Clinical trial NCT04610580
Conditions: Healthy
Keywords: Bioavailability Healthy
Sponsor: Alexion Pharmaceuticals, Inc.
Start date: 2021-01-31; Completion date: 2021-04-26
Enrollment: 48 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The study will assess the relative bioavailability of 2 different formulations of ALXN1840 in healthy participants.

Detailed description:
This is a two-way crossover study consisting of 2 dosing periods assessing a test and reference formulation of ALXN1840. A dose-proportionality parallel group design extension period will be conducted following completion of the two-way crossover period of the study and will assess 5 different ascending doses of ALXN1840. There will be at least a 14-day washout following doses between Periods 1 and 2 and also at least a 14-day washout following the dose in Period 2 and the following dose in the Dose-Proportionality Extension Period.

Safety will be assessed throughout the study.

Arms: arm 1: Participants will first receive a single dose of ALXN1840 test formulation on Day 1 of Period 1. After a washout period of 14 days, they will then receive a single dose of ALXN1840 reference formulation on Day 1 of Period 2. arm 2: Participants will first receive a single dose of ALXN1840 reference formulation on Day 1 of Period 1. After a washout period of 14 days, they will then receive a single dose of ALXN1840 test formulation on Day 1 of Period 2. arm 3: Participants will receive a single dose of ALXN1840. arm 4: Participants will receive a single dose of ALXN1840. arm 5: Participants will receive a single dose of ALXN1840. arm 6: Participants will receive a single dose of ALXN1840.
Interventions: intervention 1: ALXN1840
Intervention descriptions: intervention 1: ALXN1840 will be administered orally.

Protocol documents:
Prot_000.pdf: 
A Phase 1, Randomized, 2-Period, 2-Sequence, Crossover 
with Parallel-group Extension, Open-label Study to 
Compare the Relative Bioavailability of 2 Oral Formulations 
of ALXN1840 in Healthy Adult Participants 
Unique Protocol ID: 
NCT Number 
Date of Protocol 
ALXN1840-HV-109 
NCT04610580 
18 December 2020 


Protocol Amendment 2 
 
ALXN1840-HV-109 
18 Dec 2020 
Page 1 of 60 
Alexion Confidential 
TITLE PAGE 
Protocol Title:  
A Phase 1, randomized, 2‑period, 2‑sequence, crossover with parallel-group extension, open 
label- study to compare the relative bioavailability of 2 oral formulations of ALXN1840 in 
healthy adult participants 
Protocol Number: ALXN1840-HV-109 
Amendment Number: 2 
Compound: ALXN1840 (bis-choline tetrathiomolybdate) 
Study Phase: 1 
Short Title: Phase 1, bioavailability study of 2 oral formulations of ALXN1840 
Sponsor Name: Alexion Pharmaceuticals, Inc. 
Legal Registered Address:  
121 Seaport Boulevard 
Boston, MA 02210 
USA 
Regulatory Agency Identifier Number(s): IND 119006 
Approval: 
Original Protocol 
10 Jul 2020 
Amendment 1 
16 Sep 2020 
Amendment 2 
18 Dec 2020 
 
Sponsor Signatory:  
 
Date 
 
Medical Monitor Name and Contact Information can be found in the Study Contact list. 
21-Dec-2020 | 11:49:18 EST
PPD


Protocol Amendment 2 
 
ALXN1840-HV-109 
18 Dec 2020 
Page 2 of 60 
Alexion Confidential 
INVESTIGATOR’S AGREEMENT 
I have read the study protocol amendment 2 and agree to conduct the study in accordance with 
this protocol amendment 2, all applicable government regulations, the principles of the ICH E6 
Guidelines for Good Clinical Practice, and the principles of the World Medical Association 
Declaration of Helsinki. I also agree to maintain the confidentiality of all information received or 
developed in connection with this protocol.  
 
 
 
 
____________________________________ 
Printed Name of Investigator 
 
_____________________________________ 
Signature of Investigator 
 
_______________ 
Date 
 


Protocol Amendment 2 
 
ALXN1840-HV-109 
18 Dec 2020 
Page 3 of 60 
Alexion Confidential 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
DOCUMENT HISTORY 
Document 
Date 
Original Protocol 
10 Jul 2020 
Amendment 1 
16 Sep 2020 
Amendment 2 
18 Dec 2020 
 
Amendment 2 (18 Dec 2020) 
Overall Rationale for the Amendment 
This amendment has been prepared to remove mention of biomarkers from the exploratory 
endpoint, and non-ceruloplasmin-bound copper (NCC), NCCcorrected, labile bound copper (LBC), 
ceruloplasmin, and ceruloplasmin-bound copper from the exploratory endpoints because, 
although these samples will be collected, they will not be analyzed immediately but retained for 
potential future analysis. Minor edits for consistency and accuracy have also been made. 
Details of the changes are presented in the table below. 
Changes to the Protocol 
Section # and Name 
Description of Change 
Brief Rationale and/or Clarifications 
1.1 Synopsis 
3 Objectives, Table 4 
 
Removal of biomarkers from the 
exploratory objective and 
corresponding removal of NCC, 
NCCcorrected, LBC, 
ceruloplasmin, and 
ceruloplasmin-bound copper 
from the exploratory endpoints 
It is not currently planned to analyze these 
samples at time of study completion. The 
samples will be retained and may be used for 
diagnostic biomarker development and 
research to better understand how ALXN1840 
exerts its effects in the body. 
1.2 Schema 
Removal of crossover lines 
between Dosing Periods 1 and 2 
The lines have been removed to clarify that 
each subject will receive Treatment A and 
Treatment B sequentially. The order of 
Treatment A and Treatment B will be 
randomized. 
1.3 Schedule of Activities, 
Table 1 
Removal of requirement for 
PK/PD/biomarker samples 
during Screening 
 
PK/PD/biomarker samples are not required 
during Screening. 
 
1.3 Schedule of Activities, 
Table 1 
8.2.1 Physical 
Examinations 
Removal of requirement to 
assess height, weight, and BMI 
at EOS/EOT; these assessments 
will only be performed at 
Screening 
Height, weight, and BMI will only be assessed 
at Screening. 
1.3 Schedule of Activities, 
Table 1 
10.2, Clinical Laboratory 
Tests, Table 6 
Clarification added that a 
sample for HbA1c is only 
required during the Screening 
Period. 
A sample for HbA1c is only required during 
the Screening Period, and not at every time 
point where samples for hematology, 
chemistry, urinalysis, and coagulation are 
required. 
8.6 Pharmacodynamics 
8.8 Biomarkers 
9.4.3 Pharmacokinetics/ 
Pharmacodynamics 
Analysis 
Text amended regarding the 
analysis of LBC, NCC, 
NCCcorrected, ceruloplasmin, and 
ceruloplasmin-bound copper 
As mentioned above, it is not currently planned 
to analyze these samples at time of study 
completion. 


Protocol Amendment 2 
 
ALXN1840-HV-109 
18 Dec 2020 
Page 4 of 60 
Alexion Confidential 
TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
INVESTIGATOR’S AGREEMENT ...............................................................................................2 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ............................................3 
1. 
PROTOCOL SUMMARY............................................................................................8 
1.1. 
Synopsis ........................................................................................................................8 
Two-way Crossover Period..............................................................................................................9 
Dose-Proportionality Extension Period .........................................................................................10 
1.2. 
Schema ........................................................................................................................11 
1.3. 
Schedule of Activities .................................................................................................12 
2. 
INTRODUCTION ......................................................................................................15 
2.1. 
Study Rationale ...........................................................................................................15 
2.2. 
Background .................................................................................................................15 
2.3. 
Benefit/Risk Assessment ............................................................................................16 
2.3.1. 
Risk Assessment .........................................................................................................17 
2.3.2. 
Benefit Assessment .....................................................................................................17 
2.3.3. 
Overall Benefit: Risk Conclusion ...............................................................................17 
3. 
OBJECTIVES AND ENDPOINTS ............................................................................18 
4. 
STUDY DESIGN .......................................................................................................19 
4.1. 
Overall Design ............................................................................................................19 
Two-way Crossover Period............................................................................................................19 
Dose-Proportionality Extension Period .........................................................................................20 
4.2. 
Scientific Rationale for Study Design ........................................................................20 
4.2.1. 
Participant Input into Design ......................................................................................21 
4.3. 
Justification for Dose ..................................................................................................21 
4.4. 
End of Study Definition ..............................................................................................22 
5. 
STUDY POPULATION .............................................................................................23 
5.1. 
Inclusion Criteria ........................................................................................................23 
5.2. 
Exclusion Criteria .......................................................................................................24 
5.3. 
Lifestyle Considerations .............................................................................................26 
5.4. 
Screen Failures............................................................................................................26 
6. 
STUDY INTERVENTION ........................................................................................27 


Protocol Amendment 2 
 
ALXN1840-HV-109 
18 Dec 2020 
Page 5 of 60 
Alexion Confidential 
6.1. 
Study Intervention Administered ................................................................................27 
6.2. 
Preparation/Handling/Storage/Accountability ............................................................27 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ........................................28 
6.4. 
Study Intervention Compliance ..................................................................................28 
6.5. 
Concomitant Therapy .................................................................................................29 
6.5.1. 
Allowed Medicine and Therapy .................................................................................29 
6.5.2. 
Disallowed Medicine and Therapy .............................................................................29 
6.6. 
Dose Modification ......................................................................................................30 
6.7. 
Intervention After the End of the Study .....................................................................30 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL .......................................31 
7.1. 
Discontinuation of Study Intervention........................................................................31 
7.2. 
Participant Discontinuation/Withdrawal From the Study ...........................................31 
7.3. 
Lost to Follow-up .......................................................................................................32 
8. 
STUDY ASSESSMENTS AND PROCEDURES......................................................33 
8.1. 
Efficacy Assessments .................................................................................................33 
8.2. 
Safety Assessments .....................................................................................................33 
8.2.1. 
Physical Examinations ................................................................................................33 
8.2.2. 
Vital Signs ..................................................................................................................33 
8.2.3. 
Electrocardiograms .....................................................................................................34 
8.2.4. 
Clinical Safety Laboratory Assessments ....................................................................34 
8.2.5. 
Suicidal Ideation and Behavior Risk Monitoring .......................................................35 
8.2.6. 
Pregnancy ...................................................................................................................35 
8.3. 
Adverse Events and Serious Adverse Events .............................................................35 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE Information .......................35 
8.3.2. 
Method of Detecting AEs and SAEs ..........................................................................36 
8.3.3. 
Follow-up of AEs and SAEs.......................................................................................36 
8.3.4. 
Regulatory Reporting Requirements for SAEs ...........................................................36 
8.3.5. 
Adverse Events of Special Interest .............................................................................36 
8.4. 
Treatment of Overdose ...............................................................................................36 
8.5. 
Pharmacokinetics ........................................................................................................37 
8.6. 
Pharmacodynamics .....................................................................................................37 
8.7. 
Genetics ......................................................................................................................38 


Protocol Amendment 2 
 
ALXN1840-HV-109 
18 Dec 2020 
Page 6 of 60 
Alexion Confidential 
8.8. 
Biomarkers ..................................................................................................................38 
8.9. 
Immunogenicity Assessments ....................................................................................38 
8.10. 
Health Economics Data and/or Medical Resource Utilization ...................................38 
9. 
STATISTICAL CONSIDERATIONS .......................................................................39 
9.1. 
Statistical Hypotheses .................................................................................................39 
9.1.1. 
Primary Hypothesis ....................................................................................................39 
9.2. 
Sample Size Determination ........................................................................................39 
9.3. 
Populations for Analyses ............................................................................................39 
9.4. 
Statistical Analyses .....................................................................................................39 
9.4.1. 
Efficacy Analyses .......................................................................................................40 
9.4.1.1. 
Analyses of Primary Endpoint ....................................................................................40 
9.4.1.2. 
Analyses of Secondary Endpoints ..............................................................................40 
9.4.1.3. 
Analyses of Exploratory Endpoints ............................................................................40 
9.4.2. 
Safety Analyses ..........................................................................................................40 
9.4.3. 
Pharmacokinetic/Pharmacodynamic Analysis ............................................................41 
9.5. 
Interim Analyses .........................................................................................................42 
9.6. 
Safety Review Committee ..........................................................................................42 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ..................................................................................................43 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ....................43 
10.1.1. 
Regulatory and Ethical Considerations ......................................................................43 
10.1.2. 
Financial Disclosure ...................................................................................................43 
10.1.3. 
Informed Consent Process ..........................................................................................44 
10.1.4. 
Data Protection ...........................................................................................................44 
10.1.5. 
Dissemination of Clinical Study Data ........................................................................45 
10.1.6. 
Data Quality Assurance ..............................................................................................45 
10.1.7. 
Source Documents ......................................................................................................45 
10.1.8. 
Study and Site Start and Closure ................................................................................46 
10.1.9. 
Publication Policy .......................................................................................................46 
10.2. 
Appendix 2: Clinical Laboratory Tests .......................................................................47 
10.3. 
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting........................................................................49 
10.3.1. 
Definition of AE .........................................................................................................49 


Protocol Amendment 2 
 
ALXN1840-HV-109 
18 Dec 2020 
Page 7 of 60 
Alexion Confidential 
10.3.2. 
Definition of SAE .......................................................................................................49 
10.3.3. 
Recording and Follow-Up of AE and/or SAE ............................................................50 
10.3.4. 
Reporting of SAEs ......................................................................................................52 
10.4. 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information .................................................................................................................53 
10.5. 
Appendix 5: Biomarkers .............................................................................................55 
10.6. 
Appendix 6: Abbreviations .........................................................................................56 
10.7. 
Appendix 7: Protocol Amendment History ................................................................58 
11. 
REFERENCES ...........................................................................................................60 
 
LIST OF TABLES 
Table 1: 
Schedule of Activities .................................................................................................12 
Table 2: 
Detailed Timing of Assessments on Day 1 of Each Dosing Period and on 
Day 1 of the Dose-Proportionality Extension Period .................................................14 
Table 3: 
Potential Risks and Mitigation Strategy .....................................................................17 
Table 4: 
Mapping Objectives to Endpoints/Estimands .............................................................18 
Table 5:  
Details of Study Intervention Administered ...............................................................27 
Table 6: 
Laboratory Assessments .............................................................................................47 
Table 7:  
List of Abbreviations and Definitions of Terms .........................................................56 
 
 
LIST OF FIGURES 
Figure 1: 
Study Design Schematic .............................................................................................11 
 
 


Protocol Amendment 2 
 
ALXN1840-HV-109 
18 Dec 2020 
Page 8 of 60 
Alexion Confidential 
1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Protocol Title: A Phase 1, randomized, 2‑period, 2‑sequence, crossover with parallel-group 
extension, open -label study to compare the relative bioavailability of 2 oral formulations of 
ALXN1840 in healthy adult participants 
Short Title: Phase 1, bioavailability study of 2 oral formulations of ALXN1840 
Rationale: 
The purpose of this study is to assess relative bioavailability of the 1.25 mg enteric-coated (EC) 
mini-tablet formulation of ALXN1840 compared with the 15 mg EC tablet that is currently used 
in clinical studies and to assess dose proportionality between 2.5 mg (2 × 1.25 mg), 5 mg 
(4 × 1.25 mg), 10 mg (8 × 1.25 mg), 15 mg (12 × 1.25 mg), and 30 mg (24 × 1.25 mg) EC 
mini-tablet doses. 
The 1.25 mg EC mini-tablet is in development for treating patients with Wilson disease (WD) 
who may require a lower dose and/or who may have difficulty swallowing the 15 mg EC tablet 
(eg, pediatric patients with WD). Several of the 1.25 mg EC mini-tablets could be administered 
together with acidic soft foods to protect the enteric coating through to the site of absorption in 
the gastrointestinal tract. To support this alternative administration method, further investigation 
of the formulation stability of the 1.25 mg EC mini-tablets in acidic soft foods is also planned. 
Objectives and Endpoints 
Objective 
Endpoints/Estimands 
Primary 
To assess the relative bioavailability of equal doses of 
ALXN1840 administered as 1.25 mg EC mini-tablets 
versus a single 15 mg EC tablet 
PK parameters for plasma total Mo and PUF Mo (Cmax, 
AUCt, and AUC∞) 
Secondary 
To assess dose-proportionality between 2.5 mg (2 × 
1.25 mg), 5 mg (4 × 1.25 mg), 10 mg (8 × 1.25 mg), 
15 mg (12 × 1.25 mg), and 30 mg (24 × 1.25 mg) EC 
mini-tablet doses 
Dose-normalized PK parameters for plasma total Mo and 
PUF Mo (Cmax_n, AUCt_n, and AUC∞_n) 
Safety 
To assess the overall safety and tolerability of 
ALXN1840, administered as 1.25 mg EC mini-tablets 
and as a single 15 mg EC tablet 
Incidence of TEAEs and TESAEs, physical examination, 
vital signs measurements, clinical laboratory, and 12-lead 
ECG results 
Exploratory  
To explore relationships between total Mo and PUF Mo 
clearance and body size — body weight (kg) and BMI 
(kg/m2) 
CL/F, body weight, and BMI 
To explore PD of ALXN1840 either as a single 15 mg 
EC tablet or EC mini-tablets of 1.25 mg at different total 
dose strengths 
Absolute and percent changes from pre-dose baseline of 
plasma Cu concentrations: total Cu and PUF Cu 
Abbreviations: AUC∞ =  area under the plasma concentration versus time curve from time 0 to infinity; AUCt = area under the 
plasma concentration versus time curve from time 0 to the last quantifiable concentration; BMI = body mass index; 
CL/F = apparent oral clearance; Cmax = maximum observed concentration; Cu = copper; EC = enteric-coated; 
ECG = electrocardiogram; Mo = molybdenum; n = dose-normalized; PD = pharmacodynamic(s); PK = pharmacokinetic(s); 
PUF = plasma ultrafiltrate; TEAE = treatment-emergent adverse events; TESAE = treatment-emergent serious adverse event. 
Overall Design 


Protocol Amendment 2 
 
ALXN1840-HV-109 
18 Dec 2020 
Page 9 of 60 
Alexion Confidential 
This is a 2-period, 2-sequence crossover study with parallel group extension designed to assess 
the relative bioavailability of equal doses of ALXN1840 administered as 1.25 mg EC 
mini-tablets versus a single 15 mg EC tablet, and to assess dose-proportionality between 2.5 mg 
(2 × 1.25 mg), 5 mg (4 × 1.25 mg), 10 mg (8 × 1.25 mg), 15 mg (12 × 1.25 mg), and 30 mg 
(24 × 1.25 mg) EC mini-tablet doses in the Dose-Proportionality Extension Period. The safety 
and tolerability of the 2 formulations of ALXN1840 in healthy participants will also be assessed. 
ALXN1840 pharmacokinetics (PK) in plasma as measured via total molybdenum (Mo) and 
plasma ultrafiltrate (PUF) Mo will be determined. 
Disclosure Statement: This is a randomized, 2-period, 2-sequence, open-label crossover study 
with parallel group extension. There are 2 treatment arms in the first and second periods, and 
4 treatment arms in the Dose-Proportionality Extension period. 
Number of Participants: 
Approximately 48 male or female participants will be enrolled and randomly assigned to 1 of 2 
treatment sequences (24 participants in each sequence) to ensure a minimum of 40 participants 
complete the study. 
Note: “Enrolled” means a participant’s agreement to participate in a clinical study following 
completion of the informed consent process and satisfying inclusion/exclusion criteria. Potential 
participants who are screened for the purpose of determining eligibility for the study, but do not 
participate in the study, are not considered enrolled, unless otherwise specified by the protocol.  
Intervention Groups and Duration: 
The study has a Screening Period (Days -28 to -2), the Two-way Crossover Period, consisting of 
2 dosing periods (Day 1 to Day 11 each), and a Dose-Proportionality Extension Period. After 
completing the Screening Period, enrolled participants will be admitted to the clinical research 
unit (CRU) on Day -1 for dosing on Day 1 in Dosing Period 1. If discharged after Dosing 
Period 1, participants will be readmitted to the CRU for Dosing Period 2 following a minimum 
washout of 14 days after the previous dose, and again for the Dose-Proportionality Extension 
Period after a minimum washout of 14 days. The end of study (EOS) visit will take place 14 days 
(± 2 days) after the dose of ALXN1840 in the Dose-Proportionality Extension Period. 
Two-way Crossover Period 
The Two-way Crossover Period is a randomized, open-label, 2-way (2-period, 2-sequence), 
crossover design to assess the relative bioavailability of 12 × 1.25 mg EC mini-tablets compared 
with the 15 mg EC tablet currently used in clinical studies. Participants will be randomized to 
one of the two treatments sequences. Randomized treatment assignment will be based on 
Baseline body mass index (BMI). Two strata for BMI (< 25, 25 to < 32 kg/m2) will be used: 
• Treatment A:  ALXN1840 12 × 1.25 mg EC mini-tablets 
• Treatment B:  ALXN1840 single 15 mg EC tablet (reference tablet, currently being 
tested in the Phase 3 Study WTX101-301) 


Protocol Amendment 2 
 
ALXN1840-HV-109 
18 Dec 2020 
Page 10 of 60 
Alexion Confidential 
Sequence Number 
Treatment Sequence 
Total 
Period 1 
Period 2 
1 
A 
B 
24 
2 
B 
A 
24 
Total 
48 
 
Blood samples for PK analysis of total and PUF Mo (as surrogate measures of ALXN1840 PK) 
and pharmacodynamic (PD)/biomarkers will be collected in each dosing period on Day 1 at 
pre-dose, and postdose at 1, 2, 3, 4, 5, 6, 8, 12 and 24 hours (Day 2) and then at 24 hour intervals 
on Days 3, 4, 5, 6, 7, 8, 9, 10, and 11.  
The 336-hour sample for Dosing Period 1 will be collected predose in Dosing Period 2. 
Participants may be discharged on Day 11 of each dosing period after completion of all 
procedures and review of all safety data. The end of Dosing Period 2 will occur on Day 15 ± 2 of 
Dosing Period 2, with the collection of the 336-hour PK sample for Dosing Period 2. 
Dose-Proportionality Extension Period 
The Dose-Proportionality Extension Period is a re-randomized, open-label, parallel group design 
to assess the dose-proportionality between 2.5 mg (2 × 1.25 mg), 5 mg (4 × 1.25 mg), 10 mg 
(8 × 1.25 mg), and 30 mg (24 × 1.25 mg) EC mini-tablet doses. The 15 mg (12 × 1.25 mg) dose 
will not be repeated during the Dose-Proportionality Extension Period. 
The Dose-Proportionality Extension Period will be conducted following completion of the 
Two-way Crossover Period of the study and after an at least 14-day washout period. Participants 
will be re-randomized as follows: 
• Treatment C (N=10-12): ALXN1840 2.5 mg (2 × 1.25 mg EC mini-tablets) 
• Treatment D (N=10-12): ALXN1840 5 mg (4 × 1.25 mg EC mini-tablets) 
• Treatment E (N=10-12): ALXN1840 10 mg (8 × 1.25 mg EC mini-tablets) 
• Treatment F (N=10-12): ALXN1840 30 mg (24 × 1.25 mg EC mini-tablets) 
The dose-proportionality evaluation will include data obtained from Treatment A of the 
Two-way Crossover Period (12 × 1.25 mg EC mini-tablets) to represent a dose of 15 mg. 
Re-randomized treatment assignment will be based on Baseline body mass index (BMI). Two 
strata for Baseline BMI (< 25, 25 to < 32 kg/m2)will be used. Block randomization will be used 
to equally randomly assign participants to each treatment. 
Participants may be discharged on Day 11 of the Dose-Proportionality Extension Period after 
completion of all procedures and review of all safety data. 
Participants may be asked or required to stay in the CRU during the Two-way Crossover Period, 
and/or at the end of the Dose-Proportionality Extension Period before the end of study (EOS) 
visit, for their own safety, and also to maintain the integrity of the conduct of the study. 
Data Monitoring Committee: There will not be a Data Monitoring Committee, but provision is 
included for an ad hoc Safety Review Committee, if needed. 


