“As high as could be”. In addition to looking at each domain the combined score (range 
of 0-300) will be determined. 
 
European Organisation for Research and Treatment of Cancer (EORTC QLQ-C30 
Questionnaire) 
The EORTC QLQ-C30 questionnaire (version 3.0) consists of 30 questions comprised of 
both multi-item scales and single-item measures to assess overall quality of life in 
subjects. Questions are designated by functional scales, symptom scales, and global 
subject QOL/overall perceived health status.  
 
For the first 28 questions the 4 possible responses are “Not at all’ (1), ‘A little’ (2), ‘Quite 
a bit’ (3) and ‘Very much’ (4).  For the remaining 2 questions the response is requested 
on a 7-point scale from 1 (‘Very poor’) to 7 (‘Excellent’).    
 
 
 
Number 
of Items 
Item 
Range* 
Item 
Numbers 
Global Health Status / QoL 
2 
6 
29, 30 
Functional Scales  
 
 
 
Physical Functioning 
5 
3 
1 to 5 
Role Functioning 
2 
3 
6, 7 
Emotional Functioning  
4 
3 
21 to 24 
Cognitive Functioning 
2 
3 
20, 25 
Social Functioning 
2 
3 
26, 27 
Symptom Scales 
 
 
 
Fatigue 
3 
3 
10, 12, 18 
Nausea and Vomiting 
2 
3 
14, 15 
Pain 
2 
3 
9, 19 
Dyspnoea 
1 
3 
8 
Insomnia 
1 
3 
11 
Appetite Loss 
1 
3 
13 
Constipation 
1 
3 
16 
Diarrhoea 
1 
3 
17 
Financial Difficulties 
1 
3 
28 
* the item range is the difference between the possible maximum and the minimum 
response to the individual items, hence for Questions 1-28 this is 3 and for Questions 29 
and 30 this is 6. 
 


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Once the raw scores are calculated, a linear transformation will be applied to obtain the 
particular score as follows:   
 
Functional Scale Scores = {1 – (Raw Score-1)/range} x 100 
Symptom Scale Scores = {(Raw score -1)/range} x 100 
Global Health Status / QoL Scale score = {(Raw score -1)/range} x 100 
 
Hence for the functional scales and the global health status a higher score indicates a 
better QoL, whilst for the symptom scale scores this is implied by a lower score. 
 
Consequently, each scale has a range of 0% - 100%. A high scale score represents a 
higher response level. Thus, a high score for a functional scale represents a high level of 
functioning but a high score for a symptom scale represents a high level of 
symptomatology. 
 
Missing data: in the case of multi-item scales missing one of the items, raw scores can 
still be calculated using the completed items as long as more than 50% of the items were 
answered. For single-item measures, the score will be set to missing. 
13.7 
Repeated or Unscheduled Assessments of Safety Parameters  
If a subject has repeated assessments before the start of investigational product, then the 
results from the average final assessments made prior to the start of investigational 
product will be used as baseline. If end of study assessments is repeated or unscheduled, 
the last post-baseline assessment will be used as the end of study assessment for 
generating descriptive statistics. However, all post-baseline assessments will be used for 
PCS value determination and all assessments will be presented in the data listings. 
13.8 
Handling of Missing, Unused, and Spurious Data  
13.8.1 Missing Data Imputation for Efficacy Endpoints 
Imputation methods are described in the sensitivity analyses in Section 6.2.2 and 
appendix 17.3. 
13.8.2 Missing Date of Investigational Product 
When the date of the last dose of investigational product is missing for a subject in the 
Safety Set, all efforts should be made to obtain the date from the investigator.  Missing 
Date Information for Prior or Concomitant Medications (Therapies/Procedures) 


