Clinical trial NCT03593200
Conditions: PNH
Keywords: PNH Paroxysmal Nocturnal Hemoglobinuria Complement inhibitor Anemia Hemoglobinuria Hemolysis Hematologic diseases Extravascular hemolysis (EVH) Intravascular hemolysis (IVH) C3 inhibitor
Sponsor: Apellis Pharmaceuticals, Inc.
Start date: 2018-08-16; Completion date: 2019-10-22
Enrollment: 4 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a Phase IIa, open-label, multiple dose, study in patients with PNH who have not received eculizumab (Soliris ®) in the past. A single cohort of subjects is planned for evaluation.

Detailed description:

Arms: arm 1: 270 mg/day (up to 360 mg/day from Day 29) from Day 1 to Day 364\*
Interventions: intervention 1: Pegcetacoplan
Intervention descriptions: intervention 1: Complement (C3) Inhibitor

Protocol documents:
Prot_000.pdf: 
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Apellis Pharmaceuticals, Inc. 
- CONFIDENTIAL - 
Page 3 of 55 
 
Protocol: APL2-202 
Version 3.0:  31-JAN-2018 
 
INVESTIGATOR AGREEMENT  
Long Title:  
 
A Phase IIa, Open Label, Multiple Dose Study to 
 
Assess the Safety, Efficacy and Pharmacokinetics of 
 
Subcutaneously Administered APL-2 in Subjects 
 
with Paroxysmal Nocturnal Hemoglobinuria (PNH) 
Protocol Number, Version 
 
APL2-202/Version 3.0/31Jan2018  
and Date: 
Study Phase:  
 
 
 
Phase IIa 
Sponsor Name and Address:   
Apellis Pharmaceuticals 
 
 
 
 
 
 
6400 Westwind Way, Suite A 
 
 
 
 
 
 
Crestwood, KY 40014 
Investigational Test Article:  
 
APL-2 
Indication Studied:  
 
PNH 
Investigator Agreement:  
 
I have read the clinical study described herein, 
 
recognize its confidentiality, and agree to conduct 
 
the described trial in compliance with Good Clinical 
 
Practices (GCP), the ethical principles contained 
 
within the Declaration of Helsinki, this protocol, and 
 
all applicable regulatory requirements.  
 
 
 
Principal Investigator:  
Name: ____________________________________
 
  
 
Signature: _________________________________  
 
 
 
 
 
 
 
Date: ______/______/______ (DD/MMM/YYYY)
 
 
 
 
 
 


 
 
Apellis Pharmaceuticals, Inc. 
- CONFIDENTIAL - 
Page 4 of 55 
 
Protocol: APL2-202 
Version 3.0:  31-JAN-2018 
TABLE OF CONTENTS 
TABLE OF CONTENTS ................................................................................................................... 4 
LIST OF TABLES ............................................................................................................................. 7 
1. SYNOPSIS ................................................................................................................................ 8 
2. STUDY FLOW CHART ............................................................................................................ 13 
3. ABBREVIATIONS .................................................................................................................... 19 
4. INTRODUCTION ..................................................................................................................... 20 
4.1 
Background .................................................................................................................... 20 
4.1.1 
Paroxysmal Nocturnal Hemoglobinuria................................................................ 21 
4.1.2 
APL-2 ................................................................................................................... 21 
4.1.3 
Nonclinical Data ................................................................................................... 22 
4.1.3.1 
Pharmacology....................................................................................... 22 
4.1.3.2 
Pharmacokinetics ................................................................................. 22 
4.1.3.3 
Toxicology ............................................................................................ 22 
4.1.4 
Clinical Data ......................................................................................................... 23 
4.1.5 
Completed Clinical Studies in Healthy Volunteers ............................................... 24 
4.1.6 
Ongoing Clinical Studies ...................................................................................... 25 
4.2 
Rationale ........................................................................................................................ 26 
4.2.1 
Purpose of the Study............................................................................................ 26 
4.2.2 
Dose Selection ..................................................................................................... 26 
4.3 
Risk/Benefit .................................................................................................................... 26 
5. STUDY OBJECTIVES AND ENDPOINTS .............................................................................. 28 
5.1 
Study Objectives ............................................................................................................ 28 
5.2 
Study Endpoints ............................................................................................................. 28 
6. STUDY DESIGN ...................................................................................................................... 28 
7. SUBJECT SELECTION ........................................................................................................... 29 
7.1 
Inclusion Criteria............................................................................................................. 30 
7.1.1 
Approved methods of contraception .................................................................... 30 
7.2 
Exclusion Criteria ........................................................................................................... 30 
8. STUDY TREATMENTS ........................................................................................................... 31 
8.1 
Allocation to Treatment .................................................................................................. 31 
8.2 
Blinding ........................................................................................................................... 31 
8.3 
Treatments Administered ............................................................................................... 31 
8.3.1 
Drug supplies ....................................................................................................... 31 
8.3.1.1 
Identity of Investigational Products....................................................... 31 
8.3.1.2 
Study Supplies...................................................................................... 31 
8.3.1.3 
Accountability ....................................................................................... 31 
8.3.2 
Planned Dose Levels and Dosing Schedule ........................................................ 31 
8.3.3 
Drug Administration.............................................................................................. 32 
8.4 
Concomitant Medications ............................................................................................... 32 
8.4.1 
Prophylactic antibiotics ........................................................................................ 32 
8.4.1.1 
Primary prophylactic antibiotic Day 1-14 .............................................. 32 
8.4.1.2 
Primary prophylactic antibiotic Day 15 onwards .................................. 32 
8.4.1.3 
Alternative prophylactic antibiotics ....................................................... 33 
8.4.2 
Rescue antibiotics ................................................................................................ 33 
8.4.3 
Vaccinations ......................................................................................................... 33 
8.4.4 
Iron Supplements ................................................................................................. 33 
8.4.5 
Phlebotomy/Venesection for iron overload .......................................................... 33 
9. STUDY PROCEDURES .......................................................................................................... 33 
9.1 
Screening ....................................................................................................................... 34 


 
 
Apellis Pharmaceuticals, Inc. 
- CONFIDENTIAL - 
Page 5 of 55 
 
Protocol: APL2-202 
Version 3.0:  31-JAN-2018 
9.2 
Part 1 - Treatment Period – (Days 1 to 28) .................................................................... 34 
9.2.1 
On Site Administration (Day 1 to Day 3 and Days 8, 15 and 22) ........................ 34 
9.2.2 
Outpatient Administration (Day 4 to Day 28) ....................................................... 34 
9.3 
Part 2A - Treatment Period – (Days 29 to 84) ............................................................... 34 
9.3.1 
On Site Administration (Days 29, 36, 43, 57 and 71) .......................................... 34 
9.3.2 
Outpatient Administration (Day 30 to Day 84) ..................................................... 35 
9.4 
Part 2B - Treatment Period – (Days 85 to 364) ............................................................. 35 
9.4.1 
On Site Administration (Days 85, 113, 141, 169, 197, 225, 253, 281, 309, and 
337) ...................................................................................................................... 35 
9.4.2 
Outpatient Administration (Day 85 to Day 364) ................................................... 35 
9.5 
Part 3 - Follow-up - (Days 365, 379, and 393) ............................................................... 35 
9.5.1 
Exit Visit (Day 414, or Day 134, or Day 78) ......................................................... 35 
9.5.2 
Unscheduled Follow-up Visits .............................................................................. 36 
9.5.3 
Scheduled End of Study ...................................................................................... 36 
9.6 
Periodic Safety Review .................................................................................................. 36 
9.6.1 
Safety Monitoring Committee ............................................................................... 36 
9.7 
Removal of Subjects from the Study .............................................................................. 36 
10. ASSESSMENTS ...................................................................................................................... 37 
10.1 Assessments .................................................................................................................. 37 
10.1.1 Body Height and Weight ...................................................................................... 37 
10.1.2 Physical Examination ........................................................................................... 37 
10.1.3 Vital Signs ............................................................................................................ 37 
10.1.4 Electrocardiogram Monitoring .............................................................................. 37 
10.1.5 Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue Scale ........ 38 
10.1.6 Linear Analog Scale Assessment (LASA) for Quality of Life ............................... 38 
10.1.7 Clinical Laboratory Tests ..................................................................................... 38 
10.1.7.1 
Hematology .......................................................................................... 38 
10.1.7.2 
Coagulation .......................................................................................... 38 
10.1.7.3 
Serum Chemistry .................................................................................. 38 
10.1.7.4 
Urinalysis .............................................................................................. 39 
10.1.7.5 
Human Chorionic Gonadotropin (Serum Pregnancy Test) and Follicle-
Stimulating Hormone ............................................................................ 39 
10.1.8 Injection/ Infusion Site and Pump Safety Assessment ........................................ 39 
10.2 Pharmacokinetic Assessments ...................................................................................... 39 
10.2.1 Blood Sampling and Processing .......................................................................... 39 
10.2.2 Analytical Method ................................................................................................. 40 
10.3 Flow Cytometry Assessments ........................................................................................ 40 
10.4 Pharmacodynamic Assessments ................................................................................... 40 
10.5 Anti- APL-2 Antibody Assessment ................................................................................. 40 
10.6 Blood Volume for Study Assessments ........................................................................... 41 
10.7 Pregnancy tests.............................................................................................................. 41 
11. ADVERSE EVENTS ................................................................................................................ 41 
11.1 Definitions ....................................................................................................................... 41 
11.2 Recording Adverse Events ............................................................................................. 42 
11.3 Assessment of Adverse Events ..................................................................................... 42 
11.3.1 Intensity ................................................................................................................ 42 
11.3.2 Causality .............................................................................................................. 43 
11.3.3 Serious Adverse Event ........................................................................................ 43 
11.4 Reporting Serious Adverse Event .................................................................................. 44 
11.5 Adverse Events of Special Interest ................................................................................ 44 
11.6 Unexpected Adverse Events or Unexpected Suspected Adverse Reactions ................ 45 


 
 
Apellis Pharmaceuticals, Inc. 
- CONFIDENTIAL - 
Page 6 of 55 
 
Protocol: APL2-202 
Version 3.0:  31-JAN-2018 
11.7 Treatment and Follow up of Adverse Events ................................................................. 45 
11.8 Pregnancy ...................................................................................................................... 45 
12. STATISTICS ............................................................................................................................ 45 
12.1 Sample Size Justification ............................................................................................... 45 
12.2 Statistical Analysis Methodology .................................................................................... 45 
12.2.1 Analysis Populations ............................................................................................ 46 
12.2.1.1 
Screened Population ............................................................................ 46 
12.2.1.2 
Safety Population/ Intent to Treat (ITT) Population .............................. 46 
12.2.1.3 
Pharmacokinetic (PK) Population......................................................... 46 
12.2.1.4 
Pharmacodynamic (PD) Population ..................................................... 46 
12.2.1.5 
Data Review for Analysis Populations ................................................. 46 
12.2.2 Study Endpoints ................................................................................................... 46 
12.2.2.1 
Safety Endpoints .................................................................................. 46 
12.2.2.2 
Efficacy Endpoints ................................................................................ 46 
12.2.2.3 
Secondary Endpoints ........................................................................... 47 
12.2.2.4 
Pharmacokinetic Endpoints .................................................................. 47 
12.2.2.5 
Exploratory Pharmacodynamic Endpoints (Markers) ........................... 47 
12.2.3 Safety Analyses ................................................................................................... 47 
12.2.3.1 
Adverse Events .................................................................................... 47 
12.2.3.2 
Clinical Laboratory Tests ...................................................................... 47 
12.2.3.3 
Vital Signs and ECGs ........................................................................... 47 
12.2.4 Efficacy and Secondary Endpoint Analyses ........................................................ 48 
12.2.5 Pharmacokinetic Analyses ................................................................................... 48 
12.2.6 Pharmacodynamic Analyses ................................................................................ 48 
12.2.7 Handling of Dropouts and/or Missing Data .......................................................... 48 
12.2.8 Other Data Analyses ............................................................................................ 48 
12.3 Interim Analyses ............................................................................................................. 49 
13. ADMINISTRATIVE CONSIDERATIONS ................................................................................. 49 
13.1 Direct Access to Source Data/Documents ..................................................................... 49 
13.2 Quality Control and Quality Assurance .......................................................................... 49 
13.2.1 Monitoring ............................................................................................................ 49 
13.3 Ethics .............................................................................................................................. 49 
13.3.1 Ethical Conduct of the Study ................................................................................ 49 
13.3.2 Institutional Review Board/Ethic Committee ........................................................ 50 
13.3.3 Subject Information and Consent ......................................................................... 50 
13.3.4 Confidentiality ....................................................................................................... 50 
13.3.5 ClinicalTrials.gov .................................................................................................. 50 
13.3.6 Termination of Study ............................................................................................ 50 
13.4 Data Handling and Record Keeping............................................................................... 50 
13.5 Protocol Amendments .................................................................................................... 51 
13.6 Report Format ................................................................................................................ 51 
13.7 Finance and Insurance ................................................................................................... 51 
13.8 Publication Policy ........................................................................................................... 51 
14. REFERENCES ........................................................................................................................ 52 
15. APPENDIX 1: FUNCTIONAL ASSESSMENT OF CHRONIC ILLNESS THERAPY (FACIT) 
FATIGUE SCALE .............................................................................................................. 53 
16. APPENDIX 2: LASA SCALE ................................................................................................... 55 
 


 
 
Apellis Pharmaceuticals, Inc. 
- CONFIDENTIAL - 
Page 7 of 55 
 
Protocol: APL2-202 
Version 3.0:  31-JAN-2018 
 
LIST OF TABLES 
 
Table 1: Summary of all clinical studies of systemically administered APL-2 (up to September 2017) 
 
 ................................................................................................................................... 23 
 
Table 2: Blood Volume during Study (up to Day 414) ......................................................... 41 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
Apellis Pharmaceuticals, Inc. 
- CONFIDENTIAL - 
Page 8 of 55 
 
Protocol: APL2-202 
Version 3.0:  31-JAN-2018 
1. SYNOPSIS 
Protocol Number 
APL2-202 
Official Title 
A Phase IIa, Open Label, Multiple Dose Study to Assess the 
Safety, Efficacy and Pharmacokinetics of Subcutaneously 
Administered APL-2 in Subjects with Paroxysmal Nocturnal 
Hemoglobinuria (PNH) 
Protocol Version 
and Date 
Version 3.0 
31 January 2018 
 
Compound 
APL-2 
Study Phase and 
Type 
Phase IIa. Open-label, evidence of activity, safety, tolerability, 
pharmacokinetics (PK), multiple dose study. 
Study Objectives 
The objectives of the study are to assess the safety, tolerability, 
efficacy and PK of multiple (SC) doses of APL-2 in subjects with 
paroxysmal nocturnal hemoglobinuria (PNH) who have not 
received treatment with eculizumab in the past. 
An exploratory objective of the study is to assess the 
pharmacodynamics (PD) of multiple SC doses of APL-2 when 
administered to PNH patients.  
Study Population 
Subjects will: 
• be male and female (using contraception as specified in the 
protocol) and at least 18 years old  
• have a diagnosis of PNH 
Number of 
Subjects 
The study will be conducted alongside the ongoing Phase Ib study 
APL2-CP-PNH-204 (PADDOCK) to investigate APL-2 in PNH 
patients who have not previously received treatment with 
eculizumab. Safety and efficacy data from both studies will be used 
to support the data obtained in the Phase III confirmatory study.  
Up to 20 subjects will be enrolled to complete 28 days of dosing. 
 


 
 
Apellis Pharmaceuticals, Inc. 
- CONFIDENTIAL - 
Page 9 of 55 
 
Protocol: APL2-202 
Version 3.0:  31-JAN-2018 
Inclusion Criteria 
At Screening (unless otherwise specified) 
• At least 18 years old (inclusive) 
• Diagnosed with PNH (white blood cell (WBC) clone >10%) 
• Lactose dehydrogenase (LD) ≥2 times the upper limit of normal 
• Screening Ferritin  normal and Total Iron Binding Capacity 
(TIBC) < LLN based on central lab reference ranges. If a subject 
is receiving iron supplements at screening, the investigator must 
ensure that his/her dose has been stable for 8 weeks prior to 
enrolment and must be maintained throughout the study (see 
Section 8.4.4) 
• Last transfusion within 12 months prior to screening 
• Platelet count of >30,000/mm3 at the screening visit 
• Absolute neutrophil count >500/ mm3 at the screening visit  
• Women of child-bearing potential (WOCBP) must have a 
negative pregnancy test at screening and must agree to use 
protocol defined methods of contraception for the duration of the 
study 
• Males must agree to use protocol defined methods of 
contraception and agree to refrain from donating sperm for the 
duration of the study 
• Vaccination against Neisseria meningitides types A, C, W, Y 
and B, Streptococcus pneumoniae and Haemophilus influenzae 
Type B (Hib) either within 2 years prior to Day 1 dosing, or within 
14 days after starting treatment with APL-2. Unless documented 
evidence exists that subjects are non-responders to vaccination 
as evidenced by titers or display titer levels within acceptable 
local limits 
• Willing and able to give informed consent 
Exclusion Criteria 
• Prior eculizumab (Soliris®) treatment 
• Active bacterial infection 
• Hereditary complement deficiency 
• History of bone marrow transplantation 
• Concurrent severe aplastic anemia (SAA), defined as currently 
receiving immunosuppressive therapy for SAA including but not 
limited to cyclosporin A, tacrolimus, mycophenolate mofetil or 
anti-thymocyte globulin 
• Participation in any other investigational drug trial or exposure 
to another investigational agent, device or procedure within 
30 days 


 
 
Apellis Pharmaceuticals, Inc. 
- CONFIDENTIAL - 
Page 10 of 55 
 
Protocol: APL2-202 
Version 3.0:  31-JAN-2018 
• Evidence of QTcF prolongation defined as >450 ms for males 
and >470 ms for females at screeningBreast-feeding women 
• History of meningococcal disease 
Endpoints 
Primary Safety Endpoint: 
The primary safety endpoints of the study are the number and 
severity of treatment emergent adverse events (TEAEs) following 
administration of multiple doses of SC APL-2. 
Primary Efficacy Endpoints: 
• Change from baseline in LD 
• Change from baseline in Haptoglobin 
• Change from baseline in Hemoglobin (Hb) 
Secondary Endpoints: 
• APL-2 plasma concentrations (and pharmacokinetic (PK) 
parameters as appropriate) 
• Change from baseline in Functional Assessment of Chronic 
Illness Therapy (FACIT) Fatigue Scale score 
• Change from baseline in reticulocyte count 
• Change from baseline in total bilirubin 
• Change from baseline in Linear Analog Scale Assessment 
(LASA) for Quality of Life 
• Number of red blood cell (RBC) transfusions per month 
Exploratory PD markers include: 
• Complement (CH50, AP50, and C3) levels 
• C3 deposition on RBC cells 
• Clonal distribution of PNH RBCs  
Planned Dose 
Levels 
The planned dose for this single cohort study will be a daily dose 
of 270 mg/day however from Part 2A onwards intra-subject dose 
escalation up to a dose of 360 mg/day may be permitted.  
The dose was determined based on cumulative safety, PK, and PD 
data from ongoing studies in PNH patients. 
Safety data from this study will be reviewed by the SMC on a 
regular basis.  
Study Design 
This is a Phase IIa, open-label, multiple dose, study in patients 
with PNH who have not received eculizumab (Soliris®) in the 
past. A single cohort is planned for evaluation.   