Protocol Amendment 2 
 
ALXN1840-HV-109 
18 Dec 2020 
Page 11 of 60 
Alexion Confidential 
1.2. 
Schema 
The study design is presented in Figure 1. 
Figure 1: 
Study Design Schematic 
 
Two-way Crossover Period 
Participants will be admitted to the CRU on Day -1 for check-in procedures. Eligible participants will be 
randomized on Day 1 immediately prior to dosing in Dosing Period 1. 
Participants will receive treatment (A [12 × 1.25 mg EC mini-tablets] or B [single 15 mg EC tablet]) based on 
randomization on Day 1 of each dosing period. 
There will be at least 14 days washout following the dose in Dosing Period 1 before the participant is readmitted to 
the CRU for Dosing Period 2 (if discharged after Dosing Period 1) and also at least 14 days washout following the 
dose in Dosing Period 2 before the participant is readmitted to the CRU for the Dose-Proportionality Extension 
Period (again, if discharged after Dosing Period 2). 
 
Dose-Proportionality Extension Period 
Participants will be block randomized by BMI and receive one of the Treatments C to F (C = 2.5 mg, D = 5 mg, E = 
10 mg, F = 30 mg) in a parallel-group design in the Dose-Proportionality Extension Period. The PK/PD/biomarker 
samples will be collected at the same time points as stated above for Dosing Period 2 of the Two-way Crossover 
Period. 
The EOS visit will take place 14 days (± 2 days) after the dose of ALXN1840 in the Dose-Proportionality Extension 
Period. 
 
Discharge from the CRU 
It is planned that participants will be discharged from the CRU on Day 11 of each Dosing Period and on Day 11 of 
the Dose-Proportionality Extension Period. However, participants may be asked or required to stay in the CRU 
during the Two-way Crossover Period, and/or at the end of the Dose-Proportionality Extension Period before the 
EOS visit, for their own safety, and also to maintain the integrity of the conduct of the study. 
 
Abbreviations: BMI = body mass index; CRU = clinical research unit; EC = enteric-coated; EOS = End of Study; 
PD = pharmacodynamics; PK = pharmacokinetics. 
 


Protocol Amendment 2 
 
ALXN1840-HV-109 
18 Dec 2020 
Page 12 of 60 
Alexion Confidential 
1.3. 
Schedule of Activities 
The Schedule of Activities (SoA) is presented in Table 1. Detailed timing of assessments on Day 1 of each Dosing Period and on 
Day 1 of the Dose-Proportionality Extension Period is presented in Table 2. 
Table 1: 
Schedule of Activities 
 Screeninga 
Each Dosing Period of the Two-way Crossover Periodb 
Dose-Proportionality Extension Period 
EOS 
or ETc 
Dosing Period: Days/ 
Hours -28 to -2 
-1d 1/ 
0 
2/ 
24 
3/ 
48 
4/ 
72 
5/ 
96 
6/ 
120 
7/ 
144 
8/ 
168 
9/ 
192 
10/ 
216 
11/ 
240 
-1 
1/ 
0 
2/ 
24 
3/ 
48 
4/ 
72 
5/ 
96 
6/ 
120 
7/ 
144 
8/ 
168 
9/ 
192 
10/ 
216 
11/ 
240 
15 ± 2/ 
336 
Informed consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Admit to unit 
 
x 
 
 
 
 
 
 
 
 
 
 
 
xb 
 
 
 
 
 
 
 
 
 
 
 
 
Discharge from unitd 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Inclusion/exclusion criteriae 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
  
xf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Re-randomization 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
xf 
 
 
 
 
 
 
 
 
 
 
 
Physical examinationg 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
x 
Height, weight, and BMI 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-Lead ECGh 
x 
 
xi 
 
 
 
 
 
 
 
 
 
 
 
xi 
 
 
 
  
 
 
 
 
 
 
 
Vital signs (heart rate, BP, 
RR & T)j 
x 
 
xi 
x 
 
 
x 
 
 
 
 
 
x 
 
x 
x 
 
 
x 
 
 
 
 
 
x 
x 
Hematology, chemistry, 
urinalysis, and coagulation 
xk 
 
x 
x 
 
 
x 
 
 
 
 
xk 
 
 
x 
x 
 
 
x 
 
 
 
 
xk 
 
x 
Serum ceruloplasmin and 
copper 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test (females 
only)l 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
x  
 
 
 
 
 
 
 
 
 
 
 
x 
FSH (postmenopausal 
females only) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol breath test and urine 
drug screen 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
HIV antibody/hepatitis B 
and C screen 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE monitoring 
 
Concomitant medications 
 
ALXN1840 administrationm 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
Plasma PK/PD biomarker 
samplesn 
 
  
xi 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
  
xi 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
a 
Within 28 days prior to Day 1 of the first dose of ALXN1840 in Dosing Period 1. Note that Screening only occurs once. 


Protocol Amendment 2 
 
ALXN1840-HV-109 
18 Dec 2020 
Page 13 of 60 
Alexion Confidential 
b 
After completion of Dosing Period 1, if discharged after Dosing Period 1, participants will be readmitted to the CRU for Dosing Period 2 following a minimum of 14 
days post dose. The assessments listed will be repeated in Dosing Period 2. After completion of Dosing Period 2, if discharged after Dosing Period 2, participants will be 
readmitted to the CRU for the Dose-Proportionality Extension Period, again following a minimum of 14 days post dose. 
c 
Participants will return to the CRU 14 days (± 2 days) following the final dose of ALXN1840 in the Dose-Proportionality Extension Period for an EOS evaluation. In the 
event of ET, the procedures listed at the EOS are performed prior to participant discharge. 
d 
Participants may be asked or required to stay in the CRU during the Two-way Crossover Period, and/or at the end of the Dose-Proportionality Extension Period before 
the EOS Visit, for their own safety, and also to maintain the integrity of the conduct of the study. 
e 
Full eligibility criteria will be assessed only for Dosing Period 1 (ie, on Day -1). On the first day of Dosing Period 2, the Investigator will confirm the participant is able 
to continue in the study. 
f 
Randomization is to occur after the participant has met all inclusion and no exclusion criteria on Day 1 in Dosing Period 1 with treatment assignment based on Baseline 
BMI. Re-randomization of patients will occur on Day 1 of the Dose-Proportionality Extension Period, with treatment assignment again based on Baseline BMI. 
g 
A full physical examination will be performed at Screening and on Day -1 of the 2 dosing periods. A symptom-driven physical examination of relevant body systems 
may be performed at other times, at the Investigator’s discretion.  
h 
12-lead ECGs in triplicate will be taken 0.5 hours pre-dose and at 6 hours post-dose on Day 1 of the first dosing period and Day 1 of the Dose-Proportionality Extension 
Period (see Table 2). 12-Lead ECGs in triplicate will be conducted before PK/PD/biomarker blood sampling if these 2 events occur at the same time. 12-lead ECGs 
should be measured after a minimum of 5 minutes in supine position. 
i 
See Table 2 for details.  
j 
At Screening, supine blood pressures will be performed to exclude volunteers with orthostatic hypotension. Supine blood pressure should be taken after a minimum of 
5 minutes in supine position. Supine blood pressure ≤ 90/60 mmHg or > 140/90 mmHg at Screening; systolic or diastolic components outside of range should result in 
exclusion. If vital sign results are abnormal, 2 additional readings will be taken. The mean of the 3 replicates will be recorded in the case report form and used to 
determine inclusion.  
k 
A sample for HbA1c is only required during the Screening Period, and not at every time point where samples for hematology, chemistry, urinalysis, and coagulation are 
required. Samples for urinalysis and coagulation will not be obtained on Day 10 of each Dosing Period.  
l 
A serum pregnancy test will be performed at Screening and urine pregnancy tests will be performed at subsequent visits. A serum pregnancy test is not required if the 
participant is confirmed to be postmenopausal.  
m 
ALXN1840 dosing will occur with the participant after an overnight fast of at least 10 hours.  
n 
Blood samples for the measurement of plasma total Mo and PUF Mo (PK) and total Cu, PUF Cu, LBC (PD), ceruloplasmin, and ceruloplasmin-bound Cu (biomarkers). 
In the Two-way Crossover Period, the 336-hour sample for Dosing Period 1 will be collected pre-dose in Dosing Period 2. Upon study completion, LBC, ceruloplasmin, 
and ceruloplasmin-bound Cu samples will be retained and potentially analyzed in the future. 
 
Abbreviations: AE = adverse event; BMI = body mass index; BP = blood pressure; CRU = clinical research unit; Cu = copper; ECG = electrocardiogram; EOS/ET = End of 
Study or Early Termination; FSH = follicle stimulating hormone; HbA1c = glycated hemoglobin; LBC = labile bound copper; Mo = molybdenum; PD = pharmacodynamics; 
PK = pharmacokinetics; PUF = plasma ultrafiltrate; RR = respiration rate; T = temperature. 
 


Protocol Amendment 2 
 
 
ALXN1840-HV-109 
18 Dec 2020 
Page 14 of 60 
Alexion Confidential 
Table 2: 
Detailed Timing of Assessments on Day 1 of Each Dosing Period and on 
Day 1 of the Dose-Proportionality Extension Period 
Time point (h) 
Pre-
dose -
0.5 
0a 
1 
2 
3 
4 
5 
6 
8 
12 
ALXN1840 (total Mo and 
PUF Mo) PK 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Plasma total and PUF Cu and 
LBC (PD); ceruloplasmin, and 
ceruloplasmin-bound Cu 
(biomarkers)b 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
ECG (triplicate)c 
X 
 
 
 
 
 
 
Xd 
 
 
Vital signs 
X 
 
 
 
 
 
 
X 
 
X 
a 
Hour 0 corresponds to the time of ALXN1840 administration. Unless stated otherwise, times listed are in 
relation to ALXN1840 dosing. 
b 
LBC, ceruloplasmin, and ceruloplasmin-bound Cu samples will be retained and potentially analyzed in the 
future. 
c 
12-lead ECGs in triplicate will be conducted before PK/PD/biomarker blood sampling if these 2 events 
occur at the same time. Note that ECGs will only be conducted on Day 1 of the first dosing period of the 
Two-way Crossover Period and on Day 1 of the Dose-Proportionality Extension Period. 
d 
12-lead ECGs in triplicate at 6 hours post-dose. 
Abbreviations: Cu = copper; ECG = electrocardiogram; LBC = labile bound copper; Mo = molybdenum; 
PD = pharmacodynamic(s); PK = pharmacokinetic(s); PUF = plasma ultrafiltrate. 
 


Protocol Amendment 2 
 
 
ALXN1840-HV-109 
18 Dec 2020 
Page 15 of 60 
Alexion Confidential 
2. 
INTRODUCTION 
ALXN1840 (bis-choline tetrathiomolybdate; formerly known as WTX101) is a novel, copper 
(Cu)-protein binding agent in development for the treatment of Wilson disease (WD). 
ALXN1840 directly targets and removes Cu from intracellular Cu stores, rapidly forms stable 
Cu-protein complexes, and promotes biliary excretion of Cu to reduce Cu overload. 
2.1. 
Study Rationale 
The purpose of this study is to assess relative bioavailability of the 1.25 mg enteric-coated (EC) 
mini-tablet formulation of ALXN1840 compared with the 15 mg EC tablet that is currently used 
in clinical studies and to assess dose proportionality between 2.5 mg (2 × 1.25 mg), 5 mg 
(4 × 1.25 mg), 10 mg (8 × 1.25 mg), 15 mg (12 × 1.25 mg), and 30 mg (24 × 1.25 mg) EC 
minitablet doses. 
The 1.25 mg EC mini-tablet is in development for treating patients with WD who may require a 
lower dose and/or who may have difficulty swallowing the 15 mg EC tablet (eg, pediatric 
patients with WD). Several of the 1.25 mg EC mini-tablets could be administered together with 
acidic soft foods to protect the enteric coating through to the site of absorption in the 
gastrointestinal tract. To support this alternative administration method, further investigation of 
the formulation stability of the 1.25 mg EC mini-tablets in acidic soft foods is also planned. 
Following completion of this study, the safety, efficacy, and pharmacokinetics 
(PK)/pharmacodynamics (PD) of the 1.25 mg EC minitablet are planned to be assessed in 
pediatric patients with WD. 
2.2. 
Background 
ALXN1840 has been selected for development in WD due to its improved stability properties 
over ammonium tetrathiomolybdate, which has previously been studied in patients with WD and 
other indications. Ammonium tetrathiomolybdate as well as bis-choline tetrathiomolybdate 
non-clinical and clinical data reported to date support the efficacy and safety of ALXN1840. 
ALXN1840 rapidly forms irreversible tetrathiomolybdate-Cu-albumin tripartite complexes 
(TPCs), which stabilize free Cu leading to a reduction in the non-ceruloplasmin-bound Cu 
(NCC) concentrations after correction for Cu bound to TPC (NCCcorrected). Alexion is developing 
a novel bioanalytical method to directly measure NCC/NCCcorrected, defined as labile bound Cu 
(LBC). PD assessments may be explored to further characterize the dynamic relationship 
between Cu and ALXN1840.  
In the Phase 2 proof -of -concept Study WTX101-201 in patients with WD, ALXN1840 
demonstrated a sustained control of free Cu as assessed by NCCcorrected. Importantly, ALXN1840 
treatment resulted in improvements in disability and neurologic symptoms as measured by the 
Unified Wilson’s Disease Rating Scale (UWDRS, Parts II and III) and stabilization of liver 
function (Weiss, 2017). Treatment with ALXN1840 resulted in an acceptable safety and 
tolerability profile when initiated at 15 mg daily with Investigator-driven, individual patient 
titration of dose based on safety, NCCcorrected, and symptoms.  
ALXN1840 is currently being evaluated in a Phase 3 multicenter, randomized study to assess the 
efficacy and safety of ALXN1840 compared with standard of care on plasma toxic Cu control as 


Protocol Amendment 2 
 
 
ALXN1840-HV-109 
18 Dec 2020 
Page 16 of 60 
Alexion Confidential 
measured by NCCcorrected. Toxic Cu in this study is to be measured via assays for plasma 
ultrafiltrate (PUF) Cu. 
Detailed descriptions of the chemistry, pharmacology, efficacy, and safety of ALXN1840 are 
provided in the Investigator’s Brochure (IB). 
2.3. 
Benefit/Risk Assessment 
Detailed information about the known and expected benefits, risks, and reasonably expected 
adverse events (AEs) of ALXN1840 may be found in the IB. Information about the known or 
potential risks and benefits are detailed in the sections following. 


Protocol Amendment 2 
ALXN1840-HV-109 
18 Dec 2020 
Page 17 of 60 
Alexion Confidential 
2.3.1. 
Risk Assessment 
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; Cu = copper; 
IB = Investigator’s Brochure; PK = pharmacokinetics; WD = Wilson Disease. 
2.3.2. 
Benefit Assessment 
This is a healthy participant study and there is no direct benefit to study participants.  
2.3.3. 
Overall Benefit: Risk Conclusion 
Taking into account the measures implemented to minimize risk to participants in this study, the 
potential risks identified in association with ALXN1840 are justified by the anticipated benefits 
that may be afforded to patients with WD. 
Table 3: 
Potential Risks and Mitigation Strategy 
Potential Risk of Clinical 
Significance 
Summary of Data/Rationale for 
Risk 
Mitigation Strategy 
ALXN1840 
Dose-dependent elevations in 
transaminases (ALT and AST) 
Generally mild to moderate in 
severity, asymptomatic and 
reversible with dose adjustments 
were reported, usually after 3-6 
weeks of treatment. 
Results obtained from studies of 
ALXN1840 and ammonium 
tetrathiomolybdate in patients with 
WD; see the IB. 
Regular monitoring of liver 
function tests.  
Dose modification or 
discontinuation (Section 6.6) 
Anemia 
Anemia has been observed in patients 
with WD, attributed to overtreatment 
and resultant Cu depletion, see the IB. 
Monitoring complete blood count. 
Dose modification or 
discontinuation (Section 6.6) 
Low white blood cell count 
(leukopenia, bone marrow 
toxicity)  
Leukopenia and bone marrow 
toxicity (myelosuppression) have 
been observed in patients with WD, 
attributed to overtreatment and 
resultant Cu depletion. 
Results obtained from studies of 
ALXN1840 and ammonium 
tetrathiomolybdate in patients with 
WD; see the IB. 
Monitoring of complete blood 
count. Dose modification or 
discontinuation (Section 6.6) 
Neurological dysfunction 
Neurological worsening may occur 
due to Cu mobilization. Peripheral 
neuropathy may be seen with over-
decoppering; however, symptoms 
such as myelosuppression is 
typically seen earlier. 
Neurologic dysfunction is not 
anticipated in the healthy volunteer 
population.  
Study Procedures 
Risks associated with the study 
design and procedures  
Participants will undergo repeated 
blood draws to measure the PK of the 
study intervention and metabolism. 
Blood draws may result in ecchymosis, 
redness and minor pain to the site. On 
rare occasion, infection or 
thrombophlebitis can occur. 
Blood draws are optimized for PK. 
A cannula may be placed to 
minimize needle sticks; however, a 
catheter may not be left in place for 
longer than 72 hours, and should be 
flushed a minimum of every 
8 hours 


Protocol Amendment 2 
ALXN1840-HV-109 
18 Dec 2020 
Page 18 of 60 
Alexion Confidential 
3. 
OBJECTIVES AND ENDPOINTS 
Table 4: 
Mapping Objectives to Endpoints/Estimands 
Objective 
Endpoints/Estimands 
Primary 
To assess the relative bioavailability of equal doses of 
ALXN1840 administered as 1.25 mg EC mini-tablets 
versus a single 15 mg EC tablet 
PK parameters for plasma total Mo and PUF Mo (Cmax, 
AUCt, and AUC∞) 
Secondary 
To assess dose-proportionality between 2.5 mg (2 × 
1.25 mg), 5 mg (4 × 1.25 mg), 10 mg (8 × 1.25 mg), 
15 mg (12 × 1.25 mg), and 30 mg (24 × 1.25 mg) EC 
mini-tablet doses 
Dose-normalized PK parameters for plasma total Mo and 
PUF Mo (Cmax_n, AUCt_n, and AUC∞_n) 
Safety 
To assess the overall safety and tolerability of 
ALXN1840, administered as 1.25 mg EC mini-tablets 
and as a single 15 mg EC tablet 
Incidence of TEAEs and TESAEs, physical examination, 
vital signs measurements, clinical laboratory, and 
12-lead ECG results 
Exploratory  
To explore relationships between total and PUF Mo 
clearance and body size — body weight (kg) and BMI 
(kg/m2) 
CL/F, body weight, and BMI 
To explore PD of ALXN1840 either as a single 15 mg 
EC tablet or EC mini-tablets of 1.25 mg at different total 
dose strengths 
Absolute and percent changes from pre-dose baseline of 
plasma Cu concentrations: total and PUF Cu 
Abbreviations: AUC∞ =  area under the plasma concentration versus time curve from time 0 to infinity; AUCt = area 
under the plasma concentration versus time curve from time 0 to the last quantifiable concentration; BMI = body 
mass index; CL/F = apparent oral clearance; Cmax = maximum observed concentration; Cu = copper; EC = enteric-
coated; ECG = electrocardiogram; Mo = molybdenum; n = dose-normalized; PD = pharmacodynamic(s); 
PK = pharmacokinetic(s); PUF = plasma ultrafiltrate; TEAE = treatment emergent adverse events; 
TESAE = treatment emergent serious adverse event. 
 


Protocol Amendment 2 
ALXN1840-HV-109 
18 Dec 2020 
Page 19 of 60 
Alexion Confidential 
4. 
STUDY DESIGN 
4.1. 
Overall Design 
This is a Phase 1 study to compare the relative bioavailability of 2 formulations of ALXN1840 in 
healthy participants. Equal doses of the 1.25 mg EC mini-tablet will be compared with a single 
15 mg EC tablet (12 × 1.25 mg and 1 × 15 mg, respectively). The study will be conducted in 
2 periods. The study will also assess dose-proportionality between 2.5 mg (2 × 1.25 mg), 5 mg 
(4 × 1.25 mg), 10 mg (8 × 1.25 mg), 15 mg (12 × 1.25 mg), and 30 mg (24 × 1.25 mg) EC 
minitablet doses in the Dose-Proportionality Extension Period. 
The study has a Screening Period (Days -28 to -2), the Two-way Crossover Period, consisting of 
2 dosing periods (Day 1 to Day 11 each), and a Dose-Proportionality Extension Period of 
14 days. After completing the Screening Period, enrolled participants will be admitted to the 
clinical research unit (CRU) on Day -1 for dosing on Day 1 in Dosing Period 1. If discharged 
after Dosing Period 1, participants will be readmitted to the CRU for Dosing Period 2 following 
a minimum washout of 14 days after the previous dose, and again for the Dose-Proportionality 
Extension Period after a minimum washout of 14 days. 
This study will be conducted with approximately 48 healthy participants enrolled to allow for a 
minimum of 40 participants to complete the Dose-Proportionality Extension Period of the study. 
Two-way Crossover Period 
The Two-way Crossover Period is a randomized, open-label, two-way (2-period, 2-sequence) 
crossover design to assess the relative bioavailability of 12 × 1.25 mg EC mini-tablets compared 
with the 15 mg EC tablet currently used in clinical studies. Participants will be randomized to 
one of the 2 treatments sequences. Randomized treatment assignment will be based on Baseline 
body mass index (BMI). Two strata for Baseline BMI (< 25, 25 to < 32 kg/m2) will be used: 
• Treatment A:  ALXN1840 12 × 1.25 mg EC mini-tablets 
• Treatment B:  ALXN1840 single 15 mg EC tablet (reference tablet, currently being 
tested in the Phase 3 Study WTX101-301) 
Blood samples for PK analysis of total and PUF molybdenum (Mo) (as surrogate measures of 
ALXN1840 PK) and PD/biomarkers will be collected in each dosing period on Day 1 at 
pre-dose, and postdose at 1, 2, 3, 4, 5, 6, 8, 12 and 24 hours (Day 2) and then at 24 hour intervals 
on Days 3, 4, 5, 6, 7, 8, 9, 10, and 11.  
The 336-hour sample for Dosing Period 1 will be collected predose in Dosing Period 2. 
Participants may be discharged on Day 11 of each dosing period after completion of all 
procedures and review of all safety data. The end of Dosing Period 2 will occur on Day 15 ± 2 of 
Dosing Period 2, with the collection of the 336-hour PK sample for Dosing Period 2. 
Participants may be asked or required to stay in the CRU during the Two-way Crossover Period, 
and/or at the end of the Dose-Proportionality Extension Period before the End of Study (EOS) 
Visit, for their own safety, and also to maintain the integrity of the conduct of the study. 