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For prior or concomitant medications, including the rescue medication of eculizumab, 
incomplete (i.e., partially missing) start date and/or stop date will be imputed.   
For a missing start date (where stop date is after start date of APL-2 dosing or missing) the 
date will be imputed as the first dose date of APL-2; for a missing stop date the date will 
be imputed as the last study date.   
The original dates (as recorded in the eCRF) will be presented in listings. 
13.8.2.1 
Incomplete Start Date  
The following rules will be applied to impute the missing numerical fields.  If the stop 
date is complete and the imputed start date is after the stop date, then the start date will be 
imputed using the stop date. 
13.8.2.1.1 
Missing Day and Month 
• 
If the year of the incomplete start date is the same as the year of the date of the first 
dose of investigational product, then the day and month of the date of the first dose 
of investigational product will be assigned to the missing fields 
• 
If the year of the incomplete start date is before the year of the date of the first dose 
of investigational product, then December 31 will be assigned to the missing fields 
• 
If the year of the incomplete start date is after the year of the date of the first dose of 
investigational product, then 01 January will be assigned to the missing fields. 
13.8.2.1.2 
Missing Month Only 
• 
The day will be treated as missing and both month and day will be replaced according 
to the above procedure in section 13.8.2.1.1. 
13.8.2.1.3 
Missing Day Only 
• 
If the month and year of the incomplete start date are the same as the month and year 
of the date of the first dose of investigational product, then the date of the first dose 
of investigational product will be assigned to the missing day 
• 
If either the year is before the year of the date of the first dose of investigational 
product or if both years are the same but the month is before the month of the date 
of the first dose of investigational product, then the last day of the month will be 
assigned to the missing day 
• 
If either the year is after the year of the date of the first dose of investigational product 
or if both years are the same but the month is after the month of the date of the first 
dose of investigational product, then the first day of the month will be assigned to 
the missing day. 


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13.8.2.2 Incomplete Stop Date  
The following rules will be applied to impute the missing numerical fields.  If the date of 
the last dose of investigational product is missing, then replace it with the last visit date.  
If the imputed stop date is before the start date (imputed or non-imputed start date), then 
the imputed stop date will be equal to the start date. If both start date and stop date are 
missing, then there will be no imputation 
13.8.2.2.1 
Missing Day and Month 
• 
If the year of the incomplete stop date is the same as the year as of the date of the last 
dose of investigational product, then the day and month of the date of the last dose 
of investigational product will be assigned to the missing fields 
• 
If the year of the incomplete stop date is before the year of the date of the last dose 
of investigational product, then the last day and month of the year (31 December) 
will be assigned to the missing fields 
• 
If the year of the incomplete stop date is after the year of the date of the last dose of 
investigational product, then the first day and month of the year (01 January) will be 
assigned to the missing fields. 
13.8.2.2.2 
Missing Month Only 
• 
The day will be treated as missing and both month and day will be replaced according 
to the procedure for Missing Day and Month. 
13.8.2.2.3 
Missing Day Only 
• 
If the month and year of the incomplete stop date are the same as the month and year 
of the date of the last dose of investigational product, then the date of the last dose 
of investigational product will be assigned to the missing day 
• 
If either the year is before the year of the date of the last dose of investigational 
product or if both years are the same but the month is before the month of the date 
of the last dose of investigational product, then the last day of the month will be 
assigned to the missing day 
• 
If either the year is after the year of the last dose of investigational product or if both 
years are the same but the month is after the month of the date of the last dose of 
investigational product, then the first day of the month will be assigned to the missing 
day. 
13.8.3 Missing Date Information for Adverse Events  
For AEs with partial start dates, non-missing date parts will be used to determine if the 
AE is treatment-emergent or not, and the calculation of study onset day, study stop day 
and duration.  If a determination cannot be made using the non-missing date parts as to 
when the AE occurred relative to study drug administration, e.g. AE start year and month 


