Clinical trial NCT03181633
Conditions: Paroxysmal Nocturnal Hemoglobinuria
Keywords: PNH Paroxysmal Hemoglobinuria ACH-0144471 ALXN2040 Danicopan
Sponsor: Alexion Pharmaceuticals, Inc.
Start date: 2017-06-22; Completion date: 2022-01-04
Enrollment: 8 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to evaluate the long-term safety and efficacy of ACH-0144471 in participants with paroxysmal nocturnal hemoglobinuria (PNH) who have demonstrated clinical benefit from ACH-0144471 in Study ACH471-100. This study is designed to include up to 12 participants.

Detailed description:

Arms: arm 1: All participants will receive ACH-0144471 during the treatment period.
Interventions: intervention 1: ACH-0144471
Intervention descriptions: intervention 1: ACH-0144471 will be administered to all participants enrolled in the study.

Protocol documents:
Prot_000.pdf: 
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ACH-0144471 
Achillion Pharmaceuticals, Inc. 
Clinical Protocol ACH471-103, Amendment 5 
04 June 2021, Version 6 
 
Confidential 
Page 2 of 70 
 
 
Confidentiality Statement 
The information contained in this document, particularly unpublished data, is the property or under the control of Achillion 
Pharmaceuticals, Inc., and is provided to you in confidence as an investigator, potential investigator, or consultant for 
review by you, your staff and an applicable Institutional Review Board and/or Independent Ethics Committee.  The 
information is only to be used by you and in connection with authorized clinical studies of the investigational drug 
described in the protocol.  You will not disclose any of the information to others without written authorization from 
Achillion Pharmaceuticals, Inc., except to the extent necessary to obtain informed consent from those persons to whom the 
drug may be administered. 


A C H- 01- U 4 71 
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S p o n s or Si g n at ur e 
St u d y Title 
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ACH-0144471 
Achillion Pharmaceuticals, Inc. 
Clinical Protocol ACH471-103, Amendment 5 
04 June 2021, Version 6 
 
Confidential 
Page 4 of 70 
 
 
Investigator’s Signature 
Study Title 
An Open-label Study to Evaluate Efficacy and Safety of Long-term 
Treatment with ACH-0144471 in Patients with PNH who Completed 
Clinical Study ACH471-100 
Study Number 
ACH471-103 
Protocol Version and 
Date 
Protocol ACH471-103, Amendment 5 
04 June 2021, Version 6 
I have read the protocol described above.  I agree to comply with all applicable regulations and to 
conduct the study as described in the protocol. 
 
 
<Name and Credentials/Title>  
<Affiliation/Company> 
<Address> 
<Address> 
<Phone Number> 
Date 


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ACH-0144471 
Achillion Pharmaceuticals, Inc. 
Clinical Protocol ACH471-103, Amendment 5 
04 June 2021, Version 6 
 
Confidential 
Page 6 of 70 
 
 
Synopsis 
Sponsor 
Achillion Pharmaceuticals, Inc., a wholly owned subsidiary of Alexion Pharmaceuticals Inc. 
1777 Sentry Parkway West,  
Building 14, Suite 200 Blue Bell, 
PA 19422 USA 
Name of Finished 
Product 
ACH-0144471 Tablet, 50, 75, and 100 mg 
Name of Active 
Ingredient 
ACH-0144471 
Name of Inactive 
Ingredient 
ACH-0144471 Tablet: Lactose, Microcrystalline Cellulose, Croscarmellose Sodium, Sodium 
Lauryl Sulphate, Magnesium Stearate, Colloidal Silicon Dioxide, and Hypromellose Acetate 
Succinate.  The coating components are polyvinyl alcohol, titanium dioxide, 
macrogol/polyethylene glycol, and talc 
Study Title 
An Open-Label Study to Evaluate Efficacy and Safety of Long-term Treatment with ACH-
0144471 in Patients with PNH who Completed Clinical Study ACH471-100 
Study Number 
ACH471-103 
Study Phase  
Phase 2 
Primary Objective  
To evaluate the safety and efficacy of long-term therapy with ACH-0144471 in patients with 
PNH 
Secondary 
Objective 
To evaluate health-related quality of life measures in patients with PNH based on patient 
reported outcome instruments and its evolution over the course of long-term therapy with 
ACH-0144471 
Exploratory 
Objectives 
N/A 
Study Design 
This is an open-label extension study designed to evaluate long-term safety and efficacy of 
ACH-0144471 in patients with PNH who have demonstrated clinical benefit from 
ACH-0144471 in study ACH471-100.  Clinical benefit will be assessed by the investigator, 
based on an improvement in hemoglobin and/or LDH.  The PI may escalate or reduce dosing to 
manage clinical benefit or for safety or tolerability reasons, as described in Section 3.2.2.  
Patients will be allowed to continue therapy until 1) ACH-0144471 is commercially available 
in their country; 2) the development of ACH-0144471 as a potential therapy for PNH is 
terminated; 3) the therapy is no longer tolerated or effective; or 4) another appropriate Alexion 
clinical study is available or in the opinion of the PI, another treatment option is available.  In 
addition, the Sponsor reserves the right to close any study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. 
Considering PNH is a serious life-threatening disease, a long-term extension study, beyond the 
dosing included in this study, may be offered to patients, if supported by clinical and 
nonclinical data. Pending regulatory and ethics committee approval of such a study, patients 
who, in the opinion of the Principal Investigator (PI), are receiving benefit from ACH-0144471 
may be enrolled directly into that study without interruption from this study, and will continue 
to receive daily treatment with ACH-0144471 and safety and efficacy monitoring. Any patients 
so enrolled will not require a dosing taper or the follow-up visits described in this protocol. 
Treatment Groups 
A single treatment group is planned 


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ACH-0144471 
Achillion Pharmaceuticals, Inc. 
Clinical Protocol ACH471-103, Amendment 5 
04 June 2021, Version 6 
 
Confidential 
Page 9 of 70 
 
 
Patient-reported 
Outcomes 
Assessments 
Quality of Life (QoL) assessments will be conducted at various time points as specified in 
schedule of assessment in Appendix 1 using the tools in Appendix 2.  The FACIT Fatigue scale 
(Version 4) questionnaire and the EORTC-QLQ-C30 scale will be administered to patients to 
collect patients’ health-related QoL at various time points during long-term treatment with 
ACH-0144471. 
In addition, interviews by independent outcomes researchers chosen by the Sponsor were 
conducted.  Patients were interviewed after approximately 3 and 9 months of treatment in this 
study (i.e., after approximately 6 and 12 months of treatment with ACH-0144471, including 
approximately 3 months of treatment during ACH471-100) to collect patients’ experience of 
ACH-0144471 treatment and their perception of the evolution of their condition.  The 
interviews were conducted over the phone by a trained, experienced interviewer and lasted 
approximately 30 minutes. These interviews were discontinued effective 30 April 2019. 
Statistical Methods  
Descriptive statistical methods will be used to evaluate the efficacy and safety of long-term 
therapy of ACH-0144471. 


ACH-0144471 
Achillion Pharmaceuticals, Inc. 
Clinical Protocol ACH471-103, Amendment 5 
04 June 2021, Version 6 
 
Confidential 
Page 10 of 70 
 
 
Table of Contents 
Sponsor Signature ........................................................................................................................................3 
Investigator’s Signature ...............................................................................................................................4 
Rationale for Amendment ............................................................................................................................5 
Synopsis .......................................................................................................................................................6 
Table of Contents .......................................................................................................................................10 
List of Tables .............................................................................................................................................14 
List of Figures ............................................................................................................................................14 
List of Appendices .....................................................................................................................................14 
List of Abbreviations and Definitions of Terms ........................................................................................15 
1 
Introduction ........................................................................................................................................17 
1.1 
Results of Nonclinical Studies ...................................................................................................17 
1.2 
Previous Human Experience with ACH-0144471 .....................................................................17 
1.3 
Rationale ....................................................................................................................................18 
1.3.1 Complement Factor D ............................................................................................................18 
1.3.2 Paroxysmal Nocturnal Hemoglobinuria (PNH) .....................................................................18 
1.3.3 Potential Advantages of ACH-0144471 in the Treatment of PNH ........................................19 
1.3.4 Safety Considerations .............................................................................................................20 
1.3.4.1 
Risk of Infection ............................................................................................................20 
1.3.4.2 
Hepatic Injury ................................................................................................................20 
2 
Study Objectives .................................................................................................................................21 
2.1 
Primary Objective ......................................................................................................................21 
2.2 
Secondary Objective ..................................................................................................................21 
2.3 
Exploratory Objectives ..............................................................................................................21 
3 
Investigational Plan ............................................................................................................................22 
3.1 
Overall Study Design and Plan ..................................................................................................22 
3.2 
Rationale for Study Design ........................................................................................................23 
3.2.1 Justification of Design ............................................................................................................23 
3.2.2 Justification of Dose ...............................................................................................................23 
3.2.3 Stopping Criteria ....................................................................................................................23 
3.3 
Study Duration and Dates ..........................................................................................................24 
4 
Study Population Selection ................................................................................................................25 
4.1 
Study Population ........................................................................................................................25 


ACH-0144471 
Achillion Pharmaceuticals, Inc. 
Clinical Protocol ACH471-103, Amendment 5 
04 June 2021, Version 6 
 
Confidential 
Page 11 of 70 
 
 
4.2 
Inclusion Criteria .......................................................................................................................25 
4.3 
Exclusion Criteria ......................................................................................................................25 
5 
Study Treatment .................................................................................................................................27 
5.1 
Description of Treatment ...........................................................................................................27 
5.1.1 Study Drug .............................................................................................................................27 
5.2 
Treatments Administered ...........................................................................................................27 
5.2.1 ACH-0144471 ........................................................................................................................27 
5.2.2 Vaccines .................................................................................................................................27 
5.3 
Selection of Timing and Dose for Each Patient .........................................................................28 
5.4 
Method of Assigning Patients to Treatment Groups .................................................................28 
5.5 
Restrictions ................................................................................................................................28 
5.5.1 Concomitant Therapy .............................................................................................................28 
5.5.2 Fluid and Food Intake .............................................................................................................29 
5.5.3 Patient Activity and Other Restrictions ..................................................................................29 
5.5.4 Contraception .........................................................................................................................29 
5.5.4.1 
Contraception for Male Participants ..............................................................................29 
5.5.4.2 
Contraception for Female Participants ..........................................................................30 
5.6 
Treatment Compliance ...............................................................................................................31 
5.7 
Packaging and Labeling .............................................................................................................31 
5.8 
Storage and Accountability ........................................................................................................31 
5.9 
Investigational Product Retention at Study Site ........................................................................32 
6 
Study Procedures ................................................................................................................................33 
6.1 
Informed Consent ......................................................................................................................33 
6.2 
Vaccination ................................................................................................................................33 
6.3 
Physical Examination ................................................................................................................33 
6.4 
Vital Signs ..................................................................................................................................33 
6.5 
Body Temperature .....................................................................................................................34 
6.6 
Electrocardiography ...................................................................................................................34 
6.7 
Clinical Laboratory Measurements ............................................................................................34 
6.8 
Pregnancy Testing ......................................................................................................................35 
6.9 
Sample Collection, Storage, and Shipping ................................................................................36 
6.9.1 Blood Collection for Complement Assays .............................................................................36 
6.9.2 PK Plasma Samples ................................................................................................................36 


ACH-0144471 
Achillion Pharmaceuticals, Inc. 
Clinical Protocol ACH471-103, Amendment 5 
04 June 2021, Version 6 
 
Confidential 
Page 12 of 70 
 
 
6.9.3 Blood Volumes .......................................................................................................................36 
6.10 
Dispensing Study Drug ..............................................................................................................37 
6.11 
Safety Assessments ....................................................................................................................37 
6.12 
Pharmacokinetic Assessments ...................................................................................................37 
6.13 
Pharmacodynamic and Efficacy Assessments ...........................................................................37 
6.14 
Patient Reported Outcomes Assessments ..................................................................................38 
6.15 
Adverse Events Assessments .....................................................................................................38 
6.15.1 Definitions ..............................................................................................................................38 
6.15.2 Criteria for Assessing Seriousness .........................................................................................40 
6.15.3 Documentation and Reporting of Adverse Events .................................................................41 
6.15.4 Treatment and Follow-up of Adverse Events .........................................................................41 
6.15.5 Timeframe for Collection of Adverse Events ........................................................................41 
6.15.6 Severity and Grading of Adverse Events ...............................................................................42 
6.15.7 Assessment of Causality .........................................................................................................42 
6.15.8 Pregnancy ...............................................................................................................................42 
6.15.9 Reporting Serious Adverse Events .........................................................................................43 
6.15.10 
Investigator Reporting Requirements for SAEs ............................................................44 
6.16 
Concomitant Medication Assessments ......................................................................................44 
6.17 
Monitoring Patient Safety ..........................................................................................................44 
6.18 
Removal of Patients from the Trial ............................................................................................45 
6.19 
Coronavirus Disease 2019 .........................................................................................................45 
7 
Study Activities ..................................................................................................................................47 
7.1.1 Clinic Visits ............................................................................................................................47 
7.1.2 Safety Follow-up at Local Laboratory ...................................................................................47 
7.1.3 Safety Follow-up After Escalation .........................................................................................47 
7.1.4 Patient Reported Outcomes Interviews ..................................................................................48 
7.1.5 Dosing Taper ..........................................................................................................................48 
7.1.6 Follow-Up Visit ......................................................................................................................48 
7.1.7 Unscheduled Visits .................................................................................................................48 
8 
Quality Control and Assurance ..........................................................................................................50 
8.1 
Routine Monitoring ....................................................................................................................50 
8.2 
Site Audits ..................................................................................................................................50 
9 
Planned Statistical Methods ...............................................................................................................51 


ACH-0144471 
Achillion Pharmaceuticals, Inc. 
Clinical Protocol ACH471-103, Amendment 5 
04 June 2021, Version 6 
 
Confidential 
Page 13 of 70 
 
 
9.1 
General Considerations ..............................................................................................................51 
9.2 
Analysis Populations ..................................................................................................................51 
9.3 
Demographics and Baseline Characteristics ..............................................................................51 
9.4 
Efficacy Analysis .......................................................................................................................51 
9.5 
Safety Analysis ..........................................................................................................................52 
9.6 
Patient-Report Outcomes Assessments .....................................................................................52 
9.6.1 Quality of Life Scales .............................................................................................................52 
9.6.2 Patient Interviews ...................................................................................................................52 
10 Administrative Considerations ...........................................................................................................53 
10.1 
Investigators and Study Administrative Structure .....................................................................53 
10.2 
Institutional Review Board (IRB) or Independent Ethics Committee (IEC) and Regulatory 
Approval ....................................................................................................................................53 
10.2.1 Ethical Approval .....................................................................................................................53 
10.2.2 Regulatory Approval ..............................................................................................................53 
10.2.3 Amendments ...........................................................................................................................53 
10.3 
Ethical Conduct of the Study .....................................................................................................53 
10.4 
Patient Information and Consent ...............................................................................................53 
10.5 
Patient Confidentiality ...............................................................................................................54 
10.6 
Study Monitoring .......................................................................................................................54 
10.6.1 Access to Information for Monitoring ....................................................................................54 
10.6.2 Access to Information for Auditing or Inspections ................................................................55 
10.7 
Case Report Forms and Study Records .....................................................................................55 
10.7.1 Recording of Data ..................................................................................................................55 
10.7.2 Source Documentation and Medical/Study Records ..............................................................55 
10.8 
Data Monitoring Committee ......................................................................................................55 
10.9 
Protocol Violations/Deviations ..................................................................................................55 
10.10 Access to Source Documentation ..............................................................................................55 
10.11 Data Generation and Analysis ...................................................................................................56 
10.12 Retention of Data .......................................................................................................................56 
10.13 Final Report, Publication and Disclosure Policy .......................................................................57 
11 References ..........................................................................................................................................58 
12 Appendices .........................................................................................................................................60 
 


ACH-0144471 
Achillion Pharmaceuticals, Inc. 
Clinical Protocol ACH471-103, Amendment 5 
04 June 2021, Version 6 
 
Confidential 
Page 14 of 70 
 
 
List of Tables 
Table 1. 
Dosing Taper Schedule ......................................................................................................27 
Table 2. 
Clinical Laboratory Tests ...................................................................................................35 
Table 3. 
Approximate Total Blood Volumes ...................................................................................37 
Table 4. 
Pharmacodynamic Markers ...............................................................................................38 
Table 5. 
Schedule of Assessments ...................................................................................................60 
Table 6: 
Potential Risks and Mitigation Measures due to COVID-19.............................................70 
 
List of Figures 
Figure 1. 
Study Schematic.................................................................................................................22 
 
List of Appendices 
Appendix 1. 
Schedule of Assessments ...................................................................................................60 
Appendix 2. 
Quality of Life Assessments ..............................................................................................62 
Appendix 3. 
Grading the Severity of Adverse Events ............................................................................67 
Appendix 4. 
Fever Management Plan ....................................................................................................68 
Appendix 5 
COVID-19 Risk Assessment .............................................................................................70 
 


ACH-0144471 
Achillion Pharmaceuticals, Inc. 
Clinical Protocol ACH471-103, Amendment 5 
04 June 2021, Version 6 
 
Confidential 
Page 15 of 70 
 
 
List of Abbreviations and Definitions of Terms 
Abbreviation 
Definition 
AE 
Adverse event 
ACIP 
Advisory Committee on Immunization Practices 
ALT 
Alanine aminotransferase 
AP 
Alternative Pathway (of complement)  
AST 
Aspartate aminotransferase 
BA 
Bioavailability 
BP 
Blood pressure 
BMI 
Body mass index 
°C 
Degrees Celsius 
C3 
C3 complement protein 
C5 
C5 complement protein 
COVID-19 
Coronavirus Disease 2019 
CRF 
Case report form 
CTCAE 
Common Terminology Criteria for Adverse Events 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
eGFR 
Estimated glomerular filtration rate 
ELISA 
Enzyme-linked immunosorbent assay 
FDA 
Food and Drug Administration 
fB 
(Complement) Factor B 
fD 
(Complement) Factor D 
FSH  
Follicle stimulating hormone 
GCP 
Good Clinical Practice 
GPI 
Glycosylphosphatidylinositol 
Hct 
Hematocrit 
Hgb 
Hemoglobin  
HIPAA 
Insurance Portability and Accountability Act of 1996 
HR 
Heart rate 
HSCT 
Hematopoietic stem cell transplantation 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human 
Use 
IEC  
Independent Ethics Committee 
IRB 
Institutional review board 
kDa 
Kilodalton 
LDH 
Lactate dehydrogenase 
LFC 
Liquid-filled capsule 
LLN 
Lower limit of normal 
MAC 
Membrane attack complex 
MAD 
Multiple ascending dose 
MDRD 
Modification of Diet in Renal Disease equation 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHRA 
Medicines and Healthcare Products Regulatory Agency 
PD 
Pharmacodynamic(s) 
PI 
Principal investigator 
PIGA 
Phosphatidylinositol N-acetylglucosaminyltransferase subunit A 
PK 
Pharmacokinetic(s) 
PNH 
Paroxysmal Nocturnal Hemoglobinuria 
PR interval 
Period that extends from the beginning of the P wave until the beginning of the QRS complex 
PRO 
Patient Reported Outcomes 
QoL 
Quality of Life 
QRS 
Group of electrocardiogram waves comprising the Q, R, and S waves 