 
 
Apellis Pharmaceuticals, Inc. 
- CONFIDENTIAL - 
Page 11 of 55 
 
Protocol: APL2-202 
Version 3.0:  31-JAN-2018 
The study will be conducted alongside the ongoing Phase Ib 
study APL2-CP-PNH-204 (PADDOCK) to investigate APL-2 in 
PNH patients who have not previously received treatment with 
eculizumab. Safety and efficacy data from both studies will be 
used to support the data obtained in the Phase III confirmatory 
study. Up to 20 subjects will be enrolled to complete 28 days of 
dosing (Part 1).  
Safety will be assessed throughout the study; serial blood and 
urine samples will be collected for these assessments. Blood 
samples will be collected for the assessment of APL-2 PK. 
Additional samples for assessment of PD will also be collected.  
The study will consist of four parts: 
• 
Part 1: subjects will receive APL-2 for 28 days.  
• 
Part 2A:  subjects may continue to receive APL-2 for a 
further 56 days if there is evidence of clinical benefit 
following review of available safety, PK and PD data by 
the investigator and sponsor 
• 
Part 2B:  subjects may continue to receive daily APL-2 
treatment for up to 364 days if there is ongoing evidence 
of clinical benefit following review of the available safety, 
PK and PD data. 
• 
Part 3: Safety follow up 
Screening will take place within 30 days prior to the start of 
dosing on Day 1. 
Subjects will be entered into Part 1 of the study on Day 1 at a 
time designated by the PI. Research nurses or other appropriately 
qualified research personnel will administer the SC infusions for a 
minimum of 3 days (Days 1-3) until the research nurse considers 
that the subject is both capable and confident  to conduct self- 
administration. The subject will continue to self-administer 
infusions at the clinic on those days when a clinic visit occurs 
(Day 8, 15 and 22) and at an off-site location convenient to the 
subject on all other days up to Day 28 in Part 1. 
Following ongoing review of available safety, PK and PD data by 
the investigator and sponsor, subjects showing evidence of 
clinical benefit may progress to Part 2A and then to Part 2B of the 
study and continue to receive daily doses of APL-2 until Day 84 
and then until Day 364. Doses will be self-administered by the 
subject throughout this period at an off-site location convenient to 
the subject with the exception of Days 29, 36, 43, 57, 71, 85, 113, 
141, 169, 197, 225, 253, 281, 309, and 337 where dosing is 
performed by the subject at the clinical site. After the conclusion 
of the treatment period (Day 364), subjects will return to the 
clinical site for follow-up study procedures on Day 365, 379, and 


 
 
Apellis Pharmaceuticals, Inc. 
- CONFIDENTIAL - 
Page 12 of 55 
 
Protocol: APL2-202 
Version 3.0:  31-JAN-2018 
 
393 and final study procedures at an Exit Visit on Day 414 See 
Study Flow Chart in Section 2. 
The planned length of participation in the study for each subject is 
approximately 444 days (14.5 months) from Day -30 through 
completion of the Day 414 Exit visit procedures). 


 
 
Apellis Pharmaceuticals, Inc. 
- CONFIDENTIAL - 
Page 13 of 55 
 
Protocol: APL2-202 
Version 3.0:   31-JAN-2018 
 
2. STUDY FLOW CHART 
Study Period 
Part 1 – Treatment (Daily from Day 1 to Day 28) 
Study Week 
-4 
1 
2 
3 
4 
Study Day -30 
1 
2 
3 
4 to 7 
8 
9 to 14 
15 
16 to 21 
22 
23 to 28 
Informed Consent 
x 
 
 
 
 
 
 
 
 
 
 
Demographics 
x 
 
 
 
 
 
 
 
 
 
 
Medical, transfusion, and thrombosis history 
x 
 
 
 
 
 
 
 
 
 
 
Vaccination. A 
 
 
 
 
 
 
 
x 
 
 
 
Review entry criteria 
 
x 
 
 
 
 
 
 
 
 
 
Preventive antibiotic. B 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Physical examination. C 
x 
 
 
 
 
 
 
 
 
 
 
12-lead electrocardiogram. D 
x 
x 
 
x 
 
x 
 
x 
 
x 
 
APL-2 administration. E 
 
S 
S 
S 
H 
S 
H 
S 
H 
S 
H 
Injection site assessment. F 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Concomitant medications 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Vital sign measurements. G 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Urinalysis 
x 
x 
 
 
 
x 
 
x 
 
x 
 
Blood. I 
x 
x 
 
 
 
x 
 
x 
 
x 
 
Pharmacokinetics. I 
 
x (I) 
x 
x 
 
x 
 
 
 
x 
 
Anti-APL-2 Ab assay 
 
x 
 
 
 
 
 
x 
 
 
 
Hematology and chemistry.  
x 
x 
 
 
 
x 
 
x 
 
x 
 
Coagulation profile 
x 
x 
 
 
 
x 
 
x 
 
x 
 
Complement profile (C3, CH50 and AP50) 
x 
x 
 
 
 
x 
 
x 
 
x 
 
Flow cytometry for PNH/C3 deposition 
x 
x 
 
 
 
x 
 
x 
 
x 
 
Plasma Hb 
x 
x 
 
 
 
x 
 
x 
 
x 
 
Pregnancy (B-human chorionic gonadotropin) 
x 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test. J 
 
x 
 
 
 
x 
 
x 
 
x 
 
FACIT fatigue Scale 
 
x 
 
 
 
 
 
x 
 
 
 
LASA QoL 
 
x 
 
 
 
 
 
x 
 
 
 
Adverse events 
 
x 
x 
x 
x 
x 
X 
x 
X 
x 
x 
Thrombosis record (MAVE). K 
 
x 
x 
x 
x 
x 
X 
x 
X 
x 
x 
See footnotes below continuation flow chart 
 
 


 
 
Apellis Pharmaceuticals, Inc. 
- CONFIDENTIAL - 
Page 14 of 55 
 
Protocol: APL2-202 
Version 3.0:   31-JAN-2018 
 
Study Period 
Part 2A - Treatment (Daily from Day 29 to Day 84) 
Study Week 
5 
6 
7 and 8 
9 and 10 
11 and 12 
Study Day 
 
29 
30 to 35 
36 
37 to 42 
43 
44 to 56 
57 
58 to 70 
71 
72 to 84 
Informed Consent 
 
 
 
 
 
 
 
 
 
 
Demographics 
 
 
 
 
 
 
 
 
 
 
Medical, transfusion, and thrombosis history 
 
 
 
 
 
 
 
 
 
 
Vaccination. A 
 
 
 
 
 
 
 
 
 
 
Review entry criteria 
 
 
 
 
 
 
 
 
 
 
Preventive antibiotic. B 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination. C 
X 
 
 
 
 
 
X 
 
 
 
12-lead electrocardiogram. D 
X 
 
X 
 
X 
 
X 
 
X 
 
APL-2 administration. E 
S 
H 
S 
H 
S 
H 
S 
H 
S 
H 
Injection site assessment. F 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital sign measurements. G 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
 
X 
 
X 
 
X 
 
X 
 
Blood. I 
X 
 
X 
 
X 
 
X 
 
X 
 
Pharmacokinetics. I 
X 
 
 
 
X 
 
 
 
X 
 
Anti-APL-2 Ab assay 
X 
 
 
 
 
 
 
 
X 
 
Hematology and chemistry.  
X 
 
X 
 
X 
 
X 
 
X 
 
Coagulation profile 
X 
 
X 
 
X 
 
X 
 
X 
 
Complement profile (C3, CH50 and AP50) 
X 
 
X 
 
X 
 
X 
 
X 
 
Flow cytometry for PNH/C3 deposition 
X 
 
X 
 
X 
 
X 
 
X 
 
Plasma Hb 
X 
 
X 
 
X 
 
X 
 
X 
 
Urine pregnancy test. J 
X 
 
X 
 
X 
 
X 
 
X 
 
FACIT fatigue Scale 
X 
 
 
 
X 
 
 
 
X 
 
LASA QoL 
X 
 
 
 
X 
 
 
 
X 
 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Thrombosis record (MAVE). K 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
See footnotes below continuation flow chart 
 


 
 
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Protocol: APL2-202 
Version 3.0:   31-JAN-2018 
 
Study Period 
Part 2B - Treatment (Daily from Day 85 to Day 364) (L) 
Study Week 
13 to 16 
17 to 20 
21 to 24 
25 to 28 
29 to 32 
33 to 36 
Study Day 
85 
86 to 112 
113 
114 to 140 
141 
142 to 168 
169 
170 to 196 
197 
198 to 224 
225 
226 to 252 
Vaccination 
X 
 
 
 
 
 
 
 
 
 
 
 
Preventive antibiotic. B 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination. C 
X 
 
 
 
 
 
 
 
 
 
 
 
12-lead electrocardiogram. D 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
APL-2 administration. E 
S 
H 
S 
H 
S 
H 
S 
H 
S 
H 
S 
H 
Injection site assessment. F 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital sign measurements. G 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Blood. I 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Pharmacokinetics. I 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Anti-APL-2 Ab assay 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Hematology and chemistry.  
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Coagulation profile 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Complement profile (C3, CH50 and AP50) 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Flow cytometry for PNH/C3 deposition 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Plasma Hb 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Urine pregnancy test. J 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
FACIT fatigue Scale 
X 
 
 
 
X 
 
 
 
X 
 
 
 
LASA QoL Scale 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Thrombosis record (MAVE) K 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
See footnotes below continuation flow chart 
 
 


 
 
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- CONFIDENTIAL - 
Page 16 of 55 
 
Protocol: APL2-202 
Version 3.0:   31-JAN-2018 
 
Study Period 
Part 2B - Treatment (Daily from Day 85 to Day 364) (L) 
Study Week 
37 to 40 
41 to 44 
45 to 48 
49 to 52 
Study Day 
253 
254 to 280 
281 
282 to 308 
309 
310 to 336 
337 
338 to 364 
Informed Consent 
 
 
 
 
 
 
 
 
Review entry criteria 
 
 
 
 
 
 
 
 
Preventive antibiotic. B 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination. C 
X 
 
 
 
 
 
X 
 
12-lead electrocardiogram. D 
X 
 
X 
 
X 
 
X 
 
APL-2 administration. E 
S 
H 
S 
H 
S 
H 
S 
H 
Injection site assessment. F 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
Vital sign measurements. G 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
 
X 
 
X 
 
X 
 
Blood. I 
X 
 
X 
 
X 
 
X 
 
Pharmacokinetics. I 
X 
 
X 
 
X 
 
X 
 
Anti-APL-2 Ab assay 
X 
 
 
 
X 
 
 
 
Hematology and chemistry.  
X 
 
X 
 
X 
 
X 
 
Coagulation profile 
X 
 
X 
 
X 
 
X 
 
Complement profile (C3, CH50 and AP50) 
X 
 
X 
 
X 
 
X 
 
Flow cytometry for PNH/C3 deposition 
X 
 
X 
 
X 
 
X 
 
Plasma Hb 
X 
 
X 
 
X 
 
X 
 
Urine pregnancy test. J 
X 
 
X 
 
X 
 
X 
 
FACIT fatigue Scale 
X 
 
 
 
X 
 
 
 
LASA QoL Scale 
X 
 
 
 
X 
 
 
 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
Thrombosis record (MAVE). K 
X 
X 
X 
X 
X 
X 
X 
X 
See footnotes below continuation flow chart 
 


 
 
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- CONFIDENTIAL - 
Page 17 of 55 
 
Protocol: APL2-202 
Version 3.0:   31-JAN-2018 
 
Study Period 
Part 3 – Follow-up and Exit. (M) 
Study Week 
53 
55 
57 
60 
Study Day 
365 
379 
393 
414 
Informed Consent 
 
 
 
 
Review entry criteria 
 
 
 
 
Preventive antibiotic. B 
X 
X 
 
  
Physical examination. C 
X 
 
 
X 
12-lead electrocardiogram. D 
X 
 
 
 
APL-2 administration. E 
 
 
 
 
Injection site assessment. F 
X 
 
 
 
Concomitant medications 
X 
X 
X 
X 
Vital sign measurements. G 
X 
X 
X 
X 
Urinalysis 
X 
X 
X 
X 
Blood. I 
X 
X 
X 
X 
Pharmacokinetics. I 
X 
X 
X 
X 
Anti-APL-2 Ab assay 
X 
 
 
X 
Hematology and chemistry. 
X 
X 
X 
X 
Coagulation profile 
X 
X 
X 
X 
Complement profile (C3, CH50 and AP50) 
X 
X 
X 
X 
Flow cytometry for PNH/C3 deposition 
X 
X 
X 
X 
Plasma Hb 
X 
X 
X 
X 
Urine pregnancy test. J 
X 
 
X 
X 
FACIT fatigue Scale 
X 
 
X 
X 
LASA QoL Scale 
X 
 
X 
X 
Adverse events 
X 
X 
X 
X 
Thrombosis record (MAVE) K 
X 
X 
X 
X 
See study flow chart footnotes on next page 
 
 
 


 
 
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- CONFIDENTIAL - 
Page 18 of 55 
 
Protocol: APL2-202 
Version 3.0:   31-JAN-2018 
 
FOOTNOTES: 
A. If required i.e. not previously vaccinated subjects will receive vaccinations against Neisseria meningitides types A, C, W, Y and B, Streptococcus 
pneumoniae and Haemophilus influenzae Type B (Hib).  If the subject’s first documented Neisseria meningitidis vaccine/s are administered at 
Day 15, a booster (for both vaccinations) should be administered after 2 months. If Pneumococcal vaccination is required, a dose of PCV13 will 
be administered at Day 15 and a dose of PPSV23 will be administered at least 8 weeks later (unless documented evidence exists that subjects 
are non-responders to vaccination as evidenced by titers or display titer levels within acceptable local limits). The PI will discuss with the Sponsor 
in regard to specific patient requirements 
B.  Preventive antibiotics will be prescribed from Day 1. Antibiotics will be taken from Day 1 until 14 days after the first dose of APL-2. Specifically: 
• 
Day 1 to Day 14: Ciprofloxacin 500 mg twice daily (take post dose ECG before Ciprofloxacin is administered on days 1). 
• 
Day 15 onwards: Penicillin V 500 mg twice daily. 
C. Full physical examination will be performed at the scheduled time points indicated. A symptom-driven physical examination may be performed at 
other times, at the PI’s discretion. 
D. If done on a dosing day, electrocardiograms (ECGs) are to be performed within 30 minutes after dosing. 
E. S = Administration at clinical site. H = Administration at subject’s home, workplace, or other location convenient to the subject. Treatment may be 
stopped at any time if the investigator and sponsor conclude that there is no demonstration of clinical benefit to continue APL-2 administration 
past this point. 
F. Injection site assessment will be performed within 30 minutes after APL-2 administration. Ambulatory syringe infusion pump training will include 
instructions to report any injection site reaction to the PI. 
G. At clinic visits, vital signs will be measured within 2 hours prior to dosing and within 30 minutes after dosing. When APL-2 is self-administered, 
pre- and post-dose vital signs will not be measured. 
H. Reserved – See note E. 
I. 
If done on a dosing day, blood samples will be taken pre-dose with the exception that on Day 1 only a pharmacokinetic sample will be taken pre-
dose and at a minimum of 2.5 hours post-dose or immediately prior to discharge from the clinic (if subject is kept at the clinic longer than 2.5 
hours). 
J. If done on a dosing day, urine pregnancy test should be completed for WOCBP prior to dosing.  
K. MAVE = Major Adverse Vascular Event. Ambulatory syringe infusion pump training will include instructions to report any events to the PI. 
L. If dose is increased during Part 2B, subjects will come back to the clinical site for safety visits every other week for the first 6 weeks of the dose 
change. These visits may alternate with the monthly visits and should be recorded as unscheduled visits. The same procedures listed under the 
monthly visits will be performed. 
M. Subjects that discontinue dosing at any time during Part 1, 2A or 2B will move directly into Part 3 for safety follow up visits.


 
 
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- CONFIDENTIAL - 
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Protocol: APL2-202 
Version 3.0:  31-JAN-2018 
3. ABBREVIATIONS 
ADA 
Anti-drug Antibodies 
ADL 
Activities of daily living 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AP50 
Alternative Pathway 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
BID 
Twice Daily 
BUN 
Blood urea nitrogen 
C 
Degrees Celsius 
C3 
Complement Component 3 
CD71+ 
Transferrin Receptor 
CK 
Creatine kinase 
cm 
Centimeter 
CRF 
Case report form 
CS 
Clinically significant abnormality 
ECG 
Electrocardiogram 
FACIT 
Functional Assessment of Chronic Illness Therapy 
FDA 
Unites States Foods and Drug Administration 
g 
Gram(s) 
GCP 
Good clinical practice 
GGT 
Gamma-glutamyl transpeptidase 
GLP 
Good laboratory practice 
µg 
Microgram(s) 
Hb 
Haemoglobin 
hERG 
Human ether-à-go-go-related gene 
Hib 
Haemophilus influenzae Type B (vaccine) 
IB 
Investigator’s brochure 
ICH 
International Conference on Harmonization 
IEC 
Institutional Ethics Committee 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
IV 
Intravenous 
IVT 
Intravitreal 
kDa 
Kilodalton 
kg 
Kilogram(s) 
L 
Litre(s) 
LASA 
Linear Analog Scale Assessment for Quality of Life 
LD 
Lactate dehydrogenase 


 
 
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- CONFIDENTIAL - 
Page 20 of 55 
Protocol: APL2-202 
Version 3.0:  31-JAN-2018 
LLN 
Lower Limit of Normal 
MAC 
Membrane attack complex 
MAVE 
Major Adverse Vascular Event 
MedDRA® 
Medical Dictionary for Regulatory Activities 
mg 
Milligram(s) 
mL 
Millilitre(s) 
MOP 
Manual of Procedures 
NCS 
Not clinically significant 
NOEL 
No observed effect level 
NOAEL 
No observed adverse effect level 
NZW 
New Zealand White 
PCV13 
Pneumococcal conjugate vaccine 
PD 
Pharmacodynamic(s) 
PEG 
Polyethylene glycol 
PEG40 
Polyethylene glycol (40 kDa nominal molecular weight) 
PI  
Principal Investigator or designee 
PK 
Pharmacokinetic(s) 
PPSV23 
Pneumococcal polysaccharide vaccine 23   
PT 
Prothrombin time 
PNH 
Paroxysmal nocturnal hemoglobinuria 
QTc 
Corrected QT interval 
QTcB 
Bazett’s correction 
QTcF 
Fridericia’s correction 
RBC 
Red blood cell 
SAA 
Severe aplastic anaemia 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous  
SMC 
Safety Monitoring Committee 
SOP 
Standard operating procedure 
t½ 
Serum half-life 
TEAE 
Treatment-emergent adverse event 
TK 
Toxicokinetic(s) 
ULN 
Upper Limit of Normal 
WBC 
White blood cell 
WHO 
World Health Organization 
WOCBP 
Woman of Child-Bearing Potential 
4. INTRODUCTION 
4.1 
Background 
This study is being conducted as part of a series of studies for the clinical development of APL-2. 
The study will be conducted in compliance with the protocol, Good Clinical Practice (GCP), and 


 
 
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- CONFIDENTIAL - 
Page 21 of 55 
Protocol: APL2-202 
Version 3.0:  31-JAN-2018 
applicable regulatory requirements. The subject population will be comprised of adult male and 
female subjects with paroxysmal nocturnal hemoglobinuria (PNH). 
4.1.1 Paroxysmal Nocturnal Hemoglobinuria 
PNH is an acquired, clonal, non-malignant hematological disease characterized by complement-
mediated RBC hemolysis with or without hemoglobinuria, an increased susceptibility to thrombotic 
episodes, and/or some degree of bone marrow dysfunction. The onset of PNH is often insidious. 
Although there have been reports of spontaneous remission, the course of the disease is generally 
chronic and progressive. 
It has been known for many years that PNH is caused by complement-mediated lysis of 
erythrocyte clones lacking functional CD55 and CD59 on their surface to protect them against this 
process. As such, these erythrocytes are particularly susceptible to the membrane attack complex 
(MAC) and have been shown to lyse readily in the presence of complement activation. 
Any therapy that effectively inhibits MAC formation is anticipated to be a plausible candidate-
treatment for PNH. Indeed, eculizumab is a monoclonal anti-C5 antibody that inhibits the formation 
of the MAC, and eculizumab treatment has been approved for the treatment of this serious 
condition. However, inhibition of MAC formation does not appear to be sufficient to fully control the 
disease, as many PNH patients receiving eculizumab treatment still suffer from anemia, with only 
roughly 13% of patients being classified as complete responders, i.e. achieving transfusion 
independence and normal Hb levels. Most of the patients (53%) were classified as partial 
responders with decreased transfusion needs and reduced LD, and 33% of patients were poor 
responders, with unchanged transfusion needs and persistent symptoms (DeZern, 2013). 
Recent studies have suggested that significant opsonization of PNH erythrocytes by C3 fragments 
is observed in patients receiving eculizumab treatment. This opsonization is believed to cause the 
removal of erythrocytes by the spleen and the liver, resulting in extravascular hemolysis. 
Extravascular hemolysis can be significant in a subset of eculizumab-treated PNH patients and is 
considered to be the principal contributor to the lack of complete eculizumab response in most 
patients. It is reasonable, therefore, to expect that a treatment able to inhibit both MAC formation 
and C3 opsonization will provide improved therapeutic benefit to PNH patients compared to 
eculizumab. 
An overview of available information regarding APL-2 follows below. Further details can be found 
in the APL-2 Investigator’s Brochure (Apellis Pharmaceuticals, June 2017). 
4.1.2 APL-2 
APL-2 is formed by a pentadecapeptide (combining a cyclic tridecapeptide active C3-inhibiting 
moiety and a 2-amino acid linker) covalently coupled to each end of a linear 40 kDa PEG chain, so 
there are two peptide moieties per molecule of APL-2. 
The peptide portion of the drug binds to complement C3 and is a broad inhibitor of the complement 
cascade, a biological process that is part of innate immunity and is involved in multiple 
inflammatory processes. The PEGylation of the molecule imparts slower elimination from 
mammalian systems following administration.  
APL-2 injection (drug product) is a solution of APL-2 in 5% dextrose or a solution of APL-2 in 
acetate-buffered mannitol or a solution of APL-2 in acetate-buffered sorbitol for SC administration. 
APL-2 is being developed for the treatment of paroxysmal nocturnal hemoglobinuria (PNH). 