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are the same as the year and month of the first dose of investigational product, then the 
AE will be classified as treatment-emergent.  
For a missing start date (where stop date is after start date of APL-2 dosing or missing) 
the date will be imputed as the first dose date of APL-2; for a missing stop date the date 
will be imputed as the last study date.   
The original dates (as recorded in the eCRF) will be presented in listings. 
13.8.3.1 Incomplete Start Date  
Follow the same rules as in Section 13.8.2.1.2. 
13.8.3.2 Incomplete Stop Date  
Follow the same rules as in Section 13.8.2.2. 
13.8.4 Missing Severity Assessment for Adverse Events  
If severity is missing for an AE starting prior to the date of the first dose of 
investigational product, then a severity of “Mild” will be assigned.  If the severity is 
missing for an AE starting on or after the date of the first dose of investigational product, 
then a severity of “Severe” will be assigned.  The imputed values for severity assessment 
will be used for incidence summaries, while the actual values will be used in data listings. 
13.8.5 Missing Relationship to Investigational Product for Adverse Events  
If the relationship to investigational product is missing for an AE starting on or after the 
date of the first dose of investigational product, a causality of “Related” will be assigned.  
The imputed values for relationship to double-blind investigational product will be used 
for incidence summaries, while both the actual and the imputed values will be presented 
in data listings. 
13.8.6 Character Values of Clinical Laboratory Variables 
If the reported value of a clinical laboratory variable cannot be used in a statistical 
analysis due to, for example, that a character string is reported for a numerical variable.  
The appropriately determined coded value will be used in the statistical analysis.  If the 
laboratory results are collected as < or > a numeric value, 0.0000000001 will be 
subtracted or added, respectively to the value. However, the actual values as reported in 
the database will be presented in data listings. 


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14. 
ANALYSIS SOFTWARE  
Statistical analyses will be performed using Version 9.4 (or newer) of SAS on a suitably 
qualified environment.   
15. 
CHANGES TO ANALYSES  
15.1 
Changes to Analyses Specified in the protocol 
following changes have been introduced in this version of the SAP from the most recent 
protocol: 
• The primary analysis specified in the protocol has been replaced by an MMRM 
analysis.  The analysis specified in the protocol is not performed. 
• The primary analyses of secondary endpoints using imputations for missing data 
and ANCOVA have been replaced by MMRM analyses. 
 
15.2 
Changes from Analyses Specified in the Previous Version of the SAP 
Version 1.0 (dated 01 October 2019) of the SAP has been amended with the following 
changes: 
• The estimand table was corrected to reflect the text in the Estimand section: 
change from the Hypothetical policy for the ICE to the while on-treatment 
strategy. This implies that all data for the primary and key secondary endpoints 
(ITT, mITT and PP sets) were set to missing after the first transfusion or if the 
subject discontinue the study. 
• Per the FDA request, a supportive analysis using nonparametric randomization 
based ANCOVA analysis for the primary endpoint was added.   
• Normalized LDH to ULN (i.e. LDH Value/ ULN) was added and will be 
computed and summarized by treatment group and by visit. 
• For subject who receives transfusion, the pre transfusion Hb value from the local 
laboratory will be used, however, if it is not collected or missing, then the pre 
transfusion central laboratory Hb value will be used. 
• All assessments that occur after Day 1 will be assigned to the Randomization 
controlled Period, whilst any assessment that occurs on or before to Day 1 (≤ Day 
1) will be assigned to the Run-in Period. 


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05 December 2019 
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• Analysis Window table was added. 
• Additional supportive analyses for the key continuous secondary endpoints using 
all available data were added. 
• Additional analyses for the number of units of PRBCs transfused and number of 
transfusions using log-incidence density ratios (non-parametric) were added. 
3- Additional analyses for the key secondary endpoints by the Number of PRBC 
transfusions within the 12 months prior to Day -28 (<4; ≥4) and by Platelet count 
at screening (<100,000; ≥100,000) were added. 
 
• Table for any TEAE infections, Serious Infections, and related infections was 
added. 
 