ACH-0144471 
Achillion Pharmaceuticals, Inc. 
Clinical Protocol ACH471-103, Amendment 5 
04 June 2021, Version 6 
 
Confidential 
Page 16 of 70 
 
 
Abbreviation 
Definition 
QT 
QT interval 
QTcF 
QT interval Fridericia Correction Formula  
RBC  
Red blood cells 
Rel BA 
Relative bioavailability study 
RR 
Respiration rate 
SAD 
Single ascending dose 
SAE  
Serious adverse event 
SAP  
Statistical Analysis Plan 
TEAE 
Treatment-emergent adverse event 
ULN 
Upper limit of normal 
WBC  
White blood cells 
 


ACH-0144471 
Achillion Pharmaceuticals, Inc. 
Clinical Protocol ACH471-103, Amendment 5 
04 June 2021, Version 6 
 
Confidential 
Page 17 of 70 
 
 
1 Introduction 
This protocol is an extension study to evaluate long-term safety and efficacy of ACH-0144471 in 
patients with PNH who have completed clinical study ACH471-100, did not experience any 
ACH-0144471-related SAEs, and demonstrated clinical benefit. 
1.1 Results of Nonclinical Studies 
Please refer to the Investigator’s Brochure (IB) [1] for an overview of the properties of ACH-0144471 
and the results of the nonclinical investigations conducted. 
1.2 Previous Human Experience with ACH-0144471 
Three clinical studies with ACH-0144471 have been conducted: ACH471-001 (single ascending dose 
[SAD]), ACH471-002 (multiple ascending dose [MAD]) and ACH471-006 (relative bioavailability [Rel 
BA]).  One hundred and fifteen (115) healthy volunteers participated in these three clinical studies of 
ACH-0144471, of which 87 received ACH-0144471, and the remaining received placebo.  Results from 
all three studies are presented in the Investigator’s Brochure [1]. 
The SAD study was performed to evaluate the safety and tolerability of single ascending doses of 
ACH-0144471.  Healthy volunteers were dosed with ACH-0144471 in five separate groups.  Groups 1 
through 4 received escalating oral doses, in the fasted state, of 200, 600, 1200, and 2400 mg, 
respectively (2400 mg was administered as two divided doses of 1200 mg separated by 12 hours).  
Group 5 received a 1200-mg dose in the fed state.  Overall, ACH-0144471 was well-tolerated at all dose 
levels.  There were no drug-related serious adverse events (SAEs), no treatment-emergent adverse 
events (TEAEs) leading to study discontinuation, and no study drug-related Grade 3 or 4 TEAEs.  There 
were no trends suggesting a drug-related effect on TEAEs, laboratory results, electrocardiogram (ECG) 
parameters, or vital signs.  There were no dose-related trends for infection, and no evidence for drug-
induced liver injury. 
The MAD study was conducted to evaluate the safety and tolerability of multiple ascending doses of 
ACH-0144471 and to determine a recommended dose and schedule for treatment of patients with PNH 
in phase 2 studies.  Healthy volunteers were dosed with ACH-0144471 in four separate groups.  Groups 
1 through 3 received multiple daily doses of 200, 500, and 800 mg, respectively, twice daily for 14 days.  
Group 4 received doses of 75 mg every 8 hours for 7 days.  All doses were given in the fasted state.  
ACH-0144471 administered as 200 mg every 12 hours for 14 days was well-tolerated.  The higher doses 
studied (500 and 800 mg administered every 12 hours for 14 days) were associated with elevations in 
alanine aminotransferase (ALT) levels in some patients.  In Group 4, a dosing regimen of 75 mg 
administered every 8 hours for 7 days was well-tolerated and resulted in ACH-0144471 trough 
concentrations that have the potential for efficacy in PNH and other complement-mediated diseases. 
The pharmacodynamics and potential for clinical efficacy for ACH-0144471 is primarily associated with 
maintenance of exposure above a target trough level.  Exploratory ex vivo AP hemolysis experiments 
using patient PNH cells showed that ACH-0144471 at concentrations of >20 ng/mL provided protection 
from hemolysis similar to eculizumab at a concentration of 35 μg/mL (an efficacious eculizumab trough 
concentration in PNH patients) [2].  Pharmacokinetic (PK) modeling based on data from the SAD and 
MAD studies predicts that plasma trough ACH-0144471 concentrations can be increased substantially 
with minimal increase Cmax or AUC, and that ACH-0144471 trough concentrations of >30 and 


ACH-0144471 
Achillion Pharmaceuticals, Inc. 
Clinical Protocol ACH471-103, Amendment 5 
04 June 2021, Version 6 
 
Confidential 
Page 18 of 70 
 
 
>60 ng/mL can be achieved with doses of 100 and 150 mg 3 times daily (TID), respectively.  Based on 
these analyses, 100 mg TID was expected to be pharmacologically active, and was selected as the 
starting dose for ACH471-100.  The starting dose was increased to 150 mg TID as emerging data from 
the first 2 patients enrolled suggested that a higher dose was needed to provide clinical efficacy.  All 
patients enrolled in ACH471-100 to date have dose escalated to 200 mg TID with no clinically 
significant alterations in liver enzymes. 
The SAD and MAD studies were conducted using liquid-filled capsules (LFC).  Studies in PNH patients 
will be performed using a tablet formulation.  A Relative BA study was performed to compare 
bioavailability of the LFC and the tablet formulations.  This was a randomized, crossover, open-label 
study to assess the relative bioavailability of ACH-0144471 in tablet and softgel capsule formulations 
relative to the extemporaneously prepared LFC used in the SAD and MAD studies.  AUC0-∞ was 
bioequivalent and Cmax slightly lower (19%) for ACH-0144471 tablets administered with food relative 
to the LFC formulation given under fasting conditions as in the SAD and MAD studies.  ACH-0144471 
was well-tolerated in this study, and there were no SAEs, no discontinuations due to TEAEs, and no 
drug-related Grade 3 or 4 TEAEs. 
Another study in patients with C3 Glomerulopathy (C3G) or Immune-Complex Membranoproliferative 
Glomerulonephritis (IC-MPGN), ACH471-201, is ongoing.  The trial will evaluate the ability of 
ACH-0144471, given for 14 days, to increase C3 levels via inhibition of fD. 
1.3 Rationale 
1.3.1 Complement Factor D 
Factor D (fD) is one of nine serine proteases in the complement system.  It is a highly specific enzyme 
with only one known substrate, factor B (fB).  Of all the complement proteins, it has the lowest 
abundance in serum with a concentration of approximately 2 µg/mL, and is the rate-limiting step of 
alternative pathway (AP) activation [3, 4].  It is a low molecular weight protein (24 kDa) that is 
primarily produced by adipocytes, but can also be produced and secreted by monocytes/macrophages 
and astrocytes in humans [3, 4].  Due to its small size, it is freely filtered at the glomerulus, and then 
taken up by the proximal tubule cell where it is catabolized with an estimated fractional catabolic rate of 
60% per hour.  It is this rapid catabolism that is responsible for maintaining low circulating fD levels.  
As a result, renal dysfunction is associated with elevated fD levels, which may lead to increased 
alternative pathway activity and inflammation [5, 6].  The biochemical, physiological, and functional 
features of fD make it an attractive target for pharmacological inhibition as this may prove useful in the 
treatment of a wide spectrum of complement-mediated diseases such as PNH. 
1.3.2 Paroxysmal Nocturnal Hemoglobinuria (PNH) 
PNH is a rare disease of unknown frequency both in the United States and worldwide.  One small study 
conducted in Great Britain and France, reported in 1995, provided an incidence rate of approximately 
1.3 cases/1 million inhabitants.  Attempts to get a more accurate incidence and to learn more about its 
natural course is currently under way under the auspices of the PNH Registry [7]. 
PNH may occur at any age; it has been reported in children as young as 2 years to adults as old as 
83 years, but it is most frequently found among adults, with a median age at diagnosis of approximately 
40 years.  Men and women are affected equally, and no familial tendencies exist.  It has been suggested 


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ACH-0144471 
Achillion Pharmaceuticals, Inc. 
Clinical Protocol ACH471-103, Amendment 5 
04 June 2021, Version 6 
 
Confidential 
Page 20 of 70 
 
 
1.3.4 Safety Considerations 
1.3.4.1 Risk of Infection 
One of the primary functions of the complement system is to fight infections as part of the innate 
immune system.  As suggested by individual case reports with complement system deficiencies 
including fD, inhibition of the complement system may result in a lifetime increased risk of infection, 
notably with Neisseria meningitidis (N. meningitidis) [12, 13, 14], and other encapsulated organisms. 
Because of this potential risk, patients who were enrolled in clinical study ACH471-100 were required 
to be previously vaccinated, or to receive vaccinations for N. meningitidis, Streptococcus pneumoniae 
(S. pneumoniae), and Haemophilus influenzae (H. influenzae) prior to receiving ACH-0144471.  Patients 
in this extension study will receive booster vaccinations as described in Section 6.2. 
During clinic visits, subjects will be monitored for the development of fever.  A specific Fever 
Management Plan (Appendix 4) has been developed for this study. 
Patients will also be counseled about behaviors to avoid and also be asked to monitor themselves 
between clinic visits (Appendix 4). 
1.3.4.2 Hepatic Injury 
In humans, elevations in ALT levels have been observed in some healthy volunteers with doses of 
500 mg twice daily and 800 mg twice daily for 14 days, doses higher than the currently anticipated 
clinical dose.  The ALT elevations were not associated with signs or symptoms of hepatic failure, 
occurred after completion of dosing, and were self-limited. 
Additionally, DILIsym simulations indicate maximal loss of hepatocytes that occurred at the high doses 
in the MAD study would not have a significant effect on liver function [15].  Simulated dosing at 250, 
300, and 325 mg TID for up to 1 year predicted minor, clinically insignificant (<1× ULN) ALT 
increases [16]. 
In nonclinical studies, hepatobiliary cholestasis has been observed in the dog toxicology studies at 
exposures higher than those intended for clinical use.  Therefore, alkaline phosphatase, gamma-glutamyl 
transferase (GGT), total/direct/indirect bilirubin, aspartate aminotransferase (AST), and ALT will be 
closely monitored in all clinical studies with ACH-0144471. 


ACH-0144471 
Achillion Pharmaceuticals, Inc. 
Clinical Protocol ACH471-103, Amendment 5 
04 June 2021, Version 6 
 
Confidential 
Page 21 of 70 
 
 
2 Study Objectives 
2.1 Primary Objective 
The primary objective of this study is to evaluate the safety and efficacy of long-term therapy with 
ACH-0144471 in patients with PNH. 
2.2 Secondary Objective 
The secondary objective of this study is to evaluate health-related quality of life measures in patients 
with PNH based on patient reported outcome (PRO) instruments and its evolution over the course of 
long-term therapy with ACH-0144471. 
2.3 Exploratory Objectives 
No exploratory objectives have been identified for this study. 


ACH-0144471 
Achillion Pharmaceuticals, Inc. 
Clinical Protocol ACH471-103, Amendment 5 
04 June 2021, Version 6 
 
Confidential 
Page 22 of 70 
 
 
3 Investigational Plan 
3.1 Overall Study Design and Plan 
This is an open-label extension study designed to evaluate long-term safety and efficacy of 
ACH-0144471 in patients with PNH who have demonstrated clinical benefit from ACH-0144471 in 
study ACH471-100.  Patients may remain in the study until 1) ACH-0144471 is commercially available 
in their country; 2) the development of ACH-0144471 as a potential therapy for PNH is terminated; 3) 
the therapy is no longer tolerated or effective; or 4) another appropriate Alexion clinical study is 
available or in the opinion of the PI, another treatment option is available.  In addition, the Sponsor 
reserves the right to close any study site or terminate the study at any time for any reason at the sole 
discretion of the Sponsor. 
In order to be eligible for long-term treatment with ACH-0144471 in this extension study, patients must 
have demonstrated a clinical benefit from ACH-0144471 in ACH471-100.  Clinical benefit will be 
assessed by the investigator, based on an improvement in hemoglobin and/or LDH.  Additionally, 
patients must not have developed any comorbidity that might make it unsafe to continue on therapy, or 
any safety concern related to treatment with ACH-0144471.  The principal investigator will ensure that 
all eligibility criteria are met and determine whether a patient is an appropriate candidate for long-term 
continuation of ACH-0144471.  Patients will continue therapy with ACH-0144471 from their primary 
study into this extension study without interruption.  Day 84 of the primary study will be Day 1 (Week 
1) of this study, and data collected as part of the final visit for ACH471-100 may be entered as the Day 1 
data for this study as appropriate.  The PI may escalate or reduce dosing to manage clinical benefit or for 
safety or tolerability reasons, as described in Section 3.2.2. 
Figure 1. 
Study Schematic 
 
Considering PNH is a serious life-threatening disease, a long-term extension study, beyond the dosing 
included in this study, may be offered to patients, if supported by clinical and nonclinical data. Pending 
regulatory and ethics committee approval of such a study, patients who, in the opinion of the PI, are 
receiving benefit from ACH-0144471 may be enrolled directly into that study without interruption from 
this study, and will continue to receive daily treatment with ACH-0144471 and safety and efficacy 
monitoring. Any patients so enrolled will not require a dosing taper or the follow-up visits described in 
this protocol. 
Months 1-6
Week
1
2
3
4
5
6
7
8
9
10 11 12 13 14 15 16 17 18 18 20 21 22 23 24
Clinic Visits
X
X
X
X
X
X
Local Lab Visits
Months >6
Week
25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56
Clinic Visits
X
X
X
X
Local Lab Visits
X
X
X
X


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ACH-0144471 
Achillion Pharmaceuticals, Inc. 
Clinical Protocol ACH471-103, Amendment 5 
04 June 2021, Version 6 
 
Confidential 
Page 24 of 70 
 
 
* Because patients may have ongoing hemolysis which may result in increased bilirubin and AST, 
increases in bilirubin and/or AST during the study must be evaluated in the context of any continuing 
hemolysis.  The PI should evaluate LDH and Hgb levels as well as baseline bilirubin and AST levels to 
determine if the increases observed are due to an effect on liver function or are secondary to hemolysis. 
In addition to the individual stopping criteria described above, the Sponsor reserves the right to close 
any study site or terminate the study at any time for any reason at the sole discretion of the Sponsor. 
3.3 Study Duration and Dates 
All patients may remain in the study until 1) ACH-0144471is commercially available in their country; 2) 
the development of ACH-0144471 as a potential therapy for PNH is terminated; 3) the therapy is no 
longer tolerated or effective; or 4) another appropriate Alexion clinical study is available or in the 
opinion of the PI, another treatment option is available.  If patients discontinue during the extension 
phase, they will have ACH-0144471 tapered and have follow-up visits. 


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ACH-0144471 
Achillion Pharmaceuticals, Inc. 
Clinical Protocol ACH471-103, Amendment 5 
04 June 2021, Version 6 
 
Confidential 
Page 27 of 70 
 
 
5 Study Treatment 
5.1 Description of Treatment 
5.1.1 Study Drug 
ACH-0144471 will be dosed as a tablet formulation containing the drug substance, lactose, 
microcrystalline cellulose, croscarmellose sodium, sodium lauryl sulphate, magnesium stearate, 
colloidal silicon dioxide, and hypromellose acetate succinate.  The coating components are polyvinyl 
alcohol, titanium dioxide, macrogol/polyethylene glycol, and talc. ACH-0144471 will be administered 
as 50, 75, or 100 mg tablets. The 75 mg tablets are no longer manufactured; therefore, the 75 mg tablet 
will not be provided once the current supply expires. 
5.2 Treatments Administered 
5.2.1 ACH-0144471 
A single treatment group is planned for patients who completed study ACH471-100. 
At the end of dosing, or if a patient is discontinued, it is recommended that a taper be implemented, 
according to the schedule in Table 1.  If dosing is terminated for safety-related reasons, the PI may 
discontinue dosing immediately if they feel it in the best interest of the patient.  Whenever possible, this 
decision should be discussed with the  Medical Monitor prior to dosing termination. 
Table 1. 
Dosing Taper Schedule 
Dose at Termination 
Taper Period 1 
(Taper Days 1 to 3) 
Taper Period 2 
(Taper Days 4 to 6) 
150 mg TID 
100 mg TID 
50 mg TID 
175 mg TID 
100 mg TID 
50 mg TID 
200 mg TID 
150 mg TID 
50 mg TID 
225 mg TID 
150 mg TID 
50 mg TID 
250 mg TID 
150 mg TID 
50 mg TID 
Abbreviations: T = taper; TID = three times a day 
During the end of treatment visit, the site staff will provide instructions for when the patient should start Taper Period 1.  
Taper day visits may be done at the clinic or by phone call on Day 3 and Day 6 respectively.  
On Taper Day 3, site staff should assess safety and give instructions to further taper dosing. On Taper Day 6, site staff should 
give instructions to terminate dosing. 
Patients entering this study should not have their ACH-0144471 dose tapered as described for the end of 
treatment in study ACH471-100. Patients who enter into Study ACH228-110 or those who are eligible 
to participate in other ACH-0144471 (danicopan) clinical studies will not need to have their 
ACH-0144471 dose tapered as long as there is no gap in dosing before starting the next clinical study. 
5.2.2 Vaccines 
Patients entering this study will have been previously vaccinated against N. meningitidis, S. pneumoniae, 
and H. influenza.  Patients in this study will receive booster vaccinations as described in Section 6.2. 


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ACH-0144471 
Achillion Pharmaceuticals, Inc. 
Clinical Protocol ACH471-103, Amendment 5 
04 June 2021, Version 6 
 
Confidential 
Page 32 of 70 
 
 
acknowledgment of receipt of each shipment of study drug (quantity and condition) and patient 
dispensing records and returned or destroyed drug.  Dispensing records will document quantities 
received from Achillion Pharmaceuticals, Inc. (or designee) and quantities dispensed to patients, 
including lot number, date dispensed, patient identifier number, patient initials, and the initials of the 
person dispensing the medication.  All drug supplies and associated documentation will be periodically 
reviewed and verified by the Study Monitor over the course of the study. 
5.9 Investigational Product Retention at Study Site 
At study initiation, the Study Monitor will evaluate the site’s Standard Operating Procedure for study 
drug disposal/destruction in order to ensure that it complies with Achillion Pharmaceuticals, Inc. 
requirements.  Drug may be returned to the Sponsor (or designee) or destroyed on an ongoing basis 
during the study, if appropriate, after drug accountability has been verified by the Study Monitor.  At the 
end of the study, following final drug inventory reconciliation by the Study Monitor, the study site will 
dispose of and/or destroy all unused study drug supplies, including empty containers, according to these 
procedures.  If the site cannot meet Achillion Pharmaceuticals, Inc. requirements for disposal, 
arrangements will be made between the site and Achillion Pharmaceuticals, Inc. or its representative, for 
destruction or return of unused study drug supplies. 