 
 
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Protocol: APL2-202 
Version 3.0:  31-JAN-2018 
4.1.3  Nonclinical Data 
4.1.3.1 Pharmacology 
Primary Pharmacology: Subcutaneous (SC) and intravenous (IV) doses of APL-2 were shown to 
be pharmacologically active (as measured by a drop in CH50) in monkeys as soon as 8 hours 
following initial administration and persisting up to 72 hours after the last dose. Ex vivo studies 
conducted with blood from PNH patients revealed that an APL-2 concentration of ≥100 µg/mL can 
protect PNH erythrocytes (RBCs) from complement-mediated lysis while simultaneously preventing 
RBC opsonization by C3 fragments.  APL-2 was as effective as eculizumab, an anti-C5 
monoclonal antibody approved for PNH, in protecting PNH erythrocytes against membrane attack 
complex-mediated hemolysis but, unlike eculizumab, APL-2 was also effective in preventing 
opsonization of those cells by C3 fragments. 
Safety Pharmacology: The potential for APL-2 to inhibit human ether-a-go-go gene (hERG)-
encoded ion channels and pose a risk for cardiac arrhythmias indicates that such a risk is low.  
Similarly, no evidence of APL-2-related adverse effects on myocardial conduction, cardiovascular 
and respiratory systems, and body temperature control mechanisms have been observed in either 
rabbits or monkeys.  
4.1.3.2 Pharmacokinetics 
Pharmacokinetic (PK) and toxicokinetic (TK) assessments of APL-2 have been investigated after 
IV and SC administration to New Zealand White (NZW) rabbits and cynomolgus monkeys. The PK 
behavior of APL-2 in rabbits and monkeys has been consistent with the expected PK behavior of a 
PEGylated peptide.  APL-2 is readily absorbed from SC injections in both species, with an 
estimated bioavailability of approximately 85% in monkeys.  Repeated administrations of APL-2 
have indicated that absorption is non-linear at higher doses, and the potential for bioaccumulation 
exists.  No gender-related differences have been observed in either species after 6 or 9 months of 
SC dosing in rabbits and monkeys, respectively.  Terminal elimination half-lives (t1/2), estimated 
during 4-week, drug-free, recovery phases of the 28-day SC studies were between 2.48–2.78 days 
in rabbits and 6.29–8.25 days in monkeys.  Similarly, the t1/2 was estimated to be between 2.3 and 
2.6 days in rabbits and 6.0 days in monkeys after two IV doses separated by 14 days. 
4.1.3.3 Toxicology 
The toxicological potential of APL-2 has been investigated in repeat-dose toxicity studies in rabbits 
and monkeys across three routes of administration (SC, IV, IVT) under a testing strategy designed 
to facilitate differentiation between potential changes attributable to APL-2 per se and those 
attributable to the PEG40 domain of the drug molecule.   
Daily subcutaneous administration of APL-2 and PEG40 for a duration of 6 months in rabbits and 9 
months in monkey were associated with little systemic toxicity noted in either species beyond 
observations in the kidney (noted below).  APL-2 and PEG40 were weakly to mildly immunogenic 
in rabbits, but not significantly immunogenic in monkeys.  Single- or multi-tissue (or multi-organ) 
macrophage vacuolation was consistently observed in both species, and generally comparable in 
incidence and severity between APL-2- and PEG40-treated groups; thus, it was concluded the 
finding were caused by the PEG40 domain present within APL-2.  Renal tubular degeneration was 
observed with a higher incidence in the monkey 9-month study in APL-2-treated animals compared 
to the PEG40-treated ones and was concluded to be APL-2 related. 
The no-observed-adverse-effect-level (NOAEL) for SC-administered APL-2 was <1 mg/kg/d in 
rabbits and approximately 7 mg/kg/d in monkeys after 6- and 9-month chronic dosing, respectively.  
Intravenous arms included in the 28-day repeat-dose SC studies of APL-2 in rabbits and monkeys 
suggested that IV-administered APL-2 was well-tolerated in both species, with only vacuolation of 


 
 
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Protocol: APL2-202 
Version 3.0:  31-JAN-2018 
tubular epithelial cells in the kidney observed microscopically in rabbits (which, again, was deemed 
to be caused in part by the PEG40 domain of APL-2).  IV APL-2 was mildly immunogenic in rabbits 
(albeit less than what was observed by the SC route), and without immunologic effects in monkeys.  
The no-observed-effect-level (NOEL) by the IV route of administration for both rabbits and 
monkeys was determined to be ≥42 mg/kg after two doses separated by 14 days. 
Repeated intravitreal administration (i.e. once every 4 weeks) of APL-2 to monkeys for up to 
9 months was well-tolerated and revealed no drug-related systemic or ophthalmological changes.  
APL-2 may be minimally immunogenic when administered intravitreally, as evidenced by a single 
monkey having a marginal titer of APL-2 antibodies.  The NOEL by the IVT route of administration 
for monkeys was determined to be ≥24.8 mg/eye. 
APL-2 has not demonstrated genotoxic potential in any in vitro or in vivo genotoxicity assays 
conducted, to date. 
4.1.4 Clinical Data 
To date, two Phase I studies in healthy volunteers have been conducted in order to assess safety 
and PK parameters of APL-2 administered as single and multiple dose SC injections and to guide 
dose selection for clinical studies in PNH subjects.  
A single Phase I single ascending dose study has evaluated intravenous dosing of APL-2 in 
healthy volunteers.  
A further five Phase I studies evaluating APL-2 delivered by SC injection are either planned or 
ongoing. These include two studies in healthy volunteers, a study in subjects with severe renal 
impairment and two ongoing clinical studies in PNH patients.  
A phase IIa study in patients with autoimmune hemolytic anemia is also ongoing.  
Table 1 summarises the information for all completed and ongoing studies evaluating systemic 
administration of APL-2.  
Table 1: Summary of all clinical studies of systemically administered APL-2 (up to 
September 2017)  
Protocol 
Number 
/Phase/Status 
Protocol Title 
Study Population 
Subjects 
Planned/Treated 
Endpoints 
Planned Dosage Regimen 
SUBCUTANEOUS 
APL-CP0713-1 
Phase I 
Complete 
Phase I, Double-blind, 
Randomized, Single 
Ascending Dose Study in 
Healthy Volunteers 
31 healthy 
volunteers 
  APL-2: 24/24 
  Placebo: 7/7 
Safety, tolerability, 
PK and PD of 
single ascending 
doses (SAD) of 
APL-2 
SAD: 45, 90, 180, 360, 720, 1440 mg 
Single dose 
 
APL-CP1014 
Phase I 
Complete 
Phase I, Double-blind, 
Randomized, Multiple 
Ascending Dose Study in 
Healthy Volunteers 
20 healthy 
volunteers 
  APL-2: 16/6 
  Placebo: 4/4 
Safety, tolerability, 
PK and PD of 
multiple ascending 
(MAD) doses of 
APL-2 
MAD: 30, 90, 180, 270 mg/day for 28 
days 
APL2-CP-PV-
205 
Phase I 
Ongoing 
A Phase I, Single-Dose, 
Open-Label Study to Evaluate 
the Effect of Renal Impairment 
on the Pharmacokinetics of 
APL-2 
8 subjects with 
severe renal 
impairment and 8 
matched controls 
APL-2: 16/1 
Comparative PK 
between subjects 
with severe renal 
impairment and 
matched controls 
270 mg single dose 
APL2-101 
Phase I 
Ongoing 
A Phase I, Double-Blind, 
Randomized Study of Daily, 
Twice-Weekly and Once-
Weekly APL-2 in Healthy 
Volunteers 
22 Healthy 
Volunteers 
APL-2: 16/0 
Placebo: 6/0 
Safety, tolerability, 
PK and PD of APL-
2 
360 mg daily 
1300 mg twice weekly 
2600 mg weekly 


 
 
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Protocol: APL2-202 
Version 3.0:  31-JAN-2018 
Protocol 
Number 
/Phase/Status 
Protocol Title 
Study Population 
Subjects 
Planned/Treated 
Endpoints 
Planned Dosage Regimen 
TBD (Final Cohort if dosed) 
APL-2-102 
Phase I 
Ongoing 
Phase I, Double-blind, 
Randomized, Single 
Ascending Dose Study in 
Healthy Japanese Volunteers 
20 Healthy 
Volunteers 
  APL-2: 16/0 
  Placebo: 4/0 
Safety, tolerability, 
PK and PD of 
single ascending 
doses (SAD) of 
APL-2 
SAD: 180, 360, 720, 1440 mg Single 
dose 
 
APL-CP0514 
Phase I 
Ongoing 
An Open Label, Single and 
Multiple Ascending Dose 
Study to Assess the Safety, 
Tolerability, Pharmacokinetics 
and Pharmacodynamics of 
APL-2 as an Add-On to 
Standard of Care in Subjects 
with PNH.  
12 patients with 
PNH – Eculizumab 
  APL-2: 12/121 
Safety, tolerability, 
PK and PD 
Cohort 1: 25 mg SD followed by 28 
days washout then 5 mg/day for 28 
days 
Cohort 2: 50 mg SD followed by 28-
day washout then 30 mg/day for 28 
days 
Cohort 3: 180 mg/day for 28 days 
Cohort 4: 270 mg/day for up to 2 
years (ongoing) 
APL2-CP-PNH-
204 
Phase Ib 
Ongoing 
A Phase Ib, Open Label, 
Multiple Ascending Dose, Pilot 
Study to Assess the Safety, 
Preliminary Efficacy and 
Pharmacokinetics of 
Subcutaneously Administered 
APL-2 in Subjects with PNH. – 
PADDOCK – 
9 patients with PNH 
- Eculizumab naïve 
  APL-2: 9/62 
Safety, tolerability, 
PK and PD 
Cohort 1: 180 mg/day for 28 days3 
Cohort 2: 270 mg/day for up to 365 
days (ongoing) 
APL2-CP-AIHA-
208 
Phase IIa 
Ongoing 
An Open Label, Prospective 
Study to Assess the Safety, 
Tolerability, Efficacy and 
Pharmacokinetics of APL-2 in 
Subjects with Warm Antibody 
Autoimmune Hemolytic 
Anemia (wAIHA) or Cold 
Agglutinin Disease (CAD) 
6 patients with 
wAIHA and 6 
patients with CAD 
APL-2: 12/0 
Safety, tolerability, 
PK and PD of SAD 
APL-2 
270 mg/day for 1 year  
 
360 mg/day for 1 year 
INTRAVENOUS 
APL2-CP-HV-
401  
Phase I 
Complete 
A Phase I, Double-blind, 
Randomized, Placebo-
Controlled, Single Ascending 
Dose Study of Intravenous 
APL-2 in Healthy Volunteers  
20 healthy 
volunteers 
   APL-2: 16/16 
   Placebo: 4/4 
Safety, tolerability, 
PK and PD of SAD 
APL-2 
SAD: 200, 600, 1500 and 2300 mg IV 
- Single dose 
4.1.5 Completed Clinical Studies in Healthy Volunteers 
The two completed clinical studies investigating the safety, tolerability and PK of single (APL-CP-
0713-1) and multiple (APL-CP-1014) SC doses of APL-2 in healthy volunteers showed that overall, 
single doses of APL-2, up to a dose of 1440 mg, and repeated daily doses of APL-2 up to a dose 
of 270 mg, appeared safe and well tolerated when administered to healthy volunteers by SC 
injection.  
                                                 
 
1 One subject is included in 3 cohorts and is counted three times and one subject is included in two cohorts and is counted twice. 
2 One subject is included in 2 cohorts and is counted twice. 
3 One subject received only a single dose of 180 mg then withdrew consent. 


 
 
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Serum APL-2 concentrations generally increased linearly with dose. APL-2 was slowly absorbed 
into the systemic circulation with median Tmax values between 4.5 and 6 days across the dose 
groups. APL-2 serum concentration declined in a steady mono-exponential manner with a 
consistent rate of decay across two studies for all dose groups. Both studies demonstrated a slow 
terminal elimination with median t½ values between 8 and 10 days. 
Plasma complement C3 increased with increasing dose and a general dose-dependent reduction 
in AP50 was observed following multiple dosing with APL-2. Pharmacodynamic (PD) observations 
were consistent with a conclusion that APL-2 interacts with complement C3 and inhibits its 
activation. 
Further details can be found in the current APL-2 Investigator’s Brochure.  
4.1.6 Ongoing Clinical Studies 
As of September 2017 there were two ongoing Phase I clinical studies evaluating SC administered 
APL-2 in PNH patients (APL-CP0514 and APL-2-CP-PNH-204). An interim analysis has been 
performed for both studies with a data cut at 85 days of treatment for all subjects: 
1. APL-2-CP-PNH-204 is a Phase Ib, open-label study in patients with PNH who are not 
receiving eculizumab. The study is comprised of 2 cohorts with three subjects in cohort 1 
(180 mg/day APL-2) and at least 6 subjects in Cohort 2 (270 mg/day APL-2). Cohort 1 
has completed and Cohort 2 is ongoing. Two of 3 subjects who have entered into Cohort 
2 have completed 3 months of treatment with APL-2 270 mg/day. The third subject 
withdrew, for personal reasons, after receiving 29 days of treatment. A protocol 
amendment allowed intra-subject dose escalations up to 360 mg/day. Based on the 
clinical benefit observed, both subjects who continued dosing beyond 29 days were 
eligible to enter an extension phase (Part 2B) allowing them to continue to receive dosing 
with APL-2 for up to 1-year. One subject withdrew for personal reasons; 1 subject entered 
the extension phase and received daily doses of APL-2 for >8 months including doses of 
360 mg for >3 months, but was diagnosed with a malignancy, unrelated to the study drug, 
and treatment was withdrawn in April 2017; the remaining subject continues to receive 
APL-2 270 mg/day. Based on the emerging data, a country specific protocol was 
submitted and the subject may continue dosing for up to 729 days. This study is currently 
being expanded into Asia. 
2. APL-CP0514 is a Phase Ib, open-label study being conducted at multiple clinical sites in 
the United States to assess the safety, tolerability, PK and PD of APL-2 as an add-on to 
eculizumab in subjects with PNH. The study is comprised of 4 cohorts in total; 3 cohorts 
(Cohorts 1-3) with two subjects per cohort, and one cohort with six subjects (Cohort 4). 
Cohorts 1 to 3 have completed and Cohort 4 is ongoing. All six subjects in Cohort 4 
completed at least 3 months of treatment with APL-2 270 mg/day. A protocol amendment 
allowed intra-subject dose escalations up to 360 mg/day. Based on the clinical benefit 
observed all subjects entered an extension phase allowing them to continue to receive 
dosing with APL-2 for up to 1 year. Two subjects have withdrawn from the study; 1 subject 
became pregnant and was withdrawn as per protocol and the 2nd subject was withdrawn 
following a number of adverse events related to other co-morbidities. Based on the 
emerging data, dosing will continue for up to 729 days. 
Across the two studies in PNH patients, a total of 14 subjects with PNH have been dosed with 
APL-2, with 9 having received 270 mg/day for 28 day and 8 having received ≥270 mg/day for 
>3 months including 2 who have received 360 mg/day for 2 months. APL-2 has been generally well 
tolerated in these subjects. At approximately bi-monthly intervals, all safety data from each study is 
reviewed by members of an independent SMC who are responsible for providing recommendations 
with respect to monitoring and continuation of the studies.  


 
 
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As of the 1st September 2017, there have been a total of seventeen SAEs reported in five out of 
fourteen subjects across the two studies. Of these, fourteen are considered to be unrelated/unlikely 
to APL-2 and three have been assigned a causality of ‘possibly related’ to APL-2 by the Sponsor. 
Those that are considered possibly related include hypersensitivity reaction, and two incidences of 
increased ALT in a single subject with a history of hepatobiliary disease and similar ALT increases 
prior to study entry. 
Overall, SC administration of APL-2 in PNH patients in the two ongoing clinical studies has been 
generally safe and well tolerated. 
4.2 
Rationale 
4.2.1 Purpose of the Study 
This study will investigate APL-2 in patients with PNH that have not received treatment with 
eculizumab in the past. The assessments of safety, tolerability, preliminary efficacy, PK, and PD 
following administration of multiples doses of APL-2 will be added to the data generated in study 
APL2-CP-PNH-204 to help guide decisions to further develop the drug. 
4.2.2 Dose Selection 
The toxicological data accumulated from the animal studies were used to guide dose selection 
during the Phase I single ascending dose and multiple ascending dose studies in HVs (protocols 
APL-CP0713-1 and APL-CP1014 respectively). In particular, the highest doses were selected 
based on exposure predicted by the PK model and compared with the exposures measured at the 
no observed adverse effect level (NOAEL) in monkeys. 
The planned dose of APL-2 is 270 mg/d. Dose selection was based on targeting a level of 
complement C3 inhibition that will not reduce the levels of uncomplexed C3 (or free C3) to no less 
than about ~10 % of the normal levels of C3 (approximately 1.0-1.3 g/L). The rationale for this limit 
was to preserve some level of complement activity required for adequate immune function. Using a 
Target Mediated Drug Disposition (TMDD) PKPD model (Magar, 2001) the relationship between 
APL-2 PK concentration and complement C3 binding has been well characterized. Subsequently, 
model predictions have been derived to investigate the APL-2 dose-response. Using this TMDD 
PKPD model, the predicted level of free C3 at the dose of 270 mg/d was calculated to be 
approximately 0.13 g/L. For comparison, at the higher dose of 360 mg/d the predicted level of free 
C3 is approximately 0.08 g/L, which is slightly below the self-determined limit of 0.1-0.13 g/L. 
Dose selection is further supported by emerging clinical data from PNH patients receiving daily 
doses of SC APL-2. To date, no safety issues have emerged that preclude further clinical 
investigation with the 270 mg/d dose. 
The proposed dose of 270 mg/d should not produce a significant increase in exposure when 
compared to the previous human experience of a bolus injection of 270 mg/d and is supported by 
the 28-day repeat dose toxicology study in cynomolgus monkeys (study 13CATX-004) and human 
PK data derived from the single- and multiple-dose ascending studies in healthy volunteers 
(protocols APL-CP0713-1 and APL-CP1014). 
4.3 
Risk/Benefit 
A number of safety monitoring practices are required by this protocol (i.e. physical examination, 
vital signs, 12-lead ECG, hematology, serum chemistry, urinalysis, coagulation, prompt reporting of 
pre-defined AEs of special interest, and AE questioning) in order to protect the subjects’ safety. 
Injection/infusion site and pump use safety will be assessed during clinical visits, and any 
significant finding from the assessment will be reported as an AE (see Section 11). 