 
 


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05 December 2019 
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16. 
REFERENCES 
FDA. (n.d.). FDA Guidance for Industry Population Pharmacokinetics. 
https://www.fda.gov/downloads/drugs/guidances/UCM072137.pdf. 
Mallinckrodt CH, L. P. (2008). recommendations for the primary analysis of continuous 
endpoints in longitudinal clinical trials. DID, 42: 30. 
Miettinen O, Nurminen M (1985). Comparative Analysis of Two Rates. Statistics in 
Medicine, 4, 213-226. 
Ratitch B, O’Kelly M, Tosiello R (2013). Missing Data in Clinical Trials: From Clinical 
Assumptions to Statistical Analysis using Pattern Mixture Models. Pharmaceutical 
Statistics. 12:337-347. 
O’Kelly, M., Ratitch, B. (editors). Clinical Trials with Missing Data: A Guide for 
Practitioners. Wiley, 2014. 
Rubin, D.B multiple Imputation for Nonresponse in Surveys, New York, Wiley, 1987. 
Christy Chaung Stein. Summarizing Laboratory data with different refrence ranges in 
multi-center clinical trials. DIA, Vol 26, pp 77-84. 
ICH E9 (R1) Addendum on Estimands and Sensitivity analysis in clinical trials to the 
guideline on statistical principles for clinical trials. 
Alex Dmitrienko and Gary G. Koch. Analysis of Clinical Trials Using SAS- A practical 
Guide- Second Edition, July 2017. Page 80-82. 
 
 
 
 
 
 


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17. 
APPENDICES  
17.1 
Schedule of Assessments 
 
Study Period 
Screenin
g 
Run-in Period 
Randomized Controlled Period 
Open-Label Period 
Follow-Up 
Study Week 
 up to -
12P 
-4 
-3 
-2 
1 
2 
4 
6 
8 
12 
16 
17 
18 
20 
22 
24 
28, 32-48 
54 & 60 
Study Day 
up to -84 
-28 
-21 
-14 
1 
14 
28 
42 
56 
84 
112 
119 
126 
140 
154 
168 
196, 224-
336 
378 & 420 
Study Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17-22 
23 & 24 
Clinic Visit Window (+/- 
Days) 
N/A 
2 
2 
2 
0 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
7 
7 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical and thrombosis 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Transfusion history 
XQ 
XQ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/ExclusionA 
X 
XA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vaccination. B 
 
X 
X 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination. C 
X 
X 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
12-lead 
electrocardiogram. D 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
APL-2 administration. E 
 
Group 1 & 2 
Group 1 
Group 1 & 2 
 
Eculizumab treatment 
 
Group 1 & 2N 
Group 2 N 
Group 2 N 
 
 
 
 


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Protocol Number: APL2-302 
05 December 2019 
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Study Period 
Screenin
g 
Run-in Period 
Randomized Controlled Period 
Open-Label Period 
Follow-Up 
Study Week 
 up to -
12P 
-4 
-3 
-2 
1 
2 
4 
6 
8 
12 
16 
17 
18 
20 
22 
24 
28, 32-48 
54 & 60 
Study Day 
up to -84 
-28 
-21 
-14 
1 
14 
28 
42 
56 
84 
112 
119 
126 
140 
154 
168 
196, 224-
336 
378 & 420 
Study Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17-22 
23 & 24 
Clinic Visit Window (+/- 
Days) 
N/A 
2 
2 
2 
0 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
7 
7 
Concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital sign 
measurements. F 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
UrinalysisR 
X 
X 
 
X 
X 
 
X 
 
X 
X 
X 
 
X 
X 
 
X 
X 
X 
Blood. G, R 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pharmacokinetics. H 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Anti-APL-2 Ab assay. I 
 
X 
X 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
XI 
X 
Direct Antibody Test 
(Coombs) 
X 
X 
 
 
X 
 
X 
 
X 
X 
X 
 
 
X 
 
X 
X 
X 
Lactate dehydrogenase 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology and 
chemistry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Reticulocyte count 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Haptoglobin 
X 
X 
 