ACH-0144471 
Achillion Pharmaceuticals, Inc. 
Clinical Protocol ACH471-103, Amendment 5 
04 June 2021, Version 6 
 
Confidential 
Page 33 of 70 
 
 
6 Study Procedures 
The required study procedures are detailed in this section.  The timeline for the procedures may be found 
in Appendix 1. 
6.1 Informed Consent 
The PI or designee is responsible for administering and obtaining freely given consent, in writing, before 
entering the patient into the study and performing any study-related procedures.  Each patient will sign 
an Ethics Committee (EC) or Institutional Review Board (IRB) -approved written informed consent 
form (ICF). 
6.2 Vaccination 
Inhibition by ACH-0144471 of factor D, and of the complement alternative pathway, may be associated 
with an increased risk of infection by N. meningitidis, H. influenza, and S. pneumoniae.  Vaccination is 
an important means to mitigate this theoretical risk.  Additional information regarding the risk of 
infection can be found in Section 6.5.1 of the Investigator's Brochure. 
Patients in Protocol ACH471-103 will have been previously vaccinated against N. meningitidis, 
S. pneumoniae, and H. influenzae as described in Protocol ACH471-100.  The need for booster 
vaccinations during Protocol ACH471-103 will be evaluated according to national and/or local 
guidelines.  If local and/or national guidelines do not exist or do not fully address vaccination against 
these organisms, investigators should consider consulting the Advisory Committee on Immunization 
Practices (ACIP) guidelines (available at https://www.cdc.gov/vaccines/acip/index.html).  Based on the 
available guidelines and each subject's vaccination history, the Investigator will assess the need for 
booster vaccinations against each organism and/or serotype. 
For any vaccines or boosters given as part of this study, full identifying information, including the 
brand, will be recorded in the participant’s CRF. 
6.3 Physical Examination 
Brief physical examinations, to include general appearance and examination of cardiovascular and 
respiratory systems, abdomen, extremities/skin, and additional organs or systems targeted to any new 
signs or symptoms, will be performed by the PI (or designee) at the times specified in the Schedule of 
Assessments (Appendix 1) or at the discretion of the Investigator or designee, and/or when patients 
present with AEs.  All clinically significant physical examination findings that are new or worsened 
since the last physical examination must be recorded in the patient’s source documents and in the 
patient’s CRF as an adverse event. 
6.4 Vital Signs 
The PI or designee will obtain blood pressure (BP), heart rate (HR), and respiration rate (RR) at the 
visits indicated in the Schedule of Assessments (Appendix 1).  Vital signs will be measured in the supine 
position following a 5-minute rest.  All vital sign measurements for an individual should be taken on the 
dominant arm (if possible) throughout the study.  Vital signs may be measured using an automated vital 


ACH-0144471 
Achillion Pharmaceuticals, Inc. 
Clinical Protocol ACH471-103, Amendment 5 
04 June 2021, Version 6 
 
Confidential 
Page 34 of 70 
 
 
signs machine.  Vital sign values will be recorded in the patient’s source documents and in the patient’s 
CRF. 
6.5 Body Temperature 
The PI or designee will obtain body temperature using an oral thermometer at the visits indicated in the 
Schedule of Assessments (Appendix 1).  Prior to discharge from the clinic on Day 1, the site will 
provide each patient with an oral thermometer, and train each patient on its proper use.  In addition, the 
Fever Management Plan (Appendix 4) outlines measures that the site must take to ensure that outside the 
clinic, the patient will be able to promptly identify a fever, and seek emergency medical attention if 
needed.  Any temperature measurement ≥38.0°C, measured either at the clinic or by the patient outside 
the clinic, requires action as outlined in the Fever Management Plan (Appendix 4). 
6.6 Electrocardiography 
The PI or designee will obtain ECG measurements at the times indicated in Appendix 1.  All ECG 
recordings should be 12-lead, and should be performed after the patient has rested quietly for at least 
5 minutes in a supine position and before blood is drawn (whenever possible).  The following 
parameters and intervals will be assessed: HR, RR, PR, QRS, QT, and QTcF.  The occurrence of 
depolarization or repolarization disorders, arrhythmic disorders or other abnormalities will be noted.  A 
designation of clinical significance shall also be noted by the PI or designee. 
In some cases it may be appropriate to repeat an abnormal ECG to rule out improper lead placement as 
contributing to the ECG abnormality.  It is important that the leads are placed in approximately the same 
positions each time in order to achieve precise ECG recordings. 
All ECGs must be read by the PI or designee.  The PI/designee needs to evaluate the finding of ECG 
abnormalities promptly (refer to Section 6.15.1 for a discussion of the circumstances under which ECG 
findings are to be reported as AEs). 
All ECG parameters and assessments must be recorded or stored in the patient’s source documents and 
in the patient’s CRF.  Any clinically significant finding must be reported as an adverse event. 
6.7 Clinical Laboratory Measurements 
Blood and urine samples will be collected for safety laboratory evaluation according to Table 2, at times 
listed in Appendix 1. 


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ACH-0144471 
Achillion Pharmaceuticals, Inc. 
Clinical Protocol ACH471-103, Amendment 5 
04 June 2021, Version 6 
 
Confidential 
Page 36 of 70 
 
 
therapy, Day 84 of ACH471-100 will be Day 1 of this study, and the final urine pregnancy test on 
Day 84 of ACH471-100 may serve as the Day 1 urine pregnancy test for this study.  
Female patients of childbearing potential who require vaccination or boosters (see Section 6.2) must also 
have a negative urine pregnancy test on the days of vaccination, before any vaccine or booster is 
administered. 
Any positive urine pregnancy test will be confirmed by a serum pregnancy test. 
6.9 Sample Collection, Storage, and Shipping 
6.9.1 Blood Collection for Complement Assays 
Samples will be collected for measurement of factor D levels and AP Wieslab activity; additional 
samples will be collected and retained for potential assessment of other non-genetic complement-
associated biomarkers.  Depending on the test, either serum or plasma may be required; aliquots of both 
serum and plasma will therefore be collected at each visit.  Whole blood will be collected and processed 
to obtain cell-free serum or plasma, which will be aliquoted into cryovials, frozen on dry ice, stored in a 
-80°C freezer and shipped frozen to the designated laboratories.  It is important that samples be 
collected, prepared, and shipped in a way that ensures minimum freeze-thaw cycles and avoids potential 
in vitro complement activation before testing.  Specific instructions for sample collection, processing, 
and shipping will be provided in a separate laboratory manual. 
Samples used for complement analyses will be stored from the beginning of this clinical study to one 
year after the clinical study report is finished. 
6.9.2 PK Plasma Samples 
Samples will be collected for pharmacokinetic analysis.  Whole blood (2 mL) will be collected and 
processed to obtain cell-free plasma, which will be aliquoted into cryovials, frozen on dry ice, stored in a 
-80°C freezer and shipped frozen to the bioanalytical laboratory.  It is important that samples be 
collected, prepared, and shipped in a way that ensures minimum freeze-thaw cycles.  Specific 
instructions for sample collection, processing, and shipping will be provided in a separate laboratory 
manual. 
6.9.3 Blood Volumes 
Approximate blood volumes for each visit are detailed in Table 3 below.  Because the duration of the 
study is not defined, calculation of the total planned blood volume to be collected per individual is not 
possible.  Unanticipated additional blood may be collected throughout the study for such things as safety 
monitoring and PK or PD assessments, should it be necessary.  Please refer to the laboratory manual for 
specific instructions regarding blood and urine volume, collection, processing, and handling. 


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ACH-0144471 
Achillion Pharmaceuticals, Inc. 
Clinical Protocol ACH471-103, Amendment 5 
04 June 2021, Version 6 
 
Confidential 
Page 38 of 70 
 
 
using LDH and hemoglobin levels and other measures of hemolysis, as well as RBC transfusion 
requirements. 
Samples for AP Weislab, fD, flow cytometry: PNH clone size, and complement-associated biomarkers 
are no longer required in the extension phase upon implementation of Protocol Amendment 5.0. 
Sampling may be performed in response to a drug-related safety event or clinical deterioration as 
determined by the Investigator and in discussion with the Medical Monitor. In this scenario, the date and 
time of the most recent dose should be recorded when available. 
Table 4. 
Pharmacodynamic Markers 
Assay Identifier 
Assay Descriptions 
LDH 
Blood test 
CBC components 
Blood test 
Free hemoglobin 
Blood test 
Haptoglobin 
Blood test 
D-dimer 
Blood test 
Direct Coombs test 
Blood test 
PNH clone size 
Flow cytometry 
AP Wieslab assay 
ELISA; LPS as activator; measurement of TCC 
fD  
ELISA 
Additional complement-associated 
biomarkers  
ELISA or other 
Refer to Appendix 1 for the schedule for each of these tests. 
6.14 Patient Reported Outcomes Assessments 
The FACIT-Fatigue scale and the EORTC-QLQ-C30 will be administered to patients at the schedule 
indicated in Appendix 1 using the tools provided in Appendix 2 to collect patients’ health-related quality 
of life during continued treatment with ACH-0144471. 
In addition, patients were interviewed by an outcomes researcher chosen by the Sponsor to collect their 
experience of PNH, its impact on everyday lives and the disease trajectory, and to collect patients’ 
experience of ACH-0144471 treatment and their perception of the evolution of their condition.  The 
interviews were conducted over the phone by a trained, experienced interviewer and lasted 
approximately 30 minutes. Patients were interviewed after approximately 3 and 9 months of treatment in 
this study (i.e., after approximately 6 and 12 months of treatment with ACH-0144471, including 
approximately 3 months of treatment during ACH471-100).  Patients who terminated early may have 
been interviewed at the time of termination. As of 30 April 2019, PRO interviews were discontinued by 
the Sponsor. 
6.15 Adverse Events Assessments 
6.15.1 Definitions 
Adverse Events (AEs) must be assessed for the investigational product in this study.  An investigational 
product is defined as a pharmaceutical form of an active ingredient or placebo being tested or used as a 
reference in the study, whether blinded or unblinded.  The term “adverse event” is defined as any 
untoward medical occurrence associated with the use of a drug in humans, whether or not considered 


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ACH-0144471 
Achillion Pharmaceuticals, Inc. 
Clinical Protocol ACH471-103, Amendment 5 
04 June 2021, Version 6 
 
Confidential 
Page 47 of 70 
 
 
7 Study Activities 
Activities for each visit are provided in the Schedule of Assessments (Appendix 1).  Additional details 
for the various activities are provided in Section 6.  There is no formal screening or eligibility visit.  For 
each patient, the PI should make the decision whether participation in this extension study would be 
appropriate on or around the Day 70 visit of study ACH471-100 and communicate this decision to the 
Medical Monitor.  Day 84 of study ACH471-100 will be Day 1 (Week 1) of this study.  Data collected 
as part of the final visit for ACH471-100 may be entered as the Day 1 data for this study as appropriate. 
During the study period, physical examinations, assessment of vital signs, ECG measurements, all 
required safety laboratory testing, pregnancy testing for women of childbearing potential, and collection 
of blood and urine samples for efficacy, PD, and PK evaluation will be performed at various time points 
throughout the study as specified in Appendix 1. 
Dosing should be at approximately the same times each day. 
During the treatment periods when multiple assessments occur at the same time, they should be 
conducted in the following order: 
ECG and vital signs prior to blood sampling 
The actual times of procedures and sample collections will be recorded in the patient’s CRF. 
7.1.1 Clinic Visits 
The procedures indicated in Appendix 1 should be followed for each visit.  As part of these activities, 
site personnel should review with the patient the instructions for how to take their medication at home, 
as described in Section 5.3. 
Visits may take place within a window of ±3 days relative to the specified day for the first 6 months, and 
then within a window of ±7 days relative to the specified day for the duration of the study. 
7.1.2 Safety Follow-up at Local Laboratory 
As indicated in Appendix 1 (Schedule of Assessments), after 6 months, the frequency of clinic visits will 
be reduced from once every 4 weeks to once every 8 weeks.  Once this happens, patients will have blood 
drawn at a local clinical laboratory 4 weeks after clinic visits for assessment of hemoglobin, free 
hemoglobin, and LDH levels.  These visits should occur within a window of ±7 days relative to the 
specified day. 
7.1.3 Safety Follow-up After Escalation 
As described in Section 3.2.2, the PI, in consultation with the Sponsor, may escalate dosing in 
increments of 50 mg to a maximum of 250 mg TID after evaluating the clinical benefit and the available 
safety, PD, and PK data (including laboratory test results) for a patient.  Patients should have blood 
drawn (locally or at the clinic) 72 to 84 hours after starting the new dose for measurement of LDH and 
liver function tests (ALT, AST, GGT, and ALP).  Patients should have a clinic visit after approximately 
2 weeks at their new dose for safety evaluation and collection of samples for efficacy and predose PK 


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ACH-0144471 
Achillion Pharmaceuticals, Inc. 
Clinical Protocol ACH471-103, Amendment 5 
04 June 2021, Version 6 
 
Confidential 
Page 50 of 70 
 
 
8 Quality Control and Assurance 
8.1 Routine Monitoring 
The PI is responsible for the validity of all data collected at the clinical site and must accept the various 
monitoring procedures employed by the Sponsor.  The purpose of monitoring is to verify that the rights 
and well-being of human subjects are protected; that study data are accurate, complete, and verifiable 
with source data; that the study is conducted in compliance with the protocol, GCP, and the applicable 
regulatory requirements. 
A monitor assigned by the Sponsor will conduct regular site visits for the purpose of monitoring various 
aspects of the study.  Visits will take place usually within a predetermined interval, but this may vary 
during the course of the study.  The PI must agree to allow the Study Monitor and authorized 
representatives of the Sponsor to inspect all CRFs and corresponding source documents, e.g., original 
medical records, subject records and laboratory raw data, access to the clinical supplies, dispensing, and 
storage areas and agree to assist with their activities if requested.  The PI should provide adequate time 
and space for monitoring visits. 
The monitor will query any missing or spurious data with the PI (or designee), which should be resolved 
in a timely manner.  A monitoring log will be maintained recording each visit, the reason for the visit, 
the monitor’s signature, and PI or designee’s confirmation signature. 
8.2 Site Audits 
For the purpose of compliance with GCP and regulatory agency guidelines, it may be necessary for 
Sponsor authorized Quality Assurance personnel and/or authorized personnel from an external 
regulatory agency to conduct an audit/inspection of an investigational site.  The purpose of an audit is to 
assess the quality of data with regard to accuracy, adequacy, and consistency, and to assure that studies 
are in accordance with GCP, and Regulatory Agency guidelines.  Having the highest quality data from 
studies is an essential aspect of drug development. 
The PI will be given sufficient notice to prepare for such visits, which are planned to take usually 
between one and two days and may be conducted at any stage during the study.  The audit will involve 
the review of all study related documentation, which is required by GCP to be maintained by each site, 
review of drug storage, dispensing, and return, review of all study related supplies and review of source 
documents against the CRFs to assure the adequacy and accuracy of the information that has been 
recorded, including the verification of any AEs that have occurred. 
In the event of the site being notified of a regulatory inspection, the Sponsor will help with the 
preparation and it is essential that they be notified of the inspection as soon as possible. 


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ACH-0144471 
Achillion Pharmaceuticals, Inc. 
Clinical Protocol ACH471-103, Amendment 5 
04 June 2021, Version 6 
 
Confidential 
Page 52 of 70 
 
 
9.5 Safety Analysis 
Treatment-emergent AEs (TEAEs) will be summarized and listed by system-organ-class and preferred 
term using the most current version of the Medical Dictionary for Regulatory Activities (MedDRA®).  
All SAEs and discontinuation due to AEs will be listed in tabulated format. 
All clinical laboratory data (hematology, serum chemistry, and urinalysis) with normal ranges, out-of-
range flags, and toxicity grades will be listed by patient.  Descriptive summary statistics may be 
provided for selected lab tests. 
Data on vital signs and ECGs will be examined either through patient listings or by summary statistics 
of selected parameters. 
Other exploratory techniques, e.g., graphic presentations, may also be employed to facilitate clinical 
interpretations of the safety results. 
9.6 Patient-Report Outcomes Assessments 
9.6.1 Quality of Life Scales 
Total score and change from baseline total score on the FACIT Fatigue scale instrument will be 
computed for each patient at each time point.  Both mean change total scores and individual patients’ 
change total scores may be plotted over time to provide visual examination on the improvement of 
fatigue condition. 
Similar analysis and presentations will be provided for each domain score of the EORTC-QLQ-C30 
instrument. 
9.6.2 Patient Interviews 
De-identified transcripts of the patients’ interviews will be qualitatively analyzed following a thematic 
analysis.  The analysis of patient interviews will be based on the grounded theory approach, allowing the 
voice of the patient to be heard rather than apply a priori concepts or hypotheses [18].  A validated 
software package [19] will be used to facilitate the storage, coding, analysis, and retrieval of qualitative 
data. 
Other analysis procedures relevant to interview data may also be explored.  A separate analysis plan 
and/or report will be provided for the interview data if deemed feasible and clinically appropriate. 


ACH-0144471 
Achillion Pharmaceuticals, Inc. 
Clinical Protocol ACH471-103, Amendment 5 
04 June 2021, Version 6 
 
Confidential 
Page 53 of 70 
 
 
10 Administrative Considerations 
10.1 Investigators and Study Administrative Structure 
The PI must maintain a screening log of all patients seen and considered for the study.  For those 
patients who are not eligible to participate in the study, the reason for their exclusion should be 
recorded. 
10.2 Institutional Review Board (IRB) or Independent Ethics Committee (IEC) and 
Regulatory Approval 
10.2.1 Ethical Approval 
The study protocol, patient information and consent form, the Investigator Brochure, available safety 
information, patient recruitment procedures (e.g., advertisements), information about payments and 
compensation available to the patients and documentation evidencing the investigator’s qualifications 
should be submitted by the investigator to the EC or IRB for ethical review and approval according to 
local regulations, prior to the start of the study.  The written approval should identify all documents 
reviewed by name, version, and the date on which the committee met and granted the approval. 
Any modifications to EC or IRB approved documents must also be submitted to the EC or IRB for 
approval before implementation. 
10.2.2 Regulatory Approval 
As required by local regulations, the Sponsor’s (or designee’s) Regulatory Affairs group will ensure all 
legal aspects are covered, and approval of the appropriate regulatory bodies obtained, prior to study 
initiation. 
10.2.3 Amendments 
Any amendments to the protocol will require IRB/IEC approval before implementation of changes made 
to the study design, except for changes necessary to eliminate an immediate hazard to study participants. 
10.3 Ethical Conduct of the Study 
This study will be performed in accordance with: 1) the principles of ICH Guideline E6 for Good 
Clinical Practice (CPMP/ICH/135/95 January 1997); 2) European Directive 2001/20/EC, 3) standard 
operating procedures and/or guidelines, 4) the U.S. Food and Drug Administration (FDA) regulations, 
5) the Declaration of Helsinki, and 6) all applicable federal, state, and local laws, rules and regulations 
relating to the conduct of the clinical study. 
10.4 Patient Information and Consent 
In obtaining and documenting informed consent, the investigator should comply with the applicable 
regulatory requirements and should adhere to ICH GCP (E6).  Each patient must be adequately informed 
in a language that they can understand and read of the aims, methods, anticipated benefits, potential 
hazards and the discomfort the study may entail, as well as their right to abstain from participating in the 
study and to withdraw their consent at any time without affecting their medical care.  If important new 


ACH-0144471 
Achillion Pharmaceuticals, Inc. 
Clinical Protocol ACH471-103, Amendment 5 
04 June 2021, Version 6 
 
Confidential 
Page 54 of 70 
 
 
information is incorporated in the ICF and approved by the EC, all patients still actively participating in 
the study must be re-consented. 
Written informed consent should be documented by the patient’s personally dated signature and the 
personally dated signature of the investigator or designee who conducted the informed consent 
discussion.  The investigator or designee should supply all enrolled patients with a copy of their signed 
informed consent.  The monitor will inspect the original consent form for all patients. 
10.5 Patient Confidentiality 
The investigators and Sponsor and its designees will preserve the confidentiality of all patients taking 
part in the study, in accordance with GCP, local regulations and, to the extent applicable, the Health 
Insurance Portability and Accountability Act of 1996 (“HIPAA”).  Subject to the requirement for source 
data verification by the study personnel by reference to the patient’s notes, confidentiality of all patient 
identities will be maintained.  Only date of birth, subject identification number, and study number will 
be used on the CRF and in all study correspondence, as permitted.  No material bearing a patient’s name 
will be kept on file by the Sponsor. 
Audio files of the interviews will be transcribed and de-identified (any identifying information such as 
dates, names, locations will be removed).  The de-identified transcripts will be delivered for analysis and 
a single audio file will be kept as a source document in the Trial Master File.  Any copies of the audio 
file will be destroyed immediately upon confirmation of receipt of the transcript. 
Data protection and privacy regulations will be observed in capturing, forwarding, processing, and 
storing patient contact details and data.  Patients will be informed accordingly and will be requested to 
give their consent on contact details data handling procedures in accordance with national regulations.  
In order to secure data privacy protection, patient contact details will be sent to a dedicated unit in 
charge of scheduling and setting up the interviews independently from study Sponsor, monitor, data 
management and data analysis structures and other study stakeholders.  The specific information about 
patient contact details management will be provided on a Contact Order Form to be completed by 
Investigator and patient, signed by the patient and sent to the unit in charge of scheduling and setting up 
the interviews.  This form will not include health data. 
10.6 Study Monitoring 
10.6.1 Access to Information for Monitoring 
In accordance with ICH-GCP guidelines, the Study Monitor must have direct access to the investigator’s 
source documentation in order to verify the consistency of the data recorded in the CRFs. 
The Study Monitor is responsible for routine review of the CRFs at regular intervals throughout the 
study, to verify adherence to the protocol, and the completeness, consistency, and accuracy of the data 
being entered.  The Study Monitor should have access to any patient records needed to verify the entries 
on the CRFs.  The investigator agrees to cooperate with the Study Monitor to ensure that any problems 
detected in the course of these monitoring visits are resolved. 