 
 
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The volume of blood planned for collection from each subject over the course of the study (see 
Section 10.6) will be minimized, in order to minimize the impact on the overall health of these 
anemic subjects. If dose is increased during part 2B, additional blood draws will be required. 
Systemic complement inhibition might predispose individuals to infections caused by encapsulated 
organisms, including Streptococcus pneumoniae, Neisseria meningitides, and Haemophilus 
influenzae. Prophylactic antibiotic therapy  (ciprofloxacin 500 mg BID) will be prescribed to all 
subjects from Day 1 (commencing after first administration of APL-2 and the subsequent post-dose 
PK sample and ECG) to Day 14. At Day 15 all subjects will discontinue treatment with ciprofloxacin 
and receive vaccinations, if required, against Streptococcus pneumoniae, Neisseria meningitides 
A, C, W, Y and B, and Haemophilus influenza.  Prophylactic antibiotic therapy (penicillin V 500 mg 
twice a day) will be prescribed to all subjects from Day 15 and will be taken by subjects until 14 
days after the final dose of APL-2 to minimize potential infection risk.  Body temperature and vital 
signs will be monitored periodically and relevant blood parameters monitored regularly throughout 
the study to assess for signs of infection. The principal investigator (PI) should be contacted 
immediately in the event of a suspected infection despite prophylactic antibiotic treatment for 
guidance and appropriate action to be taken. 
Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in 
patients on beta-lactam antibiotic (e.g. penicillin, amoxicillin, etc.) therapy. These reactions are 
more likely to occur in individuals with a history of penicillin hypersensitivity. Before initiating 
therapy with penicillin V, careful inquiry should be made concerning previous hypersensitivity 
reactions to penicillins or cephalosporins. Patients with a known hypersensitivity to 
penicillin/amoxicillin may be prescribed erythromycin 500 mg twice daily or Azithromycin 500 mg 3 
times per week as alternative treatments at the outset as an alternative treatment at the outset 
(see Section 8.4 for details). 
Other frequently reported adverse effects in patients taking penicillin are diarrhea/loose stools, 
nausea, skin rashes, urticaria and vomiting. Patients should, therefore, be advised that these 
reactions may occur. Treatment may be switched to erythromycin 500 mg twice daily or 
Azithromycin 500 mg 3 times per week (see Section 8.4 for details) if there is evidence of penicillin-
related intolerability (such as nausea and diarrhea).  
There is an anticipated health benefit for trial participants from receipt of study drug. At the 
proposed dose levels of APL-2, a significant decrease in complement-mediated hemolytic activity 
was observed in all APL-2-treated subjects (both treatment-naïve and treated previously with 
eculizumab) in PNH Phase Ib studies and in HV studies. APL-2 is therefore expected to reduce 
complement-mediated hemolytic activity in PNH patients. In this context, a careful evaluation of the 
risk/benefit ratio should be made. APL-2 at the proposed doses has been deemed safe for up to 9 
months of administration in preclinical and 28 days in healthy volunteer studies. In addition, in both 
studies in subjects with PNH (See Section 4.1.4), ongoing treatment with APL-2 270 mg/day has 
been well-tolerated and has provided clinical benefit to subjects either alone or as an add-on to 
eculizumab. Based on this data we propose to continue to administer APL-2 to PNH patients for up 
to 364 days (1 year). See Planned Dose Levels and Dosing Schedule in Section 8.3.2. 
If efficacious and safe, APL-2 is expected to continue to improve Hb levels and reduce transfusion 
dependency in these subjects throughout the treatment period of 364 days. Subjects will be 
assessed by the Investigator every month for Part 2A and Part 2B. The available safety, PK and 
PD data will be reviewed by the Investigator and Sponsor on an ongoing basis. If the dose of APL-
2 is increased to above 270 mg/day, the subject will be assessed by the investigator every 2 weeks 
(recorded as unscheduled visits) for the first 6 weeks after the dose increase, subjects will then 
revert to appropriate time intervals for site visits according to the protocol schedule. APL-2 will only 
be continued in the absence of any safety concerns and with evidence of clinical benefit to the 
subject, as determined by the Investigator and the Sponsor. 


 
 
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If a benefit is observed an extension study will be considered and will be submitted as a further 
protocol amendment or as a follow-up study. 
5. STUDY OBJECTIVES AND ENDPOINTS 
5.1 
Study Objectives 
The objectives of the study are to assess safety, tolerability, preliminary efficacy and PK of multiple 
SC doses of APL-2 in subjects with paroxysmal nocturnal hemoglobinuria (PNH) who have not 
received treatment with eculizumab (Soliris)® in the past. 
An exploratory objective of the study is to assess the pharmacodynamics (PD) of multiple SC 
doses of APL-2 when administered to PNH subjects. See “Study Endpoints” in Section 5.2. 
5.2 
Study Endpoints 
Primary Safety Endpoint: 
The primary safety endpoints of the study are the number and severity of treatment emergent 
adverse events (TEAEs) following administration of multiple doses of SC APL-2. 
Primary Efficacy Endpoints: 
• 
Change from baseline in LD 
• 
Change from baseline in Haptoglobin 
• 
Change from baseline in Hb 
Secondary Endpoints: 
• 
APL-2 plasma concentrations (and PK parameters as appropriate) 
• 
Change from baseline in FACIT Fatigue Scale score 
• 
Change from baseline in reticulocyte count 
• 
Change from baseline in total bilirubin 
• 
Number of RBC transfusions per month 
• 
Change from baseline in Linear Analog Scale Assessment (LASA) for Quality of Life 
Exploratory PD markers include: 
• 
Complement (CH50, AP50, and C3) levels 
• 
C3 deposition on RBC cells 
• 
Clonal distribution of PNH RBCs 
6. STUDY DESIGN 
This is a Phase IIa, open-label, multiple dose, study in patients with PNH who have not received 
eculizumab (Soliris®) in the past. A single cohort of subjects is planned for evaluation.  
Safety will be assessed throughout the study; serial blood and urine samples will be collected for 
these assessments. Blood samples will be collected for the assessment of APL-2 PK. Additional 
samples for assessment of PD will also be collected.  
The study will consist of four parts; 
• 
Part 1: Subjects will receive APL-2 for 28 days.  


 
 
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• 
Part 2A: Following review of available safety, PK and PD data by the investigator and 
sponsor, subjects showing evidence of clinical benefit may progress to Part 2A of the study 
and continue to receive daily doses of APL 2 until Day 84.  
• 
Part 2B: Following review of available safety, PK and PD data by the investigator and 
sponsor subjects showing evidence of clinical benefit may progress to Part 2B of the study 
and continue to receive daily doses of APL 2 until Day 364.  
• 
Part 3: Safety follow up 
Screening will take place within 30 days prior to the start of dosing on Day 1.  
Subjects will be entered into Part 1 of the study on Day 1 at a time designated by the PI. Research 
nurses or other appropriately qualified research personnel will administer the SC infusions for a 
minimum of 3 days (Days 1-3) until the research nurse considers that the subject is both capable 
and confident  to conduct self- administration. The subject will continue to self-administer infusions 
at the clinic on those days when a clinic visit occurs (Day 8, 15 and 22) and at an off-site location 
convenient to the subject on all other days up to Day 28 in Part 1. Following review of available 
safety, PK and PD data by the investigator and sponsor subjects demonstrating clinical benefit 
from the treatment may progress to Part 2A of the study and continue to receive daily doses of 
APL-2 until Day 84, and then may progress to Part 2B of the study and continue to receive daily 
doses of APL-2 until Day 364. Doses will be self-administered throughout this period at an off-site 
location convenient to the subject with the exception of Days 29, 36, 43, 57, 71, 85, 113, 141, 169, 
197, 225, 253, 281, 309, and 337 where dosing is performed by the subject at the clinical site. If a 
subject has a sub-optimal clinical response during daily dosing with 270 mg APL-2, the dose may 
be increased up to 360 mg/day during part 2A, and doses will be administered at the clinical site 
every 2 weeks for the first 6 weeks after commencing the higher dose. After the conclusion of the 
treatment period (Day 364), subjects will enter Part 3 of the study and return to the clinical site for 
follow-up study procedures on Day 365, 379, and 393 and final study procedures at an Exit Visit on 
Day 414. See Study Flowchart in Section 2.  
The planned length of participation in the study for each subject is approximately 444 days (from 
Day –30 through completion of the Day 414 Exit visit procedures). Interim PK and PD analyses 
may be performed to reconsider the sampling time points as the study progresses.  
An independent Safety Monitoring Committee (SMC) will assess the progress and cumulative 
safety/tolerability data of the study on a regular basis. 
Continuation of treatment – Decision scheme 
 
7. SUBJECT SELECTION 
The study will be conducted alongside the ongoing Phase Ib study APL2-CP-PNH-204 
(PADDOCK) to investigate APL-2 in PNH patients who have not previously received treatment with 
eculizumab. Safety and efficacy data from both studies will be used to support the data obtained in 
the Phase III confirmatory study. Up to 20 subjects will be enrolled to complete 28 days of dosing. 
 


 
 
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7.1 
Inclusion Criteria 
At Screening (unless otherwise specified), subjects must fulfill all of the following inclusion criteria 
to be eligible for participation in the study: 
1. At least 18 years old (inclusive) 
2. Diagnosed with PNH (WBC clone >10%) 
3. Lactose dehydrogenase ≥2 times the upper limit of normal 
4. Screening Ferritin  normal and Total Iron Binding Capacity (TIBC) < LLN based on central 
lab reference ranges. If a subject is receiving iron supplements at screening, the 
investigator must ensure that his/her dose has been stable for 8 weeks prior to enrolment 
and must be maintained throughout the study (see Section 8.4.4) 
5. Last transfusion within 12 months prior to screening 
6. Platelet count of >30,000/mm3 at the screening visit 
7. Absolute neutrophil count >500/ mm3 at the screening visit  
8. Women of child-bearing potential (WOCBP) must have a negative pregnancy test at 
screening and must agree to use protocol defined methods of contraception for the duration 
of the study 
9. Males must agree to use protocol defined methods of contraception and agree to refrain 
from donating sperm for the duration of the study 
10. Vaccination against Neisseria meningitides types A, C, W, Y and B, Streptococcus 
pneumoniae and Haemophilus influenzae Type B (Hib) either within 2 years prior to Day 1 
dosing, or within 14 days after starting treatment with APL-2. Unless documented evidence 
exists that subjects are non-responders to vaccination as evidenced by titers or display titer 
levels within acceptable local limits 
11.  Willing and able to give informed consent 
7.1.1 Approved methods of contraception 
Approved methods of contraception include: oral contraceptives, intrauterine device, medically 
acceptable barrier methods (diaphragm or condom), implantable or injectable contraceptives (like 
Norplant or DepoProvera) or removable birth control device (like NuvaRing or Evra patches); 
and/or surgical sterilization (at least 6 months before dosing). Subjects practicing abstinence and 
coitus interruptus (pull out method) must agree to use an approved method of contraception during 
the study. 
7.2 
Exclusion Criteria 
Subjects will be excluded from the study if there is evidence of any of the following criteria at 
screening or check-in, as appropriate. 
1. Prior eculizumab (Soliris®) treatment  
2. Active bacterial infection 
3. Hereditary complement deficiency 
4. History of bone marrow transplantation 
5. Concurrent SAA, defined as currently receiving immunosuppressive therapy for SAA 
including but not limited to cyclosporin A, tacrolimus, mycophenolate mofetil or anti-
thymocyte globulin 


 
 
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6. Participation in any other investigational drug trial or exposure to other investigational 
agent, device or procedure within 30 days 
7. Evidence of QTcF prolongation defined as >450 ms for males and >470 ms for females at 
screening 
8. Breast-feeding women 
9. History of meningococcal disease 
8. STUDY TREATMENTS 
8.1 
Allocation to Treatment 
Each subject will be assigned a unique identification number upon screening. Subjects who 
complete the study screening assessments and meet all the eligibility criteria will be scheduled to 
enter the study and receive study treatment. 
8.2 
Blinding 
None; this is an open-label study. 
8.3 
Treatments Administered 
Sterile solutions of APL-2 up to 40 mg/mL in acetate-buffered mannitol administered by 
Subcutanoues infusion. 
8.3.1 Drug supplies 
8.3.1.1 Identity of Investigational Products 
APL-2 will be supplied as a sterile solution of APL-2 in acetate-buffered mannitol at concentrations 
of up to 40 mg/mL, supplied in stoppered glass vials.   
8.3.1.2 Study Supplies 
The Sponsor will supply sufficient quantities of APL-2 drug product to allow completion of this 
study. The lot numbers, manufacture dates, and expiration dates of the drugs supplied will be 
recorded in the final report. The Sponsor will also supply needles, syringes, and ambulatory 
syringe infusion pumps as required. Refer to the Study Operations Manual for further information. 
APL-2 acetate-buffered mannitol solution should be stored at 2-8°C. A pharmacist or appropriately 
qualified designated person will be responsible for storing the APL-2 appropriately; dispensing the 
vials of APL-2 to the subject, study nurse, or other study personnel, and for maintaining 
accountability records.  
8.3.1.3 Accountability 
Records will be made of the receipt and dispensing of APL-2 for administration both on and off-
site. 
At the conclusion of the study, any unused investigational product will either be destroyed at the 
investigator site or be returned to the Sponsor or designee for destruction, and destruction will be 
documented appropriately. If no supplies remain, this fact will be documented appropriately. 
8.3.2 Planned Dose Levels and Dosing Schedule 
Starting on Day 1 (Visit 3), subjects will receive SC APL-2 daily for up to 364 days. 
Planned doses will be as follows: 


 
 
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Cohort 
Planned dosing schedule  
Single cohort 
270 mg/day (up to 360 mg/day from Day 29) from Day 1 to 
Day 364* 
* The dose may be increased up to 360 mg/day during Part 2A if the clinical response is sub-optimal. The volume to 
be administered will depend on the final concentration provided and will be administered as a SC infusion. 
The dose for this study was determined based on safety, PK, and PD data from the ongoing 
studies in PNH patients. 
Intra-subject dose escalations will be agreed by the Investigator and Sponsor and will be 
implemented on an individual subject basis and not necessarily applied across all subjects in the 
cohort. The dose for an individual subject will not exceed 360 mg/day (estimated to reach 
approximately 85 % of the Cmax of the NOAEL observed in monkeys) without a protocol 
amendment. 
8.3.3 Drug Administration 
All doses will be administered as SC infusions.  
 The preferred site of injection will be the abdomen; however, if a subject does not tolerate 
administration into the abdomen alternative sites may be selected e.g. thigh or upper arm. Subjects 
will self-administer the SC infusions after receiving appropriate training by a research nurse or 
other study personnel. The injections will be administered at the clinic on those days when a clinic 
visit occurs and at an off-site location convenient to the subject on all other days. 
Doses will be administered while subjects are seated. 
Dosing records will be maintained at the clinical site and available for review by the sponsor. 
8.4 
Concomitant Medications 
8.4.1 Prophylactic antibiotics 
Prophylactic antibiotic therapy will be prescribed to all subjects to minimize potential infection risk. 
Prophylactic antibiotics will be initiated on day 1 following administration of APL-2 dosing and 
continue until 2 weeks after the last dose. 
8.4.1.1 Primary prophylactic antibiotic Day 1-14 
• 
Ciprofloxacin 500 mg twice daily, initial administration on Day 1 will take place at the initial 
APL-2 dosing, following ECG collection postdose.   
8.4.1.2 Primary prophylactic antibiotic Day 15 onwards 
• 
Penicillin V 500 mg twice daily 
Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in 
patients on beta-lactam antibiotic (e.g. penicillin, amoxicillin, etc.) therapy. These reactions are 
more likely to occur in individuals with a history of penicillin hypersensitivity. Before initiating 
therapy with penicillin V, careful inquiry should be made concerning previous hypersensitivity 
reactions to penicillins or cephalosporins. If subjects have a known hypersensitivity to 
penicillin/amoxicillin they may be prescribed an alternative antibiotic at the outset. 
Other frequently reported adverse effects in patients taking penicillin are diarrhea/loose stools, 
nausea, skin rashes and urticaria, and vomiting. Patients should, therefore, be advised that these 
reactions may occur. 


 
 
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8.4.1.3 Alternative prophylactic antibiotics 
• 
Erythromycin 500 mg twice daily 
• 
Azithromycin 500 mg 3 times per week 
Erythromycin 500 mg twice daily or Azithromycin 500 mg 3 times per week may be considered as 
suitable alternatives in subjects who are unable to tolerate penicillin. 
The PI will discuss and agree to a suitable alternative with the sponsor’s medical monitor. The 
agreement will be noted in the subject’s medical records. 
8.4.2 Rescue antibiotics 
Body temperature, vital signs and relevant blood parameters will be monitored regularly throughout 
the study to assess for signs of infection. The PI should be contacted immediately in the event of a 
suspected infection despite prophylactic antibiotic treatment for guidance and appropriate action to 
be taken. Action to be taken may include administration of a broad spectrum antibiotic to cover 
possible resistant organisms such as resistant pneumococcus (e.g. levofloxacin). 
8.4.3 Vaccinations 
Vaccination against Neisseria meningitides types A, C, W, Y and B, Streptococcus pneumoniae 
and Haemophilus influenzae Type B (Hib) is required to participate in this study, either within 
2 years prior to Day 1 dosing, or within 14 days after starting treatment with APL-2. 
 
If required i.e. not previously vaccinated subjects will receive vaccinations against Neisseria 
meningitides types A, C, W, Y and B, Streptococcus pneumoniae and Haemophilus influenzae 
Type B (Hib).  If the subject’s first documented Neisseria meningitidis vaccine/s are administered at 
Day 15, a booster (for both vaccinations) should be administered after 2 months. If Pneumococcal 
vaccination is required, a dose of PCV13 will be administered at Day 15 and a dose of PPSV23 will 
be administered at least 8 weeks later (unless documented evidence exists that subjects are non-
responders to vaccination as evidenced by titers or display titer levels within acceptable local 
limits). The PI will discuss with the Sponsor in regard to specific patient requirements 
8.4.4 Iron Supplements 
For subjects receiving iron supplements at the time of APL-2 initiation, iron supplement doses 
should be maintained stable throughout the study unless iron levels (ferritin and TIBC) increase to 
unaccepatable levels above ULN during the study. Change in dose of iron supplementation should 
be discussed with the Sponsor prior to implemntation  
8.4.5 Phlebotomy/Venesection for iron overload 
Phlebotomy/Venesection should only be considered if the Hb is within the normal range and may 
only be initiated if the need and frequency have been discussed and agreed to with the Sponsor. 
9. STUDY PROCEDURES 
Please see the Study Flow Chart in Section 2 for a summary of the schedule of study participation 
and procedures. The schedule of visit dates should be established, either, prior to, or at the time of 
screening allowing subjects an opportunity to assess whether there are likely to be significant 
conflicts with other activities or planned absences. To the extent possible, subjects will be 
expected to adhere to the visit schedule and any re-scheduling of visits must be agreed, in 
advance, with the investigator and sponsor to ensure that the dosing of study medication can 
continue daily as required. 
If a subject’s dose is increased beyond 270 mg/day in Part 2B additional site visits will be 
scheduled for the first 6 weeks of dose increase, alternating with the monthly visits in the protocol. 


 
 
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i.e. subjects will return to the clinical site every two weeks for 6 weeks. These will be scheduled by 
the investigator and the same procedures as the monthly visits will be performed. These visits will 
be recorded as unscheduled visits. 
9.1 
Screening 
Screening will begin within 30 days prior to dosing to confirm that subjects meet the subject 
selection criteria for the study. Informed consent will be obtained at screening (see Section 13.3.3). 
Subjects will have to meet all eligibility criteria before being enrolled into the study (see Section 7). 
The following will be recorded at screening: medical history and demographic data, including, sex, 
age, race, body weight (kg), height (cm). 
Screening procedures are listed in the Study Flow Chart in Section 2. 
9.2 
Part 1 - Treatment Period – (Days 1 to 28) 
Subjects will receive daily SC doses of APL-2 on Days 1 to 28. APL-2 will be administered at the 
clinical site by study personnel  during the first 3 days  and thereafter by the subject under 
supervision whilst at the clinical site or off-site self-administered by the subject. Subjects will be 
trained to prepare and administer their infusions of APL-2, complete the administration diary and 
injection site assessment.   
9.2.1 On Site Administration (Day 1 to Day 3 and Days 8, 15 and 22) 
The first 3 daily SC doses of APL-2 (Day 1 to 3) will be administered by study personnel. Doses on 
8, 15 and 22 will be administered, by the subject under supervision, at the clinical site. Subjects will 
remain in the clinic for at least 2.5 hours after receiving the first dose of APL-2 on Day 1. 
If required subjects will receive vaccinations on Day 15 with boosters scheduled appropriately. 
Antiobiotic therapy will be changed from ciprofloxacin to penicillin V. 
Blood samples for laboratory analysis, PK/PD, and antigenicity will be taken during site visits as 
outlined in the Study Flow Chart in Section 2. 
Specific procedures for each visit are listed in the Study Flow Chart.  
9.2.2 Outpatient Administration (Day 4 to Day 28) 
From Day 4 to Day 28 daily doses of APL-2 will be self-administered by the subject at home with 
the exception of Days 8, 15 and 22 (see above). 
Subjects will be trained to notify the PI or other study personnel in the event that an injection site 
reaction occurs after self-administration of APL-2. All clinically significant findings, as determined 
by the investigator, from injection site or related to pump use will be recorded as AEs. 
9.3 
Part 2A - Treatment Period – (Days 29 to 84) 
Each subject will receive daily SC doses of APL-2 on Days 29 to 84. APL-2 will be administered by 
the subject. If a clinical benefit is not observed, treatment will stop on Day 28. The subject will skip 
Part 2A and enter Part 3 for safety follow up visits.  
9.3.1 On Site Administration (Days 29, 36, 43, 57 and 71) 
Daily SC doses of APL-2 on Days 29, 36, 43, 57 and 71 will be administered at the clinical site by 
the subject.  
Blood samples for laboratory analysis, PK/PD and antigenicity will be taken during site visits as 
outlined in the Study Flow Chart in Section 2. 