 
X 
 
X 
 
X 
X 
X 
 
 
X 
 
X 
X 
X 
Coagulation profile. J 
 
X 
 
 
X 
 
 
 
X 
 
X 
 
 
 
 
X 
XJ 
XJ 
Complement profile (C3, 
CH50 and AH50) 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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05 December 2019 
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Study Period 
Screenin
g 
Run-in Period 
Randomized Controlled Period 
Open-Label Period 
Follow-Up 
Study Week 
 up to -
12P 
-4 
-3 
-2 
1 
2 
4 
6 
8 
12 
16 
17 
18 
20 
22 
24 
28, 32-48 
54 & 60 
Study Day 
up to -84 
-28 
-21 
-14 
1 
14 
28 
42 
56 
84 
112 
119 
126 
140 
154 
168 
196, 224-
336 
378 & 420 
Study Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17-22 
23 & 24 
Clinic Visit Window (+/- 
Days) 
N/A 
2 
2 
2 
0 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
7 
7 
Flow cytometry for PNH 
and C3 deposition 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
Plasma (free) Hb 
X 
X 
 
 
X 
 
X 
 
X 
X 
X 
 
 
X 
 
X 
X 
X 
Ferritin 
X 
X 
 
 
X 
 
X 
 
X 
X 
X 
 
 
X 
 
X 
X 
X 
Pregnancy (B-HCG) or 
FSH. K 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Genotyping for Gilbert’s 
SyndromeL 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test. M 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
FACIT fatigue Scale 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
LASA Scale 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
EORTC QLQ-C30 
Questionnaire 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense Investigational 
Product 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Return Investigational 
ProductO 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Protocol Number: APL2-302 
05 December 2019 
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FOOTNOTES: 
A. Laboratory values from Screening will be used in addition to inclusion/exclusion criteria to confirm patient eligibility on Day -28. 
B. If required; e.g., not previously-vaccinated subjects will receive vaccinations against Neisseria meningitidis types A, C, W, Y and B, 
Streptococcus pneumoniae and Hemophilus influenzae Type B (Hib). If the subject’s first documented Neisseria meningitidis vaccine(s) are 
administered during the Run-in Period (Day -14), a booster (for both vaccinations) should be administered after 2 months. If Pneumococcal 
vaccination is required, please refer to Section 13.2.1 of the protocolfor vaccination scenarios. The PI will discuss with the Sponsor in regard 
to specific patient requirements. 
C. Full physical examination will be performed at the D-28, D1, Wk16, Wk48 and Exit Visit. A symptom-driven physical examination may be 
performed at other times, at the PI’s discretion. 
D. Triplicate 12-lead electrocardiograms (ECGs) are to be performed pre-dose (-45, -30, and -15 minutes) and 6 hours post-dose on D-28, D1, 
Wk16 and Wk48. Triplicate 12-lead ECGs will be performed at all other visits (prior to dosing, if dosing will occur during the study visit). 
E. Subjects will self-administer SC APL-2 twice weekly (or every 3 days subject to pre-approved dose adjustment), after receiving appropriate 
training by a research nurse or other personnel. Every subject will administer APL-2 at the study site through the Run-in Period (Visit 2-Visit 4) 
and at Visit 5 (Day 1). For subjects randomized to APL-2, following Visit 5 (Day 1), every effort should be made to ensure that the subject’s 
APL-2 dosing schedule aligns with study visit days, and subjects should administer APL-2 at the study site and complete the post-
administration study procedures. Details regarding APL-2 dosing during study visits can be found in Section 13 f the protocol. 
F. Vital signs will be measured before venipuncture and ECG, vital signs measured post-dose will be timed from the completion of the study 
drug administration. Additional monitoring of vital signs will occur on D-28, D-25 (home or clinic visit), D1, Wk16 and Wk48 (pre-dose, 30 
minutes, 2, 4 and 6 hours post-dose). At all other visits, if APL-2 and/or eculizumab is administered at the study site, vital signs will be 
measured pre-dose and 30 minutes post-dose. 
G. Blood samples will be taken pre-dose (exception: see H below). 
H. On D-28, D1, Wk16 and Wk48 only, pharmacokinetic samples will be taken pre-dose and at 6 hours (+/- 30 minutes) post-dose. PK 
samples will be taken pre-dose at all other visits. 
I. Anti-APL-2 assay to be performed only on Week 32 and Week 48. 
J. Coagulation profile to be completed only on Week 32, Week 48, and Week 60. The use of silica reagents in coagulation panels should be 
avoided in subjects treated with APL-2. 
K. B-HCG for WOCBP; FSH for post-menopausal women. 
L. Sample for genotyping to be obtained via buccal swab test completed at the Screening Visit.  