Protocol Amendment 2 
ALXN1840-HV-109 
18 Dec 2020 
Page 20 of 60 
Alexion Confidential 
Dose-Proportionality Extension Period 
The Dose-Proportionality Extension Period is a re-randomized, open-label, parallel group design 
to assess the dose-proportionality between 2.5 mg (2 × 1.25 mg), 5 mg (4 × 1.25 mg), 10 mg 
(8 × 1.25 mg), and 30 mg (24 × 1.25 mg) EC mini-tablet doses.  
The Dose-Proportionality Extension Period will be conducted following completion of the 
Two-way Crossover Period of the study and after an at least 14-day washout period. Participants 
will be re-randomized as follows: 
• Treatment C (N=10-12): ALXN1840 2.5 mg (2 × 1.25 mg EC mini-tablets) 
• Treatment D (N=10-12): ALXN1840 5 mg (4 × 1.25 mg EC mini-tablets) 
• Treatment E (N=10-12): ALXN1840 10 mg (8 × 1.25 mg EC mini-tablets) 
• Treatment F (N=10-12): ALXN1840 30 mg (24 × 1.25 mg EC mini-tablets) 
The 15 mg dose will not be repeated during the Dose-Proportionality Extension Period. For the 
purpose of evaluating dose-proportionality of the EC mini-tablet, data obtained from Treatment 
A of the Two-way Crossover Period (12 × 1.25 mg EC tablets) will be included to represent a 
dose of 15 mg. 
Re-randomized treatment assignment will be based on body mass index (BMI). Two strata for 
BMI (< 25, 25 to < 3Baseline BMI (< 25, 25 to < 32 kg/m2)  will be used. Block randomization 
will be used to equally randomly assign participants to each treatment. 
4.2. 
Scientific Rationale for Study Design 
This study is being conducted in healthy participants so that the assessments are not confounded 
by disease activity, comorbidities, or concomitant medications. The inclusion and exclusion 
criteria for this study are consistent with Phase 1 clinical pharmacology studies that assess the 
medication of interest and to minimize assignment bias. As the key objectives of the study are 
assessments of bioavailability and dose-exposure proportionality, a blinded design is not 
necessary. 
The Two-way Crossover Period was adopted to control the variability within and between 
participants. A minimum of 14 days between dose administration is considered sufficient to 
eliminate, on average, approximately more than 99.2% of the plasma total Mo. 
Following ALXN1840 administration, the active drug moiety tetrathiomolybdate rapidly binds 
Cu to form the TPC in the liver and blood and presents as such in the systemic circulation. If 
TPC is not rapidly formed, tetrathiomolybdate spontaneously undergoes serial hydrolysis to form 
molybdate, the most common form of nutrient Mo, and is excreted in the urine. Total Mo 
concentration has been measured as a surrogate of ALXN1840 PK; however, total Mo 
concentration cannot distinguish whether the Mo is complexed with Cu and albumin (as in TPC), 
free active ALXN1840 drug, intermediate hydrolysis products, or molybdate which may be from 
ALXN1840 hydrolysis. To better characterize the amount of non-TPC bound ALXN1840 and its 
degradation products, PUF Mo, which represents the free parent drug (ALXN1840), short-lived 
intermediate hydrolysis products, and molybdate, will be measured. Total Mo and PUF Mo 
concentrations also include physiologic molybdate concentrations from dietary micronutrient 
molybdate intake. While it is not feasible to separate and quantify ALXN1840 directly in the 


Protocol Amendment 2 
ALXN1840-HV-109 
18 Dec 2020 
Page 21 of 60 
Alexion Confidential 
plasma, total Mo PK and PUF Mo PK provide surrogate measures to characterize ALXN1840 
exposure. To better characterize the absorption, distribution, metabolism, and excretion (ADME) 
of ALXN1840, the PK of both total Mo and PUF Mo will be characterized and described. The 
primary PK measure is total Mo, whereas PUF Mo is an exploratory measure. 
4.2.1. 
Participant Input into Design 
Not applicable as this is a study in healthy participants.  
4.3. 
Justification for Dose 
The 15 mg dose to be used in the Two-way Crossover Period of the study has been chosen 
because it is the dose most commonly used in the ongoing Phase 3 Study WTX101-301 and is 
expected to be the prescribed starting dose in adult and adolescent patients with WD aged 
12 years and older. 
The 15 mg tablet is the only dose strength currently available as a reference dose for the relative 
bioavailability test. If a dose of 30 mg or greater is required, a patient with WD will be 
administered 2 or more 15 mg EC tablets, rather than ≥ 24 EC mini-tablets. 
The EC mini-tablet doses of 2.5, 5, 10, and 30 mg to be tested in the Dose-Proportionality 
Extension Period of the study, in addition to the 15 mg dose to be tested in the Two-way 
Crossover Period, will cover the entire anticipated dose range recommended in the planned study 
in the pediatric population. Selection of the starting and maximum doses for the planned study in 
the pediatric population aged 3 to < 12 years is based on a combination of standard body weight 
based allometric principles and age-based changes in liver volume. To support the dose 
selection, PK simulations were conducted based on the allometric scaling of population PK 
model using PK data (ie, total Mo) from Study WTX101-201 in patients with WD and 
Study WTX101-102 in healthy participants who were administered the EC tablet. The general 
approach of dose selection for pediatric investigation used here is consistent with the United 
States Food and Drug Administration guidance (https://www.fda.gov/media/90358/download) as 
well as European Medicines Agency (EMA) guidance ICH E11(R1) (EMA, 2017). 
For patients aged 3 to < 12 years, a lower starting dose of 2.5 mg/day will be administered for 
4 weeks based on scaling of the starting dose of 15 mg/day in patients with WD aged 12 years 
and above in the ongoing Phase 3 Study WTX101-301. After 4 weeks, up titration to 5 mg once 
daily may be performed at the discretion of the Investigator, if the disease is not adequately 
controlled, taking into account the patient’s clinical status and free blood Cu concentration based 
on pre-defined criteria, as measured by LBC, and provided none of the dose modification criteria 
apply. Further dose increases up to a maximum dose of 30 mg/day in 5 mg increments at least 
4 weeks apart are possible at the discretion of the Investigator following the same 
aforementioned criteria.  
For patients aged 3 to < 6 years, the population PK modeling results showed that a 5 mg dose has 
comparable exposure to 15 mg administered to adult patients, and that a 15 mg dose has a higher 
exposure than 30 mg, but a lower exposure than 60 mg administered to adult patients. Hence, the 
predicted dose range for patients aged 3 to < 6 years is 5 mg to 15 mg, which is anticipated to 
provide comparable safety and efficacy outcomes to those in adolescent and adult patients over 
12 years of age with a dose range of 15 mg to 60 mg currently allowed in the ongoing Phase 3 


Protocol Amendment 2 
ALXN1840-HV-109 
18 Dec 2020 
Page 22 of 60 
Alexion Confidential 
Study WTX101-301. Therefore, the EC mini-tablet doses of 2.5, 5, 10, 15, and 30 mg will be 
tested in this study, which covers the entire anticipated dose range recommended in the planned 
study in the pediatric population. 
An inductively coupled plasma-mass spectroscopy (ICP-MS) method, with a lower limit of 
quantification (LLOQ) of 1.00 ng/mL and 0.25 ng/mL for the assays of total Mo and PUF Mo, 
respectively, has been previously implemented for analyzing plasma samples from Study 
WTX101-HV-106. In that study, for the 15 mg and 60 mg doses, %AUCextrap ranged from 1.3% - 
12.2% (all were less than 20%). In the current study, a maximum observed concentration (Cmax) 
for total Mo of approximately 40 ng/mL is anticipated after the lowest ALXN1840 dose of 
2.5 mg and with an assay LLOQ of 1.00 ng/mL, it would be possible to detect measurable total 
Mo concentrations at a mean of 1.25 ng/mL for approximately 5 half-lives with reasonably low 
expectation for excess AUC extrapolation of over 20% for AUC∞ estimation. A Cmax for PUF 
Mo of approximately 2 ng/mL is anticipated after the lowest ALXN1840 dose of 2.5 mg and 
with an assay LLOQ of 0.25 ng/mL, it would be possible to detect measurable PUF Mo 
concentrations at a mean of 0.25 ng/mL for approximately 3 half-lives with possibility of AUC 
extrapolation of over 20% for AUC∞ estimation. 
4.4. 
End of Study Definition 
The planned study duration is approximately 10 weeks, which includes an up to 28-day 
Screening period, 2 periods of approximately 11 days in the Two-way Crossover Period (with at 
least 14 days from the previous dose of ALXN1840 before the next dose is administered), plus a 
14 -day period in the Dose--Proportionality Extension Period (again, 11 days in the CRU with at 
least 14 days from the previous dose before the next dose is administered). 
The EOS for each participant is defined as completion of the EOS Visit on Day 15 ± 2 days of 
the Dose-Proportionality Extension Period. 
The EOS is defined as the date of the last participant’s last scheduled visit (ie, the last visit as 
scheduled/foreseen by the protocol, including the scheduled Follow-up Visit). 


Protocol Amendment 2 
ALXN1840-HV-109 
18 Dec 2020 
Page 23 of 60 
Alexion Confidential 
5. 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted.  
5.1. 
Inclusion Criteria 
Male and female participants are eligible to be included in the study only if all of the following 
criteria apply: 
Age 
1. Participants must be ≥ 18 to 55 years of age inclusive, at the time of signing the informed 
consent. 
Type of Participant and Disease Characteristics 
2. Participants who are healthy as determined by medical evaluation with no clinically 
significant or relevant abnormalities as determined by medical history, physical 
examination, vital signs, 12-lead electrocardiogram (ECG), and clinical laboratory 
evaluation (hematology, biochemistry, coagulation, and urinalysis) that are reasonably 
likely to interfere with the participant's participation in or ability to complete the study, or 
to potentially confound interpretation of study results, as assessed by the Investigator. 
3. Adequate venous access in the left or right arm to allow collection of study-required 
blood samples. 
Weight 
4. Body weight ≥ 50 to ≤ 100 kg and BMI within the range 18 to < 32 kg/m2 for all 
participants. 
Sex 
5. Contraceptive use by men or women should be consistent with local regulations 
regarding the methods of contraception for those participating in clinical studies. 
a. Male participants: 
• Male participants, if heterosexually active and with a female spouse or partner of 
childbearing potential or a pregnant or breastfeeding spouse or partner, must agree to 
use barrier contraception (male condom) for the duration of the study and for at least 
3 months after the end of systemic exposure of the study intervention (ie, 3 months 
after the EOS Visit). Male participants must not donate sperm for at least 3 months 
after the end of systemic exposure of the study intervention (ie, 3 months after the 
EOS Visit). 
• Female spouses or partners of male participants who are of childbearing potential 
must use highly effective contraception as defined in Section 10.4 starting at least 
6 weeks before (the male participant’s) first study intervention administration and 
continuing until at least 3 months after the end of their male partner’s systemic 
exposure to the study intervention (ie, 3 months after the EOS Visit). 


Protocol Amendment 2 
ALXN1840-HV-109 
18 Dec 2020 
Page 24 of 60 
Alexion Confidential 
• Barrier contraception is required even with documented medical assessment of 
surgical success of a vasectomy. For male participants who have had a vasectomy 
(with documented evidence of azoospermia if possible) and agree to use a barrier 
method (male condom) for the stated time period, no additional contraceptive method 
is required by their female partner. 
b. Female participants: 
• Female participants or female partners of male participants of childbearing potential 
(including breastfeeding females), if heterosexually active, must be willing to follow 
protocol specified contraception guidance starting at least 6 weeks before first study 
intervention administration and continuing for at least 3 months after the end of 
systemic exposure of the study intervention (ie, 3 months after the EOS Visit). 
Female participants must not donate ova for at least 3 months after the EOS (ie. 3 
months after the EOS Visit). 
• Female participants who are documented as being of non-childbearing potential as 
defined in Section 10.4 are exempt from contraception requirements.  
• Highly effective contraceptive methods for female participants and female partners of 
male participants are detailed in Section 10.4. 
Informed Consent 
6. Capable of giving signed informed consent as described in Section 10.1.3 which includes 
compliance with the requirements and restrictions listed in the informed consent form 
(ICF) and in this protocol. 
5.2. 
Exclusion Criteria  
Participants are excluded from the study if any of the following criteria apply: 
1. History or presence of/significant history of or current cardiovascular, respiratory, 
hepatic, renal, gastrointestinal, endocrinological, hematological, or neurological 
disorders, or psychiatric disorder. Any surgical or medical history which may 
significantly alter the absorption, metabolism, or elimination of drugs or constitute a risk 
when taking the study intervention; or interfering with the interpretation of data (eg, 
gastric bypass, cyclical vomiting, etc). 
2. Supine blood pressure ≤ 90/60 mmHg or > 140/90 mmHg at Screening; systolic or 
diastolic components outside of range should result in exclusion. Supine blood pressure 
should be taken after a minimum of 5 minutes in supine position. If vital signs are 
abnormal, 2 additional readings will be taken. The mean of the 3 replicates will be 
recorded in the case report form (CRF) and used to determine inclusion.   
3. Lymphoma, leukemia, or any malignancy within 5 years except for basal cell or 
squamous epithelial carcinomas of the skin that have been resected with no evidence of 
metastatic disease for 3 years. 
4. Alanine aminotransferase (ALT), aspartate aminotransferase (AST) or total bilirubin 
> upper limit of normal (ULN) of laboratory reference range at Screening. At the 


Protocol Amendment 2 
ALXN1840-HV-109 
18 Dec 2020 
Page 25 of 60 
Alexion Confidential 
discretion of the Investigator, a single repeat analysis may be performed to assess 
eligibility during the Screening period. 
5. Serum Cu or serum ceruloplasmin below lower limit of normal on laboratory reference 
range at Screening. 
6. History of anemia or hemoglobin < 130 g/L for men and hemoglobin < 115 g/L for 
women at Screening. At the discretion of the Investigator, a single repeat analysis may be 
performed to assess eligibility, with the agreement of the Medical Monitor. 
7. History of benign ethnic neutropenia or absolute neutrophil count < 1500/µL; lymphocyte 
<1000/µL.  
8. Blood donation or blood loss in excess of 500 mL in the 60 days prior to Screening.  
9. QT interval corrected using Fridericia’s formula (QTcF) > 450 ms for male participants; 
QTcF > 470 ms for female participants. 
10. Current or chronic history of liver disease or known hepatic or biliary abnormalities 
(except for asymptomatic gallstones). Participants with elevated total bilirubin or history 
of Gilbert’s will be excluded from the study. 
11. Any other significant disease or disorder which, in the opinion of the Investigator, may 
put the participant at risk or confound the interpretation of the results.  
12. History of hypersensitivity to ALXN1840 or its excipients or any significant allergic 
reaction (eg, anaphylaxis or angioedema) to any product (eg, food, pharmaceutical).  
Prior/Concomitant Therapy 
13. Use or intended use of prescription medications (excluding oral contraceptives) within 
21 days or 5 half-lives of the drug (whichever is longer) prior to Day -1, and/or intended 
use at any point over the duration of the study except with prior approval of Alexion.  
14. Use of nonprescription/ over-the-counter medications, including herbal remedies and 
supplements, within 7 days or 5 half-lives of the drug (whichever is longer) prior to 
Day -1 and/or intended use at any point over the duration of the study.  
Prior/Concurrent Clinical Study Experience 
15. Current enrollment or past participation, within the last 90 days, before signing of 
consent in this or any other clinical study involving an investigational study intervention 
or any other type of medical research. Participants, involved in intervention studies using 
investigation or non-investigational drug with prolonged half-lives, are not eligible unless 
the time since last treatment has exceeded 90 days or 5 half-lives of the study 
intervention, whichever is longer.  
Diagnostic Assessments 
16. Presence of hepatitis B surface antigen or positive hepatitis C antibody or RNA test result 
at Screening. NOTE: participants with positive hepatitis C antibody due to prior resolved 
disease can be enrolled if a confirmatory negative hepatitis C RNA test result is obtained. 
NOTE: The RNA test is optional and participants with negative hepatitis C antibody test 
are not required to also undergo hepatitis C RNA testing. 


Protocol Amendment 2 
ALXN1840-HV-109 
18 Dec 2020 
Page 26 of 60 
Alexion Confidential 
17. Positive human immunodeficiency virus (HIV) antibody test. 
Other Exclusions 
18. Female participants who are pregnant, as evidenced by a positive serum pregnancy test 
result at Screening, or breastfeeding. 
19. Prior exposure to ALXN1840. 
20. Major surgery or hospitalization within 90 days prior to dosing on Day 1.  
21. Use of tobacco in any form (eg, smoking, chewing or vaping), other nicotine-containing 
products in any form (eg, gum, patch, electronic cigarettes, or vapes), or any recreational 
inhalational product within 6 months prior to the planned first day of dosing.   
22. Use of known drugs of abuse within 6 months prior to the planned first day of dosing. 
23. Regular alcohol consumption within 6 months prior to the study defined as: an average 
weekly intake of > 14 units/week for males or > 7 units/week for females. One unit is 
equivalent to 8 g of alcohol: a half pint (~240 mL) of beer, one ~4 oz glass (125 mL) of 
wine or 1 (25 mL) measure of spirits. 
24. Positive urine drug toxicology screen at Screening or check-in (Day -1).   
25. Alcohol consumption within 24 hours prior to study intervention administration or 
positive alcohol breath test at Screening or check-in (Day -1). 
26. Sensitivity to any of the study interventions, or components thereof, or drug or other 
allergy that, in the opinion of the Investigator or Medical Monitor, contraindicates 
participation in the study. 
5.3. 
Lifestyle Considerations 
Participants must be able and willing to adhere to the lifestyle restrictions detailed in the 
exclusion criteria (Section 5.2). 
5.4. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomly assigned to study intervention. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details (eg, failed eligibility criteria), and any AEs, including any serious adverse 
events (SAEs) and any related concomitant medication, occurring during the Screening Period. 
Individuals who do not meet the criteria for participation in this study (screen failure) due to a 
reason that is expected to resolve or has resolved, may be rescreened based on discussion and 
agreement between the Investigator and the Alexion Medical Monitor. 


Protocol Amendment 2 
ALXN1840-HV-109 
18 Dec 2020 
Page 27 of 60 
Alexion Confidential 
6. 
STUDY INTERVENTION 
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to the 
study protocol. 
6.1. 
Study Intervention Administered 
Details of ALXN1840 administered in the study are provided in Table 5. ALXN1840 will be 
administered with up to 240 mL (8 fluid ounces) of water after an overnight fast of at least 
10 hours, as per FDA guidance (https://www.fda.gov/media/121313/download). Participants can 
take approximately 5 minutes to drink the water. Participants will remain fasted for a minimum 
of 4 hours following each dose administration. Additional water is permitted ad libitum except 
for the period 1 hour before to 1 hour after administration of ALXN1840. 
Table 5:  
Details of Study Intervention Administered 
ARM Name 
Treatments A, C, D, E, F 
Treatment B 
Study Intervention 
Name 
ALXN1840 
ALXN1840 
Type  
Drug 
Drug 
Dose Formulation 
White, round, EC mini-tablet, diameter 
3 mm 
White, round, EC tablet, diameter 5 mm 
Unit Dose Strength(s) 
1.25 mg EC mini-tablet supplied as 4 × 
1.25 mg EC mini-tablets within a size 0 
capsule. Capsules will be opened to 
access the individual mini-tablets 
(details will be provided in the Study 
Manual). 
15 mg 
Dosage Level(s) 
Treatment A: 12 × 1.25 mg EC mini-
tablets (15 mg) 
Treatment C: 2 × 1.25 mg EC mini-
tablets (2.5 mg) 
Treatment D: 4 × 1.25 mg EC mini-
tablets (5 mg) 
Treatment E: 8 × 1.25 mg EC mini-
tablets (10 mg) 
Treatment F: 24 × 1.25 mg EC mini-
tablets (30 mg) 
15 mg 
Route of 
Administration 
Oral 
Oral 
Use 
Test 
Reference 
Packaging and 
Labeling 
ALXN1840 will be provided in bottles. 
Each bottle will be labeled as required 
per country requirements. 
ALXN1840 will be provided in treatment 
kits. Each kit will be labeled as required 
per country requirements. 
Abbreviation: EC = enteric coated. 
6.2. 
Preparation/Handling/Storage/Accountability 
1. The Investigator, or designee, must confirm appropriate temperature conditions have 
been maintained during transit for all study intervention received and any discrepancies 
are reported and resolved before use of the study intervention. 