 
 
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Specific procedures for each visit are listed in the Study Flow Chart.  
9.3.2 Outpatient Administration (Day 30 to Day 84) 
From Day 30 to Day 84 daily doses of APL-2 will be self-administered by the subject at an off-site 
location convenient to the subject, with the exception of Days 36, 43, 57 and 71 (see above) where 
the dose will be administered at the clinical site by the subject. 
9.4 
Part 2B - Treatment Period – (Days 85 to 364) 
Each subject will receive daily SC doses of APL-2 on Days 85 to 364. APL-2 will be administered 
at the site by the subject. If a clinical benefit is not observed, treatment will stop on Day 84. The 
subject will skip Part 2B and enter Part 3 for safety follow up visits.  
9.4.1 On Site Administration (Days 85, 113, 141, 169, 197, 225, 253, 281, 309, 
and 337) 
Daily SC doses of APL-2 on Days 85, 113, 141, 169, 197, 225, 253, 281, 309, and 337 will be 
administered at the clinical site by the subject.  
Blood samples for laboratory analysis, PK/PD and antigenicity will be taken during site visits as 
outlined in the Study Flow Chart in Section 2. 
Specific procedures for each visit are listed in the Study Flow Chart.  
9.4.2 Outpatient Administration (Day 85 to Day 364) 
From Day 85 to Day 364 daily doses of APL-2 will be self-administered by the subject, with the 
exception of Days when the subject attends clinic visits (see above). 
9.5 
Part 3 - Follow-up - (Days 365, 379, and 393)  
All subjects that complete Part 2B of the study will be asked to return to the clinical facility in Part 3 
for follow-up visits on Days 365, 379, and 393. All subjects that complete Part 2A but do not enter 
Part 2B of the study will be asked to return to the clinical facility in Part 3 for follow-up visits on 
Days 85, 99 and 113. All subjects that are not eligible to enter Part 2A of the study will be asked to 
return to the clinical facility in Part 3 for follow-up visits on Days 29, 43 and 57. 
Specific procedures including blood collection for laboratory analysis, PK/PD and antigenicity for 
each visit are listed in the Study Flow Chart. 
9.5.1 Exit Visit (Day 414, or Day 134, or Day 78)  
All subjects will be asked to return to the clinical facility for the Exit Visit 7 weeks after the final dose 
of APL-2. 
Study participation for each subject will be concluded following completion of the Exit Visit. 
Subjects that complete Part 2B and Part 3 of the study will attend an Exit Visit on Day 414. 
Subjects that are not eligible to enter Part 2B but complete Part 2A of the study will attend an Exit 
Visit on Day 134. Subjects that are not eligible to enter Part 2A but complete Part 3 of the study will 
attend an Exit Visit on Day 78. If a subject withdraws from the study prior to the scheduled Exit 
Visit, all Exit Visit evaluations should be performed at the subject’s final visit to the clinic, including 
the collection of blood samples for PK and/or PD assessments, as well as a post-dose antigenicity 
sample if not yet collected. 
The Exit Visit procedures are listed in the Study Flow Chart in Section 2. 


 
 
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9.5.2 Unscheduled Follow-up Visits 
All subjects will be asked to return to the clinical facility for additional follow-up visits if considered 
necessary by the PI or if PK/PD sampling schedule is modified or extended based on interim 
results. 
Unscheduled follow-up visits may include any of the procedures listed in the Study Flow Chart in 
Section 2. 
9.5.3 Scheduled End of Study 
The end of the study is scheduled after completion of the Exit Visit evaluations.  
9.6 
Periodic Safety Review 
A periodic safety review will take place on a regular (approximately bi-monthly) basis as detailed 
below.  
9.6.1 Safety Monitoring Committee 
A Safety Monitoring Committee (SMC) will review cumulative safety/tolerability data (e.g., physical 
examinations, ECGs, vital signs, clinical laboratory tests, and adverse events [AEs]), efficacy (LD 
levels, haptoglobin levels, Hb levels, reticulocyte counts, and RBC transfusions) and PK data 
including predicted exposures based on emerging PK data. The SMC will have the responsibility to 
conduct a thorough safety assessment at regular intervals during the treatment phase of the study. 
A key responsibility of the SMC will be to decide whether to continue or modify the study based on 
recommendations by the sponsor and upon an evaluation of emerging safety and efficacy data. 
The first SMC meeting will be scheduled within 3 months after the first subject is randomized, and 
a future intervals presented within the SMC charter. Regular or ad hoc SMC data reviews may be 
recommended by the SMC or requested by the Sponsor.  
If efficacious and safe, APL-2 may reduce LD levels, improve Hb levels and reduce transfusion 
dependency in these patients. The SMC will be responsible for reviewing individual subject data to 
understand if there is a health benefit in these individuals at any time during the treatment period. If 
a benefit is observed the SMC may recommend extending the treatment beyond 364 days either 
through a protocol amendment or an extension study. 
The remit, roles, and responsibilities of the SMC will be specified in a separate SMC charter. 
9.7 
Removal of Subjects from the Study 
Subject participation in this study may be discontinued for any of the following reasons: 
1. Occurrence of any medical condition or circumstance that exposes the subject to 
substantial risk and/or does not allow the subject to adhere to the requirements of the 
protocol. 
2. Any SAE, clinically significant AE, severe laboratory abnormality, intercurrent illness, or 
other medical condition that indicates to the PI that continued participation is not in the best 
interest of the subject. 
3. Subject's decision to withdraw. 
4. Subject failure to comply with protocol requirements or study-related procedures. 
5. Termination of the study by the Sponsor, FDA, or other regulatory authorities. 
The clinical report will include reason(s) for subject withdrawals as well as details relevant to the 
subject withdrawal. If a subject is withdrawn from the study prior to study completion, the subject 
will undergo all procedures scheduled for study completion (Exit Visit) as the situation allows. Any 


 
 
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subject withdrawn due to an AE (whether serious or non-serious) or clinically significant abnormal 
laboratory test values will be evaluated by the PI or a monitoring physician and will be treated 
and/or followed up until the symptoms or values return to normal or acceptable levels, as judged by 
the PI. 
Subjects who are withdrawn may be replaced. Replacement of subjects will be discussed on a 
case by case basis. 
10.  ASSESSMENTS 
10.1 
Assessments 
Assessments to be performed during the study are described below. Every effort should be made 
to ensure that the protocol-required assessments are completed as described.  
If deemed necessary, additional safety measurements will be performed at the discretion of the PI. 
10.1.1 Body Height and Weight 
Body height (cm) and body weight (kg) will be measured at screening as part of the physical 
examination.  
10.1.2 Physical Examination 
All physical examinations will include, at a minimum, assessment of the following: general, head, 
ears, eyes, nose and throat, dentition, thyroid (endocrine), heart, chest, lungs, abdomen, skin, 
extremities, back/neck, musculoskeletal, and lymph nodes. 
A licensed physician employed at the study site will examine each subject as outlined in the Study 
Flow Chart in Section 2. 
Medical history will be recorded at screening.  
A symptom-driven physical examination may be performed at various unscheduled time points if 
deemed necessary by the PI. 
10.1.3 Vital Signs 
Single measurements of body temperature, respiratory rate, blood pressure, and heart rate will be 
measured as outlined in the Study Flow Chart in Section 2. 
Vital signs may be taken at any other times, if deemed necessary. Blood pressure and heart rate 
measurements will be performed with subjects in a seated position after resting for 5 minutes, 
except when they are supine or semi-reclined because of study procedures and/or AEs (e.g., 
nausea, dizziness) or if deemed necessary by the PI. 
Vital signs will be measured before venipuncture and ECG. 
At clinic visits vital signs will be measured pre- and post-dose. Vital signs will be measured within 2 
hours prior to dosing for the pre-dose time point. Post-dose vital signs readings will be performed 
within approximately 30 minutes after dosing. 
10.1.4 Electrocardiogram Monitoring 
Single 12-lead ECGs will be done at the time points outlined in the Study Flow Chart in Section 2. 
If done on dosing days, ECGs will be performed within approximately 30 min after dosing. 
ECGs will be taken following resting in the supine position for 10 min in a quiet environment. 
ECGs will be interpreted and signed and dated by the PI. The ECGs will be classified as normal, 
having a not clinically significant (NCS) abnormality, or having a clinically significant (CS) 


 
 
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abnormality. In addition, ECG parameters of ventricular rate, PQ or PR interval, QRS duration, and 
QT interval (corrected using both Bazett’s and Fridericia’s method and uncorrected) will be noted 
on the CRF. All CS findings will be recorded as AEs. 
10.1.5 Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue 
Scale 
The FACIT Fatigue Scale is a 13 item Likert scaled instrument which is self-administered by the 
subjects during clinic visits on as outlined in the Study Flow Chart in Section 2. The subject is 
presented with 13 statements and is asked to indicate their response 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, some responses are reversed to ensure that the higher score corresponds to a 
higher quality of life. The FACIT Fatigue Scale and scoring guidelines are provided in the Manual 
of Procedures (MOP). 
10.1.6 Linear Analog Scale Assessment (LASA) for Quality of Life 
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. A representation of the scale is presented in Appendix 2 
(see Appendix 2). LASA is self-administered by the subjects during clinic visits as outlined in the 
Schedule of Events in Section 2. Scores for the three individual components of the scale and the 
combined score will be included in the analysis and this will be described in the Statistical Analysis 
Plan. 
10.1.7 Clinical Laboratory Tests 
All tests listed below will be performed as outlined in the Study Flow Chart in Section 2. In addition, 
laboratory safety tests may be performed at various unscheduled time points, if deemed necessary 
by the PI or recommended by the SMC. The clinical laboratory tests include (but are not limited) 
the following: 
10.1.7.1 Hematology 
• 
Hb 
• 
Hematocrit 
• 
RBC count 
• 
Platelet count  
• 
WBC count with differential 
• 
Reticulocytes 
10.1.7.2 Coagulation 
• 
Prothrombin time (PT) 
• 
Fibrinogen 
• 
Activated partial thromboplastin 
time (aPTT) 
• 
D-Dimer 
10.1.7.3 Serum Chemistry 
• 
Blood urea nitrogen (BUN) 
• 
Creatinine 
• 
Estimated creatinine clearance 
(using Cockcroft-Gault formula) –
screening only 
• 
Bilirubin (total and direct) 
• 
Albumin 
• 
Aspartate aminotransferase 
(AST) 
• 
ALT 
• 
Uric acid 
• 
Glucose  
• 
Sodium 


 
 
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• 
Alkaline phosphatase (ALP) 
• 
Lactate dehydrogenase (LD) 
• 
Haptoglobin 
• 
Gamma-glutamyl transpeptidase 
(GGT) 
• 
Creatine kinase (CK) 
• 
Potassium 
• 
Chloride 
• 
Ferritin 
• 
B12/folate 
• 
Total Iron Binding Capacity 
(TIBC) 
10.1.7.4 Urinalysis 
• 
pH 
• 
Specific gravity 
• 
Protein 
• 
Glucose 
• 
Ketones 
• 
Bilirubin 
• 
Blood 
• 
Nitrite 
• 
Urobilinogen 
• 
Leukocyte esterase 
If an abnormality is noted for protein, blood, nitrite and/or leukocyte esterase, a 
microscopic examination will be performed. 
10.1.7.5 Human Chorionic Gonadotropin (Serum Pregnancy Test) and Follicle-
Stimulating Hormone 
Serum Pregnancy Test will be performed for females only. FSH will be performed for 
postmenopausal females at screening only. 
10.1.8 Injection/ Infusion Site and Pump Safety Assessment 
On the days of clinical visits, an assessment of the APL-2 injection site, and pump use safety will 
be performed within 30 minutes after study drug administration. The assessment will be performed 
by a physician or other licensed health care provider (e.g. study nurse) as delegated by the 
investigator. The injection site and the surrounding area will be inspected for redness, swelling, 
induration, and bruising; and the subject will be asked about the presence of pain and/or 
tenderness, and any issue related to pump use. The date, time, and outcome of the injection site 
assessment will be recorded on the source documents and CRFs.  
Subjects will be trained to notify the PI or other study personnel in the event that an injection site 
reaction occurs after self-administration of APL-2. All clinically signficant findings, as determined by 
the investigator, from injection site or related to pump use will be recorded as AEs. 
10.2 
Pharmacokinetic Assessments 
10.2.1 Blood Sampling and Processing 
Blood samples for PK assessment of APL-2 will be collected via direct venipuncture at the time 
points delineated in the Study Flow Chart in Section 2. 
On Day 1 only, a PK sample will be taken pre-dose and at a minimum of 2.5 hours post-dose (or 
later depending on how long the subject is kept at the clinic). All PK samples on other study days 
will be collected pre-dose. 
Instructions for collection, handling, processing, storage, and shipping of samples will be provided 
in a separate sample handling manual prior to study initiation. 


 
 
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10.2.2 Analytical Method 
Serum sample analysis will be performed using GLP-compliant validated procedures and methods. 
The methods used and the results obtained will be included in the final report as an appendix. 
10.3 
Flow Cytometry Assessments 
Blood samples will be collected via direct venipuncture at the time points delineated in the Study 
Flow Chart in Section 2. Flow cytometry assessment will include, but not be limited to: PNH clonal 
distribution of RBCs, CD71+ immature reticulocytes, monocytes and granulocytes and C3 
deposition on RBCs.  
Instructions for collection, handling, processing, storage, and shipping of samples will be provided 
in a separate sample handling manual prior to study initiation. 
10.4 
Pharmacodynamic Assessments 
Blood samples will be collected via direct venipuncture at the time points delineated in the Study 
Flow Chart in Section 2. for PD assessment of complement activation through the classical (e.g., 
CH50) and alternative (e.g., AP50) pathways. Blood samples will also be collected to measure C3 
levels. Other relevant PD markers may also be assessed. 
Instructions for collection, handling, processing, storage, and shipping of samples will be provided 
in a separate Laboratory Reference Manual prior to study initiation. 
10.5 Anti- APL-2 Antibody Assessment  
Patients who test positive for anti-APL-2 antibodies at any time will be followed with ADA samples 
being collected every 6 months until the antibody levels revert to baseline.  Samples that test 
positive will be characterized by an assay that will determine antibody titer, binding to the cyclic 
peptide or PEG domains, and measure neutralizing capacity. 
The proposed ADA sampling schedule was established to capture the ADA signal at baseline, 
along with any potential early onset and the dynamic profile (transient or persistent) of antibody 
formation while minimizing APL-2 level in the sample. 
 
 


 
 
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10.6 
Blood Volume for Study Assessments 
Table 2: Blood Volume during Study (up to Day 414) 
Assay 
Number of 
Time Points 
Approximate 
Volume per 
Time Point * 
(mL) 
Approximate Sample 
Volume Over Course 
of Study (mL) 
Pharmacokinetics 
19 
2 
38 
Anti-APL-2 Ab assay 
9 
2 
18 
Hematology 
20 
3 
60 
Chemistry (Incl. screen serology and pregnancy) 
20 
3 
60 
Coagulation profile 
20 
4.5 
90 
Complement profile (C3, CH50 and AP50) 
20 
4 
80 
Flow cytometry for PNH and C3 deposition 
20 
2 
40 
Plasma Hb 
20 
4 
80 
Total Approximate Blood Volume for Study: 
466** 
• 
* Represents the largest collection volume planned over the duration of the study (smaller tubes will be 
used whenever possible). 
• 
** If dose is increased to 360 mg/day, additional blood draws will be scheduled. 
 
10.7 
Pregnancy tests 
For WOCBP, a serum pregnancy test will be performed at screening, and subjects with a positive 
test will be excluded from the study. A follow up urine pregnancy test will be performed on Day 1 
pre-dose (a negative urine pregnancy test must be received before dosing with study drug). A urine 
pregnancy test will also be performed at each site visit (pre-dose) if applicable. A final urine 
pregnancy test will be performed at the final Exit Visit. Male subjects will be counseled to avoid 
donating sperm after dosing on Day 1 until the final Exit Visit. 
11.  ADVERSE EVENTS 
11.1 
Definitions 
An adverse event (AE) is any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. An AE can therefore be any unfavorable and 
unintended sign, including a clinically significant abnormal laboratory finding, symptom, or disease 
temporally associated with the use of a study drug, whether or not considered related to the study 
drug.  
Adverse events include the onset of new illness and the exacerbation of pre-existing conditions. 
Any medical condition that is present at the time that the subject is screened should be recorded 
on the medical history eCRF and not reported as an AE. However, if that condition deteriorates or 
severity changes at any time during the study, it should be recorded as an AE. 
Any AEs that occur prior to dosing on Day 1 will be categorized as pre-treatment events. 
Treatment-emergent adverse events (TEAEs) will be defined as those AEs that occur after dosing 
on Day 1 and up to 30 days after the last dose of study medication.  
A suspected adverse reaction means any AE for which there is a reasonable possibility that the 
drug caused the AE. Reasonable possibility means there is evidence to suggest a causal 
relationship between the drug and the AE.  


 
 
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11.2 
Recording Adverse Events 
Subjects will be monitored for adverse events throughout the study. Adverse events may be 
volunteered spontaneously by the study subject, or discovered by the study staff during physical 
examinations, or by asking open, non-leading questions (e.g. “How have you been feeling since 
the last clinic visit?”). Subjects will be instructed to inform the investigator and/or study staff of any 
AEs that may occur at any time during the study. 
All AEs occurring from screening through the final Exit visit will be recorded in detail in the source 
documents and documented on the appropriate AE or SAE eCRF. The nature of the AE, date (and 
time, if known) of AE onset, duration, severity, and action taken will be documented, together with 
the PI’s assessment of the seriousness of the AE and relationship to study drug. All AEs should be 
recorded in the study subject’s own words (verbatim), unless in the opinion of the PI, the AE 
constitutes a recognized condition, disease, or syndrome. In that case, the condition, disease or 
syndrome should be named rather than the individual symptoms. The AEs will be coded using the 
current Medical Dictionary for Regulatory Activities (MedDRA).  
Outcome will be recorded as:  
• 
Ongoing  
• 
Resolved 
• 
Resolved with sequela  
• 
Death or  
• 
Unknown 
11.3 
Assessment of Adverse Events 
Each AE will be assessed by the PI or physician designee with regard to the categories discussed 
in the sections below. 
11.3.1 Intensity 
The PI will determine the severity of each AE. AEs will be graded according to the Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03. The following definitions for rating 
severity will be used: 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated. 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; 
limiting age-appropriate instrumental Activities of Daily Living 
(ADL)*. 
Grade 3 
Severe or medically significant but not immediately life-
threatening; hospitalization or prolongation of hospitalization 
indicated; disabling; limiting self-care ADL**. 
Note: An experience may be severe but may not be serious, e.g., 
severe headache). 
Grade 4 
Life-threatening consequences; urgent intervention indicated. 
Grade 5 
Death related to AE 
• 
A semi-colon indicates ‘or’ within the description of the grade. 
• 
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing 
money, etc. 
• 
**Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and 
not bedridden. 


 
 
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When changes in intensity of an AE occur more frequently than once a day, the maximum intensity 
for the event should be noted for that day. Any change in severity of signs and/or symptoms over a 
number of days will be captured and recorded as a new AE, with the amended severity grade, and 
the date and time (if known) of the change. 
11.3.2 Causality 
The relationship of an AE to the study drug will be assessed using the following criteria: 
Definitely 
Related 
• 
Event or laboratory test abnormality, with plausible time relationship to drug intake 
• 
Cannot be explained by disease or other drugs 
• 
Response to withdrawal plausible (pharmacologically, pathologically) 
• 
Event definitive pharmacologically or phenomenologically (i.e. an objective and specific 
medical disorder or a recognized pharmacological phenomenon) 
• 
Rechallenge satisfactory, if necessary 
Possibly 
Related 
• 
Event or laboratory test abnormality, with reasonable time relationship to drug intake 
• 
Could also be explained by disease or other drugs 
• 
Information on drug withdrawal may be lacking or unclear 
Unlikely 
Related 
• 
Event or laboratory test abnormality, with a time to drug intake that makes a 
relationship improbable (but not impossible) 
• 
Disease or other drugs provide plausible explanations 
Not Related 
• 
Event or laboratory test abnormality, is plausibly related to the participant’s clinical 
state, underlying disease, or the study procedure/conditions 
• 
Time relationship to drug intake makes a relationship unreasonable 
• 
Other obvious causes for event or laboratory test abnormality exist 
Unknown 
• 
Report suggests an adverse event, however, cannot be judged at this time because 
information is insufficient or contradictory 
• 
More data for proper assessment is needed, or additional data is under examination 
 
11.3.3 Serious Adverse Event 
A serious adverse event (SAE) is defined as any untoward medical occurrence that at any dose: 
• 
Results in death; 
• 
Is life-threatening: this means that the subject was at risk of death at the time of the event; it 
does not mean that the event might have caused death had it occurred in a more severe 
form; 
• 
Required hospitalization or prolongation of existing hospitalization; 
• 
Results in persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions; 
• 
Is a congenital anomaly or birth defect. 
Important medical events that may not result in death, be life-threatening, or require hospitalization 
may be considered serious when, based upon appropriate medical judgment, they may jeopardize 
the patient or subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in the above definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias 
or convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse. 
Medical and scientific judgment should be exercised in deciding if an AE is serious and if expedited 
reporting is appropriate. 