ACH-0144471 
Achillion Pharmaceuticals, Inc. 
Clinical Protocol ACH471-103, Amendment 5 
04 June 2021, Version 6 
 
Confidential 
Page 55 of 70 
 
 
10.6.2 Access to Information for Auditing or Inspections 
Representatives of regulatory authorities or Achillion Pharmaceuticals, Inc. may conduct inspections or 
audits of the clinical study.  If the investigator is notified of an inspection by a regulatory authority, the 
investigator agrees to notify the Achillion Pharmaceuticals, Inc. Medical Monitor immediately.  The 
investigator agrees to provide to representatives of a regulatory agency or Achillion Pharmaceuticals, 
Inc. access to records, facilities, and personnel for the effective conduct of any inspection or audit. 
10.7 Case Report Forms and Study Records 
10.7.1 Recording of Data 
All data collected during the study will be recorded in individual, patient-specific electronic case report 
forms (eCRFs).  All eCRFs should be completed by the investigator (or designee), who should be 
identified and agreed upon with the Sponsor before the start of the study.  A signature log identifying 
personnel who can enter data and/or sign off an eCRF will be maintained.  Instructions for data entry 
will be provided. 
A CRF must be completed for each patient who signs a consent form and is admitted to the study.  
Corrections to the data on the CRF will only be made by the investigator (or designee). 
CRFs should be kept current to enable the Study Monitor to review the patient status throughout the 
course of the study.  CRFs will be completed within 5 days of the last patient visit. 
10.7.2 Source Documentation and Medical/Study Records 
The patient’s number and date of entry into the study, along with the study code, should be recorded in 
the patient’s medical/study records by the investigator (or designee).  The investigator (or designee) 
should also record, in the medical/study records, confirmation of written and oral consent, the patient’s 
clinical status/disease being treated, date of every study visit, date study drug started and stopped, 
concomitant medications, copies of all relevant reports and laboratory tests, comments on results and 
reference to any AEs. 
10.8 Data Monitoring Committee 
There will be no formal data monitoring committee. 
10.9 Protocol Violations/Deviations 
Protocol deviations will be assessed on a case-by-case basis.  Significant protocol deviations will be 
reported to the EC or IRB according to local regulations. 
10.10 Access to Source Documentation 
The investigator and staff must agree to allow the Study Monitor and authorized representatives of the 
Sponsor to inspect all eCRFs and corresponding source documents, e.g., original medical records, 
patient records, and laboratory raw data; to have access to the clinical supplies, and dispensing and 
storage areas; and to agree to assist with their activities if requested.  The investigator and staff should 
provide adequate time and space for monitoring visits. 


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ACH-0144471 
Achillion Pharmaceuticals, Inc. 
Clinical Protocol ACH471-103, Amendment 5 
04 June 2021, Version 6 
 
Confidential 
Page 57 of 70 
 
 
10.13 Final Report, Publication and Disclosure Policy 
All information contained in this protocol and the study results are considered to be confidential.  The 
investigator agrees to use this information for purposes of conducting this study.  It is understood that 
Achillion Pharmaceuticals, Inc. may use data derived from this study for the purpose of research and 
development.  The data may be disclosed by Achillion Pharmaceuticals, Inc. to other investigators, the 
FDA, other government agencies, or foreign drug regulatory authorities, or to the public.  No publication 
of study design or results is permitted without specific Achillion Pharmaceuticals, Inc. approval.  To 
gain approval, a copy of the manuscript for review must, therefore, be sent to Achillion Pharmaceuticals, 
Inc. 60 days before submission for publication. 
It is the intent of Achillion Pharmaceuticals, Inc. to present the results of this study at future scientific 
meetings.  Additionally, it is the intent of Achillion Pharmaceuticals, Inc. to publish the results of this 
study in leading scientific journals.  The investigator of each investigative site will be invited to be an 
author in conjunction with the investigator(s) from Achillion Pharmaceuticals, Inc.  Achillion 
Pharmaceuticals, Inc. will determine additional authors.  Presentations and manuscripts will be provided 
and agreed to by the authors and Achillion Pharmaceuticals, Inc. 
 
 


ACH-0144471 
Achillion Pharmaceuticals, Inc. 
Clinical Protocol ACH471-103, Amendment 5 
04 June 2021, Version 6 
 
Confidential 
Page 58 of 70 
 
 
11 References 
 
1. 
Apelian D. ACH-0144471 Investigator’s Brochure Version 5.0. New Haven (CT): Achillion 
Pharmaceuticals, Inc.; 2017. 95 p. 
2. 
Yang G. Comparative Evaluation of ACH-0144471 and Eculizumab in Functional CAP Assays 
and in a Physiological Hemolysis Assay with PNH Patient Cells. New Haven, CT: Achillion 
Pharmaceuticals, Inc.; 2017. DRAFT IN PREPARATION Report No.: ACH-17-074. 
3. 
Volanakis JE, Narayana SV. Complement factor D, a novel serine protease. Protein Science. 
1996;5(4):553-64. 
4. 
Figueroa JE, Densen P. Infectious diseases associated with complement deficiencies. Clinical 
microbiology reviews. 1991;4(3):359-95. 
5. 
Miyata T, Inagi R, Oda O, et al. Deterioration of immune complex solubilization activity of serum 
by increased concentration of factor D. Nephron. 1991;59(3):409-15. 
6. 
Kobayakawa H, Miyata T, Inagi R, et al. Effects of excess factor D on early- and late-phase 
activation of the complement cascade. Nihon Jinzo Gakkai Shi. 1992;34(1):103-6. 
7. 
Späth-Schwalbe E, Schrezenmeier H, Heimpel SH. [Paroxysmal nocturnal hemoglobinuria. 
Clinical experiences with 40 patients at one center over 25 years]. Dtsch Med Wochenschr 
120:1027-1033, 1995. PMID: 7628314. 
8. 
Schubert J, Roth A. Update on paroxysmal nocturnal haemoglobinuria: on the long way to 
understand the principles of the disease. Eur J Haematol. 2015;94(6):464-73. 
9. 
Hill A, Rother RP, Arnold L, et al. Eculizumab prevents intravascular hemolysis in patients with 
paroxysmal nocturnal hemoglobinuria and unmasks low-level extravascular hemolysis occurring 
through C3 opsonization. Haematologica. 2010;95(4):567-73. 
10. 
Rondelli T, Risitano AM, Peffault de Latour R, et al. Polymorphism of the complement receptor 1 
gene correlates with the hematologic response to eculizumab in patients with paroxysmal 
nocturnal hemoglobinuria. Haematologica. 2014;99(2):262-6. 
11. 
Nishimura J, Yamamoto M, Hayashi S, et al. Genetic variants in C5 and poor response to 
eculizumab. The New England Journal of Medicine. 2014;370(7):632-9. 
12. 
Hiemstra PS, Langeler E, Compier B, Keepers Y, Leijh PC, van den Barselaar MT, Overbosch D, 
Daha MR. Complete and partial deficiencies of complement factor D in a Dutch family. J Clin 
Invest. 1989 Dec;84(6):1957-61. 
13. 
Biesma DH, Hannema AJ, van Velzen-Blad H, Mulder L, van Zwieten R, Kluijt I, Roos D. A 
family with complement factor D deficiency. J Clin Invest. 2001 Jul;108(2):233-40. 
14. 
Sprong T, Roos D, Weemaes C, Neeleman C, Geesing CL, Mollnes TE, van Deuren M. Deficient 
alternative complement pathway activation due to factor D deficiency by 2 novel mutations in the 
 


ACH-0144471 
Achillion Pharmaceuticals, Inc. 
Clinical Protocol ACH471-103, Amendment 5 
04 June 2021, Version 6 
 
 
complement factor D gene in a family with meningococcal infections. Blood. 2006 Jun 
15;107(12):4865-70. 
15. 
Siler S, Howell B. DILIsym Services Final Report “Assessment of Clinical Biomarkers and 
Prediction of Hepatocyte Loss for ACH4471 Clinical Trials.” Research Triangle Park, NC, USA. 
January 12, 2017. 
16. 
Yang, K, Siler S, Howell B, DILIsym Services Final Report “Prediction of Hepatotoxicity Risk 
for ACH4471 Based on Mechanistic Modeling with DILIsym®” Research Triangle Park, NC, 
USA August 29, 2017. 
17. 
U.S. Department of Health and Human Services, National Institutes of Health, National Cancer 
Institute. Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0. [CTCAE 
4.03 June 2010]. Downloaded from https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_8.5x11.pdf 01 April 2017. 
18. 
Bowen GA. Grounded theory and sensitizing concepts. International Journal of Qualitative 
Methods. September 2006; 5 (3). http://www.ualberta.ca/~iiqm/backissues/5_3/PDF/bowen.pdf. 
19. 
Friese S. ATLAS.ti 7.0. User Guide and Reference. http://atlasti.com/wp-
content/uploads/2014/05/atlasti_v7_manual_201312.pdf?q=/uploads/media/atlasti_v7_manual_20
1312.pdf Gmbh, Berlin: ATLAS.ti Scientific Sofware Development; 2013. 
 


ACH-0144471 
Achillion Pharmaceuticals, Inc. 
Clinical Protocol ACH471-103, Amendment 5 
04 June 2021, Version 6 
 
Confidential 
Page 60 of 70 
 
 
12  Appendices 
Appendix 1. Schedule of Assessments 
Table 5. 
Schedule of Assessments  
 
Months 1-6 (Weeks 1-25)1 
>6 Months2 
Taper and Follow-
up5 
Dose Esc3 
14 
5 
9 
13 
17 
21 
25 
Clinic 
Visits 
Local 
Labs 
T3 
T6 
F/U 
3-4 
Day 
~2 
Wk 
Enrollment Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/ Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vaccination Boosters 
See Section 6.2 
 
 
Urine Pregnancy Test 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
Patient-Reported Outcomes Assessment 
Interviews6 
Interviews will be conducted after approximately 3 and 9 months,  
as described in Section 7.1.4 
 
 
Dosing and Drug Distribution 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ACH-0144471 Dosing 
X 
X 
X 
 
 
 
Study Drug Dispensing 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Clinical Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
 
 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
 
X 
Body Temperature 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
 
X 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
 
 
Patient-Reported Outcome Measures Assessments 
(QoL Questionnaires) 
X 
 
 
X 
 
X 
 
X6 
 
 
 
X 
 
 
12-Lead ECGs (single) 
X 
 
 
X 
 
 
X 
X7 
 
 
 
 
 
 
AEs/SAEs 
X 
Concomitant Medications, including 
transfusions 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
Laboratory Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology, Chemistry, and Urinalysis8 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
X9 
X 
Free Hemoglobin, Haptoglobin, D-dimer, Direct 
Coombs 
X 
 
X 
 
X 
 
X 
X 
 
 
 
 
 
X 
Local Labs: Hgb, Free Hgb, LDH10  
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
PK samples11 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
X 
PNH Clone Size12 
X 
 
 
 
 
 
X 
X12 
 
 
 
 
 
 
Factor D, AP Wieslab12 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 


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ACH-0144471 
Achillion Pharmaceuticals, Inc. 
Clinical Protocol ACH471-103, Amendment 5 
04 June 2021, Version 6 
 
Confidential 
Page 62 of 70 
 
 
Appendix 2. 
Quality of Life Assessments 
FACIT Fatigue Scale (Version 4) 
EORTC-QLQ-C30 (Version 3) 
These QoL assessments will be done at the clinic visits specified in Appendix 1. 
 
 


ACH-0144471 
Achillion Pharmaceuticals, Inc. 
Clinical Protocol ACH471-103, Amendment 5 
04 June 2021, Version 6 
 
Confidential 
Page 63 of 70 
 
 
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 


ACH-0144471 
Achillion Pharmaceuticals, Inc. 
Clinical Protocol ACH471-103, Amendment 5 
04 June 2021, Version 6 
 
Confidential 
Page 64 of 70 
 
 
An16 
I have to limit my social activity because I am tired
0 
1 
2 
3 
4 
 
English (Universal) 
 
16 November 2007 
Copyright 1987, 1997 
 
Page 64 of 1 
 
 


ACH-0144471 
Achillion Pharmaceuticals, Inc. 
Clinical Protocol ACH471-103, Amendment 5 
04 June 2021, Version 6 
 
Confidential 
Page 65 of 70 
 
 
 
EORTC-QLQ-C30 (Version 3)  
We are interested in some things about you and your health.  Please answer all of the questions yourself by 
circling the number that best applies to you.  There are no "right" or "wrong" answers.  The information that you 
provide will remain strictly confidential. 
Please fill in your initials: 
 
Your birthdate (Day, Month, Year): 
 
Today's date (Day, Month, Year):  
 
_____________________________________________________________________________________ 
 
 
 
 
 
 
 
 
 
 
Not at A 
Quite Very 
 
 
 
 
 
 
 
 
 
 
All 
Little a Bit 
Much 
1. 
Do you have any trouble doing strenuous activities,  
 
like carrying a heavy shopping bag or a suitcase? 
1 
2 
3 
4 
 
2. 
Do you have any trouble taking a long walk? 
1 
2 
3 
4 
 
3. 
Do you have any trouble taking a short walk outside of the house? 
1 
2 
3 
4 
 
4. 
Do you need to stay in bed or a chair during the day? 
1 
2 
3 
4  
 
5. 
Do you need help with eating, dressing, washing  
 
yourself or using the toilet? 
1 
2 
3 
4 
 
During the past week:   
 
 
 
 
 
Not at A 
Quite Very 
 
 
 
 
 
 
 
 
 
 
All 
Little a Bit 
Much 
6. 
Were you limited in doing either your work or other daily activities? 
1 
2 
3 
4 
 
7. 
Were you limited in pursuing your hobbies or other 
 
leisure time activities? 
1 
2 
3 
4 
 
8. 
Were you short of breath? 
1 
2 
3 
4 
 
9. 
Have you had pain? 
1 
2 
3 
4 
 
10. Did you need to rest? 
1 
2 
3 
4 
 
11. Have you had trouble sleeping? 
1 
2 
3 
4 
 
12. Have you felt weak? 
1 
2 
3 
4 
 
13. Have you lacked appetite? 
1 
2 
3 
4 
 
14. Have you felt nauseated? 
1 
2 
3 
4 
 
15. Have you vomited? 
1 
2 
3 
4 
 
16. Have you been constipated? 
1 
2 
3 
4 


ACH-0144471 
Achillion Pharmaceuticals, Inc. 
Clinical Protocol ACH471-103, Amendment 5 
04 June 2021, Version 6 
 
Confidential 
Page 66 of 70 
 
 
 
Please go on to the next page 
During the past week:   
 
 
 
 
 
Not at A 
Quite Very 
 
 
 
 
 
 
 
 
 
 
All 
Little a Bit 
Much 
 
17. Have you had diarrhea? 
1 
2 
3 
4 
 
18. Were you tired? 
1 
2 
3 
4 
 
19. Did pain interfere with your daily activities? 
1 
2 
3 
4 
 
20. Have you had difficulty in concentrating on things, 
 
like reading a newspaper or watching television? 
1 
2 
3 
4 
 
21. Did you feel tense? 
1 
2 
3 
4 
 
22. Did you worry? 
1 
2 
3 
4 
 
23. Did you feel irritable? 
1 
2 
3 
4 
 
24. Did you feel depressed? 
1 
2 
3 
4 
 
25. Have you had difficulty remembering things? 
1 
2 
3 
4 
 
26. Has your physical condition or medical treatment 
 
interfered with your family life? 
1 
2 
3 
4 
 
27. Has your physical condition or medical treatment 
 
interfered with your social activities? 
1 
2 
3 
4 
 
28. Has your physical condition or medical treatment 
 
caused you financial difficulties? 
1 
2 
3 
4 
 
 
For the following questions please circle the number between 1 and 7 that  
best applies to you 
 
29. How would you rate your overall health during the past week? 
 
 
 1 
2 
3 
4 
5 
6 
7 
 
 Very poor 
 
 
 
 
 
Excellent 
 
 
30. How would you rate your overall quality of life during the past week? 
 
 
 1 
2 
3 
4 
5 
6 
7 
 
 Very poor 
 
 
 
 
 
Excellent 
 
© Copyright 1995 EORTC Quality of Life Group.  All rights reserved.  Version 3.0 
 


ACH-0144471 
Achillion Pharmaceuticals, Inc. 
Clinical Protocol ACH471-103, Amendment 5 
04 June 2021, Version 6 
 
Confidential 
Page 67 of 70 
 
 
Appendix 3. 
Grading the Severity of Adverse Events 
Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0, Published: May 28, 2009 
(v4.03: June 14, 2010) 
To view or print the table, go to:  
https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf 
 
 


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ACH-0144471 
Achillion Pharmaceuticals, Inc. 
Clinical Protocol ACH471-103, Amendment 5 
04 June 2021, Version 6 
 
Confidential 
Page 70 of 70 
 
 
Appendix 5 COVID-19 Risk Assessment 
Paroxysmal nocturnal hemoglobinuria can cause irreversible morbidity and even mortality, if untreated. 
As such, and due to the limited number of available treatment options, the benefit a participant may 
receive from joining an investigational study with a therapeutic treatment is potentially significant. 
Given that treatment for PNH does involve immunosuppression, there is a theoretical concern that the 
risk for infection may be higher than in patients not receiving immunosuppressants. However, there is 
no specific data to further inform this risk. The Investigator will therefore balance the risk/benefit 
considerations in the patient taking these factors into account. 
The potential risks identified and mitigation measures put in place in light of the COVID-19 pandemic 
are provided in Table 6. 
Table 6: 
Potential Risks and Mitigation Measures due to COVID-19 
Risks Category 
Summary of Data/ 
Rationale for Risk 
Mitigation Strategy 
Potential risks 
Healthcare institution 
availability for 
non-COVID-19 related 
activities  
COVID-19 pandemic may impact the workload 
of healthcare institutions globally and may 
reduce staff availability to perform non-urgent 
activities and non-COVID-19 related activities. 
During the time that the COVID-19 
pandemic is active, Alexion will not open 
study sites or enroll new patients at sites 
unless the sites have the resourcing and 
capabilities to implement the study per 
protocol. 
Data quality and 
integrity 
Lack of availability of site personnel to perform 
study assessments and capture study-specific 
data in a timely manner and to maintain adequate 
quality standards. 
 