Protocol Amendment 2 
ALXN1840-HV-109 
18 Dec 2020 
Page 28 of 60 
Alexion Confidential 
2. Only participants randomized in the study may receive the study intervention and only 
authorized site staff may supply or administer the study intervention. All study 
intervention must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions with access 
limited to the Investigator and authorized site staff. 
3. The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records). 
a. This responsibility includes the reporting of any product complaints to 
 within 1 business day. A product complaint is 
defined as any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, durability, reliability, usability, safety, effectiveness, or 
performance of a product or clinical study material and/or its packaging components 
after it is has been released for distribution to an end customer that affects the 
performance of such product. 
4. Further guidance and information for the final disposition of unused study interventions 
are provided in the Pharmacy Manual. 
6.3. 
Measures to Minimize Bias: Randomization and Blinding 
• This is an open-label, 2-period study where, in order to minimize selection bias in 
treatment assignment, each participant will be randomized to one of 2 treatment 
sequences (Treatment A and B) in the Two-way Crossover Period. The randomization 
will be stratified by Baseline BMI. Two strata for Baseline BMI (< 25, 25 to 
< 32 kg/m2) will be used. 
• Eligible participants who meet all inclusion and no exclusion criteria included in the 
study will be assigned unique study participant numbers during randomization to one 
of 2 treatment sequences (Treatments A and B). Study participant numbers will not be 
reallocated once assigned.  
• Participants will be re-randomized in the Dose-Proportionality Extension Period to 
one of 4 treatment sequences (Treatments C, D, E, and F). The re-randomized 
treatment assignment will be based on Baseline BMI as for the Two-way Crossover 
Period, with 2 strata for Baseline BMI (< 25, 25 to < 32) to be used. Block 
randomization will be used to equally randomly assign participants to each treatment. 
6.4. 
Study Intervention Compliance 
When participants are dosed at the site, they will receive study intervention directly from the 
Investigator or designee, under medical supervision. The date and time of each dose 
administered in the clinic will be recorded in the source documents and recorded in the CRF (if 
the CRF is not the source document). The dose of study intervention and study participant 
identification will be confirmed at the time of dosing by a member of the study site staff other 
than the person administering the study intervention. Study site personnel will examine each 
participant’s mouth to ensure that the study intervention was ingested. 
PPD


Protocol Amendment 2 
ALXN1840-HV-109 
18 Dec 2020 
Page 29 of 60 
Alexion Confidential 
For additional information on study intervention compliance and management, refer to the 
Pharmacy Manual.  
6.5. 
Concomitant Therapy 
Any medication (including over-the-counter or prescription medicines, vitamins, and/or herbal 
supplements), vaccine, or other specific categories of interest that the participant is receiving 
from 14 days prior to the first dose of study intervention until the EOS visit must be recorded 
along with: 
• Reason for use 
• Dates of administration including start and end dates 
• Dosage information including dose and frequency 
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
6.5.1. 
Allowed Medicine and Therapy 
• Paracetamol/acetaminophen at doses of a maximum 1000 mg per day is permitted for 
use as an exception with the approval of the Investigator.  
• As per the ALXN1840 IB, in this study, Investigators should use caution in the 
co-administration of drugs known to be substrates of cytochromes 2C9 and 2B6 
(CYP2C9 and CYP2B6). Common substrates of CYP2C9 include ibuprofen, which is 
permitted in this study. The Investigator must use ibuprofen with caution during the 
conduct of the study, and the ibuprofen dose must not exceed 1200 mg in any 24-hour 
period. Ibuprofen may only be used with approval of the Investigator.  
• Concomitant procedures are not allowed unless medically indicated and/or permitted 
by Alexion or the Investigator or designee.  
• Concomitant medications may be used during the study if deemed medically 
indicated by the Investigator. The Investigator or designee will notify Alexion of any 
AEs requiring administration of prescription medication(s) while on study. 
6.5.2. 
Disallowed Medicine and Therapy 
• Participants must abstain from taking prescription or nonprescription drugs (including 
vitamins and dietary or herbal supplements) within 7 days (or 14 days if the drug is a 
potential enzyme inducer) or 5 half-lives (whichever is longer) before the start of 
study intervention until completion of the Follow-up Visit, unless, in the opinion of 
the Investigator and Alexion, the medication will not interfere with the study. 
• Participants must abstain from taking prescription medications within 21 days or 
5 half-lives (whichever is longer) of Day -1 or nonprescription drugs (including 
vitamins and dietary or herbal supplements) within 7 days or 5 half-lives (whichever 
is longer) before Day -1 and until completion of the Follow-up Visit. 


Protocol Amendment 2 
ALXN1840-HV-109 
18 Dec 2020 
Page 30 of 60 
Alexion Confidential 
6.6. 
Dose Modification 
No dose modification is anticipated or planned. The highest single dose in this study will be 
30 mg ALXN1840. In the completed Studies WTX101-101, WTX101-102, and 
WTX101-HV-106, single doses of up to 60 mg ALXN1840 were well tolerated in healthy male 
and female participants, with no maximum tolerated dose having been identified. 
6.7. 
Intervention After the End of the Study 
This is a healthy participant study and no follow-up intervention is planned. 


Protocol Amendment 2 
ALXN1840-HV-109 
18 Dec 2020 
Page 31 of 60 
Alexion Confidential 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1. 
Discontinuation of Study Intervention 
In rare instances, it may be necessary for a participant to permanently discontinue (definitive 
discontinuation) the study intervention. If the study intervention is definitively discontinued, the 
participant should remain in the study to be evaluated for safety follow-up. See the SoA 
(Table 1) for data to be collected at the time of discontinuation of study intervention and follow-
up and for any further evaluations that need to be completed. 
Discontinuation of study intervention for abnormal liver function should be considered by the 
Investigator if the Investigator believes that it is in best interest of the participant. 
If a clinically significant finding is identified (including, but not limited to changes from baseline 
in QTcF) after enrollment, the Investigator or qualified designee will determine if the participant 
can continue in the study and if any change in participant management is needed. This review of 
the ECG printed at the time of collection must be documented. Any new clinically relevant 
finding should be reported as an AE. 
Participants must be considered for discontinuation from intervention if any of the following 
occur during the study: 
• Serious hypersensitivity reaction; 
• Severe uncontrolled infection; 
• Use of disallowed medication; 
• Pregnancy or planned pregnancy (see Section 8.2.6); or 
• Alexion or the Investigator deems it is necessary for the participant. 
See the SoA (Table 1) for samples and data to be collected at the time of study intervention 
discontinuation and follow-up and for any further evaluations that need to be completed. 
7.2. 
Participant Discontinuation/Withdrawal From the Study 
• All efforts should be made to ensure participants are willing to comply with study 
participation prior to conducting the screening procedures. The study staff should 
notify Alexion and their site monitor of all study withdrawals as soon as possible. The 
reason for participant discontinuation must be recorded in the source documents and 
CRF. 
• A participant may withdraw from the study at any time at his/her own request, or may 
be withdrawn at any time at the discretion of the Investigator for safety, behavioral, 
compliance, or administrative reasons. This is expected to be uncommon. 
• At the time of discontinuation from the study, participants will be seen and assessed 
by the Investigator or study physician and whenever possible, will undergo the 
procedures associated with the ET Visit. as shown in the SoA. See the SoA (Table 1) 
for data to be collected at the time of study discontinuation and follow-up and for any 
further evaluations that need to be completed. 


Protocol Amendment 2 
ALXN1840-HV-109 
18 Dec 2020 
Page 32 of 60 
Alexion Confidential 
• The participant will be permanently discontinued both from the study intervention 
and from the study at that time. 
• If the participant withdraws consent for disclosure of future information, Alexion may 
retain and continue to use any data collected before such a withdrawal of consent. 
• If a participant withdraws from the study, he/she may request destruction of any 
samples taken and not tested, and the Investigator must document this in the site 
study records. 
7.3. 
Lost to Follow-up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
• The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to and/or 
should continue in the study. 
• Before a participant is deemed lost to follow-up, the Investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the participant’s medical record. 
• If the participant is unreachable, then participant is lost to follow-up (not withdrawn, 
since withdrawn is a distinct event of removing informed consent) 
Discontinuation of the study as a whole is handled as part of Section 10.1.8. 


Protocol Amendment 2 
ALXN1840-HV-109 
18 Dec 2020 
Page 33 of 60 
Alexion Confidential 
8. 
STUDY ASSESSMENTS AND PROCEDURES 
• Study procedures and their timing are summarized in the SoA (Table 1). Protocol 
waivers or exemptions are not allowed. 
• Immediate safety concerns should be discussed with Alexion immediately upon 
occurrence or awareness to determine if the participant should continue or 
discontinue study intervention. 
• Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. 
• All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The Investigator will maintain a screening log 
to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable. 
8.1. 
Efficacy Assessments 
No efficacy assessments will be obtained during this study. 
8.2. 
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA (Table 1). 
When multiple procedures are scheduled to occur at the same time, the following order of events 
should be strictly adhered to whenever possible: ECG, vital signs, blood sampling, study 
intervention administration, and meal.  
PK collection should occur as close as possible to the scheduled time. Blood samples for 
assessing plasma PK/PD should be collected within ± 10% in minutes, or 30 minutes relative to 
the scheduled time, whichever is less. 
All routine safety laboratory samples should be drawn following a minimum of 10 hours fasting. 
8.2.1. 
Physical Examinations 
• A complete physical examination will include, at a minimum, assessments of the 
cardiovascular, respiratory, gastrointestinal, and neurological systems. Height and 
weight will be measured and recorded at Screening only. 
• A symptom-driven physical examination may be performed at other times, at the 
Principal Investigator’s discretion. 
• Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
8.2.2. 
Vital Signs 
• Body temperature, heart rate, respiratory rate, and systolic and diastolic blood 
pressure (mmHg) will be assessed using consistent methods and equipment to allow 
comparability and reproducibility throughout the study. 


Protocol Amendment 2 
ALXN1840-HV-109 
18 Dec 2020 
Page 34 of 60 
Alexion Confidential 
• Blood pressure and pulse measurements will be assessed with a completely 
automated device. Manual techniques will be used only if an automated device is not 
available. 
• Blood pressure and pulse measurements should be preceded by at least 5 minutes of 
rest in supine position for the participant in a quiet setting without distractions (eg, 
television, cell phones). Ideally, the same arm for each participant should be used for 
measurements. 
• Vital signs will be measured and include temperature, systolic and diastolic blood 
pressure, and heart rate. Vital signs will consist of a single pulse and blood pressure 
measurement. If vital signs are abnormal as defined by inclusion/ exclusion criteria, 
2 additional vital signs measurements will be made. The average of the 3 vital signs 
measurements will be recorded in the CRF and used to determine participant 
eligibility. The average of the blood pressure readings will be recorded in the CRF. 
8.2.3. 
Electrocardiograms 
• Triplicate 12-lead ECGs will be conducted as outlined in the SoA (see Table 1 and 
Table 2) to obtain heart rate, PR, QRS, QT, and QTc intervals, and should be taken 
after the participant has been in supine position for a minimum of 5 minutes. 
• Refer to Section 7.1 for QTc withdrawal criteria and any additional QTc readings that 
may be necessary. As with vital signs, if ECG interval measurements are abnormal, 
an additional 2 replicate measures will be performed with the mean of the 3 measured 
interval values used to confirm eligibility and recorded in the CRF.   
8.2.4. 
Clinical Safety Laboratory Assessments 
• See Section 10.2 for the list of clinical laboratory tests to be performed and to the 
SoA (Section 1.3) for the timing and frequency.  
• The Investigator must review the laboratory report, document this review, and record 
any clinically relevant changes occurring during the study in the AE section of the 
CRF. The laboratory reports must be filed with the source documents. Clinically 
significant laboratory values are those deemed by the Investigator to be clinically 
significant resulting in further evaluation or treatment or those associated with an AE 
or clinical signs or symptoms. All repeated laboratory test values must be recorded in 
the CRF. 
• All laboratory test results with values considered abnormal and clinically significant 
during participation in the study after the last dose of study intervention should be 
repeated until the values return to normal or baseline or are no longer considered 
clinically significant by the Investigator or Medical Monitor. 
− If such values do not return to normal/baseline within a period of time judged 
reasonable by the Investigator, the etiology should be identified, and Alexion 
notified. 
− All protocol-required laboratory assessments, as defined in Section 10.2, must be 
conducted in accordance with the Laboratory Manual and the SoA.  


Protocol Amendment 2 
ALXN1840-HV-109 
18 Dec 2020 
Page 35 of 60 
Alexion Confidential 
8.2.5. 
Suicidal Ideation and Behavior Risk Monitoring 
Not applicable to this study. 
8.2.6. 
Pregnancy 
• Pregnancy data from female participants and female spouses/partners of male participants 
will be collected from the first dose of study intervention through 3 months postdose. 
Any female participant who becomes pregnant while participating in the study will be 
discontinued from the study intervention. If a pregnancy is reported, the Investigator must 
immediately inform Alexion within 24 hours of awareness of the pregnancy and follow 
the procedures outlined in Section 10.4.  
• For all Alexion products, both in development or post approval, exposure during 
pregnancy must be recorded and the pregnancy followed until the outcome of the 
pregnancy is known (ie, spontaneous miscarriage, elective termination, normal birth, or 
congenital abnormality), even if the participant discontinues the study intervention or 
withdraws from the study. The corresponding infant must be followed for 3 months 
postpartum. 
• Pregnancy is not considered as an AE (Section 10.3.1) unless there is a suspicion that the 
study intervention may have interfered with the effectiveness of a contraceptive 
medication. However, complications of pregnancy and abnormal outcomes of pregnancy 
are AEs and may meet the criteria for an SAE (eg, ectopic pregnancy, spontaneous 
abortion, intrauterine fetal demise, neonatal death, or congenital anomaly) (Section 10.3). 
Elective abortions without complications should not be reported as AEs.  
8.3. 
Adverse Events and Serious Adverse Events 
The definitions of AEs and SAEs can be found in Section 10.3. 
All AEs will be reported to the Investigator or qualified designee by the participant (or, when 
appropriate, by a caregiver, surrogate, or the participant’s legally authorized representative). 
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the study intervention or study procedures, or that 
caused the participant to discontinue the study intervention (see Section 7.1). 
Procedures for recording, evaluating, follow-up, and reporting AEs and SAEs are outlined in 
Section 10.3.  
8.3.1. 
Time Period and Frequency for Collecting AE and SAE Information 
All AEs and SAEs will be collected from the signing of the ICF until the EOS Visit. 
All SAEs will be recorded and reported to Alexion or the designee immediately and under no 
circumstance should this exceed 24 hours, as indicated in Section 10.3. The Investigator will 
submit any updated SAE data to Alexion within 24 hours of it being available. 
Investigators are not obligated to actively seek AE or SAE data after conclusion of the study 
participation. However, if the Investigator learns of any SAE, including a death, at any time after 


Protocol Amendment 2 
ALXN1840-HV-109 
18 Dec 2020 
Page 36 of 60 
Alexion Confidential 
a participant has been discharged from the study, and he/she considers the event to be reasonably 
related to the study intervention or study participation, the Investigator must promptly notify 
Alexion. 
8.3.2. 
Method of Detecting AEs and SAEs 
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Section 10.3.  
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about AE 
occurrences.  
8.3.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the Investigator is required to proactively follow-up on each 
participant at subsequent visits/contacts. All SAEs will be followed up until resolution, 
stabilization, the event is otherwise explained, or the participant is lost to follow-up (as defined 
in Section 7.3). Further information on follow-up procedures is provided in Section 10.3. 
8.3.4. 
Regulatory Reporting Requirements for SAEs  
• Prompt notification of an SAE by the Investigator to Alexion is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the 
safety of a study intervention under clinical investigation are met. 
• Alexion has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. Alexion will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review 
Boards/Independent Ethics Committees (IRBs/IECs), and Investigators. 
• Suspected unexpected serious adverse reactions (SUSARs) must be reported 
according to local regulatory requirements and Alexion policy and forwarded to 
Investigators as necessary. 
• An Investigator who receives an Investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from Alexion will 
review and then file it along with the IB and will notify the IRB/IEC, if appropriate 
according to local requirements. 
8.3.5. 
Adverse Events of Special Interest  
There are no AEs of special interest for this study. 
8.4. 
Treatment of Overdose 
For this study, any dose of ALXN1840 greater than that specified in the protocol will be 
considered an overdose. 
Alexion does not recommend specific treatment for an overdose. 


Protocol Amendment 2 
ALXN1840-HV-109 
18 Dec 2020 
Page 37 of 60 
Alexion Confidential 
Overdoses are medication errors that are not considered AEs unless there is an untoward medical 
occurrence resulting from the overdose. 
In the event of an overdose or suspected overdose, the Investigator/treating physician should: 
1. Contact the Medical Monitor immediately. 
2. Closely monitor the participant for any AE/SAE.  
3. Obtain a plasma sample for PK analysis if requested by the Medical Monitor (determined 
on a case-by-case basis).  
4. Document the quantity of the excess dose as well as the duration of the overdose in the 
CRF. 
Decisions regarding dose interruptions or modifications will be made by the Investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the participant. 
8.5. 
Pharmacokinetics 
• Whole blood samples will be collected for the measurement of plasma concentrations 
of total Mo and PUF Mo as specified in the SoA (Table 1) via ICP-MS. Samples 
collected within ± 10% in minutes, or 30 minutes of the scheduled time, whichever is 
less, will not be considered a protocol deviation. 
• Instructions for the collection and handling of biological samples will be provided by 
Alexion. The actual date and time (24-hour clock time) of each sample will be 
recorded. 
• Samples will be used to evaluate the PK of ALXN1840. Samples collected for 
analyses of plasma concentrations may also be used to evaluate safety aspects related 
to concerns arising during or after the study. 
• Excess/additional samples may be stored for up to 5 years and used for PD and/or 
diagnostic biomarker development and research to understand the pathways 
associated with the mechanism of action of ALXN1840. These samples will not be 
used for genetic analyses (ie, RNA or DNA analyses). 
• Genetic analyses will not be performed on these whole blood samples. Participant 
confidentiality will be maintained.  
8.6. 
Pharmacodynamics 
• Plasma total Cu, PUF Cu, and LBC are considered to be PD assessments. Samples for 
assessment of LBC will be retained and may be analyzed in the future. See 
Section 8.8 for assessment of plasma ceruloplasmin and ceruloplasmin-bound Cu. 
• Blood samples will be collected as described in the SoA (Table 1) for plasma 
isolation as per the Laboratory Manual. Plasma samples will be used for ICP-MS 
measurement of total Cu, and toxic Cu as measured by PUF Cu at the time points 
indicated in the SoA. 


Protocol Amendment 2 
ALXN1840-HV-109 
18 Dec 2020 
Page 38 of 60 
Alexion Confidential 
• Excess/additional samples may be stored for up to 5 years and used for PD and/or 
diagnostic biomarker development and research to understand the pathways 
associated with the mechanism of action of ALXN1840. These samples will not be 
used for genetic analyses (ie, RNA or DNA analyses). 
8.7. 
Genetics 
Genetics are not evaluated in this study. 
8.8. 
Biomarkers 
• Plasma ceruloplasmin and ceruloplasmin-bound Cu samples will be retained and may 
be analyzed in the future. 
• Blood samples will be collected as described in the SoA (Table 1) for plasma 
isolation as per the Laboratory Manual.  
• Excess/additional samples may be stored for up to 5 years and used for PD and/or 
diagnostic biomarker development and research to understand the pathways 
associated with the mechanism of action of ALXN1840. These samples will not be 
used for genetic analyses (ie, RNA or DNA analyses). 
8.9. 
Immunogenicity Assessments 
Not applicable. 
8.10. 
Health Economics Data and/or Medical Resource Utilization 
Health economic and medical resource utilization parameters are not evaluated in this study. 


Protocol Amendment 2 
ALXN1840-HV-109 
18 Dec 2020 
Page 39 of 60 
Alexion Confidential 
9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Statistical Hypotheses 
9.1.1. 
Primary Hypothesis 
The primary objective of this study is to assess the relative bioavailability of 12 × 1.25 mg EC 
tablets (Treatment A, test) versus a single 15 mg EC tablet (Treatment B, reference). This will be 
done using the Analysis of Variance (ANOVA) statistical model, model based least square 
geometric mean ratios of PK parameter and confidence intervals (90%) will be provided. There 
is no formal null hypothesis to be statistically tested. 
9.2. 
Sample Size Determination 
A sample size of 48 male or female participants (24 participants in each sequence) has been 
selected based on practicality and convention for this type of study. Considering potential for 
drop-out of the study (approximately 15%), a total of 48 participants will be enrolled to ensure a 
minimum of 40 participants complete the study. 
9.3. 
Populations for Analyses 
The population sets used for analysis sets are defined as follows: 
Population 
Description 
Enrolled Set 
All participants who agree to participate in the study following completion of the 
informed consent process and who satisfy the inclusion/exclusion criteria and are 
randomized.  
Safety Set  
All participants who receive at least 1 dose of ALXN1840  
Pharmacokinetic Set 
All participants who receive at least 1 dose of ALXN1840 and have evaluable PK 
data for total and/or PUF Mo (as surrogate measures of ALXN1840 PK) in plasma  
Pharmacodynamic Set 
All participants who receive at least 1 dose of ALXN1840 and have evaluable PD 
data in plasma 
Abbreviations: ICF = informed consent form; Mo = molybdenum; PD = pharmacodynamics; PK = 
pharmacokinetics; PUF = plasma ultrafiltrate. 
9.4. 
Statistical Analyses 
In general, descriptive statistics for continuous variables will include number of non-missing 
values, arithmetic mean, SD, median, minimum, and maximum. Categorical variables will be 
summarized using percentages and frequency counts. Descriptive statistics and percentages and 
frequency counts will be summarized by treatment, and period, where appropriate.  
All statistical analyses will be conducted using SAS® for Windows® Version 9.4 or higher. 
A Statistical Analysis Plan (SAP) will be developed and finalized before data cutoff/database 
lock and will further describe the participant populations to be included in the analyses, and 
procedures for accounting for missing, unused, and spurious data as appropriate. This section is a 
high-level summary of the planned statistical analyses of the primary and secondary endpoints. 