 
 
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11.4 
Reporting Serious Adverse Event 
The reporting period for adverse events begins as soon as the subject’s written consent to 
participate in the study has been obtained, and continues through the final Exit visit, or 30 days 
after the final dose of study medication. The PI is responsible for reporting all SAEs to the Safety 
Monitor, whether or not the event is considered related to the study drug.  
If an SAE occurs, the PI should complete and sign the SAE Report Form, and fax or email it to the 
Safety Monitor at the number/address which will be provided separately to the investigator sites, 
within 24 hours of becoming aware of the event:  
The initial SAE Report should include, at a minimum, the following information: 
• 
Study number 
• 
Subject number/ID 
• 
Gender 
• 
Date of birth 
• 
Name of PI and full clinical site address 
• 
Details of SAE 
• 
Criterion for classification as “serious” 
• 
Study drug name and treatment start date 
• 
Date of SAE onset 
• 
Causality assessment (if sufficient information is available to make this determination) 
The Safety Monitor, or designee, will request clarification of omitted or discrepant information from 
the initial report. The PI or designee is responsible for emailing or faxing the requested information 
to the Safety Monitor within 24 hours of the request.  
Initial reports of SAEs must be followed later with detailed descriptions, including clear copies of 
supporting documents as necessary (e.g. hospital discharge summary, laboratory reports, autopsy 
reports, etc.), with the subject’s personal identifiers removed. If a new SAE Report Form is faxed, 
the PI must sign and date the form.  
The PI must report all SAEs to the IRB/IEC according to the institutional IRB/IEC policy.  
11.5 
Adverse Events of Special Interest 
An adverse event of special interest is one of scientific and medical concern specific to the 
Sponsor’s product or program where ongoing monitoring and rapid communication by the PI to the 
Sponsor may be appropriate. These adverse events may be serious or non-serious. Applicable 
adverse events may require further investigation in order to characterize and understand, and 
depending upon the nature of the event, rapid communication by the trial Sponsor to other parties 
may also be required. These adverse events of special interest must be reported promptly to the 
sponsor. The adverse events of special interest include the following: 
• 
Local or systemic infection of any origin 
• 
Thrombosis 
• 
Clinically significant decrease in kidney function 
• 
Injection site reactions 
If an adverse event of special interest occurs in a study subject, the study subject will be followed 
for resolution of the adverse event. A decision will be made by the Sponsor concerning further 
exposure to the study treatment and further participation in the study. 


 
 
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11.6 
Unexpected Adverse Events or Unexpected Suspected Adverse Reactions 
An AE or suspected adverse reaction is considered “unexpected” if it is not listed in the 
Investigator’s Brochure (IB) or is not listed at the specificity or severity that has been observed; or 
is not consistent with the risk information described in the general investigational plan or elsewhere 
in the current application. For example, under this definition, hepatic necrosis would be unexpected 
(by virtue of increased severity) if the IB referred only to elevated hepatic enzymes or hepatitis.  
The Sponsor will be responsible for reporting any serious and unexpected adverse events to the 
applicable regulatory agencies as required.  
11.7 
Treatment and Follow up of Adverse Events 
AEs (whether serious or non-serious), including clinically significant abnormal laboratory test 
values, will be evaluated by the Investigator and treated and/or followed up until the symptoms or 
value(s) return to baseline or are clinically stable. Treatment of AEs will be performed by 
appropriately trained medical personnel, either at the clinical site or at a nearby hospital 
emergency room. When appropriate, medical tests and/or examinations will be performed to 
document resolution of the event(s).  
AEs continuing after completion of the study will be followed up by telephone or with visits per the 
discretion of the PI. If possible, the outcome of any AE that caused discontinuation from the study 
or was present at the end of the study should be reported, particularly if the AE was considered by 
the PI to be related to the study drug. 
11.8 
Pregnancy  
Although pregnancy is not considered an AE, the outcome of a pregnancy, if there is a 
spontaneous abortion, congenital anomaly or other adverse fetal outcome, may be an SAE. All 
SAEs are to be reported to the study sponsor on the SAE Reporting Form. Pregnancies will be 
reported using a pregnancy report form. 
WOCBP and males with female partners of child-bearing potential will be instructed to practice an 
acceptable method of birth control (as defined in Section 7.1.1) for the duration of the study. 
If a female subject or partner of a male subject becomes pregnant during the study, the PI should 
report the pregnancy to the Safety Monitor within 24 hours of being notified. The subject or partner 
should be followed by the PI until completion of the pregnancy. At the completion of the pregnancy, 
the PI will document and report the outcome. If the outcome of the pregnancy meets the criteria for 
classification as an SAE (i.e. postpartum complication, stillbirth, neonatal death, or congenital 
anomaly) the PI should follow the procedures for reporting an SAE (Section 11.4).   
12. STATISTICS  
12.1 
Sample Size Justification 
The study will be conducted alongside the ongoing Phase Ib study APL2-CP-PNH-204 
(PADDOCK) to investigate APL-2 in PNH patients who have not previously received treatment with 
eculizumab. Safety and efficacy data from both studies will be used to support the data obtained in 
the Phase III confirmatory study. Up to 20 subjects will be enrolled to complete 28 days of dosing. 
The sample size is considered sufficient to obtain useful safety, tolerability, PD and PK data to 
support the clinical program.  
12.2 
Statistical Analysis Methodology  
A formal Statistical Analysis Plan (SAP) will be developed and finalized prior to locking the 
database. The full details of data presentations and analyses will be provided therein. Additional 
statistical analyses other than those described in this section may be performed if deemed 


 
 
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appropriate and included in the SAP. Any deviations from the final analysis plan or from what is 
outlined in the protocol will be discussed in the final study report. 
No formal inferential statistics will be applied to data collected in the study. 
The data from this study will also be pooled with the Cohort 2 data from the Phase Ib study APL2-
CP-PNH-204 (PADDOCK), which also investigates 270mg/day APL-2 in PNH patients who have 
not previously received treatment with eculizumab.  The details of reporting this pooled data will be 
documented in a separate SAP. 
12.2.1  Analysis Populations 
12.2.1.1 Screened Population 
The Screened Population will include all subjects who signed the informed consent form and are 
screened for participation in this study. This set will be used only for the purpose of describing 
subject disposition.  
12.2.1.2 Safety Population/ Intent to Treat (ITT) Population 
The Safety Population will include all subjects eligible to receive study medication and who receive 
at least one dose of study medication. The Intent to Treat Population will be identical to the Safety 
Population for this study. All baseline characteristics, demographic and efficacy endpoint data will 
be presented using the ITT Population.  
12.2.1.3 Pharmacokinetic (PK) Population 
The PK Population will include all subjects in the Safety Population who have at least one 
quantifiable concentration of APL-2. 
12.2.1.4 Pharmacodynamic (PD) Population 
The PD Population will include all subjects in the Safety Population who have at least one 
quantifiable post dose PD parameter. 
12.2.1.5 Data Review for Analysis Populations 
 
After all the data have been verified/coded/entered into the database, a review will be performed. 
The purpose of this review will be to define the analysis populations. The review will also check the 
quality of the data, identifying outliers, and making decisions on how to deal with problems in any 
data (e.g., missing values, withdrawals, protocol deviations). After the pre-analysis review, 
resolution of all issues and documentation of all decisions, the database will be locked. 
12.2.2 Study Endpoints 
12.2.2.1 Safety Endpoints  
The primary safety endpoints of the study are the number and severity of TEAEs. Safety will also 
be assessed through vital signs, 12-lead ECG and laboratory safety data. Changes from baseline 
will be calculated using the last measurement prior to the start of dosing as baseline. 
12.2.2.2 Efficacy Endpoints 
Changes from baseline and percentage changes from baseline in LD, haptoglobin and Hb are the 
primary efficacy endpoints. They will be calculated for each post dose assessment, where the 
baseline will be taken as the last measurement prior to the start of dosing. 


 
 
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12.2.2.3 Secondary Endpoints 
Secondary endpoints include: 
• 
changes from baseline in FACIT Fatigue Scale (Version 4)  
• 
changes from baseline and percentage changes from baseline in reticulocyte count 
• 
changes from baseline and percentage changes from baseline in total bilirubin 
• 
changes from baseline in the number of RBC transfusions per month and number of units 
transfused per month 
• 
changes from baseline in LASA scale scores (individual and combined). 
Baseline will be taken as the last measurement prior to the start of dosing. For transfusions 
baseline will be taken from the 12 month transfusion history. 
12.2.2.4 Pharmacokinetic Endpoints  
Plasma concentrations of APL-2 will be determined from multiple samples taken between Day 1 
and the Exit Visit. 
12.2.2.5 Exploratory Pharmacodynamic Endpoints (Markers) 
Changes from baseline and percentage changes from baseline will be calculated for each of the 
complement parameters (CH50, AP50 and C3), C3 deposition on RBC cells and clonal distribution 
of PNH RBCs. Baseline will be taken as the last measurement prior to the start of dosing. 
12.2.3 Safety Analyses 
All safety endpoints will be evaluated using the Safety Population. 
12.2.3.1 Adverse Events 
Treatment emergent adverse events (TEAE) are defined as those AEs that develop or worsen after 
the first dose of study medication and up to 30 days beyond the last dose of study medication. The 
current version of Medical Dictionary for Regulatory Activities (MedDRA) will be used to classify all 
AEs. 
TEAE will be summarized by system organ class and preferred term. Tabulations will be produced 
for all TEAEs, for those considered potentially treatment related (causality to study drug is reported 
as possibly or probably, or where causality is not reported) and for TEAE of special interest. 
Number of subjects reporting SAEs will also be tabulated.   
A by-subject TEAE data listing, including verbatim term, preferred term, treatment, severity, and 
investigator judgment of relationship to treatment, will be provided. 
12.2.3.2 Clinical Laboratory Tests 
A by-subject listing will be provided including changes from baseline. Laboratory values that are 
outside the laboratory reference range will be flagged. 
12.2.3.3 Vital Signs and ECGs 
Observed and change from baseline values for vital sign and ECG parameter will be listed. 
Values of potential clinical significance (e.g. change in QTcF ≥30ms from baseline) will be flagged 
in listings and summarized. 


 
 
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12.2.4 Efficacy and Secondary Endpoint Analyses 
The efficacy and secondary endpoints will be evaluated for the ITT Population.  
Absolute values, changes from baseline and percentage changes from baseline (where 
appropriate) will be summarised, using descriptive statistics, by study visit. Data will be plotted by 
study day. 
The number of RBC transfusions per month and number of units transfused per month will be 
summarized over the study.   
12.2.5 Pharmacokinetic Analyses  
The PK concentrations will be evaluated using the PK Population. 
Individual concentration over time profile plots will be presented. Median profiles of the 
concentration-time data, using nominal sampling times, will also be presented. Both linear-linear 
and linear-log plots will be presented. APL-2 concentrations will be summarized by study visit using 
descriptive statistics. 
Where appropriate, steady-state PK parameters for APL‐2 will be estimated from the individual 
serum concentrations-time data, using actual sample times using a non-compartmental approach. 
PK parameters will include: 
AUCtotal: The area under the serum concentration versus time curve, from time 0 (pre-dose Day 1) 
to the last measurable concentration (t) at the end of study. 
Ctrough,max: Maximum observed pre-dose serum concentration. 
PK parameters will be summarized using descriptive statistics.  
PK data will be combined with the prior data collected in earlier clinical studies and then used to 
update the APL-2 population PK model (Apellis Data on File). 
12.2.6 Pharmacodynamic Analyses 
The PD parameters will be evaluated using the PD Population. 
Absolute values, changes from baseline and percentage changes from baseline will be 
summarised, using descriptive statistics, by study visit. Individual parameter over time profile plots 
will be presented. Median profiles over time, using nominal sampling times, will also be presented. 
12.2.7 Handling of Dropouts and/or Missing Data 
No imputation of missing data for early terminations will be performed.  
Where appropriate screen values may be used as baseline in the event of missing Day 1 
measurements. 
Missing dates/times will be reviewed on a case by case basis for potential imputations, but the 
original data will always be presented in data listings.  
PK concentration values below the limit of quantification will take the value of 0 in individual linear-
linear profile plots and the limit of quantification in linear-log profile plots. 
12.2.8 Other Data Analyses 
Demographic data, baseline characteristics, physical examination, concomitant medication and 
medical history data will be listed. The current versions of the World Health Organization (WHO) 
and MedDRA coding dictionaries will be used for the concomitant medications and medical 
histories respectively. 


 
 
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12.3 
Interim Analyses 
As mentioned in Section 9.6, a periodic safety review will take place on a regular basis by the SMC 
to review safety/tolerability, PK and PD data. 
Data may be reported while the study is ongoing to help guide decisions to further develop APL-2. 
These reports will be performed on data that will have been fully checked and considered as final. 
Any changes to the data previously reported will be fully auditable and discussed in subsequent 
reports. 
13. ADMINISTRATIVE CONSIDERATIONS 
13.1 
Direct Access to Source Data/Documents 
The PI must maintain, at all times, the primary records (i.e. source documents) of each subject’s 
data for data verification. Examples of source documents are medical records, laboratory reports, 
study drug records, and eCRFs that are used as the source. 
The PI will permit trial-related monitoring, audits, and inspections by the Sponsor and/or its’ 
designee, IRB/IEC, and the regulatory agencies at any time during the study. The PI will ensure 
that the auditor is allowed direct access to the source data, medical records, eCRFs, and the Site’s 
regulatory file for the study and any other pertinent information.  
13.2 
Quality Control and Quality Assurance 
This study is to be performed in full compliance with the protocol, Good Clinical Practices (GCP), 
and applicable regulatory requirements. The PI, Sponsor and/or its’ designee are responsible for 
ensuring that the study staff receive appropriate training on the protocol, study procedures and any 
other relevant information.  
Quality assurance and quality control systems are implemented and maintained using written 
Investigative site, Sponsor and/or designee Standard Operating Procedures (SOPs) to ensure that 
the study is conducted and data are generated, documented (recorded), and reported in 
compliance with the protocol, GCP, and the applicable regulatory requirement(s) and local laws, 
rules, regulations. 
Quality control (QC) checks will be applied at each stage of data handling (e.g. edit checks) to 
ensure that all data are reliable and have been processed correctly.  
13.2.1 Monitoring 
On-site monitoring will be performed by the Sponsor’s designee for the duration of the study. The 
monitor will ensure that the study is conducted, recorded and reported in accordance with the 
protocol, SOPs, GCP, and the applicable regulatory requirements. The monitor will verify the 
accuracy and completeness of the eCRF entries, source documents, and other study-related 
records against each other. The PI will provide direct access to source data/documents for study-
related monitoring. It is important that the PI and the staff are available at these visits. The monitor 
will record the date of each visit together with a summary of the status and progress of the study. 
Proposed actions will be documented in writing to the PI. 
13.3 
Ethics 
13.3.1 Ethical Conduct of the Study 
This research will be carried out in accordance with the protocol, applicable regulations, the ethical 
princliples set forth in the Declaration of Helsinki, and the ICH Harmonized Tripartite Guidance for 
Good Clinical Practice, E6, R1 (ICH GCP). 


 
 
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13.3.2 Institutional Review Board/Ethic Committee 
The study protocol, any amendments to the protocol, informed consent form, the Investigator’s 
Brochure, and other study specific information will be reviewed and approved by the IRB/IEC. The 
study will not be initiated until the IRB/IEC has approved the protocol or a modification thereof. All 
records pertaining to IRB/IEC submission and approval should be kept in the site’s regulatory files 
and Sponsor’s Trial Master File (TMF). 
The IRB/IEC must be constituted and operate in accordance with the principles and requirements 
described in ICH Guidance E6 and local regulations as deemed appropriate. 
13.3.3 Subject Information and Consent 
The PI is responsible for obtaining an informed consent. A written informed consent, in compliance 
with ICH Guidance E6, must be obtained from each subject prior to screening and enrollment or 
performing any study related procedures. 
The purpose of the study, the procedures to be carried out and the potential hazards will be 
described to the subjects in non-technical terms. The subject will be given sufficient time to 
consider the study’s implications before deciding to participate in the study. The subject and/or 
legal guardian (if permitted by local national legislation) will be required to sign and date an 
Informed Consent Form (ICF) and will be assured that they may withdraw from the study at any 
time without jeopardizing their medical care. The PI shall retain the original, signed informed 
consent for study participation in the subject’s medical record and shall provide the subject and/or 
legal guardian with a copy of the signed consent. 
If there are any changes/amendments to the approved protocol, which may directly affect the 
subject’s decision to continue participation in the study, the ICF shall be amended to incorporate 
the changes to the protocol and the subject must re-sign the IRB/IEC approved amended ICF. 
13.3.4 Confidentiality  
Confidentiality of subject’s information must be maintained in accordance with local privacy laws. 
13.3.5 ClinicalTrials.gov  
This study has been listed with ClinicalTrials.gov, as required. 
13.3.6 Termination of Study 
The Sponsor reserves the right to suspend or discontinue this study for administrative and/or 
safety reasons at any time. The PI reserves the right to discontinue dosing subjects at any time for 
safety reasons. 
13.4 
Data Handling and Record Keeping 
The PI must maintain all documentation related to this study. All essential documents (as defined 
in the ICH Guideline E6) and the data generated in connection with this study, together with the 
original copy of the final report, will be retained for at least 5 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or at least 5 years have elapsed since the formal discontinuation of 
clinical development of the investigational product. These documents should be retained for a 
longer period if required by the applicable regulatory requirements or by an agreement with the 
Sponsor.  
It is the responsibility of the Sponsor to inform the PI/Institution as to when these documents no 
longer need to be retained. 


 
 
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13.5 
Protocol Amendments 
Any amendments to the study protocol deemed necessary as the study progresses will be 
discussed between Sponsor and the PI. The PI will not implement any changes to the protocol 
without an agreement by the Sponsor and prior review and documented approval from the IRB/IEC of 
an amendment, except where necessary to eliminate immediate hazards to study subject or when the 
changes involve only logistical or administrative aspects of the study (e.g., change in staff, telephone 
numbers). 
Changes resulting in amendments will be made jointly between the Sponsor and the PI and must 
be confirmed in writing. Amendment(s) will be approved and signed off in the same way as the 
protocol.  
13.6 
Report Format 
According to the ICH Harmonized Tripartite Guideline (Organization of the Common Technical 
Document for the Registration of Pharmaceuticals for Human Use M4 and the ICH M2 Expert 
Working Group), the final report will be written according to the ICH E3 Guideline (Structure and 
Content of Clinical Study Reports). 
13.7 
Finance and Insurance 
Finance and insurance will be addressed in a Clinical Trial Agreement between the PI/Institution 
and the Sponsor (or CRO authorized to enter into Clinical Trial Agreements for and on behalf of the 
Sponsor). 
 
13.8 
Publication Policy 
The data generated for this study are considered confidential information and are the property of 
the Sponsor. All study information provided to the PI and Site personnel by the Sponsor shall not 
be published or disclosed to a third party without the prior written consent of the Sponsor.  
After the completion of the study, the data may be reported at a scientific meeting and/or submitted 
for publication in a scientific journal with the prior written consent of the Sponsor. The Sponsor 
must be given at a minimum 30 days to review the materials to be presented at a scientific meeting 
and/or for publication in a scientific journal.  
 