Lack of availability of site personnel to ensure 
adequate and continuous chain of custody, 
storage conditions, and monitoring for 
investigational product and biological samples. 
 
Inability of study monitors and quality personnel 
to conduct in-person visits to exercise adequate 
oversight of study execution at investigational 
sites. 
 
Missing data (COVID-19 pandemic may impact 
study visit schedules and increase missed visits 
and/or participant study discontinuations 
inadvertently resulting in missing data [eg, for 
protocol-specified procedures]). 
During the time that the COVID-19 
pandemic is active, Alexion will only open 
study sites that report enough personnel 
capacity to sufficiently conduct clinical 
study-related activities. 
 
During this timeframe, site capacity will be 
reviewed by the site Investigator and the 
study Medical Monitor prior to Screening. 
Each site is also evaluated for the capacity 
to perform remote monitoring visits and 
remote source data verification. 
 
During the time that the COVID-19 
pandemic is active, it will be important to 
capture specific information in the eCRF 
that explains the reason the data is missing 
(eg, missed study visits or patient study 
discontinuations due to COVID-19). 
Abbreviations: COVID19 = coronavirus disease 2019; eCRF = electronic case report form 

SAP_001.pdf: 
 
Ale xi o n P har mace uticals, I nc.  
 
 
S T A TI S TI C A L A N A L Y SI S P L A N  
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St u d y Title:   
A n O pe n -La bel St u d y t o E val uate Efficac y a n d Safet y of L o n g -Ter m 
Treat me nt Wit h A C H -0 1 4 4 4 7 1 i n Patie nts wit h P N H W h o C o m plete d 
Cli nical St u d y A C H 4 7 1 -1 0 0  
 
St u d y N u m ber:   
  
A C H 4 7 1 -1 0 3  
St u d y P h ase:   
 
  
2  
Pr o d uct N a me:   
  
Da nic o pa n ( A L X N 2 0 4 0, pre vi o usl y A C H -0 1 4 4 4 7 1)  
Pr ot oc ol V ersi o n:  
  
A me n d me nt 4 ( Versi o n 5. 0), date d 1 3 Marc h 2 0 1 8  
 
A ut h or:   
 
 
 
 
Versi o n N u m ber:  
  
V 1. 0  
Effecti ve D ate:   
  
2 3 Fe br uar y 2 0 2 1  
 
 
 
 
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A P P R O V A L SI G N A T U R E S  
 
 
  
 
  
Date d d M m m y y y y  
 
  
 
  
Date d d M m m y y y y  
  
 
  
 
  
 
  
Date d d M m m y y y y  
 
0 1 - M a r - 2 0 2 1  |  1 5 : 2 0 : 2 1  E S T
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Pr o prietar y a n d C o nfi de ntial                                                                                                                       P a ge 3  of 2 4   
2.   
T A B L E O F C O N T E N T S, L I S T O F T A B L E S, A N D LI S T O F 
FI G U R E S  
T A B L E O F C O N T E N T S  
1.  
A P P R O V A L SI G N A T U R E S  .......................................................................................2  
2.  
T A B L E O F C O N T E N T S, L I S T O F T A B L E S, A N D LI S T O F FI G U R E S .................3  
3.  
LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N S O F  T E R M S ...............................5  
4.  
D E S C RI P TI O N O F T H E P R O T O C O L  .......................................................................7  
4. 1.  
C ha n ges fr o m A nal ys es S pecifie d i n t he Pr ot oc ol  .......................................................8  
4. 2.  
C ha n ges fr o m A nal ys es S pecifie d i n t he Pre vi o us Versi o n of t he Statistic 
A nal ysis Pla n  ................................................................................................................8  
5.  
D E FI NI TI O N S  .............................................................................................................9  
5. 1.  
Efficac y  .........................................................................................................................9  
5. 1. 1.  
Efficac y E n d p oi nts  ........................................................................................................9  
5. 1. 2.  
Q ualit y of Lif e E n d p oi nts  .............................................................................................9  
5. 1. 3.  
Ot her Effi cac y E n d p oi nts  .............................................................................................9  
5. 2.  
Safet y  ............................................................................................................................9  
5. 2. 1.  
A d verse E v e nts ( A Es)  ...................................................................................................9  
5. 2. 2.  
La b orat or y Ass ess me nts  .............................................................................................1 0  
5. 2. 3.  
Vital Si g ns  ..................................................................................................................1 0  
5. 2. 4.  
Electr ocar di o gra m  .......................................................................................................1 0  
5. 2. 5.  
P h ysical E x a mi nati o n  .................................................................................................1 0  
6.  
D A T A S E T S A N A L Y Z E D ( S T U D Y P O P U L A TI O N S)  ...........................................1 1  
6. 1.  
F ull A nal ysis ( F A) Set  ................................................................................................1 1  
6. 2.  
S afet y Set  ....................................................................................................................1 1  
7.  
S T A TI S TI C A L A N A L Y SI S  ......................................................................................1 2  
7. 1.  
St u d y Patie nts  .............................................................................................................1 2  
7. 1. 1.  
Dis p osi ti o n of Patie nts ................................................................................................1 2  
7. 1. 2.  
Pr ot oc ol De viati o ns  ....................................................................................................1 2  
7. 1. 3.  
De m o gra p hics, Dis ease C haracteristics, a n d Me dical Hist or y  ...................................1 2  
7. 1. 3. 1.  
De m o gra p hics  .............................................................................................................1 3  
7. 1. 3. 2.  
Disease C haracteristics  ...............................................................................................1 3  
7. 1. 3. 3.  
Me dical / S ur gi cal Hist or y  ..........................................................................................1 3  
7. 1. 4.  
C o nc o mita nt Me dicati o ns / T hera pies  ........................................................................1 3  


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Pr o prietar y a n d C o nfi de ntial                                                                                                                       P a ge 4  of 2 4   
7. 2.  
Efficac y A nal yses  .......................................................................................................1 4  
7. 2. 1.  
Pri mar y A nal ysis  ........................................................................................................1 4  
7. 2. 1. 1.  
Ha n dli n g of Dr o p o uts or Missi n g Data  ......................................................................1 4  
7. 2. 1. 2.  
S u b gr o u p A nal ysis  ......................................................................................................1 5  
7. 2. 1. 3.  
M ultice nter St u dies  .....................................................................................................1 5  
7. 2. 1. 4.  
H y p ot hesis T esti n g a n d Si g nifica nce Le v el  ...............................................................1 5  
7. 2. 1. 5.  
Se nsiti vit y A nal ys es  ....................................................................................................1 5  
7. 2. 2.  
Sec o n dar y A nal ys es  ....................................................................................................1 5  
7. 2. 2. 1.  
F A CI T Fati g ue Scale ( Versi o n 4)  ...............................................................................1 5  
7. 2. 2. 2.  
E O R T C -Q L Q -C 3 0 ( Versi o n 3)  ..................................................................................1 5  
7. 2. 3.  
Ot her Effi cac y A nal yses  .............................................................................................1 6  
7. 2. 4.  
P har mac o ki netic a n d P har mac o d y na mic A nal yses  ....................................................1 6  
7. 3.  
Safet y A nal yses  ..........................................................................................................1 7  
7. 3. 1.  
Treat me nt D urati o n a n d Treat me nt C o m plia nce  ........................................................1 7  
7. 3. 2.  
A d verse E v e nts ( A Es)  .................................................................................................1 7  
7. 3. 2. 1.  
O verall S u m mar y of A d v erse E ve nts  .........................................................................1 7  
7. 3. 2. 2.  
A Es a n d S A Es b y S yste m Or ga n Class ( S O C) a n d Preferre d Ter m ( P T)  ..................1 8  
7. 3. 2. 3.  
A Es a n d S A Es b y S O C, P T, a n d Relati o ns hi p  ...........................................................1 8  
7. 3. 2. 4.  
A Es a n d S A Es b y S O C, P T, a n d Se verit y  ..................................................................1 8  
7. 3. 2. 5.  
Deat hs, Ot her S A Es, a n d O t her Si g nifica nt A d verse E ve nts .....................................1 8  
7. 3. 3.  
Ot her Safet y  ................................................................................................................1 9  
7. 3. 3. 1.  
A nal ys es f or La b orat or y Tests  ....................................................................................1 9  
7. 3. 3. 2.  
Vital Si g ns  ..................................................................................................................1 9  
7. 3. 3. 3.  
Electr ocar di o gra m  .......................................................................................................2 0  
7. 3. 3. 4.  
P h ysical E x a mi nati o n  .................................................................................................2 0  
7. 4.  
C O VI D -1 9 Relate d A nal ys es  .....................................................................................2 0  
8.  
R E F E R E N C E S  ...........................................................................................................2 1  
9.  
A P P E N DI C E S  ............................................................................................................2 2  
9. 1.  
Pr ot oc ol Sc he d u le of Ass ess me nts .............................................................................2 2  
9. 2.  
Sc ori n g t he E O R T C Q L Q -C 3 0 versi o n 3. 0  ................................................................2 3  
9. 3.  
Tec h nical S pecificati o ns f or Deri ve d Varia bles  .........................................................2 4  


Ale xi o n P har mace uticals  
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A C H 4 7 1 -1 0 3: 1 3 Marc h 2 0 1 8  (A me n d me nt 4, Versi o n 5 ) 
2 3 F E B 2 0 2 1, V 1. 0  
Pr o prietar y a n d C o nfi de ntial                                                                                                                       P a ge 5  of 2 4   
3.   
LI S T O F A B B R E VI A TI O N S A N D D E FI N I TI O N S O F T E R M S 
T a ble  1 .  
A b bre vi ati o ns a n d acr o n y ms  
A b bre vi ati o n or acr o n y m   
E x pl a n ati o n  
A E  
A d verse e ve nt  
A L T  
Ala ni ne a mi n otra nsferas e ( S G P T)  
A S T  
As partate a mi n otra nsferase ( S G O T)  
A T C  
A nat o mical T hera pe utic C he mical  
B MI  
B o d y mass i n de x  
B P  
Bl o o d press ure  
B U N  
Bl o o d urea nitr o ge n  
C B C  
C o m plete bl o o d c o u nt  
c m 
Ce nti meters  
C T C A E  
C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts  
E C G  
Electr ocar di o gra m  
e G F R  
Esti mate d Gl o mer ular Filtrati o n Rate  
F A  
F ull A nal ysis  
G G T  
Ga m ma -gl uta m yl tra nsferase  
H C O 3  
Bicar b o nate  
Hct  
He mat ocrit  
H D L -C  
Hi g h -d e nsit y li p o pr otei n c h olester ol  
H g b  
He m o gl o bi n  
H R  
Heart rate  
k g  
Kil o gra m  
L D H  
Lactate d e h y dr o ge n ase  
L D L -C  
L o w -de nsit y li p o pr otei n c h olester ol  
M C H  
Mea n c or p usc ular h e m o gl o bi n  
M C H C  
Mea n c or p usc ular h e m o gl o bi n c o nce ntrati o n  
M C V  
Mea n c or p usc ular v ol u m e  
Me d D R A  
Me dical Dicti o nar y f or R e g ul at or y Acti vities  
M P V  
Mea n platelet v ol u me  
N CI  
Nati o nal Ca ncer I nstit ute  
P D  
P har mac o d y na mic(s)  
P K  
P har mac o ki netic(s)  
P N H  
Par o x ys mal n o ct ur nal he m o gl o bi n uria  
P R i nter val  
Peri o d t hat e xte n ds fr o m t he be gi n ni n g of t he P wa ve u ntil 
t he be gi n ni n g of t he Q R S c o m ple x 
P R O  
Patie nt -re p orte d o utc o m e 
P T  
Preferre d ter m ( Me d D R A)  
Q o L  
Q ualit y of life  
Q R S  
Gr o u p of electr ocar di o gra m wa ves c o m prisi n g t he Q, R, a n d 
S wa ves  
Q T i nter val  
Peri o d fr o m deflecti o n of Q R S c o m ple x t o e n d of T wa ve  
Q Tc F  
Q T i nter val Fri derici a C orrecti o n F or m ula  


Ale xi o n P har mace uticals  
Statistical A nal ysis Pla n  
A C H 4 7 1 -1 0 3: 1 3 Marc h 2 0 1 8  (A me n d me nt 4, Versi o n 5 ) 
2 3 F E B 2 0 2 1, V 1. 0  
Pr o prietar y a n d C o nfi de ntial                                                                                                                       P a ge 6  of 2 4   
A b bre vi ati o n or acr o n y m   
E x pl a n ati o n  
R D W  
Re d cell distri b uti o n wi dt h  
R B C  
Re d bl o o d cells  
R R i nter val  
peri o d bet wee n Q R S c o m ple x es  
S A E  
Seri o us a d verse e ve nt  
S A S ®  
Statistical A nal ysis S oft ware ®  
S o A  
Sc he d ule of Assess me nts  
S O C  
S yste m Or ga n Class ( M e d D R A)  
T E A Es  
Treat me nt -e mer ge nt a d v erse e v e nts  
TI D  
T hree ti mes dail y  
V L D L -C  
Ver y l o w -d e nsit y li p o pr otei n  c h olester ol  
W B C  
W hite bl o o d cell  
W H O  
W orl d Healt h Or ga nizati o n  


Ale xi o n P har mace uticals  
Statistical A nal ysis Pla n  
A C H 4 7 1 -1 0 3: 1 3 Marc h 2 0 1 8  (A me n d me nt 4, Versi o n 5 ) 
2 3 F E B 2 0 2 1, V 1. 0  
Pr o prietar y a n d C o nfi de ntial                                                                                                                       P a ge 7  of 2 4   
4.   
D E S C RI P TI O N O F T H E P R O T O C O L  
T his is a P hase 2 o p e n -la bel e xte nsi o n st u d y d esi g ne d t o e v al uate l o n g ter m safet y a n d effi cac y of 
da nic o pa n ( A L X N 2 0 4 0, f or merl y A C H -0 1 4 4 4 7 1) i n m o n ot hera p y i n p ati e nts wit h par o x ys m al 
n oct ur nal he m o gl o bi n uria ( P N H) w h o de m o nstrat e d cli nical be nefit fr o m d a nic o pa n i n t he pri mar y 
st u d y A C H 4 7 1-1 0 0 a n d di d n ot de v el o p a n y s afet y c o n cer ns rel ate d t o da nic o pa n treat me nt. 
Cli nical be nefit i n St u d y A C H 4 7 1 -1 0 0 was assesse d b y t he Pri nci pal I n vesti gat or ( PI), bas e d o n 
a n i m pr o ve me nt i n he m o gl o bi n ( H g b) a n d/ or lact ate de h y dr o ge nas e ( L D H). T he PI ma y escalat e 
or re d uce d osi n g d uri n g t his st u d y t o ma na ge cli ni cal be nefit or f or safet y or t olera bilit y reas o ns. 
It is a ntici pate d t hat n o m ore t ha n 1 2 patie nts will be e ntere d i nt o t his st u d y. Patie nts will be 
all o we d t o c o nti n ue t hera p y u ntil 1) d a nic o pa n is c o m merciall y a v aila ble i n t heir c o u ntr y; 2) t he 
de vel o p me nt of da nic o pa n as a p ote ntial t h era p y f or P N H is ter mi nate d; or 3) t h e t hera p y is n o 
l o n ger t olerate d or effecti ve. I n a d diti o n, t he s p o ns or reser ves t he ri g ht t o cl ose a n y st u d y site or 
ter mi nate t he st u d y at a n y ti me f or a n y reas o n at t he s ole discreti o n of t he s p o ns or. 
Eac h patie nt will retai n t he sa me s u bject i de ntifi cati o n as i n St u d y A C H 4 7 1 -1 0 0, b ut t he st u d y 
i de ntificati o n part is t o be re place d b y A C H 4 7 1-1 0 3. Patie nts e ntere d t his st u d y at t he d ose t h e y 
were recei vi n g at t he c o m pleti o n of A C H 4 7 1 -1 0 0. Patie nts are t o be d ose d 3 ti mes dail y (ti d) 
a p pr o xi matel y 8 h o ur s a p art bet wee n d osi n g. D osi n g ma y b e i ncrease d i n i ncre me nts of 2 5 m g t o 
a ma xi m u m of 2 5 0 m g ti d if necessar y a n d ma y b e re d uce d f or s afet y or t olera bilit y reas o ns.  
T he pri mar y o bjecti ve of t his st u d y is t o e v al uate t he safet y a n d effi cac y of l o n g -ter m t hera p y wit h 
da nic o pa n i n patie nts wit h P N H.  
T he sec o n dar y o bj ecti ve of t his st u d y is t o e val uate healt h -relate d q ualit y of life meas ures i n 
patie nts wit h P N H base d o n patie nt -re p orte d o utc o me ( P R O) i nstr u me nts a n d its e v ol uti o n o ver 
t he c o urse of l o n g-ter m t hera p y wit h da nic o p a n. 
Safet y assess m e nts i ncl u de a d v erse e ve nts, cli nical la b orat or y tests, p h ysi cal e x a mi nati o ns, vital 
si g ns a n d el ectr ocar di o gra m ( E C G) meas ure me nts at s pecifie d st u d y visits.  
Efficac y will be e val uate d b y meas uri n g L D H le vels, H g b le v els, a n d retic ul oc yt e c o u nts at 
s pecifie d st u d y visits. T he n u m ber a n d fre q u e nc y of re d bl o o d cell tra nsf usi o ns d uri n g t he st u d y 
will als o be e x a mi ne d.  
Bl o o d sa m ples will be c ollecte d pri or t o d osi n g at s pecifie d cli nic visits f or d eter mi nati o n of tr o u g h 
plas ma c o nce ntrati o ns of da nic o pa n.  
P har mac o d y na mics will be e v al uate d usi n g ser u m, plas ma, a n d w h ol e bl o o d sa m ples c ollecte d at 
s pecifie d ti me p oi nts d uri n g t he st u d y. 
Q ualit y of Life ( Q o L) ass ess me nts will be c o n d u cte d at s pecifie d st u d y visits. T he F A CI T Fati g ue 
scale q uesti o n naire a n d t he E O R T C-Q L Q -C 3 0 scale will be a d mi nistere d t o patie nts t o c ollect 
healt h -rel ate d Q o L d uri n g l o n g-ter m treat me nt wit h da nic o pa n. I n a d diti o n, patie nts will be 
i nter vie we d b y i n de pe n d e nt o utc o mes researc hers after a p pr o xi matel y 3 a n d 9 m o nt hs of treat me nt 
i n t his st u d y t o c ollect t heir e x perie nce of P N H, e x perie nce of da nic o pa n treat me nt a n d perce pti o n 
of t he e v ol uti o n of t heir c o n diti o n (t hese i nter vie ws were disc o nti n ue d i n 2 0 1 9).  