Protocol Amendment 2 
ALXN1840-HV-109 
18 Dec 2020 
Page 40 of 60 
Alexion Confidential 
9.4.1. 
Efficacy Analyses 
No efficacy endpoints are included as part of this study, therefore, there is no analysis of 
efficacy. 
9.4.1.1. 
Analyses of Primary Endpoint 
The primary analysis will be based on the PK Set. 
The PK parameters for total and PUF Mo (Cmax, AUCt, and AUC∞) will be evaluated using an 
ANOVA statistical model with dosing period, treatment, and sequence as the fixed effects, and 
participant as a random effect, using the natural logarithms of the data. Confidence intervals (CI, 
90%) will be constructed for the least squares geometric mean ratio (GMR) for the ALXN1840 
12 × 1.25 mg versus single 15 mg ALXN1840 dose for all 3 parameters using the natural log-
transformed data. The GMRs and associated 90% confidence limits will be exponentiated back 
to the original scale. 
The within-participant CV for the Cmax, AUCt, and AUC∞ will be estimated using the mean 
squared error from the ANOVA. In addition, the geometric means and the associated 95% CIs of 
Cmax, AUCt, and AUC∞ will be reported for each treatment. 
Detailed PK analyses will be described in the SAP.  
9.4.1.2. 
Analyses of Secondary Endpoints 
All secondary analyses will be based on the PK Set. 
Dose-proportionality will be assessed across all EC mini-tablet treatments (2.5 mg, 5 mg, 10 mg, 
15 mg, 30 mg ALXN1840) graphically and by using a power model (Smith, 2000; Newlands, 
2006; EMA, 2010). The following dose-normalized PK parameters will be assessed for dose 
proportionality: Cmax_n, AUCt_n and AUC∞_n. The log (PK parameters for plasma total and PUF 
Mo) will be included as a response variable and log (dose) will be included as a fixed effect in 
the power model: 
log(PK Parameter) = mu + beta*log(Dose) 
where beta = 1 indicates perfect dose proportionality. Estimation of beta, along with its 90% CI, 
will be provided.  
Additional approaches to test dose proportionality, such as an ANOVA model, will be explored 
(Calvo, 2005). 
9.4.1.3. 
Analyses of Exploratory Endpoints 
Details of the analysis of exploratory endpoints will be provided in the SAP. 
9.4.2. 
Safety Analyses 
All safety analyses will be performed on the Safety Set.  
Safety analyses will include an analysis of all AEs, ECGs, clinical laboratory data, physical 
examinations, and vital sign measurements using descriptive statistics. No inferential statistical 
analyses are planned on the safety parameters of this study. The incidence of AEs and SAEs will 
be summarized, by System Organ Class and Preferred Term for each period, treatment and 


Protocol Amendment 2 
ALXN1840-HV-109 
18 Dec 2020 
Page 41 of 60 
Alexion Confidential 
overall, by relationship to study intervention. Adverse events will also be summarized by period, 
treatment and overall by severity. Serious AEs and AEs resulting in withdrawal from the study 
will be listed. Participants having multiple AEs within a category (eg, overall, System Organ 
Class, Preferred Term) will be counted once in that category. For severity tables, a participant’s 
most severe event within a category will be counted.   
Changes from baseline in vital sign measurements and laboratory assessments (eg, chemistry, 
cell blood count with differential, and urinalysis) will be summarized by period (Two-way 
Crossover Period and Dose-Proportionality Extension Period) and treatment. Laboratory 
parameter values will be graded according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events (CTCAE). Shift tables by treatment will be produced 
for these laboratory parameters. These tables will summarize the number of participants with 
each baseline grade relative to the reference ranges and changes to the worst highest grade 
assessed post-dose during the study. 
The ECG parameters will be measured at the specified time points, including heart rate, PR, RR, 
QRS, QT, and corrected QTcF intervals. The average of the triplicate ECG readings at the time 
points collected will be calculated, and changes from pretreatment baseline values will be 
assessed by period and treatment.   
All concomitant medications will be coded and summarized using the World Health 
Organization (WHO) Drug Dictionary. 
9.4.3. 
Pharmacokinetic/Pharmacodynamic Analysis  
Pharmacokinetic analyses will be performed using the PK Set.  
The following plasma PK parameters will be calculated as endpoints for total and PUF Mo (as 
surrogate measures of ALXN1840 PK) using noncompartmental methods with Phoenix® 
WinNonlin® (Certara USA Inc., Princeton, New Jersey) Version 8.0 or higher or SAS Version 
9.4 or higher (SAS Institute Inc., Cary, North Carolina), as applicable. Calculations of individual 
PK parameters will be based on measured total Mo and, when feasible, PUF Mo concentrations 
and the actual sampling times elapsed from the actual reference dosing time data recorded during 
the study. 
• Time delay between the time of dosing and time of appearance of drug concentration 
in plasma (Tlag; for plasma total Mo with ALXN1840 administration) 
• Maximum observed concentration in plasma (Cmax) 
• Dose-normalized Cmax (Cmax_n); n = dose normalized 
• Time to Cmax (Tmax)   
• Area under the plasma concentration (AUC) versus time curve from time 0 to the last 
quantifiable concentration (AUCt) 
• Dose-normalized AUCt (AUCt_n) 
• AUC versus time curve from time 0 to infinity (AUC∞) 
• Dose-normalized AUC∞ (AUC∞_n) 
• AUC extrapolated from time t to infinity as a percentage of total AUC∞ (%AUCextrap)  


Protocol Amendment 2 
ALXN1840-HV-109 
18 Dec 2020 
Page 42 of 60 
Alexion Confidential 
• Apparent terminal‑phase elimination rate constant (λz) 
• Terminal elimination half-life (t½) 
• Apparent oral clearance (CL/F) 
• Apparent volume of distribution (Vd/F) 
• Relative bioavailability (Frel) between test and reference treatments  
Additional plasma PK parameters may be calculated if deemed appropriate. 
Plasma concentrations of total and PUF Mo and time deviation data will be presented in a data 
listing by participant. Plasma concentration data will be summarized separately by time point for 
each treatment using the following descriptive statistics: number of participants, arithmetic 
mean, SD, CV, geometric mean, geometric CV, median, minimum, and maximum. Mean plasma 
concentration versus scheduled time profiles will be presented in figures on both linear and 
semilogarithmic scales. Individual plasma concentration versus actual time profiles will be 
presented similarly. 
Pharmacokinetic parameters derived from plasma concentrations of total and PUF Mo will be 
presented in data listings and summarized separately using the following descriptive statistics: 
number of participants, arithmetic mean, SD, arithmetic CV, geometric mean, geometric CV, 
median, minimum, and maximum. 
Pharmacodynamic analyses will be performed using the PD Set.  
Individual ALXN1840 PD, assessed as plasma total Cu and PUF Cu concentration versus time 
data will be listed and summarized with descriptive statistics and plotted. The same analyses will 
be conducted on the absolute and percent changes from baseline of these concentration versus 
time data.  
9.5. 
Interim Analyses  
An interim analysis is planned after completion of the Two-way Crossover Period of the study to 
enable reporting of results that will inform the decision on safe and appropriate dosing with the 
1.25 mg EC mini-tablets in the planned study in pediatric patients with WD who will be required 
to be treated with the starting dose of 2.5 mg ALXN1840. 
9.6. 
Safety Review Committee 
An ad-hoc Safety Review Committee must convene within 24 hours in the case of a treatment-
emergent serious adverse event (TESAE) or the withdrawal of any subject due to an adverse 
reaction to determine whether any group toxicity rules apply and the impact on study 
continuation. 
There is an option to have additional ad hoc Safety Review Committee meetings to discuss 
urgent issues should the need arise. The membership roster and requirements for documenting 
meeting discussions and outcome will be outlined in the Safety Review Committee charter. 
Further internal or external experts may be consulted by the Safety Review Committee as 
necessary.   


Protocol Amendment 2 
ALXN1840-HV-109 
18 Dec 2020 
Page 43 of 60 
Alexion Confidential 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
10.1.1. 
Regulatory and Ethical Considerations 
• This study will be conducted in accordance with the protocol and with the following: 
− Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
− Applicable International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines 
− Applicable laws and regulations 
• The protocol, protocol substantial amendments, ICF, IB, and other relevant 
documents (eg, advertisements) must be submitted to an IRB/IEC by the Investigator 
and reviewed and approved by the IRB/IEC before the study is initiated.  
• Any substantial 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.  
• The Investigator will be responsible for the following: 
− Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
− Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
− Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 Code of Federal Regulations (CFR), ICH guidelines, the 
IRB/IEC, Directive 2001/20/EC, European regulation 536/2014 for clinical 
studies (if applicable), and all other applicable local regulations 
10.1.2. 
Financial Disclosure 
Investigators and Sub-Investigators will provide Alexion with sufficient, accurate financial 
information as requested to allow Alexion to submit complete and accurate financial certification 
or disclosure statements to the appropriate regulatory authorities. Investigators are responsible 
for providing information on financial interests during the course of the study and for 1 year after 
completion of the study. 


Protocol Amendment 2 
ALXN1840-HV-109 
18 Dec 2020 
Page 44 of 60 
Alexion Confidential 
10.1.3. 
Informed Consent Process 
• It is the responsibility of the Investigator to obtain signed (written or electronic 
signature) informed consent from all study participants prior to performing any 
study -related procedures including screening assessments.   
• The Investigator or his/her representative will explain the nature of the study 
(including but not limited to the objectives, potential benefits and risks, 
inconveniences, and the participant’s rights and responsibilities) to the participant or 
his/her legally authorized representative, defined according to local and country 
regulations where the study is taking place, and answer all questions regarding the 
study.  
• Participants must be informed that their participation is voluntary. Participants or 
their legally authorized representative will be required to sign a statement of informed 
consent or a certified translation if applicable, that meets the requirements of 21 CFR 
50, local regulations, EU General Data Protection Regulation (GDPR), ICH GCP 
guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IRB/IEC or study site.  
• The medical record must include a statement that signed (written or electronic) 
informed consent was obtained before any screening procedures were performed with 
a participant, and the date the written consent was obtained. The authorized person 
obtaining the informed consent must also sign the ICF(s).  
• Participants must be reconsented to the most current version of the ICF(s) during their 
participation in the study, as applicable.  
• A copy of the signed (written or electronic) informed consent documentation (ie, a 
complete set of participant information sheets and fully executed signature pages) 
must be provided to the participant or the participant’s legally authorized 
representative, as applicable. This document may require translation into the local 
language. Original, signed (written or electronic) consent [or assent] forms must 
remain in each participant’s study file and must be available for verification at any 
time. 
10.1.4. 
Data Protection 
• Participants will be assigned a unique identifier by Alexion. Any participant records 
or datasets that are transferred to Alexion will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred.  
• Participants must be informed that their personal study-related data will be used by 
Alexion in accordance with local data protection law. The level of disclosure must 
also be explained to the participants who will be required to give consent for their 
data to be used as described in the informed consent  
• Participants must be informed that their medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by Alexion, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 


Protocol Amendment 2 
ALXN1840-HV-109 
18 Dec 2020 
Page 45 of 60 
Alexion Confidential 
10.1.5. 
Dissemination of Clinical Study Data 
Study-related information and study results may be posted on publicly accessible clinical study 
databases (eg, the US website www.clinicaltrials.gov or the EU website 
www.clinicaltrialsregister.eu), as appropriate, and in accordance with national, regional, and 
local regulations. 
10.1.6. 
Data Quality Assurance 
• All participant data relating to the study will be recorded on printed or electronic 
CRFs unless transmitted to Alexion or designee electronically (eg, laboratory data). 
The Investigator is responsible for verifying that data entries are accurate and correct 
by physically or electronically signing the CRF.  
• The Investigator must maintain accurate documentation (source data) that supports 
the information entered in the CRF.  
• The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.  
• Alexion or designee is responsible for the data management of this study including 
quality checking of the data.  
• Study monitors will perform ongoing source data verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of participants are being 
protected; and that the study is being conducted in accordance with the currently 
approved protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements.  
• Records and documents, including signed ICFs, pertaining to the conduct of this 
study must be retained by the Investigator for 5 years after study completion, unless 
local regulations or institutional policies require a longer retention period. No records 
may be destroyed during the retention period without the written approval of Alexion. 
No records may be transferred to another location or party without written 
notification to Alexion.  
10.1.7. 
Source Documents 
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. The Investigator or designee will prepare and maintain adequate 
and accurate source documents (eg, medical records, ECGs, AE and concomitant medication 
reporting, raw data collection forms) designed to record all observations and other pertinent data 
for each participant. 
Data reported on the CRF that are transcribed from source documents must be consistent with 
the source documents or the discrepancies must be explained. The Investigator may need to 
request previous medical records or transfer records, depending on the study. Also, current 
medical records must be available. Source documents are filed at the Investigator’s site. 


Protocol Amendment 2 
ALXN1840-HV-109 
18 Dec 2020 
Page 46 of 60 
Alexion Confidential 
10.1.8. 
Study and Site Start and Closure 
The study start date is the date on which the first participant is consented. 
Alexion reserves the right to close the study site or terminate the study at any time for any reason 
at the sole discretion of Alexion. Study sites will be closed after the study is completed or 
following the decision to close or terminate the study. A study site is considered closed when all 
participants have completed the EOS or ET Visit, all data have been collected and entered into 
an electronic data capture (EDC) system, all required documents and study supplies have been 
collected and reconciled, and a study-site closure visit has been performed. 
The Investigator may initiate study site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by Alexion or Investigator may include but are not 
limited to: 
• Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, Alexion’s procedures, or ICH GCP guidelines 
• Inadequate recruitment of participants by the Investigator 
• Discontinuation of further study intervention development 
If the study is prematurely terminated or suspended, Alexion shall promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified by the 
applicable regulatory requirements. The Investigator shall promptly inform the participant and 
should assure appropriate participant therapy and/or follow-up. 
10.1.9. 
Publication Policy 
The full terms regarding publication of the results of this study are outlined in the applicable 
Clinical Study Agreement. 


Protocol Amendment 2 
ALXN1840-HV-109 
18 Dec 2020 
Page 47 of 60 
Alexion Confidential 
10.2. 
Appendix 2: Clinical Laboratory Tests 
• The tests detailed in Table 6 will be performed by the local laboratory.  
• Protocol-specific requirements for inclusion or exclusion of participants are detailed 
in Section 5 of the protocol.   
• Additional tests may be performed at any time during the study as determined 
necessary by the Investigator or required by local regulations. Investigators must 
document their review of each laboratory safety report and indicate whether out of 
range results are clinically significant or not clinically significant. All repeated 
laboratory test values must be recorded in the CRF. 
• Women of childbearing potential should only be enrolled after a negative serum 
pregnancy test result at Screening. Additional urine pregnancy testing will be 
standard for the protocol unless serum testing is required by site policies, local 
regulation, or IRBs/IECs and should be performed per the time points specified in the 
SoA (Section 1.3). Screening pregnancy criteria are detailed in Section 5.1. 
Table 6: 
Laboratory Assessments 
Laboratory Assessments 
Parameters 
Clinical Chemistrya 
Blood urea nitrogen 
Potassium 
Creatinine 
Creatine kinase 
Sodium 
Chloride 
Potassium 
Glucose 
HbA1cb 
Bicarbonate  
AST 
Gamma glutamyltransferase 
ALT 
Alkaline phosphatase 
Urea 
Magnesium 
Total and direct bilirubin 
Total protein 
Albumin 
Calcium 
Phosphate 
Hematology 
Platelets 
White blood cell count with differential (neutrophils, lymphocytes, monocytes, 
eosinophils, basophils) 
Mean cell hemoglobin 
Neutrophils 
Monocytes 
Basophils 
Hemoglobin 
Mean corpuscular volume 
Mean cell hemoglobin concentration 


Protocol Amendment 2 
ALXN1840-HV-109 
18 Dec 2020 
Page 48 of 60 
Alexion Confidential 
Lymphocytes 
Eosinophils 
Coagulation 
Prothrombin time - International Normalized Ratio 
Partial thromboplastin time  
Urinalysis 
Bilirubin 
Glucose 
Leukocytes 
Nitrite 
Protein 
Urobilinogen 
Blood 
Ketones 
Microscopy, if required 
pH 
Specific gravity 
Red blood cells 
Other Tests 
Human immune deficiency virus (HIV)-1 and HIV-2 antibodies, hepatitis B surface 
antigen, and anti-hepatitis C virus with confirmation by hepatitis C virus RNA 
Ceruloplasmin (serum) (safety) 
Serum Cu (safety) 
Ceruloplasmin (plasma)c  
Ceruloplasmin-bound Cuc  
Highly sensitive serum or urine human chorionic gonadotropin pregnancy test (as 
needed for women of childbearing potential) 
Alcohol breath and urine drug screen (to include at minimum: amphetamines, 
barbiturates, benzodiazepines, cocaine, opiates, phencyclidine, methamphetamine, 
3,4-methylenedioxy-methamphetamine, methadone, and tetrahydrocannabinol 
[cannabinoids])d 
Total Cu and total Mo 
PUF Mo and Cu 
LBCc 
Follicle-stimulating hormone (postmenopausal females only) 
a All events of ALT or AST ≥ 3 × ULN or bilirubin ≥ 1.5 × ULN (> 35% direct bilirubin) or INR > 1.5, must be 
reported as an AE. 
b A sample for HbA1c is only required during the Screening Period, and not at every time point where samples for 
hematology, chemistry, urinalysis, and coagulation are required. 
c Ceruloplasmin, ceruloplasmin-bound Cu, and LBC samples will be retained and may be used for diagnostic 
biomarker development. 
d Local urine testing will be standard for the protocol unless serum testing is required by local regulation or 
IRB/IEC. 
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; Cu = copper; HbA1c = glycated 
hemoglobin; IEC = independent Ethics Committee; IgG/M = immunoglobulin G/M; IRB = Institutional Review 
Board; INR = international normalized ratio; LBC = labile bound copper; Mo = molybdenum; PUF = plasma 
ultrafiltrate; SAE = serious adverse event; ULN = upper limit of normal. 
 
 


Protocol Amendment 2 
ALXN1840-HV-109 
18 Dec 2020 
Page 49 of 60 
Alexion Confidential 
10.3. 
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
10.3.1. 
Definition of AE 
AE Definition 
• 
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An 
AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or 
not related to the medicinal (investigational) product. 
 
Events Meeting the AE Definition  
• 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other safety 
assessments (eg, ECG, radiological scans, vital signs measurements), including those that worsen from 
baseline, considered clinically significant in the medical and scientific judgment of the Investigator. 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an increase in frequency 
and/or intensity of the condition. 
• 
New conditions detected or diagnosed after study intervention administration even though it may have been 
present before the start of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study intervention or a 
concomitant medication. Overdose per se will not be reported as an AE/SAE unless it is an intentional 
overdose taken with possible suicidal/self-harming intent. Such overdoses should be reported regardless of 
sequelae.  
 
Events Not Meeting the AE Definition  
• 
Medical or surgical procedure (eg, endoscopy, appendectomy): The condition that leads to the procedure is 
the AE. Situations in which an untoward medical occurrence did not occur (eg, hospitalization for elective 
surgery if planned before the signing the ICF, admissions for social reasons or for convenience).  
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected at the start of 
the study that do not worsen.  
• 
A medication error (including intentional misuse, abuse, and overdose of the product) or use other than what 
is defined in the protocol is not considered an AE unless there is an untoward medical occurrence as a result 
of a medication error.  
• 
Cases of pregnancy that occur during maternal or paternal exposure to study intervention are to be reported 
within 24 hours of Investigator/site awareness. Data on fetal outcome and breastfeeding will be collected for 
regulatory reporting and safety evaluation.  
• 
Situations in which an untoward medical occurrence did not occur (social and/or convenience admission to a 
hospital). 
10.3.2. 
Definition of SAE 
 
An SAE is defined as any untoward medical occurrence that, at any dose: 
1. Results in death 
2. Is life-threatening 
The term “life-threatening” in the definition of “serious” refers to an event in which the participant was at risk of 
death at the time of the event. It does not refer to an event, which hypothetically might have caused death, if it 
was more severe. 


Protocol Amendment 2 
ALXN1840-HV-109 
18 Dec 2020 
Page 50 of 60 
Alexion Confidential 
An SAE is defined as any untoward medical occurrence that, at any dose: 
3. Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the participant has been detained (usually involving at least an overnight 
stay) at the hospital or emergency ward for observation and/or treatment that would not have been appropriate in 
the physician’s office or outpatient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is serious. When in doubt as 
to whether “hospitalization” occurred or was necessary, the AE should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from baseline is not 
considered an AE. 
4. Results in persistent disability/incapacity 
• 
The term disability means a substantial disruption of a person’s ability to conduct normal life functions. 
• 
This definition is not intended to include experiences of relatively minor medical significance such as 
uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma (eg, sprained ankle) 
which may interfere with or prevent everyday life functions but do not constitute a substantial disruption. 
5. Is a congenital anomaly/birth defect 
6. Other situations: 
• 
Medical or scientific judgment should be exercised in deciding whether SAE reporting is appropriate in 
other situations such as important medical events that may not be immediately life-threatening or result in 
death or hospitalization but may jeopardize the participant or may require medical or surgical intervention to 
prevent one of the other outcomes listed in the above definition. These events should usually be considered 
serious. 
• 
Examples of such events include invasive or malignant cancers, intensive treatment in an emergency room 
or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization, 
or development of drug dependency or drug abuse. 
 
A suspected unexpected serious adverse reactions (SUSARs) is defined as: 
A serious event that is not listed in the IB and that the Investigator identifies as related to investigational product 
or procedure. United States Title 21 CFR 312.32 and European Union Clinical Trial Directive 2001/20/EC and 
the associated detailed guidances or national regulatory requirements in participating countries require the 
reporting of SUSARs. Alexion has procedures that will be followed for the recording and expedited reporting of 
SUSARs that are consistent with global regulations and the associated detailed guidances. Suspected unexpected 
serious adverse reactions will be reported to the national competent authority and IRBs/IECs where applicable.  
 
10.3.3. 
Recording and Follow-Up of AE and/or SAE 
Recording of AE and/or SAE 
• 
When an AE/SAE occurs, it is the responsibility of the Investigator to review all documentation (eg, hospital 
progress notes, laboratory reports, and diagnostics reports) related to the event. 
• 
The Investigator will then record all relevant AE/SAE information in the CRF. 
• 
It is not acceptable for the Investigator to send photocopies of the participant’s medical records to Alexion 
in lieu of completion of the AE/SAE CRF page. 
• 
There may be instances when copies of medical records for certain cases are requested by Alexion. In this 
case, all participant identifiers, with the exception of the participant number, will be redacted on the copies 
of the medical records before submission to Alexion. 
• 
The Investigator will attempt to establish a diagnosis of the event based on signs, symptoms, and/or other 
clinical information. Whenever possible, the diagnosis (not the individual signs/symptoms) will be 
documented as the AE/SAE. 


Protocol Amendment 2 
ALXN1840-HV-109 
18 Dec 2020 
Page 51 of 60 
Alexion Confidential 
Recording of AE and/or SAE 
Assessment of Intensity 
The Investigator will make an assessment of intensity for each AE and SAE reported during the study and assign 
it to one of the following categories from National Cancer Institute CTCAE v5.0, published 27 Nov 2017:  
• 
Grade 1: Mild (awareness of sign or symptom, but easily tolerated) 
• 
Grade 2: Moderate (discomfort sufficient to cause interference with normal activities) 
• 
Grade 3: Severe (incapacitating, with inability to perform normal activities) 
• 
Grade 4: Life-threatening 
• 
Grade 5: Fatal 
 
Assessment of Causality 
• 
The Investigator is obligated to assess the relationship between the study intervention and each occurrence 
of each AE or SAE. An Investigator causality assessment must be provided for all AEs (both nonserious and 
serious). This assessment must be recorded in the CRF and on any additional forms, as appropriate. The 
definitions for the causality assessments are as follows: 
− 
Not related: There is no reasonable possibility the study intervention caused the AE.  
 
The AE has a more likely alternative etiology; it may be due to underlying or 
concurrent illness, complications, concurrent treatments, or effects of another 
concurrent drug.  
 
The event does not follow a reasonable temporal relationship to administration of the 
study intervention. 
− 
Related: There is a reasonable possibility the study intervention caused the AE. 
 
The AE has a temporal relationship to the administration of the study intervention. 
 
The event does not have a likely alternative etiology.  
 
The event corresponds with the known pharmaceutical profile of the study 
intervention. 
 