 
 
 
 
 
 
 
 
 


 
 
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14. REFERENCES 
1. DeZern AE, Dorr D, and Brodsky, RA. Predictors of Hemoglobin Response to Eculizumab 
Therapy in Paroxysmal Nocturnal Hemoglobinuria, Eur J Haematol., 2013, 90(1), p.16-24 
2. Apellis Pharmaceuticals, Inc. Product: APL-2 Injection. Investigator’s Brochure. Final 
Version 1.0. 12 June 2014. 
3. FDA Guidance for Industry: Estimating the Maximum Safe Starting Dose in Initial Clinical 
Trials for Therapeutics in Adult Healthy Volunteers. July 2005. Available online:  
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidance
s/ucm078932.pdf   
4. FDA Guidance for Industry: Toxicity Grading Scale for Healthy Adult and Adolescent 
Volunteers Enrolled in Preventive Vaccine Clinical Trials. September 2007. Available 
online: 
http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInfo
rmation/Guidances/Vaccines/ucm091977.pdf 
5. FDA Guidance for Industry and Investigators:  Safety Reporting Requirements for INDs and 
BA/BE Studies-Small Entity Compliance Guide. December 2012. Available online: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidance
s/UCM332846.pdf 
6. Ivens, I. A., Baumann, A., McDonald, T. A., Humphries, T. J., Michaels, L. A., and Mathew, 
P. (2013). PEGylated therapeutic proteins for haemophilia treatment:  a review for 
haemophilia caregivers. Haemophilia 19:  11-20 
7. Rudmann, D.G., Alston, J.T., Hanson, J.C., and Heidel, S. (2013). High molecular weight 
polyethylene glycol cellular distribution and PEG-associated cytoplasmic vacuolation is 
molecular weight dependent and does not require conjugation to proteins. Toxicol Pathol 
41:  970-983. 
8. Walpole, S.C., Prieto-Merino, D., Edwards, P., Cleland, J., Stevens, G., and Roberts, I. 
(2012). The weight of nations: an estimation of adult human biomass. BMC Public Health 
12 (1): 439. 
9. GBD 2013 Mortality and Causes of Death Collaborators (2015). Global, regional, and 
national age–sex specific all-cause and cause-specific mortality for 240 causes of death, 
1990–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 
2015;385(9963): 117–171. 
 
 


 
 
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15. APPENDIX 1: FUNCTIONAL ASSESSMENT OF CHRONIC ILLNESS THERAPY (FACIT) 
FATIGUE SCALE 
FACIT Fatigue Scale (Version 4) 
Below is a list of statements that other people with your illness have said are important. Please 
circle or mark one number per line to indicate your response as it applies to the past 7 days. 
 
 
 
 
 
 
 
 
 
 
 
 
 
Not at 
all 
A little 
bit 
Some-
what 
Quite 
a bit 
Very much 
 
HI7 
I feel fatigued
 ......................................................................................................... 
0 
1 
2 
3 
4 
HI12 
I feel weak all over
 ......................................................................................................... 
0 
1 
2 
3 
4 
An1 
I feel listless (“washed out”)
 ......................................................................................................... 
0 
1 
2 
3 
4 
An2 
I feel tired
 ......................................................................................................... 
0 
1 
2 
3 
4 
An3 
I have trouble starting things because I am tired
 ......................................................................................................... 
0 
1 
2 
3 
4 
An4 
I have trouble finishing things because I am tired
 ......................................................................................................... 
0 
1 
2 
3 
4 
An5 
I have energy
 ......................................................................................................... 
0 
1 
2 
3 
4 
An7 
I am able to do my usual activities
 ......................................................................................................... 
0 
1 
2 
3 
4 
An8 
I need to sleep during the day
 ......................................................................................................... 
0 
1 
2 
3 
4 
An12 
I am too tired to eat
 ......................................................................................................... 
0 
1 
2 
3 
4 
An14 
I need help doing my usual activities
 ......................................................................................................... 
0 
1 
2 
3 
4 
An15 
I am frustrated by being too tired to do the things I want to do
 ......................................................................................................... 
 
0 
 
1 
 
2 
 
3 
 
4 
An16 
I have to limit my social activity because I am tired
 ......................................................................................................... 
0 
1 
2 
3 
4 


 
 
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Protocol: APL2-202 
Version 3.0:  31-JAN-2018 
FACIT-Fatigue Subscale Scoring Guidelines (Version 4)  
 
Instructions:* 1. Record answers in "item response" column. If missing, mark with an X 
2. Perform reversals as indicated, and sum individual items to obtain a score. 
3. Multiply the sum of the item scores by the number of items in the subscale, then 
divide by the number of items answered. This produces the subscale score. 
4. The higher the score, the better the QOL. 
 
Subscale 
       Item Code       Reverse item?     Item response     
 Item Score  
 
FATIGUE 
 
HI7 
      
4 
- 
________ 
 
=________ 
SUBSCALE  
HI12  
4 
- 
________ 
 
=________ 
    
 
 
An1 
 
4 
- 
________ 
 
=________ 
An2 
 
4 
- 
________ 
 
=________ 
An3 
 
4 
- 
________ 
 
=________ 
An4 
 
4 
- 
________ 
 
=________ 
An5 
 
0 
+ 
________ 
 
=________ 
An7 
 
0 
+ 
________ 
 
=________ 
An8 
 
4 
- 
________ 
 
=________ 
An12  
4 
- 
________ 
 
=________ 
An14  
4 
- 
________ 
 
=________ 
An15  
4 
- 
________ 
 
=________ 
An16  
4 
- 
________ 
 
=________ 
 
Sum individual item scores: 
________ 
Multiply by 13: 
________ 
Divide by number of items 
answered: 
________ (Fatigue Subscale Score) 
*For guidelines on handling missing data and scoring options, please refer to the Administration 
and Scoring Guidelines in the manual or on-line at www.facit.org. 
NOTE: The FACIT and all related works are owned and copyrighted by, and the intellectual 
property of David Cella, Ph.D. Permission for use of the FACIT-FATIGUE questionnaire is 
obtained by contacting Dr. Cella at information@facit.org 
 
 
Score range: 0-52 


 
 
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16. APPENDIX 2: LASA SCALE 
 
 

SAP_001.pdf: 
Apellis                                                          CONFIDENTIAL 
Page 1 of 32 
Statistical Analysis Plan Final version 1.0 
Protocol Number: APL2-202 
[17 Jul 2019] 
STATISTICAL ANALYSIS PLAN
APL-2 
PHASE IIa 
A Phase IIa, Open Label, Multiple Dose Study to Assess the Safety, Efficacy and 
Pharmacokinetics of Subcutaneously Administered APL-2 in Subjects with 
Paroxysmal Nocturnal Hemoglobinuria (PNH) 
PROTOCOL IDENTIFIER: APL2-202 
Study Sponsor(s): 
Apellis Pharmaceuticals 
6400 Westwind Way,  
Suite A, 
Crestwood, KY 40014 
USA 
Author: 
 
 
Protocol: 
 
Version 1.0 (30th November 2017) 
 
Version 2.0 (17th January 2018) 
 
Version 3.0 (31st January 2018) 
SAP Version #:  
1.0 
SAP Date: 
 
17 Jul 2019  
Status: 
  
Final 
Notice of Confidential and Proprietary Information: 
This document is confidential. It contains proprietary information of Apellis Pharmaceutical, Inc. Any 
viewing or disclosure of such information that is not authorized in writing by Apellis Pharmaceutical, Inc is 
strictly prohibited. Such information may be used solely for the purpose of reviewing or performing this 
study. 
PPD


PPD
PPD
PPD
PPD
PPD
PPD
PPD


Apellis                                                          CONFIDENTIAL 
Page 3 of 32 
Statistical Analysis Plan Final version 1.0 
Protocol Number: APL2-202 
[17 Jul 2019] 
REVISION HISTORY 
Version  
Issue Date 
Summary of Changes 
1.0 
17 Jul 2019 
New Document 
 
 
 
 
 
 
 


Apellis                                                          CONFIDENTIAL 
Page 4 of 32 
Statistical Analysis Plan Final version 1.0 
Protocol Number: APL2-202 
[17 Jul 2019] 
TABLE OF CONTENTS 
REVISION HISTORY ..................................................................................................... 3 
TABLE OF CONTENTS ................................................................................................. 4 
ABBREVIATIONS ........................................................................................................... 7 
1. 
INTRODUCTION ................................................................................................. 8 
2. 
OBJECTIVES, ESTIMAND(S), AND ENDPOINTS ........................................ 8 
2.1 
Objectives ........................................................................................................... 8 
2.2 
Estimands ........................................................................................................... 8 
2.3 
Endpoints............................................................................................................ 8 
2.3.1 Primary Endpoints ...................................................................................... 8 
2.3.2 Secondary Endpoints .................................................................................. 9 
2.3.3 Safety Endpoints ......................................................................................... 9 
2.3.4 Pharmacokinetic Endpoints ........................................................................ 9 
2.3.5 Pharmacodynamics Endpoints .................................................................... 9 
3. 
STUDY DESIGN ................................................................................................. 10 
3.1 
General Description ......................................................................................... 10 
3.2 
Randomization ................................................................................................. 11 
3.3 
Blinding ............................................................................................................ 12 
3.4 
Sample Size and Power Considerations ........................................................... 12 
4. 
STATISTICAL ANALYSIS SETS .................................................................... 12 
4.1 
Screened Set ..................................................................................................... 12 
4.2 
Safety Set ......................................................................................................... 12 
4.3 
Intent-to-Treat Set ............................................................................................ 12 
4.4 
Pharmacokinetic Set ......................................................................................... 12 
4.5 
Pharmacodynamic Set ...................................................................................... 12 
5. 
STUDY SUBJECTS ............................................................................................ 13 
5.1 
Disposition of Subjects .................................................................................... 13 
5.2 
Demographic and Other Baseline Characteristics ............................................ 13 
5.3 
Medical History ................................................................................................ 13 
5.4 
Prior Medications ............................................................................................. 13 


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Statistical Analysis Plan Final version 1.0 
Protocol Number: APL2-202 
[17 Jul 2019] 
5.5 
Concomitant Medications ................................................................................ 13 
5.6 
Exposure to Investigational Product ................................................................ 14 
5.7 
Measurements of Treatment Compliance ........................................................ 14 
5.8 
Protocol Deviations .......................................................................................... 14 
6. 
EFFICACY ANALYSES.................................................................................... 14 
6.1 
Analyses of Primary Efficacy Endpoints ......................................................... 15 
6.2 
Analyses of Secondary Efficacy Endpoints ..................................................... 15 
6.2.1 FACIT Fatigue Scale ................................................................................ 15 
6.2.2 Reticulocytes and Total Bilirubin ............................................................. 16 
6.2.3 RBC Transfusions ..................................................................................... 16 
6.2.4 Linear Analog Scale Assessment (LASA) for Quality of Life ................. 16 
7. 
SAFETY ANALYSIS .......................................................................................... 17 
7.1 
Adverse Events ................................................................................................. 17 
7.2 
Clinical Laboratory Data .................................................................................. 18 
7.3 
Vital Signs ........................................................................................................ 18 
7.4 
Electrocardiogram (ECG) ................................................................................ 19 
7.5 
Other Safety Data ............................................................................................. 19 
8. 
PHARMACOKINETIC ANALYSIS ................................................................ 19 
8.1 
Handling BLQ Values ...................................................................................... 19 
8.2 
Drug Concentration .......................................................................................... 19 
8.3 
Pharmacokinetic Parameters ............................................................................ 20 
9. 
PHARMACODYNAMIC ANALYSIS .............................................................. 20 
9.1 
Handling BLQ Values ...................................................................................... 20 
9.2 
Pharmacodynamic Data ................................................................................... 20 
10. 
OTHER ANALYSES .......................................................................................... 21 
11. 
INTERIM ANALYSIS ....................................................................................... 21 
13. 
DATA HANDLING CONVENTIONS ............................................................. 21 
13.1 
General Data Reporting Conventions .............................................................. 21 
13.2 
Definition of Baseline ...................................................................................... 22 
13.4 
Repeated or Unscheduled Assessments of Safety Parameters ......................... 23 
13.5 
Handling of Missing, Unused, and Spurious Data ........................................... 23 


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13.5.1 Missing Data Imputation for Efficacy Endpoints ..................................... 23 
13.5.2 Missing Date of Investigational Product ................................................... 23 
13.5.3 Missing Date Information for Prior or Concomitant Medications 
(Therapies/Procedures) ............................................................................. 23 
13.5.3.1 Incomplete Start Date ................................................................. 23 
13.5.3.2 Incomplete Stop Date ................................................................. 24 
13.5.4 Missing Date Information for Adverse Events ......................................... 25 
13.5.4.1 Incomplete Start Date ................................................................. 25 
13.5.4.2 Incomplete Stop Date ................................................................. 26 
13.5.5 Missing Severity Assessment for Adverse Events .................................... 26 
13.5.6 Missing Relationship to Investigational Product for Adverse Events ...... 26 
14. 
ANALYSIS SOFTWARE .................................................................................. 26 
15. 
CHANGES TO ANALYSIS SPECIFIED IN PROTOCOL ........................... 26 
17. 
APPENDICES ..................................................................................................... 27 
17.1 
Schedule of Activities ...................................................................................... 27 
 


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ABBREVIATIONS 
AE 
Adverse Event 
AUC 
Area Under the Curve 
BLQ 
Below Limit of Quantification 
CSR 
Clinical Study Report 
ECG 
Electrocardiograms 
FACIT 
Functional Assessment of Chronic Illness Therapy 
ITT 
Intent To Treat 
LASA 
Linear Analog Scale Assessment 
LDH  
Lactate Dehydrogenase 
LLN 
Lower Limit of Normal 
LLOQ 
Lower Limit of Quantification 
MedDRA 
Medical Dictionary for Regulatory Activities 
QTcB 
Heart Rate Corrected QT interval, using Bazett’s formula 
QTcF 
Heart Rate Corrected QT interval, using Fridericia’s formula 
PD 
Pharmacodynamics 
PNH 
Paroxysmal Nocturnal Hemoglobinuria 
PK 
Pharmacokinetics 
PRBCs 
Packed Red Blood Cells 
RBC 
Red Blood Cells 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous 
SMC 
Safety Monitoring Committee 
SOC 
System Organ Class 
TEAE 
Treatment-Emergent Adverse Event 
TFLs 
Tables, Figures, Listings 
ULN 
Upper Limit of Normal 
WHO 
World Health Organization 
 


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1. 
INTRODUCTION  
This statistical analysis plan (SAP) provides a technical and detailed elaboration of the 
statistical analyses of safety, efficacy and pharmacokinetic/pharmacodynamic data as 
described in the final study protocol version 3.0 dated 31st January 2018.  Specifications 
for tables, figures, and listings are contained in a separate document. Any amendments to 
the SAP will be made prior to database lock. Any additional analyses not described in the 
final SAP or deviations from the final SAP will be documented in the clinical study report 
(CSR). 
At the end of 2018 the sponsor took the decision to close enrollment into this study. At this 
point only 4 subjects had enrolled. These subjects have been allowed to complete the study.  
As a result only an abbreviated CSR will be produced for this study. 
2. 
OBJECTIVES, ESTIMAND(S), AND ENDPOINTS 
2.1 
Objectives 
The objectives of the study are to assess safety, tolerability, preliminary efficacy and 
pharmacokinetic (PK) of multiple subcutaneous (SC) doses of APL-2 in subjects with 
paroxysmal nocturnal hemoglobinuria (PNH) who have not received treatment with 
eculizumab (Soliris)® in the past. 
An exploratory objective of the study is to assess the pharmacodynamics (PD) of multiple 
SC doses of APL-2 when administered to PNH subjects.  
2.2 
Estimands 
Estimands are not defined due to the decision to close enrollment for this study after only 
4 subjects had been enrolled. 
2.3 
Endpoints 
Unless stated otherwise changes from baseline will be calculated taking baseline as the last 
measurement prior to the first dose of investigational product. 
2.3.1 Primary Endpoints 
• Change from baseline in lactase dehydrogenase (LDH) 
• Change from baseline in haptoglobin 
• Change from baseline in hemoglobin. 


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2.3.2 Secondary Endpoints 
• Change from baseline in Functional Assessment of Chronic Illness Therapy 
(FACIT) Fatigue Scale score 
• Change from baseline in reticulocyte count 
• Change from baseline in total bilirubin 
• Number of red blood cell (RBC) transfusions per month 
• Change from baseline in Linear Analog Scale Assessment (LASA) for Quality of 
Life. 
2.3.3 Safety Endpoints 
• Incidence and severity of treatment-emergent adverse events (TEAEs) 
• Changes from baseline in vital signs 
• Changes from baseline in laboratory parameters 
• Changes from baseline in ECG parameters. 
2.3.4 Pharmacokinetic Endpoints 
• APL-2 serum concentrations 
• PK parameters for APL-2 will be estimated from the individual serum 
concentration-time data over the whole time period using a non-compartmental 
approach.  PK parameters will include: 
AUCtotal 
 
 
The area under the serum concentration versus time curve, from 
time 0 (pre-dose on Day 1) to the last measurable concentration 
(t) at the end of the study. 
Ctrough,max 
Maximum observed pre-dose serum concentration, calculated for 
both 270mg and 360mg where subjects receive both doses. 
2.3.5 Pharmacodynamics Endpoints 
• Changes from baseline and percentage changes from baseline in complement C3 
levels 
• Changes from baseline and percentage of baseline in complement CH50 and AP50 
levels  
• Changes from baseline and percentage changes from baseline in C3 deposition on 
RBC cells 
• Changes from baseline and percentage changes from baseline in Clonal distribution 
of PNH RBCs 
 
In addition the following endpoints will be derived: 


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• 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 Phase IIa, open-label, multiple dose study in patients with PNH who have not 
received eculizumab (Soliris®) in the past.  
Safety will be assessed throughout the study; serial blood and urine samples will be 
collected for these assessments. Blood samples will be collected for the assessment of  
APL-2 PK. Additional samples for assessment of PD will also be collected. 
The study will consist of four parts; 
• Part 1: Subjects will receive APL-2 for 28 days. 
• Part 2A: Following review of available safety, PK and PD data by the investigator 
and sponsor, subjects showing evidence of clinical benefit may progress to Part 2A 
of the study and continue to receive daily doses of APL-2 until Day 84. 
• Part 2B: Following review of available safety, PK and PD data by the investigator 
and sponsor subjects showing evidence of clinical benefit may progress to Part 2B 
of the study and continue to receive daily doses of APL-2 until Day 364. 
• Part 3: Safety follow up. 
The planned dose for this single cohort study will be a daily dose of 270 mg/day however 
from Part 2A onwards intra-subject dose escalation up to a dose of 360 mg/day may be 
permitted. All doses will be administered as SC infusions. APL-2 will be supplied as a 
sterile solution of APL-2 in acetate-buffered mannitol or in acetate buffered sorbitol, at 
concentrations of up to 40 mg/mL. 
Screening will take place within 30 days prior to the start of dosing on Day 1. 
Subjects will be entered into Part 1 of the study on Day 1 at a time designated by the 
Investigator. Research nurses or other appropriately qualified research personnel will 
administer the SC infusions for a minimum of 3 days (Days 1-3) until the research nurse 


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considers that the subject is both capable and confident to conduct self-administration. The 
subject will continue to self-administer infusions at the clinic on those days when a clinic 
visit occurs (Day 8, 15 and 22) and at an off-site location convenient to the subject on all 
other days up to Day 28 in Part 1. Following review of available safety, PK and PD data 
by the investigator and sponsor subjects demonstrating clinical benefit from the treatment 
may progress to Part 2A of the study and continue to receive daily doses of APL-2 until 
Day 84, and then may progress to Part 2B of the study and continue to receive daily doses 
of APL-2 until Day 364. Doses will be self-administered throughout this period at an off-
site location convenient to the subject with the exception of Days 29, 36, 43, 57, 71, 85, 
113, 141, 169, 197, 225, 253, 281, 309, and 337 where dosing is performed by the subject 
at the clinical site. If a subject has a sub-optimal clinical response during daily dosing with 
270 mg APL-2, the dose may be increased up to 360 mg/day during part 2A, and doses will 
be administered at the clinical site every 2 weeks for the first 6 weeks after commencing 
the higher dose. After the conclusion of the treatment period (Day 364), subjects will enter 
Part 3 of the study and return to the clinical site for follow-up study procedures on Day 
365, 379, and 393 and final study procedures at an Exit Visit on Day 414. If a benefit is 
observed an extension study will be considered and will be submitted as a further protocol 
amendment or as a follow-up study  
The planned length of participation in the study for each subject is approximately 444 days 
(from Day –30 through completion of the Day 414 Exit visit procedures). Interim PK and 
PD analyses may be performed to reconsider the sampling time points as the study 
progresses. 
An independent Safety Monitoring Committee (SMC) will assess the progress and 
cumulative safety/tolerability data of the study on a regular basis. 
Continuation of treatment – Decision scheme 
 
3.2 
Randomization 
Each subject will be assigned a unique identification number upon entering screening.  
Subjects who complete the study screening assessments and meet all eligibility criteria will 
be scheduled to enter the study and receive APL-2 treatment. 