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Protocol Number: APL2-302 
05 December 2019 
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M. Urine pregnancy test should be completed for WOCBP prior to dosing on Day 1. 
N. On Day 1, subjects will receive their last dose of APL-2 and may receive their last dose of eculizumab depending on their dosing schedule. 
During the Run-in Period for all subjects (Visit 2 [Week -4 (Day -28)] to Visit 4 [Week -2]) and through the Randomized Controlled Period for 
subjects randomized to eculizumab (Visit 5 [Day 1] to Visit 11 [Week 16]), there is no requirement for eculizumab to be administered on the 
day of a study visit. Details regarding eculizumab dosing requirements during the study can be found in Section 13 of the protocol. 
O. Return of investigational product only to be completed at Week 54 during the Follow-up Period. 
P. If a subject’s screening visit is completed greater than 28 days prior to dosing, a screening hematology panel should be repeated within 28 
days of dosing to confirm patient eligibility [Inclusion Criteria 4, 5, 6, and 7]. 
Q. Transfusion history from the previous 12 months should be collected at the Visit 1 Screening Visit. At Visit 2, transfusion history should be 
reviewed, and any transfusions received between Visit 1 and Visit 2 should be recorded. 
R. During the Screening Period (from up to Week -12 to Week -4 (day -28)), clinical laboratory tests (e.g. hematology, coagulation, serum 
chemistry, flow cytometry, urinalysis) may be repeated with written approval from the Sponsor (including the assigned Medical Monitor), with 
no requirement to designate the subject as a screen failure. Subjects that do not meet clinical laboratory-related screening criteria may still 
qualify for study entry without having to complete the full rescreening process as long as all clinical laboratory-related values meet the criteria 
for study entry within the Screening Period.


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CCI


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17.3 
Sensitivity Analyses for the Primary Efficacy Endpoint 
 