There is improvement on discontinuation and/or reappearance on rechallenge. 
• 
The Investigator will use clinical judgment to determine the relationship. 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, as well as the 
temporal relationship of the event to study intervention administration will be considered and investigated. 
• 
The Investigator will also consult the IB and/or Product Information, for marketed products, in his/her 
assessment. 
• 
For each AE/SAE, the Investigator must document in the medical notes that he/she has reviewed the 
AE/SAE and has provided an assessment of causality. 
• 
There may be situations in which an SAE has occurred, and the Investigator has minimal information to 
include in the initial report to Alexion. However, it is very important that the Investigator always make an 
assessment of causality for every event before the initial transmission of the SAE data to Alexion. 
• 
The Investigator may change his/her opinion of causality in light of follow-up information and send an SAE 
follow-up report with the updated causality assessment. 
• 
The causality assessment is one of the criteria used when determining regulatory reporting requirements. 
 
Follow-up of AEs and SAEs 
• 
The Investigator is obligated to perform or arrange for the conduct of supplemental measurements and/or 
evaluations as medically indicated or as requested by Alexion to elucidate the nature and/or causality of the 
AE or SAE as fully as possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other health care professionals. 
• 
If a participant dies during participation in the study or during a recognized follow-up period, the 
Investigator will provide Alexion with a copy of any post-mortem findings including histopathology. 
• 
New or updated information will be recorded in the originally completed CRF. 
• 
The Investigator will submit any updated SAE data to Alexion within 24 hours of receipt of the 
information. 


Protocol Amendment 2 
ALXN1840-HV-109 
18 Dec 2020 
Page 52 of 60 
Alexion Confidential 
10.3.4. 
Reporting of SAEs  
SAE Reporting to GDS via Paper Safety Reporting Form 
• 
All SAEs will be recorded and reported to Alexion or designee immediately and within 24 hours 
awareness. 
• 
SAEs will be reported using the Serious Adverse Event Report Form and submitted to Alexion Global 
Drug Safety (GDS). The Investigator must complete, sign, and date the Serious Adverse Event Report 
Form, verify the accuracy of the information recorded with the corresponding source documents, and send 
a copy via email or facsimile to the contact information provided below: 
− 
Email: 
 or Fax: 
 
• 
Additional follow-up information, if required or available, should be entered into the CRF and also sent to 
Alexion GDS within 24 hours of the Investigator or study site staff becoming aware of this additional 
information via the reporting process outlined above.  
• 
For all SAEs, the Investigator must provide the following: 
− 
Appropriate and requested follow-up information in the time frame detailed above 
− 
Causality of the SAE(s) 
− 
Treatment/intervention for the SAE(s) 
− 
Outcome of the SAE(s) 
− 
Medical records and laboratory/diagnostic information 
• 
All paper forms and follow-up information submitted to Alexion GDS must be accompanied by a cover 
page signed by the Investigator.  
• 
Paper source documents and/or reports should be kept in the appropriate section of the study file. 
PPD
PPD


Protocol Amendment 2 
ALXN1840-HV-109 
18 Dec 2020 
Page 53 of 60 
Alexion Confidential 
10.4. 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information 
 
CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE: 
• 
 Highly Effective Methodsb That Have Low User Dependency  
• 
Implantable progestogen-only hormone contraception associated with inhibition of ovulationc 
• 
Intrauterine device (IUD): female participants with a Cu-containing IUD are excluded from study 
• 
Intrauterine hormone-releasing system (IUS)c 
• 
Bilateral tubal occlusion 
• 
Vasectomized partner 
o 
(Vasectomized partner is a highly effective contraceptive method provided that the partner is the sole 
sexual partner of the woman of childbearing potential and the absence of sperm has been confirmed. If 
not, an additional highly effective method of contraception should be used. Spermatogenesis cycle is 
approximately 90 days.) 
• 
 Highly Effective Methodsb That Are User Dependent 
• 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of 
ovulationc 
o 
Oral 
o 
Injectable 
o 
Intravaginal 
o 
Transdermal 
• 
Progestogen-only hormone contraception associated with inhibition of ovulationc 
o 
Oral 
o 
Injectable 
• 
Sexual abstinence 
o 
(Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study intervention. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the 
preferred and usual lifestyle of the participant.) 
a)  Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for those participating in clinical studies. 
b)  Failure rate of <1% per year when used consistently and correctly. Typical use failure rates differ from those 
when used consistently and correctly. 
c.)  If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable 
contraceptive methods are limited to those which inhibit ovulation as the primary mode of action. 
 
Note: Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhea method (LAM) are not acceptable methods of contraception for 
this study. Male condom and female condom should not be used together (due to risk of failure with friction) 
Female participants of nonchildbearing potential are exempt from contraception requirements. Nonchildbearing 
potential for female participants is defined as any of the following: 
• 
Prior to first menses 
• 
Postmenopausal, as documented by amenorrhea for at least 1 year prior to the Day 1 visit and 
follicle stimulating hormone (FSH) serum levels consistent with postmenopausal status 
• 
Permanent sterilization at least 6 weeks prior to the Day 1 visit: 
− 
Hysteroscopic sterilization 
− 
Bilateral tubal ligation or bilateral salpingectomy 
− 
Hysterectomy 
− 
Bilateral oophorectomy 


Protocol Amendment 2 
ALXN1840-HV-109 
18 Dec 2020 
Page 54 of 60 
Alexion Confidential 
Collection of pregnancy information: 
• 
If a female participant or a male participant’s female spouse/partner becomes pregnant during the 
conduct of this study, the Investigator must submit the “Pregnancy/Breastfeeding Reporting and 
Outcome Form” to Alexion GDS via fax or email: 
Email: 
 or Fax: 
 
When the outcome of the pregnancy becomes known, the form should be updated and submitted to 
Alexion GDS. If additional follow-up is required, the Investigator will be requested to provide the 
information. 
 
Exposure of an infant to an Alexion product during breastfeeding must also be reported (via the 
“Pregnancy/Breastfeeding Reporting and Outcome Form”) and any AEs experienced by the infant must be 
reported to Alexion GDS or designee via email or facsimile (see Section 10.3 for contact information). 
 
PPD
PPD


Protocol Amendment 2 
ALXN1840-HV-109 
18 Dec 2020 
Page 55 of 60 
Alexion Confidential 
10.5. 
Appendix 5: Biomarkers 
• Blood samples will be collected for biomarker analyses and the data will be used for 
research (eg, exploratory) related to ALXN1840 or WD and related diseases. The 
samples may also be used to develop tests/assays including diagnostic tests related to 
ALXN1840 and WD.  
• The samples may be analyzed as part of a multistudy assessment of biomarkers in the 
response to ALXN1840 to understand study disease or related conditions. 
• The results of biomarker analyses may be reported in the CSR or in a separate study 
summary. 
• Alexion or designee will store the samples obtained for biomarker analyses in a 
secure storage space with adequate measures to protect confidentiality. 
• The samples will be retained while research on ALXN1840 continues but no longer 
than 5 years after all data have been collected for the study or other period as per 
local requirements. 


Protocol Amendment 2 
ALXN1840-HV-109 
18 Dec 2020 
Page 56 of 60 
Alexion Confidential 
10.6. 
Appendix 6: Abbreviations 
A list of abbreviations and terms used in this study protocol is provided in Table 7. 
Table 7:  
List of Abbreviations and Definitions of Terms 
Abbreviation 
Definition 
λz 
apparent terminal-phase elimination rate constant 
ADME 
absorption, distribution, metabolism, and excretion 
AE 
adverse event  
ALT 
alanine aminotransferase  
ANOVA 
Analysis of Variance 
AST 
aspartate aminotransferase  
AUC 
area under the plasma concentration versus time curve 
AUCt 
area under the plasma concentration versus time curve from time 0 to the last 
quantifiable concentration  
AUC∞ 
area under the plasma concentration versus time curve from zero to infinity  
BMI 
body mass index 
CFR 
Code of Federal Regulations 
CIOMS 
Council for International Organizations of Medical Sciences 
CTFG 
Clinical Trial Facilitation Group 
CL/F 
apparent oral clearance 
Cmax 
maximum observed concentration  
CONSORT 
Consolidated Standards of Reporting Trials  
CRF 
case report form  
CRU 
clinical research unit  
CTCAE 
Common Terminology Criteria for Adverse Events  
Cu 
copper 
CYP 
cytochrome P450  
CV 
coefficient of variation 
CYP2C9/2B6 
cytochromes 2C9 and 2B6 
EC 
enteric-coated 
ECG 
electrocardiogram 
EDC 
electronic data capture 
EMA 
European Medicines Agency 
EOS 
End of Study  
ET 
Early Termination 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice  
GDPR 
General Data Protection Regulation 
GDS 
Global Drug Safety  
GMR 
geometric mean ratio 
HbA1c 
glycated hemoglobin 


Protocol Amendment 2 
ALXN1840-HV-109 
18 Dec 2020 
Page 57 of 60 
Alexion Confidential 
HIPAA 
Health Insurance Portability and Accountability Act  
HIV 
human immunodeficiency virus 
IB 
Investigator’s Brochure  
ICF 
informed consent form  
ICH 
International Council for Harmonisation 
ICP-MS 
inductively coupled plasma mass spectrometry 
IEC 
Independent Ethics Committee  
IRB 
Institutional Review Board 
IUD 
intrauterine device 
IUS 
intrauterine hormone-releasing system 
LBC 
labile bound copper 
Mo 
molybdenum  
NCC 
non-ceruloplasmin-bound copper 
NCCcorrected 
NCC corrected for the amount of Cu bound to the TPC 
PD 
pharmacodynamic(s) 
PK 
pharmacokinetic(s)  
PUF 
plasma ultrafiltrate  
QTcF 
QT interval corrected for heart rate using Fridericia’s formula  
SAE 
serious adverse event  
SAP 
Statistical Analysis Plan  
SoA 
Schedule of Activities 
SUSAR 
suspected unexpected serious adverse reaction 
t½ 
terminal elimination half-life  
Tlag 
time delay between the time of dosing and time of appearance of Mo concentration 
tmax 
time to maximum concentration  
TEAE 
treatment-emergent adverse event  
TESAE 
treatment-emergent serious adverse event 
ULN 
upper limit of normal 
UWDRS 
Unified Wilson Disease Rating Scale 
Vd/F 
apparent volume of distribution  
WD 
Wilson disease  
WHO 
World Health Organization 


Protocol Amendment 2 
ALXN1840-HV-109 
18 Dec 2020 
Page 58 of 60 
Alexion Confidential 
10.7. 
Appendix 7: Protocol Amendment History 
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents. 
DOCUMENT HISTORY 
Document 
Date 
Original Protocol 
10 Jul 2020 
Amendment 1 
16 Sep 2020 
Amendment 2 
18 Dec 2020 
 
Amendment 1 (16 Sep 2020) 
Overall Rationale for the Amendment 
This amendment has been prepared to address comments from the clinical research unit that will 
perform the study, so as to expand the population that can be enrolled, as well as to clarify 
procedures. Minor administrative edits were also made for clarification and consistency 
throughout the protocol. Details of the changes are presented in the table below. 
Changes to the Protocol 
Section # and Name 
Description of Change 
Brief Rationale and/or Clarifications 
Section 1.1, Synopsis 
Section 4.1, Study Design 
Section 4.2, Scientific 
Rationale for Study Design 
Section 6.3, Measures to 
Minimize Bias: 
Randomization and 
Blinding 
Section 9.2, Sample Size 
Determination 
Text relating to balance between 
males and females removed 
from the protocol 
It is not necessary to balance for sex, as it is not 
expected that weight and sex will be 
confounding factors in a crossover study design 
and with stratification by BMI. 
Section 1.3, Schedule of 
Activities, Table 1 
Copper added to ceruloplasmin 
in the Schedule of Activities 
Added to the sample collected for safety 
assessment 
Section 1.3, Schedule of 
Activities, Table 1 
Requirement for PK/PD samples 
removed from Day -1 
assessments 
PK/PD samples are already collected at 
Screening, so are not also required on Day -1 
Section 5.1, Inclusion 
Criteria 
Revision of limits on weight, 
BMI, and age for all 
participants: 
• 
≥ 18 to 55 years 
• 
BMI: 18-32 kg/m2 
• 
Weight: 50-100 kg 
To expand the potential population that can be 
enrolled in the study 
Section 1.1, Synopsis 
Section 4.1, Study Design 
Section 6.3, Measures to 
Minimize Bias: 
Randomization and 
Blinding 
Initial randomized treatment 
assignment will be based on 
Baseline BMI, in addition to at 
re-randomization. 
BMI adjusted to 32, as per the 
change in inclusion criterion. 
Sex will not be included as a 
factor in randomization or 
re-randomization. 
Randomization and re-randomization will be 
based on the same factor (Baseline BMI).  
To remove sex as stratification factor as a 
limited number of female participants are 
expected to enroll in the study 


Protocol Amendment 2 
ALXN1840-HV-109 
18 Dec 2020 
Page 59 of 60 
Alexion Confidential 
Section 1.3, Schedule of 
Activities, Table 1 
Section 8.2.2, Vital Signs 
Section 8.2.3, 
Electrocardiograms 
Clarified that 5 minutes in the 
supine position is required for 
all vital sign measurements, 
including blood pressure and 
ECGs 
To clarify the procedures 
Section 6.1, Study Drug 
Administration 
Text added stating that 
ALXN1840 will be 
administered with up to 240 mL 
of water following an overnight 
fast of at least 10 hours, and that 
participants will remain fasted 
for a minimum of 4 hours 
following each dose 
administration 
To be in-line with FDA guidance for fasting 
pre- and post-dose 
(https://www.fda.gov/media/121313/download) 
Section 8.2, Safety 
Assessments 
Fasting time changed from 8 
hours to 10 hours before 
laboratory assessments 
To be in-line with FDA guidance for fasting as 
added to Section 6.1 
Section 8.2.4, Clinical 
Safety Laboratory 
Assessments 
Section 10.2, Appendix 2: 
Clinical Laboratory Tests 
Removal of text stating that all 
laboratory values from non-
protocol specified laboratory 
assessments must also be 
recorded in the CRF. Addition 
of text that all repeated 
laboratory test values must be 
recorded in the CRF. 
The previous text required collection of all 
laboratory test results outside of those specified 
in the protocol. Clinically significant laboratory 
test abnormalities will be reported as AEs. 
Clarified that all repeated laboratory test values 
must be recorded in the CRF. 
All 
Minor administrative edits 
For clarification and consistency throughout 
the protocol 
 


Protocol Amendment 2 
ALXN1840-HV-109 
18 Dec 2020 
Page 60 of 60 
Alexion Confidential 
11. 
REFERENCES 
Calvo E, Zafar H, Goetz A, et al. Analysis of dose proportionality testing methods in phase I 
clinical trials of anticancer agents. 2005;46. 
EMA. Committee for medicinal products for human use (CHMP): Guideline on the Investigation 
of Bioequivalence (CPMP/EWP/QWP/1401/98 Rev. 1). Available from: 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/01/WC500
070039.pdf. 2010. 
EMA. Committee for medicinal products for human use (CHMP): ICH E11(R1) guideline on 
clinical investigation of medicinal products in the pediatric population. Step 5. 2017. 
Newlands A. Statistics and Pharmacokinetics in Clinical Pharmacology Studies.  SAS 
Conference Proceedings: Pharmaceutical Users Software Exchange; Dublin, Ireland, 2006. 
Smith BP, Vandenhende FR, DeSante KA, et al. Confidence interval criteria for assessment of 
dose proportionality. Pharm Res. 2000;17(10):1278-1283. 
Weiss K, Askari F, Czlonkowska A, et al. Bis-choline tetrathiomolybdate in patients with 
Wilson's disease: an open-label, multicentre, phase 2 study. Lancet Gastroenterol Hepatol. 
2017;12:869-876. 
 

SAP_001.pdf: 
A Phase 1, Randomized, 2-Period, 2-Sequence, Crossover 
with Parallel-group Extension, Open-label Study to 
Compare the Relative Bioavailability of 2 Oral Formulations 
of ALXN1840 in Healthy Adult Participants 
Unique Protocol ID: 
NCT Number 
Date of SAP 
ALXN1840-HV-109 
NCT04610580 
11 March 2021 


 
 
 
 
 
 
 
 
 
 
 
This document is confidential. 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
 
Page 1 of 35 
Statistical Analysis Plan for Interventional Studies 
 
 
SAP Version Number: 1.0 
SAP Date: 11-Mar-2021 
 
Sponsor Name: Alexion Pharmaceuticals, Inc. 
 
Protocol Number: ALXN1840-HV-109 
Protocol Title: A Phase 1, randomized, 2‑period, 2‑sequence, crossover with parallel-group 
extension, open- label study to compare the relative bioavailability of 2 oral formulations of 
ALXN1840 in healthy adult participants 
 
Protocol Version and Date: Protocol Amendment 2, 18-Dec-2020 
 
Syneos Health Project Code:  7017347  
  
Authors:
 
 
 
 
 
 
 
 
 
 
Notice of Confidential and Proprietary Information: 
The information contained in this document is confidential belonging to Alexion Pharmaceuticals, Inc.. 
Acceptance of this document constitutes agreement by the recipient that no information contained herein 
will be published or disclosed without prior written authorization from an official of Alexion 
Pharmaceuticals, Inc.. However, this document may be disclosed to appropriate Institutional Review 
Board and Ethics Committees or duly authorized representatives of a national regulatory authority under 
the condition that they are requested to keep it confidential. In the event of an actual or suspected breach 
of this obligation, Syneos Health should be notified promptly. 
 
 
PPD


Statistical Analysis Plan for Interventional Studies 
Sponsor: Alexion Pharmaceuticals, Inc.; Protocol No.: ALXN1840-HV-109 
SAP Version: 1.0 11-Mar-2021 
 
 
This document is confidential. 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
 
Page 2 of 35 
I confirm that I have reviewed this document and agree with the content. 
Approvals 
Syneos Health Approval 
 
 
 
 
 
 
  
 
Signature 
 
Date (DD-Mmm-
YYYY) 
 
 
 
 
 
 
 
Signature 
 
Date (DD-Mmm-
YYYY) 
 
 
 
 
 
 
 
 
Signature 
 
Date (DD-Mmm-
YYYY) 
Alexion Pharmaceuticals, Inc. Approval 
 
 
 
 
 
 
  
Alexion Pharmaceuticals  
 
Signature 
 
Date (DD-Mmm-
YYYY) 
 
 
 
 
 
 
 
 
Alexion Pharmaceuticals 
 
Signature 
 
Date (DD-Mmm-
YYYY) 
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


Statistical Analysis Plan for Interventional Studies 
Sponsor: Alexion Pharmaceuticals, Inc.; Protocol No.: ALXN1840-HV-109 
SAP Version: 1.0 11-Mar-2021 
 
 
This document is confidential. 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
 
Page 3 of 35 
Table of Contents 
Approvals .................................................................................................................................. 2 
 
Glossary of Abbreviations ................................................................................................... 6 
 
Purpose .............................................................................................................................. 9 
 
Study Objectives .............................................................................................................. 10 
 
Study Details/Design ........................................................................................................ 11 
 
Endpoints ......................................................................................................................... 15 
 
Analysis Sets .................................................................................................................... 16 
 
General Aspects for Statistical Analysis ........................................................................... 17 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Alexion Pharmaceuticals, Inc.; Protocol No.: ALXN1840-HV-109 
SAP Version: 1.0 11-Mar-2021 
 
 
This document is confidential. 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
 
Page 4 of 35 
 
Participant Disposition, Demographic, Other Baseline Characteristics and Medication .... 19 
 
Pharmacokinetics ............................................................................................................. 21 
 
Exploratory Analysis ......................................................................................................... 25 
 
Pharmacodynamics .......................................................................................................... 26 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Alexion Pharmaceuticals, Inc.; Protocol No.: ALXN1840-HV-109 
SAP Version: 1.0 11-Mar-2021 
 
 
This document is confidential. 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
 
Page 5 of 35 
 
Safety ............................................................................................................................... 27 
 
Interim Analyses ............................................................................................................... 32 
 
Changes from Analysis Planned in Protocol ..................................................................... 33 
 
Reference List .................................................................................................................. 34 
 
Quality Control ................................................................................................................. 35 
 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Alexion Pharmaceuticals, Inc.; Protocol No.: ALXN1840-HV-109 
SAP Version: 1.0 11-Mar-2021 
 
 
This document is confidential. 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
 
Page 6 of 35 
 
Glossary of Abbreviations 
Abbreviation 
Description 
%AUCextrap 
AUC extrapolated from time t to infinity as a percentage of total AUC∞ 
λz 
 
Apparent terminal phase elimination rate constant 
AE 
Adverse Event 
ALT 
Alanine aminotransferase  
ANOVA 
Analysis of Variance 
AST 
Aspartate aminotransferase  
ATC 
Anatomical Therapeutic Chemical 
AUC 
Area under the plasma concentration versus time curve 
AUCt 
Area under the plasma concentration versus time curve from time 0 to the last 
quantifiable concentration  
AUCt_n 
Dose-normalized AUCt 
AUC∞ / AUCinf 
Area under the plasma concentration versus time curve from zero to infinity  
AUC∞_n / AUCinf_n 
Dose-normalized AUC∞ / AUCnf 
BMI 
Body Mass index 
CI 
Confidence Interval 
CL/F 
Aapparent oral clearance 
Cmax 
Maximum observed concentration  
Cmax_n 
Dose-normalized Cmax 
CRF 
Case Report Form 
CRU 
Clinical Research Unit 
CTCAE 
Common Terminology Criteria for Adverse Events 
Cu 
Copper 
CV 
Coefficient of Variation 
EC 
Enteric-coated 
ECG 
Electrocardiogram 
EMA 
European Medicines Agency 
EOS 
End of Study  
ET 
Early Termination 
FDA 
Food and Drug Administration 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Alexion Pharmaceuticals, Inc.; Protocol No.: ALXN1840-HV-109 
SAP Version: 1.0 11-Mar-2021 
 
 
This document is confidential. 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
 
Page 7 of 35 
Frel 
Relative bioavailability between test and reference treatments 
FSH 
Follicle-stimulating hormone 
GMR 
Geometric mean ratio 
HbA1c 
Glycated Hemoglobin 
HIV 
Human Immunodeficiency Virus 
IB 
Investigator’s Brochure  
ICF 
Informed Consent Form  
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee  
IQR 
Interquartile range 
IUD 
Intrauterine device 
IUS 
Intrauterine hormone-releasing system 
LBC 
Labile bound copper 
Max 
Maximum 
MedDRA 
Medical Dictionary for Regulatory Activities 
Min 
Minimum 
Mo 
Molybdenum 
N/A 
Not Applicable 
NCC 
Non-ceruloplasmin-bound copper 
NCCcorrected 
NCC corrected for the amount of copper bound to the TPC 
PD 
Pharmacodynamic(s) 
PK 
Pharmacokinetic(s)  
PT 
Preferred Term 
PUF 
Plasma ultrafiltrate 
Q1 
First quartile, 25th percentile of the data 
Q3 
Third quartile, 75th percentile of the data 
QC 
Quality Control 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Alexion Pharmaceuticals, Inc.; Protocol No.: ALXN1840-HV-109 
SAP Version: 1.0 11-Mar-2021 
 
 
This document is confidential. 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
 
Page 8 of 35 
SE 
Standard Error 
SI 
Standard International System of Units 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
t½ 
Terminal elimination half-life  
TEAE 
Treatment-Emergent Adverse Event 
TESAE 
Treatment-Emergent Serious Adverse Event 
TFL 
Table, Figure and Listing 
Tlag 
time delay between the time of dosing and time of appearance of molybdenum 
concentration 
tmax 
time to maximum concentration  
ULN 
Upper limit of normal 
Vd/F 
Apparent volume of distribution  
WD 
Wilson disease  
WHO 
World Health Organization 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Alexion Pharmaceuticals, Inc.; Protocol No.: ALXN1840-HV-109 
SAP Version: 1.0 11-Mar-2021 
 
 
This document is confidential. 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
 
Page 9 of 35 
 
Purpose 
The purpose of this statistical analysis plan (SAP) is to ensure that the data listings, summary tables and 
figures which will be produced, and the statistical methodologies which will be used, are complete and 
appropriate to allow valid conclusions regarding the study objectives. 
 