Ale xi o n P har mace uticals  
Statistical A nal ysis Pla n  
A C H 4 7 1 -1 0 3: 1 3 Marc h 2 0 1 8  (A me n d me nt 4, Versi o n 5 ) 
2 3 F E B 2 0 2 1, V 1. 0  
Pr o prietar y a n d C o nfi de ntial                                                                                                                       P a ge 8  of 2 4   
A d diti o nal details are des cri be d i n t he pr ot oc ol, pr ot oc ol a d mi nistrati ve letters, a n d t he Sc he d ule 
of Assess me nt ( S o A) is i ncl u de d i n A p pe n di x 9. 1.  
4. 1.   
C h a n ges fr o m A n al yses S pecifie d i n t he Pr ot o c ol 
Fi nalizati o n of t he S A P bef ore e nr oll me nt of t he last patie nt i n t he st u d y as pla n ne d i n t he 
pr ot oc ol was n ot d o ne.  T his S A P was fi nalize d pri or t o data base l o c k.  
4. 2.   
C h a n ges fr o m A n al yses S pecifie d i n t he Pre vi o us Versi o n of t he 
St atistic A n al ysis Pl a n  
N ot a p plica ble.  
 


Ale xi o n P har mace uticals  
Statistical A nal ysis Pla n  
A C H 4 7 1 -1 0 3: 1 3 Marc h 2 0 1 8  (A me n d me nt 4, Versi o n 5 ) 
2 3 F E B 2 0 2 1, V 1. 0  
Pr o prietar y a n d C o nfi de ntial                                                                                                                       P a ge 9  of 2 4   
5.   
D E FI NI TI O N S  
5. 1.   
Effic ac y  
5. 1. 1.   
Effic ac y E n d p oi nts  
T he effi cac y e n d p oi nts i ncl u de t he f oll o wi n g:  
 C ha n ge fr o m bas eli ne i n L D H le vel  
 C ha n ge fr o m bas eli ne i n H g b le vel i n t he a bse n ce of re d bl o o d cell tra nsf usi o n  
 C ha n ge fr o m bas eli ne i n retic ul oc yte c o u nts  
 N u m ber of re d bl o o d cell ( R B C) u nits tra nsf use d a n d tra nsf usi o n i nsta nces  
5. 1. 2.   
Q u alit y of Life E n d p oi nts  
T he Q o L e n d p oi nts i ncl u de t he patie nt -re p orte d o utc o me assess me nts i ncl u di n g:  
 C ha n ge fr o m bas eli ne i n F A CI T Fati g ue scale  
 C ha n ge fr o m bas eli ne i n E O R T C -Q L Q -C 3 0 d o mai n scales  
T he F A CI T Fati g u e scale a n d t he E O R T C -Q L Q -C 3 0 will be a d mi nistere d t o patie nts at t he 
pr ot oc ol s pecifie d visit sc he d ule t o c ollect patie nts’ healt h -relat e d q ualit y of life d uri n g c o nti n ue d 
treat me nt wit h da nic o pa n. T hese t o ols are pr o vi de d i n A p pe n di x 2 of t he pr ot oc ol.  
5. 1. 3.   
Ot her Effic ac y E n d p oi nts  
Ot her efficac y e n d p oi nts i ncl u de c ha n ge fr o m baseli ne f or t he f oll o wi n g bi o mar kers:  
 Free H g b  
 Ha pt o gl o bi n  
 C o m plete bl o o d c o u nt ( C B C) c o m p o ne nts  
 P N H cl o ne size  
 fact or D l e vel  
 A P Wiesla b  
 D -di mer  
 Direct C o o m bs  
5. 2.   
S afet y  
T he safet y a n d t olera bilit y of d a nic o pa n  will be e val uate d b y p h ysical e x a mi nati o ns, vital si g ns, 
electr ocar di o gra ms ( E C Gs), la b orat or y assess me nts, a n d i nci de nce of a d verse e v e nts ( A Es) a n d 
seri o us a d verse e v e nts ( S A Es). Details of a nal ysis is s pecifie d bel o w.  
5. 2. 1.   
A d verse E ve nts ( A Es)  
A Es wit h a n o nset date after t he p atie nt pr o vi des i nf or me d c o ns e nt will be rec or de d. A treat me nt -
e mer ge nt a d verse e ve nt ( T E A E) is d efi ne d as a n A E t hat e mer ges d uri n g treat me nt, h a vi n g bee n 
a bse nt pri or t o treat me nt, or w ors e ns relati ve t o t h e pretreat me nt stat e. I n t h is st u d y, a n y A E first 
assesse d after recei pt of t he first d ose of da ni c o pa n u ntil t he fi nal f oll o w -u p visit will be c o nsi dere d 


Ale xi o n P har mace uticals  
Statistical A nal ysis Pla n  
A C H 4 7 1 -1 0 3: 1 3 Marc h 2 0 1 8  (A me n d me nt 4, Versi o n 5 ) 
2 3 F E B 2 0 2 1, V 1. 0  
Pr o prietar y a n d C o nfi de ntial                                                                                                                       P a ge 1 0  of 2 4  
treat me nt-e mer ge nt. A n A E wit h o nset bef ore t he c o m pleti o n of t he pri mar y st u d y a n d o n g oi n g at 
A C H 4 7 1 -1 0 3 e nr oll me nt will be f ol l o we d u p u ntil res ol uti o n or sta bilizati o n.  
Eac h A E will be assess e d re gar di n g its seri o us ness, se verit y a n d ca us al relati o ns hi p wit h t he st u d y 
dr u g. T h e se verit y of a n a d verse e ve nt will be gra de d acc or di n g t o t he Nati o nal Ca ncer I nstit ute 
( N CI) C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts ( C T C A E) v ersi o n 4. 0 3 ( p u blis he d 1 4 
J u n 2 0 1 0). Ca usal relati o ns hi p assess me nt will f oll o w t he cate g ories of “ u nrelate d”, “ u nli kel y”, 
“ p ossi ble”, “ pr o ba ble” a n d “ defi nite”. F or s u m mar y ta bles, assess me nts of “ u nrelate d” a n d 
“ u nli kel y” will be c o m bi ne d i nt o t he cate g or y of u nrelate d, a n d “ p ossi ble”, “ pr o ba ble” a n d 
“ defi nite” will be c o m bi ne d i nt o t he cate g or y of relate d.  
F urt her details are pr o vi d e d i n t he pr ot oc ol Secti o n 6. 1 5.  
5. 2. 2.   
L a b or at or y Assess me nts  
Bl o o d a n d uri ne sa m p les will be c ollecte d at pr ot oc ol-s pecifie d visits f or safet y e val uati o n. T he 
la b orat or y tests perf or me d as he mat ol o g y, c h e mistr y, uri nal ysis, a n d ot her assess me nts are liste d 
i n Ta ble 2 i n t he pr ot oc ol Secti o n 6. 7. 
5. 2. 3.   
Vit al Si g ns  
Vital si g n meas ure me nts i ncl u de bl o o d press ure ( B P), heart rate ( H R), res pirati o n rate, b o d y 
te m perat ur e, a n d wei g ht at pr ot oc ol-s pecifie d visits. Vital si g ns will be meas ure d i n t he s u pi ne 
p ositi o n o n t he d o mi na nt ar m (if p ossi ble) f oll o wi n g a 5 -mi n ute rest. B o d y te m perat ure will be  
meas ure d usi n g a n oral t her m o meter.  
5. 2. 4.   
Electr oc a r di o gr a m  
1 2 -lea d E C G rec or di n gs will be perf or me d at pr ot oc ol-s pecifie d visits i n a s u pi ne p ositi o n a n d 
bef ore bl o o d is dra w n ( w he ne ver p ossi ble) f oll o wi n g a 5 -mi n ute rest. 
Meas ure me nts of t he 
f oll o wi n g para met ers will be o btai ne d: H R, R R i nter val, P R i nter val, Q R S d urati o n, Q T i nter val, 
a n d Fri derici a’s f or m ula c orrecte d Q T i nter val ( Q Tc F). T he o cc urre nce of de p ol arizati o n or 
re p olarizati o n dis or ders, arr h yt h mic dis or ders or ot her a b n or malities a n d t h e cli nical si g nifica n ce 
of t he occ urre n ce will b e n ote d. A n a b n or mal E C G ma y be re p eate d t o r ule o ut i m pr o per lea d 
place me nt as c o ntri b uti n g t o t he E C G a b n or malit y.  
5. 2. 5.   
P h ysic al E x a mi n ati o n  
Brief p h ysi cal e x a mi nati o ns i ncl u di n g ge neral a p peara nce, car di o vasc ul ar a n d r es pirat or y s yste ms, 
a b d o me n, e xtre mities/s ki n, a n d a d diti o nal or ga ns or s yste ms tar get e d t o a n y ne w si g ns or 
s y m pt o ms will be perf or me d at ti mes s pecifie d i n t he S o A or as necessar y. All cli nicall y si g nifica nt 
p h ysical e x a mi nati o n fi n di n gs t hat are ne w or w orse ne d si nce t h e last p h ysical e x a mi nati o n m ust 
be rec or de d.  
 


Ale xi o n P har mace uticals  
Statistical A nal ysis Pla n  
A C H 4 7 1 -1 0 3: 1 3 Marc h 2 0 1 8  (A me n d me nt 4, Versi o n 5 ) 
2 3 F E B 2 0 2 1, V 1. 0  
Pr o prietar y a n d C o nfi de ntial                                                                                                                       P a ge 1 1  of 2 4  
6.   
D A T A S E T S A N A L Y Z E D ( S T U D Y P O P U L A TI O N S)  
6. 1.   
F ull A n al ysis ( F A) Set  
All patie nts w h o recei ve at least o ne d ose of da nic o pa n  i n t his st u d y will be i ncl u de d i n t he f ull a nal ysis set. 
Efficac y a nal yses will be perf or me d usi n g t he f ull a nal ysis set.  
6. 2.   
S afet y Set  
All patie nts w h o recei ve at least o ne d ose of da nic o pa n i n t his st u d y will be i ncl u de d i n t he safet y set. Safet y 
a nal yses will be perf or me d usi n g t he safet y set.  
 


Ale xi o n P har mace uticals  
Statistical A nal ysis Pla n  
A C H 4 7 1 -1 0 3: 1 3 Marc h 2 0 1 8  (A me n d me nt 4, Versi o n 5 ) 
2 3 F E B 2 0 2 1, V 1. 0  
Pr o prietar y a n d C o nfi de ntial                                                                                                                       P a ge 1 2  of 2 4  
7.   
S T A TI S TI C A L A N A L Y SI S  
Descri pti ve a n d e x pl orat or y statistical met h o ds will be utilize d f or data a nal ysis. Des cri pti ve 
statistics f or c o nti n u o us varia bles will mi ni mall y i n cl u de t he n u m ber of partici pa nts, mea n, 
sta n dar d de viati o n, mi ni m u m, me dia n, a n d ma xi m u m. F or cate g orical varia bles, fre q ue n cies a n d 
perce nt a ges will be prese nte d. Gra p hical dis pla ys will be pr o vi de d as a p pr o priate. All data 
c ollecte d i n t his st u d y will be prese nte d i n listi n gs. Assess me nts fr o m u nsc he d ule d visits will n ot 
be i ncl u de d i n ta ble s u m maries b ut will be i ncl u de d i n listi n gs.  
O nl y d ata fr o m A C H 4 7 1 -1 0 3 will be i ncl u de d i n a nal ysis. T he b aseli ne data fr o m t h e pri mar y 
St u d y A C H 4 7 1 -1 0 0 will be carrie d o ver t o t his st u d y f or c o nti n uit y i n data prese ntati o n a n d cli nical 
i nter pretati o n of l o n g-t er m safet y a n d effi cac y, i ncl u di n g p atie nt de m o gra p hics, baseli ne disease 
c haracteristics, me di cal/s ur gical hist or y dat a, a n d first d ose d ate. Baseli n e val ues of la b orat or y 
tests, vital si g ns, electr ocar di ogra m data, F A CI T fati g ue scale a n d 
E O R T C -Q L Q -C 3 0 
q uesti o n naire d ata fr o m t he pri mar y st u d y A C H 4 7 1 -1 0 0 will als o be carrie d o ver f or t he 
calc ulati o n of c ha n ge fr o m baseli ne. Carrie d -o v er data will be i ncl u de d i n data listi n gs if t he y are 
prese nte d i n s u m mar y ta bles.  
F or e val uati n g l o n g -ter m safet y a n d efficac y of d a nic o pa n, u nless s pecifie d ot her wise, Bas eli ne is 
defi ne d as t he Baseli ne i n t he pri mar y st u d y a n d Da y 1 ( Wee k 1) visit i n t his st u d y is Da y 8 4 visit 
i n t he pri mar y st u d y. 
A nal ys es will be perf or m e d usi n g t he S A S ®  (Statistical A nal ysis S oft ware ® ) s oft ware Versi o n 9. 4 
or hi g her.  
7. 1.   
St u d y P atie nts  
7. 1. 1.   
Dis p ositi o n of P atie nts  
T he n u m ber of p atie nts w h o c o m plete d t he pri m ar y st u d y will be prese nte d. T he n u m b er a n d 
perce nt of patie nts w h o e nr olle d i n t he e xte ns i o n st u d y, c o m plete d t he st u d y, a n d disc o nti n ue d t he 
st u d y will be s u m marize d. F or patie nts w h o disc o nti n ue d t he st u d y, t he reas o n f or disc o nti n uati o n 
will be s u m marize d. Patie nts w h o disc o nti n ue d st u d y treat me nt will als o be s u m marize d b y reas o n 
f or treatme nt disc o nti n uati o n. Data will be re p orte d usi n g all F A Set.  
7. 1. 2.   
Pr ot oc ol D e vi ati o ns  
All pr ot oc ol de viati o ns will be a p pr o priatel y cat e g orize d, a n d t h e se v erit y d eter mi ne d ( maj or or 
mi n or) pri or t o data base l oc k. T he n u m ber a n d perce nta ge of patie nts wit h pr ot oc ol de viati o ns will 
be s u m marize d b y pr ot o c ol de viati o n cate g or y a n d maj or/ mi n or desi g nati o ns. A listi n g will als o 
be pr o vi de d.  
7. 1. 3.   
De m o gr a p hics, Dise ase C h ar acteristics, a n d Me dic al Hist or y  
All de m o gra p hi c, baseli ne c haracteristics a n d me dical hist or y data will be carrie d o ver fr o m t he 
pri mar y st u d y a n d will be s u m marize d usi n g descri pti ve statistics f or t he F A Set. Listi n gs will als o 
be pr o vi de d.  


Ale xi o n P har mace uticals  
Statistical A nal ysis Pla n  
A C H 4 7 1 -1 0 3: 1 3 Marc h 2 0 1 8  (A me n d me nt 4, Versi o n 5 ) 
2 3 F E B 2 0 2 1, V 1. 0  
Pr o prietar y a n d C o nfi de ntial                                                                                                                       P a ge 1 3  of 2 4  
7. 1. 3. 1.  
De m o gr a p hics  
T he f oll o wi n g d e m o gra p hic varia bles will be s u m marize d:  
 
A ge (i n years)  
 
Ge n der ( n, %)  
 
Race ( n,  %)  
 
Et h nicit y ( n, %)  
 
Wei g ht ( k g)  
 
Hei g ht (c m)  
 
B o d y mass i n de x ( B MI, k g/ m 2) 
7. 1. 3. 2.  
Dise ase C h ar acteristi cs  
Baseli ne dise ase c haracteristics are t o be carrie d fr o m t he pri mar y St u d y A C H 4 7 1-1 0 0, a n d will 
be s u m marize d usi n g des cri pti ve statistics f or t he f oll o wi n g para meters:  
 
D urati o n of P N H ( m o nt hs)  
 
Tra nsf usi o n hist or y  
 
Pac ke d R B Cs tra nsf use d wit hi n 3 years pri or t o first d ose of st u d y dr u g ( u nits)  
 
P N H t y pe III R B C cl o ne size ( %)  
 
P N H t y pes II & III R B C cl o ne size ( %)  
 
He m o gl o bi n ( g/ d L)  
 
R B C c o u nts ( 1 0 6/ u L) 
 
Retic ul oc y te c o u nts ( 1 03/ u L) 
 
Free H g b ( m g %)  
 
Ha pt o gl o bi n ( g/ L) platelet c o u nts ( 1 0 3/ u L) 
 
A bs ol ute ne utr o p hil c o u nts ( 1 0 3/ u L) 
 
A L T (I U/ L)  
 
A S T (I U/ L)  
 
A L P (I U/ L)  
 
G G T (I U/ L)  
 
T otal bilir u bi n ( m g/ d L)  
 
I n direct bilir u bi n ( m g/ d L) 
 
Direct bilir u bi n ( m g/ d L)  
7. 1. 3. 3.  
Me dic al / S ur gic al Hist or y  
Me dical hist or y will be c o de d usi n g t he latest versi o n of M e dical Dicti o nar y f or Re g ulat or y 
Acti vities ( Me d D R A) a v aila ble. N u m ber a n d perce nta ge of p atie nts wit h me dical hist or y fi n di n gs 
will be s u m marize d b y s yste m or ga n class ( S O C) a n d preferre d ter m ( P T). A d diti o nall y, t he 
Me d D R A preferre d t er m a n d ver bati m te xt descri bi n g eac h dia g n osis will b e pres e nte d i n a listi n g.  
7. 1. 4.   
C o nc o mit a nt Me dic ati o ns / T her a pies  
C o nc o mita nt me dicati o n is defi ne d as me dicati o ns t hat eit her starte d pri or t o first d ose of st u d y 
dr u g a n d were c o nti n ui n g at t he ti me of first d ose of t he st u d y dr u g or start e d o n or after t he dat e 
of t he first d ose of t he st u d y dr u g. As patie nts i n t his st u d y alrea d y recei ve d st u d y dr u g treat me nt 