1- Control-based Imputation method 
A control-based multiple imputation approach will be used as a sensitivity analysis to 
consider the Missingness Not At Random (MNAR) mechanism for monotone missing 
data. The mean change from baseline in Hb level at Week 16 will be analyzed based on 
the data observed while the subject remains on study treatment as well as the data 
imputed using multiple imputation (MI) methodology for the time points with missing 
values. Imputation of outcome values in the Eculizumab group will rely on the MAR 
assumption. Imputation of the primary outcome values in the APL-2 group will be done 
as if the subject had been on Eculizumab. Imputed values in the APL-2 group will be 
sampled using the imputation model of the Eculizumab group, i.e., conditional on the 
outcome values observed at the time points prior to discontinuation. This approach does 
not assume a sustained benefit of APL-2 after discontinuation but rather assumes a post-
discontinuation effect like that of Eculizumab and time effects based the estimated 
correlations among the time points in the Eculizumab arm. The number of imputations 
will be 500 (NIMPUTE=500) and the random seed will be 123876 for both partial 
imputation and sequential regression imputation detailed in Steps 1 and 2. The approach 
will be implemented as follows: 
• Step 1: Non-monotone missing data will be imputed first based on the MAR 
assumption and a multivariate joint Gaussian imputation model using the Markov 
chain Monte Carlo (MCMC) method using the MCMC statement in PROC MI. 
As a result, each imputed data set will only have missing data at the end of each 
subject’s record, i.e., a monotone missing data pattern. The MCMC method in 
PROC MI will be invoked with multiple chains (CHAIN=MULTIPLE), 200 burn-
in iterations and a non-informative prior.  A separate imputation model will be 
used for each treatment group. The imputation models will represent a simplified 
version of the primary analysis model and will include the following terms: 
stratification variables, baseline Hb level and Hb levels at each time point. In case 
of non-convergence or other issues, a ridge prior and a single imputation model 
will be considered with the treatment term added to the model.  
• Step 2:  The resulting monotone missing data for all subjects who discontinue 
study treatment early will be imputed using a sequential regression multiple 
imputation model estimated based on the data from the Eculizumab group only. 
Each sequential regression model for imputation of outcome values at a given 
time point will include the following terms: stratification variables, baseline Hb 
level and Hb levels at all previous time points. Missing values at a given time 
point in both treatment groups will be imputed from the same imputation model, 
conditional on the subject values observed or imputed at previous time points.  


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• Step 3: The change from baseline in Hb level to each scheduled post-baseline visit 
will be calculated based on the observed and imputed data. Each of the 1000 
imputed complete data sets from Step 2 will be analyzed using the primary 
analysis model.  
• Step 4: The results obtained in each imputed data set, including the treatment 
differences and their standard errors, will be combined using Rubin’s imputation 
rules (Rubin, 1987) to produce a pooled estimate of the treatment differences, 
corresponding 95% confidence interval and a pooled treatment effect P-value 
using PROC MIANALYZE. 
2- Imputation based on the delta-adjusted stress testing method 
In addition to the control-based imputation method, sensitivity to departures from the 
MAR assumption will also be investigated using a tipping point analysis based on the 
delta-adjusted stress testing method. Departures from MAR in the APL-2 group will be 
evaluated assuming that subjects who discontinue study treatment have, on average, 
efficacy outcomes after discontinuation that are worse by a pre-defined amount (delta) 
compared to the value which would have been assumed under an MAR model.  
A series of analyses based on this method will be performed with increasing values of the 
delta until the treatment difference is no longer statistically significant. The smallest 
value of the delta parameter that overturns the primary conclusions is known as a tipping 
point. An interpretation of clinical plausibility of the assumptions underlying the tipping 
point will be provided.  
The mean change from baseline in Hb level at Week 16 will be analyzed based on the 
data observed while a subject remains on study treatment as well as the data imputed 
using MI methodology for the time points with missing primary outcome values. Imputed 
values in the APL-2 group will first be sampled from an MAR-based multiple imputation 
model and then the delta-adjusted method described will be applied as described below. 
The analyses will be performed using the delta starting from 0 with decrement of 0.2 until 
the null hypothesis can no longer be rejected. 
As with the control-based imputation method, this approach uses MCMC for partial 
imputation of non-monotone data under MAR followed by sequential MI regression for 
monotone data.  
• Step 1:  The step is equivalent to the corresponding step for the control-based 
imputation method for non-monotone missing data (see Step 1). 
• Step 2: The resulting monotone missing data will be imputed using sequential 
regression multiple imputation, where a separate regression model is estimated for 
imputation of outcome values at each time point. Each regression model will 
include the following terms: stratification variables, baseline Hb level and Hb 


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Protocol Number: APL2-302 
05 December 2019 
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Page 65 of 65 
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levels at all previous time points. The delta adjustment will be imposed on all 
imputed values at each visit after generating all imputations under the MAR 
assumption. 
• Steps 3 and 4: The steps are equivalent to the corresponding steps for the control-
based imputation method (see Steps 3 and 4).