Responsibilities 
Syneos Health will perform the statistical analyses and is responsible for the production and quality 
control of all tables, figures and listings 
 
Timings of Analyses 
The primary analysis of safety and pharmacokinetics (PK)/pharmacodynamics (PD) is planned after all 
participants complete the final study visit or terminate early from the study. 
An interim analysis is planned after completion of the Two-way Crossover periods of the study to enable 
reporting of results that will inform the decision on safe and appropriate dosing with the 1.25 mg enteric-
coated (EC) mini-tablets in the planned Study ALXN1840-WD-302 in pediatric patients with WD who will 
be required to be treated with the starting dose of 2.5 mg ALXN1840. 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Alexion Pharmaceuticals, Inc.; Protocol No.: ALXN1840-HV-109 
SAP Version: 1.0 11-Mar-2021 
 
 
This document is confidential. 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
 
Page 10 of 35 
 
Study Objectives 
 
Objective 
Endpoints/Estimands 
Primary 
To assess the relative bioavailability of equal 
doses of ALXN1840 administered as 1.25 mg EC 
mini-tablets versus a single 15 mg EC tablet 
PK parameters for plasma total Mo and PUF Mo 
(Cmax, AUCt, and AUC∞) 
Secondary 
To assess dose-proportionality between 2.5 mg (2 
× 1.25 mg), 5 mg (4 × 1.25 mg), 10 mg (8 × 1.25 
mg), 15 mg (12 × 1.25 mg), and 30 mg (24 × 1.25 
mg) EC mini-tablet doses 
Dose-normalized PK parameters for plasma total 
Mo and PUF Mo (Cmax_n, AUCt_n, and AUC∞_n) 
Safety 
To assess the overall safety and tolerability of 
ALXN1840, administered as 1.25 mg EC mini-
tablets and as a single 15 mg EC tablet 
Incidence of TEAEs and TESAEs, physical 
examination, vital signs measurements, clinical 
laboratory, and 12-lead ECG results 
Exploratory  
To explore relationships between total Mo and 
PUF Mo clearance and body size — body weight 
(kg) and BMI (kg/m2) 
CL/F, body weight, and BMI 
To explore PD of ALXN1840 either as a single 
15 mg EC tablet or EC mini-tablets of 1.25 mg at 
different total dose strengths 
Absolute and percent changes from pre-dose 
baseline of plasma Cu concentrations: total Cu and 
PUF Cu 
Abbreviations: AUC∞ =  area under the plasma concentration versus time curve from time 0 to infinity; AUCt = area 
under the plasma concentration versus time curve from time 0 to the last quantifiable concentration; BMI = body mass 
index; CL/F = apparent oral clearance; Cmax = maximum observed concentration; Cu = copper; EC = enteric-coated; 
ECG = electrocardiogram; Mo = molybdenum; n = dose-normalized; PD = pharmacodynamic(s); 
PK = pharmacokinetic(s); PUF = plasma ultrafiltrate; TEAE = treatment-emergent adverse events; 
TESAE = treatment-emergent serious adverse event. 
 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Alexion Pharmaceuticals, Inc.; Protocol No.: ALXN1840-HV-109 
SAP Version: 1.0 11-Mar-2021 
 
 
This document is confidential. 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
 
Page 11 of 35 
 
Study Details/Design 
 
 
Brief Description 
This is a Phase 1 study to compare the relative bioavailability of 2 formulations of ALXN1840 in healthy 
participants. Equal doses of the 1.25 mg EC mini-tablet will be compared with a single 15 mg EC tablet 
(12 × 1.25 mg and 1 × 15 mg, respectively). The study will be conducted in 2 periods. The study will also 
assess dose-proportionality between 2.5 mg (2 × 1.25 mg), 5 mg (4 × 1.25 mg), 10 mg (8 × 1.25 mg), 15 
mg (12 × 1.25 mg), and 30 mg (24 × 1.25 mg) EC minitablet doses in the Dose-Proportionality Extension 
Period. 
The study has a Screening Period (Days -28 to -2), the Two-way Crossover Periods, consisting of 2 
dosing periods (Day 1 to Day 11 each), and a Dose-Proportionality Extension Period of 14 days. After 
completing the Screening Period, enrolled participants will be admitted to the clinical research unit (CRU) 
on Day -1 for dosing on Day 1 in Dosing Period 1. If discharged after Dosing Period 1, participants will be 
readmitted to the CRU for Dosing Period 2 following a minimum washout of 14 days after the previous 
dose, and again for the Dose-Proportionality Extension Period after a minimum washout of 14 days. 
This study will be conducted with approximately 48 healthy participants enrolled to allow for a minimum of 
40 participants to complete the Dose-Proportionality Extension Period of the study. 
The study design is presented in Figure 1 . 
Figure 1: 
Study Design Schematic 
 
 
Two-way Crossover Periods 
The Two-way Crossover Period is a randomized, open-label, two-way (2-period, 2-sequence) crossover 
design to assess the relative bioavailability of 12 × 1.25 mg EC mini-tablets compared with the 15 mg EC 
tablet currently used in clinical studies. Participants will be randomized to one of the 2 treatments 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Alexion Pharmaceuticals, Inc.; Protocol No.: ALXN1840-HV-109 
SAP Version: 1.0 11-Mar-2021 
 
 
This document is confidential. 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
 
Page 12 of 35 
sequences. Randomized treatment assignment will be based on Baseline BMI. Two strata for Baseline 
BMI (< 25, 25 to < 32 kg/m2) will be used: 
• 
Treatment A: ALXN1840 12 × 1.25 mg EC mini-tablets 
• 
Treatment B: ALXN1840 single 15 mg EC tablet, currently being tested in the Phase 3 Study 
WTX101-301) 
Blood samples for PK analysis of total and PUF molybdenum (as surrogate measures of ALXN1840 PK) 
and PD/biomarkers will be collected in each dosing period on Day 1 at pre-dose, and postdose at 1, 2, 3, 
4, 5, 6, 8, 12 and 24 hours (Day 2) and then at 24 hour intervals on Days 3, 4, 5, 6, 7, 8, 9, 10, and 11. 
The 336-hour sample for Dosing Period 1 will be collected predose in Dosing Period 2. Participants may 
be discharged on Day 11 of each dosing period after completion of all procedures and review of all safety 
data. The end of Dosing Period 2 will occur on Day 15 ± 2 of Dosing Period 2, with the collection of the 
336-hour PK sample for Dosing Period 2. 
 
Dose-Proportionality Extension Period 
The Dose-Proportionality Extension Period is a re-randomized, open-label, parallel group design to 
assess the dose-proportionality between EC mini-tablet doses. 
The Dose-Proportionality Extension Period will be conducted following completion of the Two-way 
Crossover Periods of the study and after an at least 14-day washout period. Participants will be re-
randomized as follows: 
Treatment C (N=10-12): ALXN1840 2.5 mg (2 × 1.25 mg EC mini-tablets) 
Treatment D (N=10-12): ALXN1840 5 mg (4 × 1.25 mg EC mini-tablets) 
Treatment E (N=10-12): ALXN1840 10 mg (8 × 1.25 mg EC mini-tablets) 
Treatment F (N=10-12): ALXN1840 30 mg (24 × 1.25 mg EC mini-tablets) 
The 15 mg dose will not be repeated during the Dose-Proportionality Extension Period. For the purpose 
of evaluating dose-proportionality of the EC mini-tablet, data obtained from Treatment A of the Two-way 
Crossover Periods (12 × 1.25 mg EC tablets) will be included to represent a dose of 15 mg. 
 
Participant Selection 
Full eligibility criteria will be assessed only for Dosing Period 1 (ie, on Day -1). In- and exclusion criteria 
are described in detail in Protocol Sections 5.1 and 5.2. 
 
Determination of Sample Size 
A sample size of 48 male or female participants (24 participants in each sequence) has been selected 
based on practicality and convention for this type of study. Considering potential for drop-out of the study 
(approximately 15%), a total of 48 participants will be enrolled to ensure a minimum of 40 participants 
complete the study. 
 
Treatment Assignment and Blinding 
• 
This is an open-label, 2-period, 2-sequence study where, in order to minimize selection bias in 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Alexion Pharmaceuticals, Inc.; Protocol No.: ALXN1840-HV-109 
SAP Version: 1.0 11-Mar-2021 
 
 
This document is confidential. 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
 
Page 13 of 35 
treatment assignment, each participant will be randomized to one of 2 treatment sequences 
(Treatment A and B) in the Two-way Crossover Periods. The randomization will be stratified by 
Baseline BMI. Two strata for Baseline BMI (< 25, 25 to < 32 kg/m2) will be used. 
• 
Eligible participants who meet all inclusion and no exclusion criteria included in the study will be 
assigned unique study participant numbers during randomization to one of 2 treatment 
sequences (Treatments A and B). Study participant numbers will not be reallocated once 
assigned. 
• 
Participants will be re-randomized in the Dose-Proportionality Extension Period to one of 4 
treatment sequences (Treatments C, D, E, and F). The re-randomized treatment assignment will 
be based on Baseline BMI as for the Two-way Crossover Periods, with 2 strata for Baseline BMI 
(< 25, 25 to < 32) to be used. Block randomization will be used to equally randomly assign 
participants to each treatment. 
 
Administration of Study Medication 
ALXN1840 will be administered with 240 mL (8 fluid ounces) of water after an overnight fast of at least 10 
hours, as per FDA guidance. Participants can take approximately 5 minutes to drink the water. 
Participants will remain fasted for a minimum of 4 hours following each dose administration. Additional 
water is permitted ad libitum except for the period 1 hour before to 1 hour after administration of 
ALXN1840.  
Details of ALXN1840 administered in the study are provided in Table 1:  
Table 1: Details of Study Intervention Administered 
ARM Name 
Treatments A, C, D, E, F 
Treatment B 
Study Intervention 
Name 
ALXN1840 
ALXN1840 
Type 
Drug 
Drug 
Dose Formulation 
White, round, EC mini-tablet, diameter 3 mm 
White, round, EC tablet, 
diameter 5 mm 
Unit Dose 
Strengths 
1.25 mg EC mini-tablet supplied as 4 × 1.25 mg EC 
mini-tablets within a size 0 capsule. Capsules will be 
opened to access the individual mini-tablets (details 
will be provided in the Study Manual). 
15 mg 
Dosage Levels 
Treatment A: 12 × 1.25 mg EC mini-tablets (15 mg) 
Treatment C: 2 × 1.25 mg EC mini-tablets (2.5 mg) 
Treatment D: 4 × 1.25 mg EC mini-tablets (5 mg) 
Treatment E: 8 × 1.25 mg EC mini-tablets (10 mg) 
Treatment F: 24 × 1.25 mg EC mini-tablets (30 mg) 
15 mg 
Route of 
Administration 
Oral 
Oral 
Use 
Test 
Reference 
Packaging and 
Labeling 
ALXN1840 will be provided in bottles.  
Each bottle will be labeled as required per country 
requirements. 
ALXN1840 will be provided 
in treatment kits. Each kit 
will be labeled as required 
per country requirements. 
 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Alexion Pharmaceuticals, Inc.; Protocol No.: ALXN1840-HV-109 
SAP Version: 1.0 11-Mar-2021 
 
 
This document is confidential. 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
 
Page 14 of 35 
 
Study Procedures and Flowchart 
Schedule of activities is in Protocol Section 1.3.  


Statistical Analysis Plan for Interventional Studies 
Sponsor: Alexion Pharmaceuticals, Inc.; Protocol No.: ALXN1840-HV-109 
SAP Version: 1.0 11-Mar-2021 
 
 
This document is confidential. 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
 
Page 15 of 35 
 
Endpoints   
 
Primary PK Endpoint 
PK parameters for plasma total molybdenum and PUF molybdenum (Cmax, AUCt, and AUC∞)  
 
 
Secondary PK Endpoints 
Dose-normalized PK parameters for plasma total molybdenum and PUF molybdenum (Cmax_n, AUCt_n, 
and AUC∞_n)  
 
 
Safety Endpoints 
Incidence of TEAEs and TESAEs, physical examination, vital signs measurements, clinical laboratory, 
and 12-lead ECG results 
 
Exploratory Endpoints 
• 
CL/F, body weight, and BMI  
• 
Absolute and percent changes from pre-dose baseline of plasma copper  concentrations: total 
copper and PUF copper  
 
 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Alexion Pharmaceuticals, Inc.; Protocol No.: ALXN1840-HV-109 
SAP Version: 1.0 11-Mar-2021 
 
 
This document is confidential. 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
 
Page 16 of 35 
 
Analysis Sets 
 
Enrolled Set 
The Enrolled Set will include all participants who agree to participate in the study following completion of 
the informed consent process and who satisfy the inclusion/exclusion criteria and are randomized. Unless 
specified otherwise, this set will be used for participant listings and summaries of participant disposition.  
 
Safety Set  
The Safety Set (SS) will include all participants who receive at least 1 dose of ALXN1840. Participants will 
be analyzed according to treatment received. The SS will be used for all analyses of safety endpoints.  
 
Pharmacokinetic/Pharmacodynamic Set  
 
Pharmacokinetic/Pharmacodynamic Set - Two-way Crossover Periods 
The Pharmacokinetic/Pharmacodynamic Set for the Two-way Crossover Periods (PKDS-CO) will include 
all participants who receive at least 1 dose of ALXN1840 in the Two-way Crossover Periods and have 
evaluable PK data for total and/or PUF molybdenum (as surrogate measures of ALXN1840 PK) in 
plasma. Plasma concentrations will be summarized for all participants in the PKDS-CO. The exclusions 
from summary statistics for total and/or PUF molybdenum plasma concentrations and/or PK parameters 
will be defined based on review of protocol deviations (if any) prior to database lock by PK scientist and 
study statistician at the discretion of the sponsor. Pharmacokinetic and pharmacodynamic analyses will 
be performed using the PKDS-CO. 
 
Pharmacokinetic Set/Pharmacodynamic - Dose-Proportionality Extension Period 
The Pharmacokinetic/Pharmacodynamic Set for the Dose-Proportionality Extension Period (PKDS-E) will 
include all participants who receive at least 1 dose of ALXN1840 in the Dose-Proportionality Extension 
Period and have evaluable PK data for total and/or PUF molybdenum (as surrogate measures of 
ALXN1840 PK) in plasma. Plasma concentrations will be summarized for all participants in the PKDS-E. 
The exclusions from summary statistics for total and/or PUF molybdenum plasma concentrations and/or 
PK parameters will be defined based on review of protocol deviations (if any) prior to database lock by PK 
scientist and study statistician at the discretion of the sponsor. Pharmacokinetic and pharmacodynamic 
analyses will be performed using the PKDS-E. 
 
Full Analysis Set 
The Full Analysis Set (FAS) will include all participants who receive at least 1 dose of ALXN1840 and who 
have sufficient plasma samples to have evaluable PD data for total copper or PUF copper. Participants 
will be analyzed according to treatment received. The FAS will be used for additional analyses of PD 
endpoints. 
 
 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Alexion Pharmaceuticals, Inc.; Protocol No.: ALXN1840-HV-109 
SAP Version: 1.0 11-Mar-2021 
 
 
This document is confidential. 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
 
Page 17 of 35 
 
General Aspects for Statistical Analysis 
 
General Methods 
• 
In general, descriptive statistics for continuous variables will include number of non-missing values, 
arithmetic mean, SD, median,interquartile range (IQR), Q1, Q3, minimum, and maximum. Categorical 
variables will be summarized using percentages and frequency counts. Descriptive statistics and 
percentages and frequency counts will be summarized by treatment, and period, where appropriate. 
• 
For the summary statistics of all continuous variables unless otherwise specified, minimum and 
maximum will be presented to the same number of decimal places as the raw data, mean, median, 
Q1, Q3, and IQR will be presented to one more decimal places than the raw data, and SD will be 
presented to two more decimal places than the raw data. 
• 
All statistical analyses will be conducted using SAS® for Windows® Version 9.4 or higher. 
• 
All relevant participant data will be included in listings. All participants entered into the database will 
be included in participant data listings. 
In general, tables will be generated separately for the Two-way Crossover Periods and the Dose-
Proportionality Extension Period.The tables for the Two-way Crossover Periods will present columns of 
treatments A, B and the tables for the Dose-Proportionality Extension Period will present columns of 
treatments C, D, E, F and a total column (see table shells for further details). 
 
Key Definitions 
 
End of Study (EOS)  
The EOS for each participant is defined as completion of the EOS Visit on Day 15 ± 2 days of the Dose-
Proportionality Extension Period.  
 
Nominal Time 
Nominal time is the scheduled measurement time relative to time 0. Time 0 is the time of study drug 
dosing on Day 1.  
 
Baseline Value 
Baseline value will be defined as the last non-mising value recorded prior to intake of study treatment in 
each dosing period. 
 
Change from Baseline (CFB) 
CFB = Post-baseline value – Value at baseline 
 
 
Missing Data 
For participants who are withdrawn from the study prior to the end of the study, all data collected up to the 
point of discontinuation will be used for analysis. There will be no imputation for missing data, unless 
otherwise specified.  
 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Alexion Pharmaceuticals, Inc.; Protocol No.: ALXN1840-HV-109 
SAP Version: 1.0 11-Mar-2021 
 
 
This document is confidential. 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
 
Page 18 of 35 
 
Visit Windows 
If there are multiple planned assessments for any study procedure at a given time point the latest non-
missing value will be used for summarization. Unscheduled assessments will be listed and will be used to 
flag baseline visit if this is the last non-missing assessment before the first dose of study drug, but 
unscheduled assessments will not be included in the summarization. 
 
Blood samples for assessing plasma PK/PD should be collected within ± 10% in minutes, or 30 minutes 
relative to the scheduled time, whichever is less. 
 
 
Pooling of Centers 
Not Applicable. 
 
Subgroups 
Not Applicable. 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Alexion Pharmaceuticals, Inc.; Protocol No.: ALXN1840-HV-109 
SAP Version: 1.0 11-Mar-2021 
 
 
This document is confidential. 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
 
Page 19 of 35 
 
Participant Disposition, Demographic, Other Baseline Characteristics 
and Medication 
 
Participant Disposition and Withdrawals 
Listings of treatment assignments, including the participant’s identification, date of randomization, and 
assignment to treatment sequence, will be presented. 
 
The following frequencies (number and percent) will be displayed for all participants in the Enrolled Set: 
participants enrolled, participants randomized, screen failures, COVID-19 related reasons for screen 
failure.  
 
The analysis sets will be summarized with counts and percentages by treatment and overall. This table 
will include the following: number of participants in Enrolled Set, participants in Safety Set, reasons for 
exclusion from the Safety Set, participants in PK/PD sets, reasons for exclusion from the PK/PD sets, 
number of participants Full Analysis Set, reasons for exclusion from the Full Analysis Set. 
 
The following frequencies (number and percent) will be displayed for all participants in the Enrolled Set: 
randomized participants, participants in the Safety Set, participants in the PK/PD Sets and participants in 
the Full Analysis Set, participants who completed each treatment period, participants who completed the 
study (including follow-up), participants who discontinued early, and participants who discontinued study 
treatment early also presented by reason for early discontinuation. The denominators will be the number 
of enrolled participants. This table will be repeated for all analysis sets. 
 
Completion/discontinuation status, inclusion/exclusion criteria definitions and Inclusion/exclusion criteria 
violations will be listed by participant.  
 
A listing of participants excluded from the analysis populations will also be generated. 
 
Protocol Deviations 
Protocol deviation management at Syneos Health is detailed in Protocol Deviation and Non-compliance 
Management (3101.W02). For details on the process for defining analysis datasets refer to (Blind) Data 
Review and Definition of Analysis Sets SOP (3911). 
All protocol deviations recorded in Clinical Trial Management System (CTMS) will be listed. The Protocol 
deviation criteria are graded as not important or important. Protocol deviations and Protocol deviations 
related to COVID-19 will be summarized by the number and percentage of participants for the Safety Set.  
 
 
Demographic and Baseline Characteristics 
Demographic and baseline characteristics, including age, sex, race, ethnicity, child-bearing potential, 
height, body weight, and BMI will be summarized using standard descriptive statistics. No formal 
statistical comparisons between populations will be performed. Demographics and informed consent data 
will be listed for all participants in the Enrolled Set.  
Height (in cm) = height (in inches) * 2.54 
Weight (in kg) = weight (in lbs) * 0.4536 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Alexion Pharmaceuticals, Inc.; Protocol No.: ALXN1840-HV-109 
SAP Version: 1.0 11-Mar-2021 
 
 
This document is confidential. 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
 
Page 20 of 35 
 
Medical History and Concomitant Diseases 
Medical history will be coded using MedDRA 23.1 and summarized for the Safety Set presenting the 
number and percentages of participants within each preferred term (PT) grouped by the system organ 
class (SOC). A participant  with multiple occurrences of an event in a PT is counted only once. Medical 
history will be listed by participant.  
 
Medication 
The WHO Drug, March 2018, B3 will be used to classify prior and concomitant medications by therapeutic 
class and drug name.  
Prior medication is defined as any medication taken before the date of the first dose of study treatment. 
Concomitant medication is defined as any medication taken on or after the date of the first dose of study 
treatment.  
Treatment/period attribution will be determined by comparing the start date and time of the concomitant 
medication with the actual date and time of dosing. The most recently administered treatment prior to the 
date and time of onset will be considered as the treatment/period at onset. If a concomitant medication is 
ongoing over more than one treatment/period it will be attributed to all treatments/periods. 
The use of prior and concomitant medications will be summarized by the number and percentage of 
participants for the Safety Set. If a participant takes a specific medication multiple times or takes multiple 
medications within a specific therapeutic class, that participant would be counted only once for the coded 
drug name or therapeutic class. 
 