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3.3 
Blinding 
The study is an open label single treatment arm study and so treatment assignment will not 
be blinded. 
3.4 
Sample Size and Power Considerations 
The planned sample size was for up to 20 subjects to be enrolled to complete 28 days of 
dosing. The sample size was considered sufficient to obtain useful safety, tolerability, PD 
and PK data to support the clinical program. The study was closed for enrollment by the 
sponsor after 4 subjects were enrolled. 
4. 
STATISTICAL ANALYSIS SETS 
4.1 
Screened Set  
The Screened Set will consist of all subjects who have signed informed consent and are 
screened for participation in this study. This set will be used only for the purpose of 
describing subject disposition and for listing the data. 
4.2 
Safety Set   
The Safety Set will consist of all subjects who receive at least one dose of study medication. 
4.3 
Intent-to-Treat Set  
The Intent to Treat (ITT) set will be identical to the Safety Set for this study. All baseline 
characteristics, demographic and efficacy endpoints data will be presented using the ITT 
Set. 
4.4 
Pharmacokinetic Set  
The Pharmacokinetic (PK) Set is defined as all subjects in the Safety Set and for whom at 
least one quantifiable PK sample (i.e. not impacted by any important protocol deviations 
or other events) post-dose PK measurement (even if below the limit of quantification). 
4.5 
Pharmacodynamic Set  
The Pharmacodynamic (PD) Set is defined as all subjects in the Safety Set with at least one 
quantifiable (i.e. not impacted by any important protocol deviations or other events) post 
dose PD evaluation. 


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5. 
STUDY SUBJECTS 
5.1 
Disposition of Subjects 
A listing of all Screen Failures (i.e., subjects who were screened but not dosed) will be 
presented along with reasons for screen fail.   
Disposition data, including whether the subject entered Parts 1, 2A, 2B and 3 with the 
corresponding start dates (and study day) will be listed. If a subject withdrew during the 
study then the reason for withdrawal will also be listed.  
A listing of the analysis sets the subjects are included in will be presented.  
5.2 
Demographic and Other Baseline Characteristics 
Demographic data (gender, race, ethnicity, age [years], weight [kg], height [cm] and BMI 
[kg/m2]) will be listed for the Safety Set.   
Time since diagnosis of PNH (years) will also be listed.  
5.3 
Medical History 
Medical history will be coded using Medical Dictionary for Regulatory Activities 
(MedDRA) Version 21.0.  Medical history will be listed for the Safety Set. 
5.4 
Prior Medications  
WHO Drug Dictionary Version 2018:03 will be used to classify prior medications by 
therapeutic class. A prior medication is defined as any medication with the start date prior 
to the date of the first dose of investigational product.  
All prior medications will be listed for the Safety Set. 
5.5 
Concomitant Medications  
WHO Drug Dictionary Version 2018:03 will be used to classify concomitant medications 
by therapeutic class. A concomitant medication is defined as any medication with the start 
date prior to the date of the first dose of investigational product and continuing after the 
first dose of investigational product or with a start date between the dates of the first and 
last doses of investigational product, inclusive.   Medications started before study dosing, 
but continuing after are considered as both prior and concomitant medications.   
All concomitant medications will be listed for the Safety Set. 


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5.6 
Exposure to Investigational Product 
All exposure data will be listed for the Safety Set.  In addition, for each subject the 
following data will be listed: 
• Days of dosing in Part 1 
• Days of dosing in Part 2A 
• Days of dosing in Part 2B 
• Last study day of dosing 
If subjects have their dose escalated to 360 mg/day separate information will be supplied 
for each dose.  This will also be done if subjects change their dose for any other reason, 
with rows of the listing being in chronological order.  
5.7 
Measurements of Treatment Compliance  
Compliance for Part 1, 2A, 2B and overall, based on the percentage of days they took study 
medication prior to discontinuation/completion will be listed for the Safety Set.  
Compliance is calculated as the number of days the subject took the investigational product 
divided by the duration the subject was in the study. If the investigator instructed the subject 
to stop taking the investigation product for a period of time e.g. due to an adverse event, 
then this period will not be included in the denominator for the compliance calculation. 
5.8 
Protocol Deviations 
Protocol deviations will be recorded by the site separately from the clinical database. 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. 
Confirmed major and minor protocol deviations will be documented in the Protocol 
Deviation tracker for the study. Major/minor protocol deviations will be listed for the 
Safety Set. 
6. 
EFFICACY ANALYSES 
All efficacy analyses will be based on the ITT Set. For each efficacy variable, the last value 
collected before the first dose of investigational product will be used as baseline for all 
analyses of that efficacy variable. 


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6.1 
Analyses of Primary Efficacy Endpoints 
Individual LDH, haptoglobin and hemoglobin will be listed together with changes from 
baseline and percentage changes from baseline by study part and study visit. For LDH the 
value relative to the upper limit of normal (ULN) (i.e. value/ULN) will also be presented 
and for haptoglobin and hemoglobin values relative to the lower limit of normal (LLN) (i.e. 
value/LLN) will also be presented. 
Absolute values, changes from baseline and percentage changes from baseline will be 
summarized, using descriptive statistics, by part of the study and study visit. The number 
and percentage of subjects ≤1X ULN and ≤ 1.5X ULN for LDH will also be summarized 
by part of the study and study visit. The number and percentage of subjects ≥ 1X LLN for 
haptoglobin and hemoglobin will also be summarized by part of the study and study visit. 
Absolute values, changes from baseline and percentage changes from baseline will be 
plotted by study day with each subject being identifiable. A dotted line will be used to 
identify follow-up (Part 3). The actual sampling day will be used on the x-axis. The changes 
and percentage changes from baseline plots will include a reference line for 0 on the y-
axis. 
Values of LDH, reticulocytes and total bilirubin related to their ULN (i.e. value/ULN) 
throughout the study will be plotted against time for each subject individually (i.e. one plot 
per subject). Hemoglobin and haptoglobin values will also be included but related to their 
LLN (i.e. value/LLN). Each parameter will have a different symbol and a legend will 
identify the parameters included. A reference line of 1 on the y-axis will be included. On 
study transfusions (Packed Red Blood Cells [PRBC] only) will be identified on the plot as 
a vertical line at the relevant study day. Above the profile plot a separate plot will be 
displayed which shows the APL-2 dose by study day. The study day on both plots will be 
aligned. 
6.2 
Analyses of Secondary Efficacy Endpoints  
6.2.1 
FACIT Fatigue Scale 
Absolute FACIT fatigue scores will be listed together with changes from baseline by study 
part and study visit. 
Absolute values and changes from baseline will be summarized, using descriptive statistics, 
by part of the study and study visit.  


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Absolute values and changes from baseline will be plotted by study day with each subject 
being identifiable. A dotted line will be used to identify follow-up (Part 3). The actual 
sampling day will be used on the x-axis. The change from baseline plots will include a 
reference line for 0 on the y-axis.  
Values of FACIT fatigue scores throughout the study will be plotted against time for each 
subject individually (i.e. one plot per subject). On study transfusions (PRBC only) will be 
identified on the plot as a vertical line at the relevant study day. Above the profile plot a 
separate plot will be displayed which shows the APL-2 dose by study day. The study day 
on both plots will be aligned. 
6.2.2 
Reticulocytes and Total Bilirubin 
Each parameter will be listed together with changes from baseline and percentage changes 
from baseline by study part and study visit. The value relative to the ULN (i.e. value/ULN) 
will also be presented. 
Absolute values, changes from baseline and percentage changes from baseline will be 
summarized, using descriptive statistics, by part of the study and study visit. The number 
and percentage of subjects ≤ 1X ULN and ≤ 1.5X ULN will also be summarized by study 
visit. 
Absolute values, changes from baseline and percentage changes from baseline will be 
plotted by study day with each subject being identifiable. A dotted line will be used to 
identify follow-up (Part 3). The actual sampling day will be used on the x-axis. The changes 
and percentage changes from baseline plots will include a reference line for 0 on the y-
axis. 
6.2.3 
RBC Transfusions 
All transfusion data will be listed by study part and study visit. 
6.2.4 
Linear Analog Scale Assessment (LASA) for Quality of Life 
Absolute values for the 3 LASA questions and the combined score (sum of the 3 individual 
LASA questions) will be listed together with change from baseline by study part and study 
visit. 
Absolute values and changes from baseline will be plotted by study day with each subject 
being identifiable. A dotted line will be used to identify follow-up (Part 3). The actual 


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sampling day will be used on the x-axis. The change from baseline plots will include a 
reference line for 0 on the y-axis.  
Values of LASA combined scores throughout the study will be plotted against time for 
each subject individually (i.e. one plot per subject). On study transfusions (PRBC only) 
will be identified on the plot as a vertical line at the relevant study day. Above the profile 
plot a separate plot will be displayed which shows the APL-2 dose by study day. The study 
day on both plots will be aligned. 
7. 
SAFETY ANALYSIS  
The safety analysis will be performed using the Safety Set. Safety variables include AEs, 
clinical laboratory variables, vital signs, and ECG variables. 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.  
All safety analyses will be conducted according to the treatment the subject actually 
received. 
7.1 
Adverse Events  
AEs will be coded using MedDRA Version 21.0. 
An AE (classified by preferred term) that occurs during the treatment phase will be 
considered a treatment-emergent AE (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 of 
investigational product, but increases in severity on or after the date of the first dose of 
investigational product.  If more than one AE with the same preferred term is reported 
before the date of the first dose of investigational product, then the AE with the greatest 
severity will be used as the benchmark for comparison to the AEs occurring during the 
treatment phase under the preferred term.  An AE that occurs more than 30 days after the 
date of the last dose of investigational product will not be counted as a TEAE. 
An overall summary of the number of subjects with TEAEs will be presented, including 
the number and percentage of subjects with any TEAEs, serious TEAEs, TEAEs related to 
investigational product and TEAEs leading to discontinuation of investigational product.  
 
The number and percentage of subjects reporting TEAEs will be tabulated by system organ 
class (SOC) and preferred term. TEAEs considered related to investigational product will 
also be summarized by SOC and preferred term. If more than one AE occurs with the same 


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preferred term for the same subject, then the subject will be counted only once for that 
preferred term using the most related occurrence for the summarization by relationship to 
investigational product. 
Summary tables will be presented over the whole study and by study part. AEs will be 
categorized by the Part in which the AE started i.e. an AE which began during Part 1 will 
be categorized under Part 1 even if it continues into Part 2A (unless it increases in severity 
during Part 2A, when it will be counted in both Parts 1 and 2A). Summaries will be ordered 
by descending order of total events. 
All TEAEs will be listed by subject and start date. Separate listings of serious TEAEs and 
TEAEs leading to discontinuation of study drug will also be generated.  The listing will 
also include duration of AE, the part of the study the AE started and the part of the study 
the AE stopped.  
7.2 
Clinical Laboratory Data 
Observed and change from baseline values will be summarized for all hematology, 
chemistry and coagulation clinical laboratory parameters using descriptive statistics, by 
part of the study and study visit.   
All laboratory data will be listed. The listing will include changes from baseline values and 
values that are outside the reference range will be flagged. 
7.3 
Vital Signs 
Observed and change from baseline values will be listed. In the listing, values of potential 
clinical significance will be flagged.  These are defined in the table below. 
Table 1: Criteria for Potentially Clinically Significant Vital Signs 
 
Vital Sign Parameter 
 
Flag 
Criteria 
Observed Value 
Systolic blood pressure 
(mmHg) 
High 
≥165 
Low 
≤80 
Diastolic blood pressure 
(mmHg) 
High 
≥95 
Low 
≤40 
Pulse rate 
(beats per minute) 
High 
≥120 
Low 
≤40 
Temperature (oC) 
High 
≥38 
Low 
- 


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7.4 
Electrocardiogram (ECG) 
Observed and change from baseline values will be listed. In the listing, values of potential 
clinical significance will be flagged.  These are defined in the table below. 
Table 2: Criteria for Potentially Clinically Significant ECG Values 
 
Vital Sign Parameter 
 
Flag 
Criteria 
Observed Value 
Change from baseline 
QT, QTcB, QTcF (msec) 
High 
≥450 
≥30 
Low 
- 
- 
PR (msec) 
High 
≥240 
- 
Low 
≤100 
- 
QRS (msec) 
High 
≥140 
- 
Low 
- 
- 
Heart rate (bpm) 
High 
≥120 
- 
Low 
≤40 
- 
 
7.5 
Other Safety Data 
Immunogenicity and physical examination data will be listed. 
8. 
PHARMACOKINETIC ANALYSIS  
All PK analyses will be based on the PK Set. 
8.1 
Handling BLQ Values 
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. 
If a BLQ value falls between two quantifiable concentrations the value will be set equal to 
the LLOQ, unless it’s exclusion can be justified (e.g. implausibility given the profile 
observed and known PK properties). 
8.2 
Drug Concentration 
Linear and log-linear individual concentration profile plots against time will be produced 
with each subject being identifiable. A dotted line will be used to identify follow-up (Part 
3). The actual sampling day will be used on the x-axis. 


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A listing of all concentration data will be presented. The actual time and deviation from 
nominal time will also be listed. 
8.3 
Pharmacokinetic Parameters 
PK parameters will be listed. 
9. 
PHARMACODYNAMIC ANALYSIS 
All PD analyses will be based on the PD Set.  
9.1 
Handling BLQ Values 
If a baseline PD value is zero, then the percentage changes from baseline will not be 
calculated. If a PD value is BLQ then the value will be set to the LLOQ. Similarly, for the 
PD plots, a BLQ value will be set equal to LLOQ. 
9.2 
Pharmacodynamic Data 
Absolute PD parameter values will be listed together with changes from baseline and 
percentage changes from baseline (for CH50 and AP50 percentage of baseline will be listed 
instead), by study part and study visit. 
Absolute values, changes from baseline and percentage changes from baseline will be 
plotted for the complement parameter C3 by study day with each subject being identifiable. 
A dotted line will be used to identify follow-up (Part 3). The actual sampling day will be 
used on the x-axis. The changes and percentage changes from baseline plots will include a 
reference line for 0 on the y-axis.  
For the complement parameters CH50 and AP50 only percentage of baseline values will 
be plotted by study day with each subject being identifiable. A dotted line will be used to 
identify follow-up (Part 3). The actual sampling day will be used on the x-axis. A reference 
line for 100 will be presented on the y-axis. 
For the complement parameter C3 values throughout the study will be plotted against time 
for each subject individually (i.e. one plot per subject). On study transfusions (PRBC only) 
will be identified on the plot as a vertical line at the relevant study day. Above the profile 
plot a separate plot will be displayed which shows the APL-2 dose by study day. The study 
day on both plots will be aligned. For the complement parameters CH50 and AP50 the 
same plot will be generated using percentage of baseline values instead. 


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Absolute values in PNH granulocytes (percent FLAER) will be plotted by study day with 
each subject being identifiable. A dotted line will be used to identify follow-up (Part 3). 
The actual sampling day will be used on the x-axis. These plots will be repeated for PNH 
monocytes (percent FLAER). 
Individual subject plots of the percentage distribution will be presented for the C3 
deposition on RBC cells parameters, with all parameters included on the same subject plot. 
A dotted line will be used to identify follow-up (Part 3). The actual sampling day will be 
used on the x-axis. The plot will identify on study transfusions (PRBC only) as a vertical 
line at the relevant study day; and above the profile plot a separate plot will be displayed 
which shows the APL-2 dose by study day. The study day on both plots will be aligned. 
These plots will be repeated for clonal distribution of PNH RBCs parameters. 
Clonal distribution of PNH RBCs (percent Type II + III) over time will be plotted with 
each subject being identifiable. A dotted line will be used to identify follow-up (Part 3). 
The actual sampling day will be used on the x-axis. These plots will be repeated for Clonal 
distribution of PNH RBCs (percent Type III), C3d deposition on RBC cells (percent Type 
II + III) and C3d deposition on RBC cells (percent Type III). 
10. 
OTHER ANALYSES 
No other analyses are planned for this study. 
11. 
INTERIM ANALYSIS  
Data may be reported while the study is ongoing to help guide decisions to further develop 
APL-2. These reports will be performed on data that will have been fully checked and 
considered as final. Any changes to the data previously reported will be fully auditable and 
discussed in subsequent reports. 
12. 
SAFETY MONITORING COMMITTEE  
A periodic safety review will take place on a regular basis by the SMC to review 
safety/tolerability, PK and PD data. The remit, roles and responsibilities of the SMC is 
specified in a separate SMC charter. 
13. 
 DATA HANDLING CONVENTIONS  
13.1 
General Data Reporting Conventions  
Categorical and count variables will be summarized by the number of subjects (n) and the 
percent of subjects in each category. Percentages will be displayed with 1 decimal place; 


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except percentages will not be presented when the count is zero and 100% will be presented 
as an integer. 
Continuous variables will be summarized using the number of observations (n), mean, 
standard deviation (SD), median, minimum, and maximum.  The estimated mean and 
median for a set of values 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.  
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). 
All data will be listed. Data listings will present study days in addition to dates, where study 
day is derived as (assessment date – first day of dosing+1). The first day of dosing will be 
identified as Study Day 1. All efficacy, PK and PD listings will present the last dose 
received prior to the assessment.   
13.2 
Definition of Baseline  
Baseline is defined as the last observed value prior to taking the first dose of investigational 
product (based on dates or date/times).  
13.3 
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 


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on a 0-100 scale with 0 representing “As low as could be” and 100 representing “As high 
as could be”. In addition to looking at each domain the combined score (range of 0-300) 
will be determined. 
13.4 
Repeated or Unscheduled Assessments of Safety Parameters  
If a subject has repeated assessments before the start of investigational product, then the 
results from the final assessment made prior to the start of investigational product will be 
used as baseline. All post-baseline assessments will be used for PCS value determination 
and all assessments will be presented in the data listings. 
13.5 
Handling of Missing, Unused, and Spurious Data  
13.5.1 Missing Data Imputation for Efficacy Endpoints 
No imputation of missing data will be performed. 
13.5.2 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.  If it is still 
missing after all efforts, then the last known date when investigational product was taken 
will be used in the calculation of treatment duration. 
13.5.3 Missing Date Information 
for 
Prior 
or 
Concomitant 
Medications 
(Therapies/Procedures) 
For prior or concomitant medications incomplete (i.e., partially missing) start date and/or 
stop date will be imputed.  When the start date and the stop date are both incomplete for a 
subject, impute the start date first.  
For a missing start date (where stop date is after first dose of investigational product or 
missing) the date will be imputed as the first dose date of investigational product; for a 
missing stop date the date will be imputed as the last study date.   
The original data will always be presented in the listings. 
13.5.3.1 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. 


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13.5.3.1.1 
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. 
13.5.3.1.2 
Missing Month Only 
• 
The day will be treated as missing and both month and day will be replaced according 
to the above procedure. 
13.5.3.1.3 
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 day of 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. 
13.5.3.2 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. 
13.5.3.2.1 
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 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 01 January will be assigned to the missing fields. 


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13.5.3.2.2 
Missing Month Only 
• 
The day will be treated as missing and both month and day will be replaced according 
to the above procedure. 
13.5.3.2.3 
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 day of 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. 
13.5.4 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 for 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 are the 
same as the year and month of the first dose of investigational product, then the AE will be 
classified as treatment-emergent. 
To facilitate categorization of AEs as treatment emergent, imputation of dates can be used.  
For AEs, the default is to only impute incomplete (i.e., partially missing) start dates. 
Incomplete stop dates may also be imputed when calculation of the duration of an AE is 
required per the protocol. If imputation of an incomplete stop date is required, and both the 
start date and the stop date are incomplete for a subject, impute the start date first. 
For a missing start date (where stop date is after first dose of investigational product or 
missing) the date will be imputed as the first dose date of investigational product; for a 
missing stop date the date will be imputed as the last study date. 
The original data will always be presented in the listings. 
13.5.4.1 Incomplete Start Date  
Follow the same rules as in Section 12.4.3.1. 


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13.5.4.2 Incomplete Stop Date  
Follow the same rules as in Section 12.4.3.2. 
13.5.5 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. 
13.5.6 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 investigational product will be used for incidence 
summaries, while both the actual and the imputed values will be presented in data listings. 
14. 
ANALYSIS SOFTWARE  
Statistical analyses will be performed using Version 9.4 (or newer) of SAS on a suitably 
qualified environment.   
PK parameters will be calculated using PKNCA (version 0.8.4 or higher) with R (version 
3.4.3 or higher) by JPharma Solutions.  
15. 
CHANGES TO ANALYSIS SPECIFIED IN PROTOCOL 
Due to the decision to close enrollment for this study after 4 subjects had enrolled only a 
subset of the analyses documented in the protocol are required for reporting. As a 
consequence the SAP only specifies the analyses required for the abbreviated CSR.  
 
 
 


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17. 
APPENDICES  
17.1 
Schedule of Activities 
 


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