Ale xi o n P har mace uticals  
Statistical A nal ysis Pla n  
A C H 4 7 1 -1 0 3: 1 3 Marc h 2 0 1 8  (A me n d me nt 4, Versi o n 5 ) 
2 3 F E B 2 0 2 1, V 1. 0  
Pr o prietar y a n d C o nfi de ntial                                                                                                                       P a ge 1 4  of 2 4  
i n t he pri mar y st u d y, all 
me dicati o ns c ollecte d i n this st u d y are c o nsi dere d c o n c o mita nt 
me dicati o ns.  
T he latest versi o n of W orl d Healt h Or ga nizati o n ( W H O) Dr u g Dicti o nar y a vaila ble will be us e d 
t o c o de t he me di cati o ns. Me dicati o ns will be s u m marize d b y A nat o mical T hera p e utic C he mical 
( A T C) le vel 2 cl ass a n d ge n eric dr u g na me.  
C o nc o mita nt me dicati o ns i n A C H 4 7 1 -1 0 3 will be s u m marize d f or t he Safet y Set. T he n u m ber a n d 
perce nt a ge of patie nts recei vi n g a n y me di cati o n will be s u m marize d, as well as t he n u m b er a n d 
perce nt a ge recei vi n g a n y me dicati o n b y A T C dr u g class a n d ge neric dr u g  n a me. Patie nts re p orti n g 
use of m ore t ha n o ne me dicati o n at eac h le vel of s u m marizati o n (a n y me dicati o n recei v e d, A T C 
class, a n d ge neric dr u g na me) will be c o u nte d o nl y o n ce. A T C class will be prese nte d 
al p ha beticall y f oll o w e d b y d ecreasi n g fre q ue n c y of g e neric na m e. C o nc o mita nt me dicati o ns will 
be prese nt e d i n listi n gs.  
A se parate b y -patie nt listi n g of vacci nati o ns will b e pr o d uce d s h o wi n g t h e date(s) a n d bra n d of 
vacci nati o ns f or eac h patie nt.  
7. 2.   
Effic ac y A n al yses  
All efficac y a n al ys es will be perf or me d o n  t he F A set.   
I n ge neral, d escri pti ve st atistics ( n, mea n, me dia n, sta n dar d de viati o n, mi ni m u m, a n d ma xi m u m) 
will be pr o vi de d f or c o nti n u o us varia bles, a n d c o u nts a n d perce nta ges will be pr o vi de d f or 
cate g orical varia bles. A nal ysis will be perf or me d at ea c h st u d y visit. A “ Last visit” will be defi ne d 
as t he last assess me nt o n treat me nt.   
All e n d p oi nts will be prese nte d i n listi n gs. S pecific listi n gs will be n ot e d o nl y w he n t he o ut c o me 
will n ot be s u m marize d i n ta b ular f or m or f urt her clarificati o n is re q u ire d.  
7. 2. 1.   
Pri m ar y A n al ysis  
T he pri mar y efficac y e n d p oi nts t o assess t he l o n g -t er m efficac y of da ni c o pa n i n P N H patie nts are: 
 C ha n ge fr o m bas eli ne i n L D H le vel    
 C ha n ge fr o m bas eli ne i n H g b le vel i n t he a bse n ce of re d bl o o d cell tra nsf usi o n  
 C ha n ge fr o m bas eli ne i n retic ul oc yte c o u nts  
 N u m ber of re d bl o o d cell ( R B C) u nits tra nsf use d a n d tra nsf usi o n i nsta nces  
F or pri mar y e n d p oi nts e x ce pt n u m ber of R B C u nits tra nsf use d or tra nsf usi o n i nsta nces, o bser ve d 
val ues a n d c ha n ge fr o m Baseli ne will be s u m mari ze d b y st u d y visits. A nal ys es will be perf or me d 
o n t he F A set. L o n git u di nal pl ots will be pr o vi de d t o dis pla y mea n a n d me dia n o ver ti me - f or 
o bser ve d val u es as well as c ha n ge fr o m bas eli ne. Occ urre nce of R B C tra nsf usi o ns d uri n g t his 
st u d y will be c o u nte d f or eac h patie nt a n d t he n u m ber of R B C tra nsf usi o ns will be s u m marize d 
usi n g descri pti ve statistics f or c o nti n u o us varia bles.  
Data will als o be prese nt e d i n a listi n g s orte d b y p atie nt, visit a n d e n d p oi nt.  
7. 2. 1. 1.  
H a n dli n g of Dr o p o uts or Missi n g D at a  
A nal ysis will be o n o bser ve d val ues a n d n o i m p utati o n will be a p plie d.  


Ale xi o n P har mace uticals  
Statistical A nal ysis Pla n  
A C H 4 7 1 -1 0 3: 1 3 Marc h 2 0 1 8  (A me n d me nt 4, Versi o n 5 ) 
2 3 F E B 2 0 2 1, V 1. 0  
Pr o prietar y a n d C o nfi de ntial                                                                                                                       P a ge 1 5  of 2 4  
7. 2. 1. 2.  
S u b gr o u p A n al ysis  
N o s u b gr o u p a nal ysis is pla n ne d.  
7. 2. 1. 3.  
M ultice nter St u dies  
Sa m ple siz e is t o o s mall t o warra nt mea ni n gf ul a n al ysis t o assess st u d y site effect.  
7. 2. 1. 4.  
H y p ot hesis Testi n g a n d Si g nific a nce Le vel  
N o ne  
7. 2. 1. 5.  
Se nsiti vit y A n al yses  
N o ne.  
7. 2. 2.   
Sec o n d ar y A n al yses  
Sec o n dar y e n d p oi nts i ncl u de t he patie nt -re p orte d o utc o me assess me nts i ncl u di n g F A CI T Fati g u e 
scale q uesti o n nair e a n d E O R T C-Q L Q -C 3 0 q uesti o n naire.  
7. 2. 2. 1.  
F A CI T F ati g ue Sc ale ( Versi o n 4)  
T here are 1 3 ite ms i n t he F A CI T Fati g ue  scale q uesti o n naire ( A p pe n di x 2 i n t he pr ot oc ol). Eac h 
ite m i ncl u des 5 p ossi ble res p o nses, 0-4, wit h 0 bei n g “ N ot at all” a n d 4 b ei n g “ Ver y m uc h”. 
T otal sc ore fr o m t hese 1 3 ite ms will be pr o vi de d f or eac h p atie nt at eac h assess me nt. Ne gati vel y 
state d ite ms m ust be re verse d bef ore bei n g a d de d t o o btai n t he t otal sc ore b y s u btracti n g t h e 
res p o nse fr o m “ 4”.  All ite ms e x ce pt ite ms # 7 a n d # 8 are ne gati vel y state d. T he t otal sc ore 
ra n ges fr o m 0 t o 5 2, wit h hi g her t otal s c ores i n dicati n g better q ualit y of life. 
F A CI T t otal sc ore a n d c h a n ge fr o m bas eli ne will be s u m marize d b y st u d y visit. F A CI T t otal sc ore 
a n d c ha n ge fr o m bas eli ne i n t otal sc ore will be prese nte d i n a listi n g.  
7. 2. 2. 2.  
E O R T C -Q L Q -C 3 0 ( Versi o n 3)  
T here are 3 0 ite ms i n t he E O R T C -Q L Q -C 3 0 q uesti o n naire ( Fa yers , 2 0 0 1). T he 2 gl o b al healt h 
stat us ite ms ha ve 7 p ossi ble res p o nses, wit h 1 bei n g p o or a n d 7 bei n g e x celle nt.  All t he ot her 2 8 
ite ms ha ve 4 p ossi ble res p o nses, wit h 1 bei n g “ N ot at All” a n d 4 bei n g “ Ver y M u c h”. T hese 3 0 
ite ms are c o m p ose d of b ot h m ulti-ite m scales a n d si n gle -ite m meas ures, w hic h i ncl u de fi ve 
f u ncti o nal scales, ni ne s y m pt o m scales/ite ms, a n d o ne gl o b al healt h stat us/ Q o L s cale as t he 
f oll o wi n g ( A p p e n di x 9. 2): 
 F u ncti o nal scal es:  
 P h ysical f u n cti o ni n g  
 R ole f u ncti o ni n g  
 E m oti o nal f u ncti o ni n g  
 C o g niti ve f u ncti o ni n g  
 S ocial f u ncti o ni n g  
 S y m pt o m sc ales/ite ms:  
 Fati g ue  
 Na usea a n d v o miti n g  


Ale xi o n P har mace uticals  
Statistical A nal ysis Pla n  
A C H 4 7 1 -1 0 3: 1 3 Marc h 2 0 1 8  (A me n d me nt 4, Versi o n 5 ) 
2 3 F E B 2 0 2 1, V 1. 0  
Pr o prietar y a n d C o nfi de ntial                                                                                                                       P a ge 1 6  of 2 4  
 Pai n  
 D ys p n o ea  
 I ns o m nia  
 A p petite l oss  
 C o nsti pati o n  
 Diarr h oea  
 Fi na ncial diffic ulties  
 Gl o bal healt h stat us/ Q o L  
 
All scales a n d si n gle -ite m meas ures will be tra nsf or me d i nt o sc ores fr o m 0 t o 1 0 0. Details f or 
tra nsf or mi n g ra w sc ores i nt o scale sc ores f or t he scales a n d si n gle-ite m meas ures are pr o vi de d i n 
A p pe n di x 9. 2.  
A hi g h scale sc ore re pres e nts a hi g her res p o nse le vel. A hi g h sc ore f or a f u ncti o nal scale re prese nts 
a hi g h/ h ealt h y le vel of f u ncti o ni n g, a n d a hi g h sc ore f or t he gl o bal h ealt h stat us/ Q o L re prese nts a 
hi g h 
Q o L, 
w hile a hi g h s c ore f or a s y m pt o m scale/ite m re prese nts a hi g h l e vel of 
s y m pt o mat ol o g y/ pr o bl ems.  
Scale sc ores a n d c ha n ge fr o m baseli ne f or eac h Q L Q -C 3 0 scale/si n gle -it e m meas ures will be 
s u m marize d b y st u d y visit. Scale sc ores a n d c ha n ge fr o m baseli ne will be prese nte d i n a listi n g.  
7. 2. 3.   
Ot her Effic ac y A n al yses  
Ot her efficac y e n d p oi nts t o m o nit or a n d e val uate t he l o n g-ter m effects of da nic o pa n o n P N H cells 
a n d c o m ple me nt A P c o m p o ne nts a n d f u ncti o n i ncl u de t he f oll o wi n g:  
 
Free H g b  
 
Ha pt o gl o bi n  
 
C B C c o m p o ne nts  
 
P N H cl o ne size  
 
Fact or D  
 
A P Wiesla b  
 D -di mer  
 Direct C o o m bs  
Si milar a nal ys es as d escri be d f or t he pr i mar y e n d p oi nts will be perf or me d f or t he a b o ve e n d p oi nts.  
O bser ve d val ues a n d c ha n ge fr o m baseli ne will be s u m marize d b y pr ot oc ol s pecifie d visits o n t he 
F A set.  
7. 2. 4.   
P h ar m a c o ki netic a n d P h ar m a c o d y n a mic A n al yses  
Bl o o d sa m ples will be c ollecte d pri or t o d osi n g at eac h cli nic visit f or deter mi nati o n of tr o u g h 
plas ma c o n ce ntrati o ns of da nic o pa n.  All i n di vi d ual tr o u g h c o nce ntrati o ns will be liste d a n d will 
be s u m marize d usi n g descri pti ve statistics ( n u m ber of n o n -missi n g o bser vati o ns ( N), arit h metic 
mea n, S D, m e dia n, c oefficie nt of variati o n ( C V %), mi ni m u m, ma xi m u m, ge o metric mea n a n d 
ge o m etric C V %).  
A nal ysis f or P D bi o mar kers of i nterest are d escri be d i n t he effi cac y a nal yses.  


Ale xi o n P har mace uticals  
Statistical A nal ysis Pla n  
A C H 4 7 1 -1 0 3: 1 3 Marc h 2 0 1 8  (A me n d me nt 4, Versi o n 5 ) 
2 3 F E B 2 0 2 1, V 1. 0  
Pr o prietar y a n d C o nfi de ntial                                                                                                                       P a ge 1 7  of 2 4  
7. 3.   
S afet y A n al yses  
All safet y a nal yses will be c o n d uct e d o n t he Safet y s et. A Es will b e  c o d e d i n Me d D R A ( Versi o n 
2 3. 1 or a b o ve)  a n d prese nte d b y M e d D R A S O C a n d preferre d ter m. N o f or mal h y p ot hesis testi n g 
is pla n ne d. U nless ot her wise s pecifie d, b aseli ne is defi ne d as t he Bas eli ne i n t he pri mar y st u d y. 
7. 3. 1.   
Tre at me nt D ur ati o n a n d Tre at me nt C o m pli a nce  
Treat me nt d urati o n ( da ys fr o m t he first d ose t o t he last d ose bef ore t a per) will be s u m marize d wit h 
descri pti ve statistics. B ot h t he date of t he first d ose fr o m t he pri mar y st u d y a n d t he d ate of first 
d ose of t his st u d y will be use d t o calc ulate treat m e nt d urati o n. D osi n g re gi me n a n d d urati o n will 
be liste d b y patie nt.  
Treat me nt c o m plia nce p erce nt a ge is defi ne d as t he act ual t otal d ose o ver t he e x pecte d t otal d ose 
f or a patie nt f or eac h d osi n g re gi me n or f or o verall. S pecificall y, 
E x pecte d t otal d ose =  Assi g ne d d ose × Dail y fre q ue nc y × D urati o n i n da ys  
Act ual t otal d ose = D os a ge str e n gt h × N u m ber of ta blets c o ns u me d  
 
W here n u m ber of ta bl ets c o ns u me d is calc ulat e d as t he differe nce b et wee n t he n u m ber of ta blets 
dis pe nse d a n d t he n u m ber of ta blets ret ur ne d.   O verall treat me nt c o m plia nce is t he s u m of act ual 
t otal d oses of all d osi n g re gi me ns o v er t he s u m of t he e x pecte d t otal d oses of all d osi n g 
re gi me ns. 
 
F or eac h s u bject, a vera ge act ual dail y d ose f or eac h d osi n g re gi me n is calc ulate d as act u al t otal 
d os e o ver t he d urati o n of da ys w he n t he s u bject is o n t hat d osi n g re gi me n. Si milarl y, t he o verall 
a vera ge act ual dail y d ose is calc ulate d as t h e act ual t otal d ose o ver t he t otal treat me nt d urati o n 
da ys.  
O verall treat me nt c o m plia nce a n d a vera ge act ual dail y d o s e will be s u m marize d a n d is o nl y base d 
o n d osi n g d uri n g t his e xte nsi o n st u d y.  
7. 3. 2.   
A d verse E ve nts ( A Es)  
T E A Es are A Es t hat h a ve t heir o nset o n or after t he first d ose of st u d y dr u g i n A C H 4 7 1 -1 0 3. 
Patie nts e nr olle d i n t his st u d y h a ve alrea d y recei ve d t heir first d ose of st u d y dr u g treat me nt i n t h e 
pri mar y st u d y ( A C H 4 7 1 -1 0 0). T heref ore, t hese A Es are all T E A Es . All A Es will be c o de d usi n g 
t he latest versi o n of Me di cal Dicti o nar y f or Re g ulat or y Acti vities ( Me d D R A) a vaila ble.  
A E o nset da y = A E o nset date - first d ose d ate  + 1 
All treat me nt e mer ge nt a d verse e v e nts ( T E A E) will be s u m marize d wit h c o u nts a n d perce n ta ges 
f or n u m ber of a d verse e v e nts a n d patie nts wit h a d verse e v e nts.   
7. 3. 2. 1.  
O ver all S u m m ar y of A d verse E ve nts  
A n o verall s u m mar y of T E A Es will s u m marize n u m ber of e ve nts a n d t h e n u m ber/ perce nta ge of 
patie nts e x perie nci n g T E A Es i n t he f oll o wi n g cate g ories:  
 A n y T E A Es  


Ale xi o n P har mace uticals  
Statistical A nal ysis Pla n  
A C H 4 7 1 -1 0 3: 1 3 Marc h 2 0 1 8  (A me n d me nt 4, Versi o n 5 ) 
2 3 F E B 2 0 2 1, V 1. 0  
Pr o prietar y a n d C o nfi de ntial                                                                                                                       P a ge 1 8  of 2 4  
 T E A Es relate d a n d n ot relate d t o st u d y dr u g  
 T E A Es b y C T C A E s e verit y gra d e  
 Seri o us a d verse e ve nts  
 T E A E lea di n g t o st u d y dr u g wit h dra wal  
 T E A E res ulti n g i n d eat h if a n y  
A listi n g of all T E A Es b y patie nt will be prese nt e d. Se parate listi n gs will be pr o d u ce d f or S A Es, 
A Es lea di n g t o st u d y dr u g wit h dra wal, A Es res ulti n g i n deat h, a n d A Es lea di n g t o wit h dra wal fr o m 
t he st u d y w he n a p plica bl e.  
F or A Es wit h o nset bef ore t he c o m pleti o n of t h e pri mar y st u d y a n d o n g oi n g at A C H 4 7 1 -1 0 3 
e nr oll me nt, a se parate listi n g will be pres e nte d.  
7. 3. 2. 2.  
A Es a n d S A Es b y S yste m Or g a n Cl ass ( S O C) a n d Preferre d Ter m ( P T)  
T he n u m ber of T E A Es a n d t he n u m ber a n d perce nta ge of patie nts wit h T E A Es will be pres e nte d 
b y S O C a n d P T. Patie nts will be c o u nte d o nce i n eac h S O C a n d P T. Perce nta ges wi ll be base d o n 
t he t otal n u m ber of p atie nts i n t he Safet y s et. S yste m or ga n class es will be liste d i n al p ha betical 
or der, a n d P Ts wit hi n a S O C will be liste d i n or der of decreasi n g fre q u e nc y, wit h ties br o ke n 
al p ha beticall y.  
7. 3. 2. 3.  
A Es a n d S A Es b y S O C, P T, a n d Rel ati o ns hi p  
T he n u m ber of T E A Es a n d t he n u m ber a n d perce nta ge of patie nts wit h T E A Es will be pres e nte d 
b y S O C, P T a n d relati o ns hi p t o st u d y dr u g (relat e d, n ot relate d). If a p atie nt has m ore t ha n o ne 
occ urre nce of a n A E, t he m ost relate d e v e nt t o st u d y tr eat me nt wit hi n o ne cate g or y will be c o u nte d 
i n t he s u m mar y ta bl e. Missi n g relati o ns hi p t o st u d y dr u g will be ass u me d t o be relate d.  
7. 3. 2. 4.  
A Es a n d S A Es b y S O C, P T, a n d Se verit y  
T he n u m ber of T E A Es a n d t he n u m ber a n d perce nta ge of patie nts wit h e ve nts will be pre se nte d 
b y S O C, P T a n d C T C A E t o xicit y gra d e. If a patie nt has m ore t ha n o ne o cc urre nce of a n A E, t he 
hi g hest t o xicit y re p ort e d will be use d. If t o xicit y is missi n g, t he A E will be treate d as 
‘ U n k n o w n’.  
7. 3. 2. 5.  
De at hs, Ot her S A Es, a n d Ot her Si g nific a nt A d verse E ve n ts 
A listi n g of patie nt deat hs will be pr o d uce d.  
E ve nts of i nterest i n t his st u d y i ncl u de T E A Es of me ni n g oc o ccal i nfecti o ns a n d li ver e nz y m e 
ele vati o ns. T hese e ve nts of i nterest will be s u m marize d. T he A E Me d D R A ter ms t hat will be 
c o nsi dere d f or t hese s u m m aries is liste d bel o w.:  
Me ni n g o c occal i nfecti o ns: Me d D R A preferre d ter ms of Me ni n g o c occal bacterae mia, 
Me ni n gitis me ni n g o c occal, Me ni n g o c occal i nfecti o n, Me ni n g o c occal se psis, Me ni n g oc o ccal 
car ditis, E nce p h alitis me ni n g oc o ccal, E n d o car ditis me ni n g oc o ccal, M y o car ditis 
me ni n g oc o ccal, O ptic ne uritis me ni n g oc occal, a n d Pericar ditis me ni n g o c o ccal.  
Li ver e nz y m es ele vati o n: Gra de 3 e ve nts wit hi n t he hi g h le vel ter m ( H L T) of Li v er f u n cti o n 
a nal ys es a n d e ve nts wit hi n t he H L T of He pat ocell ular da ma ge a n d he p atitis N E C.  


Ale xi o n P har mace uticals  
Statistical A nal ysis Pla n  
A C H 4 7 1 -1 0 3: 1 3 Marc h 2 0 1 8  (A me n d me nt 4, Versi o n 5 ) 
2 3 F E B 2 0 2 1, V 1. 0  
Pr o prietar y a n d C o nfi de ntial                                                                                                                       P a ge 1 9  of 2 4  
I n a d diti o n, a me dical r e vie w will be d o ne t o e ns ure t hat n o rel e va nt e ve nts were misse d. 
7. 3. 3.   
Ot her S afet y  
7. 3. 3. 1.  
A n al yses f or L a b or at or y Tests  
Descri pti ve statistics f or o bser ve d val ues a n d t h e c h a n ge fr o m bas eli ne b y st u d y visit will be 
prese nte d f or eac h la b or at or y para meter, e x ce pt t h ose descri be d i n t he efficac y a nal ysis. Missi n g 
la b orat or y d ata will n ot b e i m p ute d, a n d o nl y s c he d ule d assess me nts at ce ntral la b orat or y will be 
i ncl u de d i n b y-visit s u m maries. U nsc he d ul e d ass ess me nts a n d l ocal la b orat or y val u es will o nl y be 
i ncl u de d i n listi n gs.  
W here a p plica ble, la b orat or y res ults will be classifie d as “l o w,” “ n or mal,” or “ hi g h” wit h res pect 
t o t he para meter-s pecifi c refere nce ra n ges (i.e., b el o w t he l o wer li mit of t he n or mal ra n ge, wit hi n 
t he n or mal ra n ge, or a b o ve t he u p per li mit of t he n or mal ra n ge).  
F or la b orat or y t ests 
wit h C T C A E t o xicit y gra des a vaila ble, la b orat or y a b n or malities are 
s u m marize d b y w orst treat me nt-e mer ge nt gra de [treat me nt e mer ge nt ( T E) la b a b n or malities].  F or 
tests t hat ha ve C T C A E t o xicit y gra des i n b ot h hi g h a n d l o w directi o ns, e. g. s er u m gl uc ose, etc., 
t he s u m mar y t a ble s h o ul d s pecif y se p arat el y f or t he T E a b n or malities as b ei n g hi g h or bei n g l o w 
i n t o xicit y gra des.  N ot e t hat t he p ost-baseli ne la b orat or y val ue wit h t he hi g hest treat me n t-
e mer ge nt t o xicit y gra d e is re p orte d f or eac h test.  
B o x pl ots will be prese nte d f or t he f oll o wi n g ce ntral la b para m eters b y visit: He m o gl o bi n, L D H, 
bilir u bi n (t otal a n d direct), creati ni ne, e G F R, A S T, A L T, G G T, A N C, platelets, a n d D -di mer. 
A d diti o nall y, scatter pl ots of t he w orst val ue p ost first st u d y dr u g v ers us baseli ne will be 
pr o vi de d f or t he a b o ve -m e nti o ne d para m eters.  
N u m ber a n d p erce nta ge of patie nts w h o ha d p ost -baseli ne la b orat or y val ues meeti n g a n y of t he 
f oll o wi n g criteria will be s u m marize d: 
 Ala ni ne a mi n otra nsferas e ( A L T) > 3 × U L N, 5 × U L N, 8 × U L N  
 As partate a mi n otra nsferase ( A S T) > 3 × U L N, 5 × U L N, 8 × U L N  
 A L T > 3 × U L N a n d t otal bilir u bi n > 2 × U L N  
 A L T > 3 × U L N a n d t otal bilir u bi n > 2 × U L N a n d A L P < 2 × U L N  
All la b orat or y res ults as well as t h e ass ociate d n or mal ra n ges a n d hi g h/l o w i n dicat ors of a b n or mal 
res ults will be prese nte d i n listi n gs. W orst treat me nt e mer ge nt t o xicit y gra d e la b orat or y res ults will 
als o be prese nt e d i n a listi n g.  
7. 3. 3. 2.  
Vit al Si g ns  
O bser ve d val u es a n d t he c ha n ge fr o m pri mar y st u d y bas eli ne i n vital si g ns ( bl o o d press ure, heart 
rate, res pir at or y rate, b o d y te m perat ure, a n d wei g ht) at eac h visit will be s u m marize d descri pti vel y. 
Missi n g vital si g ns data will n ot be i m p ute d a n d o nl y sc h e d ule d assess me nts will be s u m marize d 
i n ta bles; u nsc he d ul e d assess me nts will be prese nte d i n b y-p atie nt data listi n gs. A listi n g of vital 
si g ns will be pres e nte d b y patie nt, vital si g n, a n d visit. 


Ale xi o n P har mace uticals  
Statistical A nal ysis Pla n  
A C H 4 7 1 -1 0 3: 1 3 Marc h 2 0 1 8  (A me n d me nt 4, Versi o n 5 ) 
2 3 F E B 2 0 2 1, V 1. 0  
Pr o prietar y a n d C o nfi de ntial                                                                                                                       P a ge 2 0  of 2 4  
7. 3. 3. 3.  
Electr oc a r di o gr a m  
All o bser ve d E C G data a n d c ha n ges fr o m pri mar y st u d y b aseli ne i n E C G data ( heart rate, P R 
i nter val, R R i nter val, Q R S d urati o n, Q T i nter val a n d Q Tc F) will be s u m marize d descri pti vel y b y 
st u d y visit. 
At eac h ti me p oi nt, t he n u m ber a n d perce nt a ge of patie nts falli n g i nt o t he f oll o wi n g treat me nt 
e mer ge nt E C G a b n or malit y cat e g ories will be prese nte d:  
 P R i nter val:  > 2 0 0 ms  
 Q Tc F act ual val u es: 4 5 0 ms, > 4 5 0 t o 4 8 0 ms, > 4 8 0 t o 5 0 0 ms, a n d > 5 0 0 ms  
 Q Tc F i ncreases fr o m b as eli ne of > 3 0 ms a n d > 6 0 ms  
All E C G data wi ll be prese nte d i n a listi n g. 
7. 3. 3. 4.  
P h ysic al E x a mi n ati o n  
Res ults of t he a b n or mal p h ysical e x a mi nati o n res ults will be liste d b y sc h e d ule d visit.  
 
7. 4.   
C O VI D -1 9 Rel ate d A n al yses  
T he f oll o wi n g C O VI D -1 9 relate d dat a will be c oll ecte d f or s u bjects w h o were  o n g oi n g  i n t his 
st u d y aft er Dece m ber 3 1, 2 0 1 9 : 
1.  M o difie d a n d misse d st u d y visits (a n d C O VI D -1 9 relate d reas o ns)  
2.  Disc o nti n uati o n (i m pacte d b y C O VI D -1 9)  
3.  C O VI D -1 9 E x p os ure  
4.  Pr ot oc ol de viati o ns relate d t o C O VI D -1 9  
 
T he n u m ber of s u bjects wit h m o difie d st u d y visits a n d t he r eas o ns f or m o difie d st u d y visits 
( C O VI D relate d or ot h er) will be s u m marize d. Si milarl y, t he n u m ber of s u bjects wit h misse d 
st u d y visits a n d t he reas o ns f or misse d st u d y visits ( C O VI D-relate d or ot her) will be 
s u m marize d.  
T he n u m ber of s u bjects wit h disc o nti n uati o n stat us i m pacte d b y C O VI D -1 9 will be s u m marize d.  
Treat me nt c o m plia nce perce nta ge will be s u m mari ze d f or s u bjects wit h C O VI D -1 9 e x p os ure 
d uri n g t he st u d y.  
Pr ot oc ol de viati o ns relate d t o C O VI D -1 9 will be s u m marize d si milarl y as t he o verall P Ds 
s pecifie d i n Secti o n 7. 1. 2.  
 


Ale xi o n P har mace uticals  
Statistical A nal ysis Pla n  
A C H 4 7 1 -1 0 3: 1 3 Marc h 2 0 1 8  (A me n d me nt 4, Versi o n 5 ) 
2 3 F E B 2 0 2 1, V 1. 0  
Pr o prietar y a n d C o nfi de ntial                                                                                                                       P a ge 2 1  of 2 4  
8.   
R E F E R E N C E S  
1.  Fa yers P M, Aar o ns o n N K, Bj or dal K, Gr oe n v ol d M, C urra n D, B ott o mle y A, o n be half of 
t he E O R T C Q ualit y of Life Gr o u p; T he E O R T C Q L Q-C 3 0 Sc ori n g Ma n u al ( 3 r d E diti o n); 
E ur o pea n Or ga nisati o n f or Researc h a n d Treat me nt of C a ncer, Br ussels 2 0 0 1.  
 


Ale xi o n P har mace uticals  
Statistical A nal ysis Pla n  
A C H 4 7 1 -1 0 3: 1 3 Marc h 2 0 1 8  (A me n d me nt 4, Versi o n 5 ) 
2 3 F E B 2 0 2 1, V 1. 0  
Pr o prietar y a n d C o nfi de ntial                                                                                                                       P a ge 2 2  of 2 4  
9.   
A P P E N DI C E S  
9. 1.   
Pr ot oc ol Sc he d ule of Assess me nts  
T a ble 3.   
Sc he d ule of Assess me nts  
 


Ale xi o n P har mace uticals  
Statistical A nal ysis Pla n  
A C H 4 7 1 -1 0 3: 1 3 Marc h 2 0 1 8  (A me n d me nt 4, Versi o n 5 ) 
2 3 F E B 2 0 2 1, V 1. 0  
Pr o prietar y a n d C o nfi de ntial                                                                                                                       P a ge 2 3  of 2 4  
 
9. 2.   
Sc ori n g t he E O R T C Q L Q -C 3 0 versi o n 3. 0  
T a ble 4.   
Sc ori n g of E O R T C Q L Q -C 3 0 versi o n 3. 0  
T he f oll o wi n g t a ble s h o ws t he c o m p o ne nt q uesti o ns of Q L Q -C 3 0 i ncl u de d i n eac h of t he s cales 
a n d si n gle -ite m meas ures a n d t heir ra n ges. 
 
* Ite m ra n ge is t he differe nce bet wee n t he p ossi ble ma xi m u m a n d t he mi ni m u m r es p o nse t o i n di vi d ual 
ite ms; m ost ite ms ta ke val ues fr o m 1 t o 4, gi vi n g ra n ge = 3.  
† Scales are t h ose t hat ha ve bee n c ha n ge d si nce versi o n 1. 0, a n d t heir s h ort na mes are i n dicate d i n t his 
ma n ual b y a s uffi x “ 2” –  f or e xa m ple, P F 2.  
 
Tra nsf or mi n g res p o nses t o scale sc ores f or eac h of t he scales a n d si n gle -ite m meas ures are as f oll o ws: 
F or all scales, t he R a w Sc ore, R S , is t he mea n res p o nses of t he c o m p o ne nt ite ms: 


Ale xi o n P har mace uticals  
Statistical A nal ysis Pla n  
A C H 4 7 1 -1 0 3: 1 3 Marc h 2 0 1 8  (A me n d me nt 4, Versi o n 5 ) 
2 3 F E B 2 0 2 1, V 1. 0  
Pr o prietar y a n d C o nfi de ntial                                                                                                                       P a ge 2 4  of 2 4  
R a w Sc ore = R S = ( I 1 + I 2 + … + I n)/ n  
T he n f or F u ncti o n al sc ales :       Sc ore = {1 −(𝑅𝑆−1 )𝑟𝑎𝑛𝑔𝑒⁄
} × 1 0 0  
a n d f or S y m pt o m sc al es/ite ms a n d Gl o b al he alt h st at us/ Q o L :  
    Sc ore = [ ( R S −1)/ r a n ge] × 1 0 0  
 
9. 3.   
Tec h nic al S pecific ati o ns f or Deri ve d V ari a bles  
Missi n g a n d P arti al D ates  
I n cases w here o nl y t h e m o nt h a n d year are pr o vi de d f or a d ate, t he d a y f or t h e date will be i m p ute d 
as 1 5. Missi n g m o nt hs will be i m p ute d as J u ne. I n cases w here t he d a y is o bser ve d  b ut t he m o nt h 
is missi n g, t he date will be i m p ute d as J u ne 1 5. S h o ul d t he date create d wit h t hese i m p utati o n r ules 
place it o utsi de t he p ossi ble ra n ge of v al ues esta blis he d b y c o m plete, k n o w n dates (s uc h as t he 
birt h date, deat h date, or t he I C F d ate f or st u d y pr oce d ures), t he cl osest k n o w n date will be use d. 
F or e x a m ple, a patie nt wit h a partial A E start date of J u ne 2 0 1 1 a n d a deat h date of J u ne 5t h 2 0 1 1 
w o ul d ha ve t he A E d ate i m p ute d as J u ne 5t h 2 0 1 1 i nstea d of t he 1 5t h.  
A n al ysis Rel ati ve D a y  
A nal ysis r elati ve da y is t he da y rel ati ve t o t he first d osi n g da y i n t he pri mar y st u d y. It will be 
calc ulate d as: a nal ysis date –  first d ose date + 1 if a nal ysis date is after t he first d ose date, or else 
as: first d ose date –  a n al ysis date. Si milarl y, a nal ysis rela ti ve d a y will als o be calc ulat e d relati ve 
t o t he first d osi n g da y i n st u d y A C H 4 7 1 -1 0 3 .  
 
 
 


C ertifi c at e Of C o m pl eti o n
E n v el o p e I d: B 2 6 1 C 4 4 D E D 1 B 4 1 B 1 8 8 8 D D E A 3 B 1 6 5 8 C 7 E
St at u s: C o m pl et e d
S u bj e ct: Pl e a s e D o c u Si g n: A C H 4 7 1- 1 0 3 S A P V 1 - 2 3 F E B 2 0 2 1. d o c x
S o ur c e E n v el o p e: 
D o c u m e nt P a g e s: 2 4
Si g n at ur e s: 3
E n v el o p e Ori gi n at or: 
C ertifi c at e P a g e s: 2
I niti al s: 0
A ut o N a v: E n a bl e d
E n v el o p eI d St a m pi n g: Di s a bl e d
Ti m e Z o n e: ( U T C- 0 5: 0 0) E a st er n Ti m e ( U S & C a n a d a)
N e w H a v e n, C T  0 6 5 1 0
I P A d dr e s s: 
R e c or d Tr a c ki n g
St at u s: Ori gi n al
             0 1- M ar- 2 0 2 1 | 1 4: 5 3
H ol d er: 
             
L o c ati o n: D o c u Si g n
Si g n er E v e nt s
Si g n at ur e
Ti m e st a m p
Al e xi o n P h ar m a c e uti c al s I n c.
S e c urit y L e v el: E m ail, A c c o u nt A ut h e nti c ati o n 
( R e q uir e d)
Si g n at ur e A d o pti o n: Pr e- s el e ct e d St yl e
Si g n at ur e I D: 
U si n g I P A d dr e s s: 
Wit h Si g ni n g A ut h e nti c ati o n vi a D o c u Si g n p a s s w or d
Wit h Si g ni n g R e a s o n s ( o n e a c h t a b): 
   I h a v e r e vi e w e d t hi s d o c u m e nt
S e nt: 0 1- M ar- 2 0 2 1 | 1 4: 5 9
Vi e w e d: 0 1- M ar- 2 0 2 1 | 1 5: 1 9 
Si g n e d: 0 1- M ar- 2 0 2 1 | 1 5: 2 0
El e ctr o ni c R e c or d a n d Si g n at ur e Di s cl o s ur e: 
      N ot Off er e d vi a D o c u Si g n
Al e xi o n P h ar m a c e uti c al s I n c.
S e c urit y L e v el: E m ail, A c c o u nt A ut h e nti c ati o n 
( R e q uir e d)
Si g n at ur e A d o pti o n: U pl o a d e d Si g n at ur e I m a g e
Si g n at ur e I D: 
U si n g I P A d dr e s s: 
Wit h Si g ni n g A ut h e nti c ati o n vi a D o c u Si g n p a s s w or d
Wit h Si g ni n g R e a s o n s ( o n e a c h t a b): 
   I a p pr o v e t hi s d o c u m e nt
S e nt: 0 1- M ar- 2 0 2 1 | 1 4: 5 9
Vi e w e d: 0 1- M ar- 2 0 2 1 | 1 5: 2 6 
Si g n e d: 0 1- M ar- 2 0 2 1 | 1 5: 2 7
El e ctr o ni c R e c or d a n d Si g n at ur e Di s cl o s ur e: 
      N ot Off er e d vi a D o c u Si g n
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D


Si g n er E v e nt s
Si g n at ur e
Ti m e st a m p
Al e xi o n P h ar m a c e uti c al s I n c.
S e c urit y L e v el: E m ail, A c c o u nt A ut h e nti c ati o n 
( R e q uir e d)
Si g n at ur e A d o pti o n: Pr e- s el e ct e d St yl e
Si g n at ur e I D: 
U si n g I P A d dr e s s: 
Wit h Si g ni n g A ut h e nti c ati o n vi a D o c u Si g n p a s s w or d
Wit h Si g ni n g R e a s o n s ( o n e a c h t a b): 
   I a m t h e a ut h or of t hi s d o c u m e nt
S e nt: 0 1- M ar- 2 0 2 1 | 1 4: 5 9
Vi e w e d: 0 1- M ar- 2 0 2 1 | 1 5: 0 0 
Si g n e d: 0 1- M ar- 2 0 2 1 | 1 5: 0 1
El e ctr o ni c R e c or d a n d Si g n at ur e Di s cl o s ur e: 
      N ot Off er e d vi a D o c u Si g n
I n P er s o n Si g n er E v e nt s
Si g n at ur e
Ti m e st a m p
E dit or D eli v er y E v e nt s
St at u s
Ti m e st a m p
A g e nt D eli v er y E v e nt s
St at u s
Ti m e st a m p
I nt er m e di ar y D eli v er y E v e nt s
St at u s
Ti m e st a m p
C ertifi e d D eli v er y E v e nt s
St at u s
Ti m e st a m p
C ar b o n C o p y E v e nt s
St at u s
Ti m e st a m p
Wit n e s s E v e nt s
Si g n at ur e
Ti m e st a m p
N ot ar y E v e nt s
Si g n at ur e
Ti m e st a m p
E n v el o p e S u m m ar y E v e nt s
St at u s
Ti m e st a m p s
E n v el o p e S e nt
H a s h e d/ E n cr y pt e d
0 1- M ar- 2 0 2 1 | 1 4: 5 9
C ertifi e d D eli v er e d
S e c urit y C h e c k e d
0 1- M ar- 2 0 2 1 | 1 5: 0 0
Si g ni n g C o m pl et e
S e c urit y C h e c k e d
0 1- M ar- 2 0 2 1 | 1 5: 0 1
C o m pl et e d
S e c urit y C h e c k e d
0 1- M ar- 2 0 2 1 | 1 5: 2 7
P a y m e nt E v e nt s
St at u s
Ti m e st a m p s
P P D
P P D
P P D
P P D
P P D
P P D