Non-Pharmacologic Therapies or Procedures 
The WHO Drug, March 2018, B3 will be used to classify non-pharmacologic therapies by therapeutic 
class. Prior non-pharmacologic therapy is defined as any non-pharmacologic therapy taken before the 
date of the first dose of study treatment. Concomitant non-pharmacologic therapy is defined as any non-
pharmacologic therapy taken on or after the date of the first dose of study treatment. 
Treatment/period attribution will be determined by comparing the start date and time of the non-
pharmacologic therapy with the actual date and time of dosing. The most recently administered treatment 
prior to the date and time of onset will be considered as the treatment/period at onset. If a non-
pharmacologic therapy is ongoing over more than one treatment/period it will be attributed to all 
treatments/periods. 
Non-pharmacologic procedure data will be listed but not summarized.  
 
 
Extent of Exposure 
Exposure data will be listed but not summarized. 
 
 
Treatment Compliance  
Not Applicable. 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Alexion Pharmaceuticals, Inc.; Protocol No.: ALXN1840-HV-109 
SAP Version: 1.0 11-Mar-2021 
 
 
This document is confidential. 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
 
Page 21 of 35 
 
Pharmacokinetics 
Pharmacokinetic analyses will be performed using the PKDS-CO and PKDS-E. 
  
PK parameters will be calculated for total and PUF molybdenum (as surrogate measures of ALXN1840 
PK) using noncompartmental methods with Phoenix® WinNonlin® (Certara USA Inc., Princeton, New 
Jersey) Version 8.0 or higher. Calculations of individual PK parameters will be based on measured total 
molybdenum and, when feasible, PUF molybdenum concentrations and the actual sampling times 
elapsed from the actual reference dosing time data recorded during the study. 
 
PK Sampling Schedule  
Two-way cross-over treatment periods 
 
Blood samples for PK analysis of total and PUF Mo (as surrogate measures of ALXN1840 PK) and 
pharmacodynamic (PD)/biomarkers will be collected in each dosing period on Day 1 at pre-dose, and 
postdose at 1, 2, 3, 4, 5, 6, 8, 12 and 24 hours (Day 2) and then at 24 hour intervals on Days 3, 4, 5, 6, 7, 
8, 9, 10, and 11.  
 
The 336-hour sample for Dosing Period 1 will be collected predose in Dosing Period 2. Participants may 
be discharged on Day 11 of each dosing period after completion of all procedures and review of all safety 
data. The end of Dosing Period 2 will occur on Day 15 ± 2 of Dosing Period 2, with the collection of the 
336-hour PK sample for Dosing Period 2. 
Dose-proportionality extension period 
The Dose-Proportionality Extension Period will be conducted following completion of the Two-way 
Crossover Periods of the study and after an at least 14-day washout period. 
A similar schedule for PK samples collection will be followed in the dose proportionality extension period 
as two-way cross-over treatment periods. Further details are given in Section 4.6. 
 
Plasma PK Endpoint 
Following PK parameters will be derived from the plasma concentrations of total and PUF molybdenum 
when feasible and supported by the available data. 
• 
Time delay between the time of dosing and time of appearance of drug concentration in plasma 
(Tlag; for plasma total molybdenum with ALXN1840 administration) 
• 
Maximum observed concentration in plasma (Cmax) 
• 
Molybdenum dose-normalized Cmax (Cmax_n); n = dose normalized 
• 
Time to Cmax (Tmax) 
• 
Area under the plasma concentration (AUC) versus time curve from time 0 to the last quantifiable 
concentration (AUCt) 
• 
Molybdenum dose-normalized AUCt (AUCt_n) 
• 
AUC versus time curve from time 0 to infinity (AUC∞) 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Alexion Pharmaceuticals, Inc.; Protocol No.: ALXN1840-HV-109 
SAP Version: 1.0 11-Mar-2021 
 
 
This document is confidential. 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
 
Page 22 of 35 
• 
Molybdenum dose-normalized AUC∞ (AUC∞_n) 
• 
AUC extrapolated from time t to infinity as a percentage of total AUC∞ (%AUCextrap) 
• 
Apparent terminal‑phase elimination rate constant (λz) 
• 
Terminal elimination half-life (t½) 
• 
Apparent oral clearance (CL/F) 
• 
Apparent volume of distribution (Vd/F) 
• 
Relative bioavailability (Frel) between test and reference treatments 
Additional plasma PK parameters may be calculated if deemed appropriate. 
 
Presentation of Concentration Data 
 
Handling of Missing Data 
Missing concentration data for all participants who are administered scheduled study treatments will be 
considered as non-informative missing and will not be imputed. No concentration estimates will be provided 
for missing sample values. 
For the derivation of AUC and for the individual plasma concentration versus time curves, the following 
rules will apply: 
• 
Concentration values below the assay’s lower limit of quantification (BLQ) in pre-dose Day 1 
samples will be treated as zero; 
• 
The sampling time of pre-dose samples relative to dosing will also be treated as zero; 
• 
BLQ’s between two quantifiable samples will be set to missing; 
• 
The first BLQ after the last measurable sample will be set to missing; any subsequent BLQ’s will 
be set to zero; 
For plasma concentration summary the following rules will apply: 
• 
All BLQ values will be set to zero; 
• 
No further imputation will be applied to any missing values. 
 
 
Listing and Presentation of Individual PK Data 
The actual and nominal sampling times of PK blood sample collection will be listed for each participant and 
will include the deviation in time from the protocol scheduled time (i.e., nominal time), if applicable. 
All measured concentrations will be presented in original precisions (i.e., significant figures) and units as 
reported by Bioanalytical lab – eg ng/mL. 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Alexion Pharmaceuticals, Inc.; Protocol No.: ALXN1840-HV-109 
SAP Version: 1.0 11-Mar-2021 
 
 
This document is confidential. 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
 
Page 23 of 35 
Plasma concentrations of total and PUF molybdenum and time deviation data will be presented in a data 
listing by participant. 
 
Summary of PK Concentrations by Matrix  
Plasma concentration data will be summarized separately by time point for each treatment using the 
following descriptive statistics: number of participants, arithmetic mean, SD, CV, geometric mean, 
geometric CV, median, minimum, and maximum.  
Mean plasma concentration versus scheduled time profiles will be presented in figures on both linear and 
semilogarithmic scales. Individual plasma concentration versus nominal time profiles will be presented 
similarly.  
 
Derivation of Pharmacokinetic Parameters 
• 
The apparent Cmax and the corresponding tmax along with Tlag will be read directly from the 
concentration-time plot (observed data). 
• 
AUCt will be calculated using the log-linear trapezoidal interpolation rule for extravascular model. 
• 
The terminal elimination rate constant (λz) will be determined by log linear regression obtained on 
at least the 3 last quantifiable concentrations and will not include Cmax; t1/2 is calculated by the 
program as ln2/λz; 
• 
AUC∞ will be calculated by the program as: AUC∞ = AUCt + AUCextrap where last is the sampling 
time point of the last measurable concentration (tlast). AUCextrap will be calculated by the program 
as: Clast/λz, where Clast is the observed concentration at time tlast and λz is the elimination rate 
constant during the apparent terminal elimination phase. AUC∞ will only be presented for 
participants with a reliable λz; 
• 
CL will be calculated by program as (molybdenum dose amount/AUC∞); 
• 
Vz will be calculated by the program as (molybdenum dose amount/AUC∞)/λz; 
• 
Dose normalized PK parameters will be calculated using the equivalent molybdenum dose and not 
the ALXN1840 dose. .  
The following PK acceptance criteria will be applied to assess the reliability of elimination parameters: 
• 
Number of points to calculate λz is greater than or equal to 3 excluding Cmax point; 
• 
The adjusted square of the correlation coefficient or coefficient of determination (Rsquare adjusted) 
for the goodness of fit of the regression line through the data points must be ≥0.90; 
• 
AUCextrap ≤20%. 
Unreliable PK parameters will be listed but flagged and excluded from summary. 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Alexion Pharmaceuticals, Inc.; Protocol No.: ALXN1840-HV-109 
SAP Version: 1.0 11-Mar-2021 
 
 
This document is confidential. 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
 
Page 24 of 35 
 
PK Parameters Summarization 
Pharmacokinetic parameters derived from plasma concentrations of total and PUF molybdenum will be 
presented in data listings and summarized separately using the following descriptive statistics: number of 
participants, arithmetic mean, SD, arithmetic CV, geometric mean, geometric CV, median, minimum, and 
maximum. 
 
Planned Statistical Models for PK Parameters and Concentrations 
The primary analysis will be based on the PKDS-CO. 
For the Period 1 and Period 2 comparisons, the PK parameters for total and PUF molybdenum (Cmax, 
AUCt, and AUC∞) will be evaluated using an ANOVA statistical model with dosing period, treatment, and 
sequence as the fixed effects, and participant(sequence) as a random effect, using the natural logarithms 
of the data. Confidence intervals (CI, 90%) will be constructed for the least squares geometric mean ratio 
(GMR) for the 12 × 1.25 mg ALXN1840 mini-tablets versus a single 15 mg ALXN1840 tablet dose for all 3 
PK parameters using the natural log-transformed data. The GMRs and the associated 90% confidence 
limits will be exponentiated back to the original scale.  
The within-subject CV for the Cmax, AUCt, and AUC∞ will be estimated using the mean squared error from 
the ANOVA.  
In addition, the geometric means and the associated 95% CIs of Cmax, AUCt, and AUC∞ will be reported 
for each treatment. 
All secondary analyses will be based on the PKDS-E. 
Dose-proportionality will be assessed across all EC mini-tablet treatments (2.5 mg, 5 mg, 10 mg, 15 mg, 
30 mg ALXN1840) graphically and by using a power model (Smith, 2000; Newlands, 2006; EMA, 2010).  
The following molybdenum dose-normalized PK parameters will be assessed for dose proportionality: 
Cmax_n, AUCt_n and AUC∞_n. The log (PK parameters for plasma total and PUF molybdenum) will be 
included as a response variable and log (molybdenum dose) will be included as a fixed effect in the 
power model: 
log(PK Parameter) = mu + beta*log(Molybdenum Dose) 
*where beta = 1 indicates perfect dose proportionality. Estimation of beta, along with its 90% CI, will be 
provided. 
 
Deviation from Analyses Planned in Protocol 
Not applicable. 
 
 
 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Alexion Pharmaceuticals, Inc.; Protocol No.: ALXN1840-HV-109 
SAP Version: 1.0 11-Mar-2021 
 
 
This document is confidential. 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
 
Page 25 of 35 
 
Exploratory Analysis 
 
Endpoints 
The endpoints are: Clearance of total molybdenum, clearance of PUF molybdenum, covariates such as 
body weight (kg), and BMI(kg/m2). 
 
Analysis of the Endpoint 
Exploratory analyses as described in this section will be performed using the PKDS-CO and PKDS-E. 
Box-whisker plots for two strata of BMI (< 25, 25 to < 32 kg/m2) (on X-axis) and corresponding 
molybdenum dose normalized clearance of total molybdenum and PUF molybdenum (on Y-axis) will be 
presented. 
For body weight, a scatter plot with a Pearson correlation will be presented with body weight on X-axis 
and clearance of total molybdenum and PUF molybdenum on Y-axis to demonstrate if any correlation 
exists between the two. If needed, Pearson correlation analyses may be performed. 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Alexion Pharmaceuticals, Inc.; Protocol No.: ALXN1840-HV-109 
SAP Version: 1.0 11-Mar-2021 
 
 
This document is confidential. 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
 
Page 26 of 35 
 
Pharmacodynamics 
 Samples for assessment of plasma total copper and PUF copper will be used for the PD analysis 
described in this SAP/section. Samples for the assessment of ceruloplasmin (Cp), ceruloplasmin-bound 
copper (CpC), non-ceruloplasmin-bound copper (NCC), and LBC will be retained and may be analyzed in 
the future.  
Plasma samples of total copper and PUF copper will be collected on Day 1: Pre-dose, 1, 2, 3, 4, 5, 6, 8, 
12 hours post-dose, Day 2, 3, 4 , 5 , 6 , 7 , 8 , 9, 10, 11 of each treatment period, details have been 
provided in Section 4.6. 
 
 
PD Endpoint and Analysis 
 
Endpoint 
Absolute and change and percent change from pre-dose baseline of plasma copper concentrations: total 
copper and PUF copper 
 
Analysis of the Endpoint 
Pharmacodynamic analyses will be performed using the PK/PD Sets. For the plasma total copper and 
PUF copper concentration summaries BLQ values will be set to zero, but no further imputation will be 
applied to any missing values.For the plasma total copper and PUF copper concentrations, actual values, 
changes from baseline and percentages change from baseline will be summarized by time point for each 
treatment. 
Mean plasma total copper and PUF copper concentration (absolute and change and percentage change 
from baseline) versus scheduled time profiles will be presented in figures. 
Individual plasma total copper and PUF copper concentration (absolute and change and percentage 
change from baseline) versus scheduled time profiles will be presented similarly. 
Plasma concentrations of total and PUF copper, absolute and change and percentage change from 
baseline will be presented in a data listing by participant. 
Biostatistics summaries of total copper and PUF copper will be repeated for the FAS using the same 
methods as described above.  In these analyses values BLOQ will be set to LLOQ.   
 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Alexion Pharmaceuticals, Inc.; Protocol No.: ALXN1840-HV-109 
SAP Version: 1.0 11-Mar-2021 
 
 
This document is confidential. 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
 
Page 27 of 35 
 
Safety 
The population used for safety analyses will be the Safety Set (SS).  
Safety analyses will include an analysis of all AEs, ECGs, clinical laboratory data, physical examinations, 
and vital sign measurements using descriptive statistics.  
No inferential statistical analyses are planned on the safety parameters of this study.  
 
Adverse Events / Adverse Drug Reactions 
AEs for all participants in the Safety Set will be included in the AE summaries.  
Adverse events will be summarized by system organ class (SOC) and preferred term (PT) for each 
treatment and overall, based on the MedDRA dictionary version 23.1.  
If the relationship to study drug is missing for TEAEs, then the relationship will be counted as related to 
study product for the summary tables. Missing severity for TEAEs will be counted as Grade 3.  
Treatment-emergent AEs are defined as AEs which commence on or after first study drug administration, 
or those that first occur before first study drug administration but worsen in frequency or severity after first 
study drug administration. 
Treatment/period attribution will be determined by comparing the start date and time of the AE with the 
actual date and time of dosing. The most recently administered treatment prior to the date and time of 
onset will be considered as the treatment/period at onset. An AE will only be attributed to the 
treatment/period when it started, even if it is ongoing over more than one treatment/period. 
If the start date of an AE is partially or completely missing, the date will be compared as far as possible 
with the date of the start of administration of study drug. The AE will be assumed to be treatment-
emergent if it cannot be definitively shown that the AE did not occur or increase in severity during the 
treatment period (worst case approach). The following general rules will be used: 
• 
If the start day is missing but the start month and year are complete, an AE will not be considered 
as being treatment-emergent only if the start month/year is before the month/year of the first 
study drug administration. 
• 
If the start day and month are missing but the start year is complete, an AE will not be considered 
as being treatment-emergent only if the start year is before the year of the first Study Drug 
administration. 
• 
If the start date is completely missing, an AE will be considered treatment-emergent unless the 
stop date is before the first study drug administration. 
Time since first/last dose will be calculated as the difference between the event start date/time and the 
date/time of the first/last dose prior to start. Time since first/last dose will be expressed in days, hours and 
minutes. If time is missing, duration will be calculated as the difference between the start date and dosing 
date plus 1 and expressed in days. Time since first/last dose and duration will only be calculated when 
both dates are complete. 
 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Alexion Pharmaceuticals, Inc.; Protocol No.: ALXN1840-HV-109 
SAP Version: 1.0 11-Mar-2021 
 
 
This document is confidential. 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
 
Page 28 of 35 
Duration will be calculated for AEs that resolve as the difference between the resolution date and onset 
date plus 1 and expressed in days.  
The summary tables will include the number of participants and the number of events. Percentages will 
be based on the number of participants. For summaries by SOC and PT, a participant will be counted 
once at the SOC level and once at each PT within the SOC level.  
For summaries by SOC, PT, and maximum severity, a participant will be counted once at the highest 
severity level for which the event occurred at the SOC level and the highest severity level for each unique 
PT within that SOC level. Therefore, participants may only contribute once to each PT and once to each 
SOC level.  
The summaries presenting frequency of AEs by SOC and PT will be ordered by overall descending 
frequency of SOC and then, within a SOC, by overall descending frequency of PT.  
The following tables will be provided: 
• 
An overall summary of the number and percentage of participants reporting TEAEs, serious 
TEAEs (TESAEs), TEAEs resulting in death, TEAEs leading to withdrawal of study drug, TESAEs 
leading to withdrawal of study drug, TEAEs by relationship and TEAEs by toxicity grade;  
• 
TEAEs overall by system organ class and preferred term;  
• 
TEAEs by maximum toxicity grade, overall and by system organ class and preferred term;  
• 
TEAEs by toxicity grade, overall and by system organ class and preferred term; 
• 
TEAEs by maximum relationship to study medication, overall and by system organ class and 
preferred term;  
• 
TEAEs by relationship to study medication, overall and by system organ class and preferred term;  
• 
TEAEs by system organ class sorted by decreasing frequency;TEAEs by preferred term sorted 
by decreasing frequency; 
• 
Related TEAEs by preferred term sorted by decreasing frequency; 
• 
TESAEs, overall and by system organ class and preferred term; 
• 
TESAEs by maximum relationship to study medication, overall and by system organ class and 
preferred term;  
• 
TESAEs by relationship to study medication, overall and by system organ class and preferred 
term;  
• 
Non-serious TEAEs overall and by system organ class and preferred term;   
• 
TEAEs leading to withdrawal of study drug, overall and by system organ class and preferred 
term;  
• 
TEAEs leading to death, overall and by system organ class and preferred term; 
Only TEAEs will be included in the summary tables, however we will generate separate listings for 
treatment-emergent and non-treatment-emergent  AEs. Additional listings will be provided for deaths, 
serious adverse events, AEs resulting in withdrawal from the study and Adverse Events Leading to Study 
Drug Withdrawal. 
 
Laboratory Evaluations 
Safety laboratory samples for hematology, chemistry, urinalysis and coagulation will be collected at 
Screening, Day 1, 2, 5 and 10 of each treatment period and EOS/ET. 
Samples for pregnancy test will be collected at Screening, Day -1 of each treatment period and EOS/ET. 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Alexion Pharmaceuticals, Inc.; Protocol No.: ALXN1840-HV-109 
SAP Version: 1.0 11-Mar-2021 
 
 
This document is confidential. 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
 
Page 29 of 35 
Samples for alcohol breath test and urine drug screen will be collected at Screening and Day -1 of each 
treatment period. 
Samples for FSH, HIV antibody/hepatitis B and C screen and serum Ceruloplasmin and serum copper will 
be collected at Screening only. 
The following parameters will be included: 
Hematology: Platelets, White blood cell count with differential (neutrophils, lymphocytes, monocytes, 
eosinophils, basophils), Mean cell hemoglobin, Neutrophils, Monocytes, Basophils, Hemoglobin, Mean 
corpuscular volume, Lymphocytes, Eosinophils. 
Clinical chemistry: Blood urea nitrogen, Potassium, Creatinine, Creatine kinase, Sodium, Chloride, 
Glucose, HbA1cb (only at screening), Bicarbonate, AST, Gamma glutamyltransferase, ALT, Alkaline 
phosphatase, Urea, Magnesium, Total and direct bilirubin, Total protein, Albumin, Calcium, Phosphate. 
Urinalysis: Bilirubin, Glucose, Leukocytes, Nitrite, Protein, Urobilinogen, Blood, Ketones, Microscopy, if 
required, pH, Specific gravity, Red blood cells. 
Coagulation: Prothrombin time - International Normalized Ratio, Partial thromboplastin time. 
Serology: Human immune deficiency virus (HIV)-1 and HIV-2 antibodies, hepatitis B surface antigen, and 
anti-hepatitis C virus with confirmation by hepatitis C virus RNA 
Highly sensitive serum or urine human chorionic gonadotropin pregnancy test (as needed for women of 
childbearing potential), Follicle-stimulating hormone (postmenopausal females only) 
Alcohol breath and urine drug screen: amphetamines, barbiturates, benzodiazepines, cocaine, opiates, 
phencyclidine, methamphetamine, 3,4-methylenedioxy-methamphetamine, methadone, and 
tetrahydrocannabinol [cannabinoids]. 
Other tests:Serum Ceruloplasmin, serum copper  
Laboratory parameter values will be graded according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events (CTCAE).  
All summaries will be based on results in SI (standard international system of units) units and will be 
output in the order listed above.  
Toxicity grading following the NCI CTCAE grades version 5.0 will also be derived for laboratory variables 
where applicable (see list below). Note, where gradings require investigator/clinical input, this will not be 
considered and only the numeric criteria will be used for the assignments. If this results in the criteria for 
more than one grade being met, the highest (worst) CTCAE grade will be assigned. For creatinine only, 
the criteria based on the upper limit of normal (ULN) will be used (changes compared to the baseline 
value will not be used), eg, CTCAE defines Grade 1 as > ULN - 1.5 x ULN or > 1 - 1.5 x baseline. Only 
the ULN – 1.5 x ULN criterion will be used (and not the baseline criterion). 
The following parameters are CTCAE gradable: 
• Hematology:Absolute neutrophil count (neutrophil) , total leukocytes (Leukocytes) , hemoglobin  (only do 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Alexion Pharmaceuticals, Inc.; Protocol No.: ALXN1840-HV-109 
SAP Version: 1.0 11-Mar-2021 
 
 
This document is confidential. 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
 
Page 30 of 35 
the grading for Anemia, no grading for Hemoglobin increased), platelet count , Lymphocyte  
• Coagulation:International normalized ratio  
• Chemistry: Alanine aminotransferase  albumin, alkaline phosphatase, aspartate aminotransferase, total 
bilirubin, creatinine, gamma-glutamyl transferase , glucose  (only do the grading the Hypoglycemia, no 
grading for Hyperglycemia), creatine kinase. 
Actual values and changes from baseline (screening) in hematology, coagulation, clinical chemistry, 
urinalysis will be summarized by treatment. 
Shift tables for hematology, clinical chemistry and coagulation from baseline CTCAE toxicity for each visit 
and to the maximum grade on treatment for each parameter will be provided. Participants with both a 
non-missing baseline and at least one non-missing post-baseline grade will be included in the shift tables. 
Unscheduled data will be included in the worst case across all scheduled and unscheduled visits after the 
first dose of study treatment. This means that if there are CTCAE grades derived from both unscheduled 
and scheduled visits data per test per participant then the highest grade will be summarized.  
For non-CTCAE gradable tests, a shift table will be provided showing shifts relative to the normal ranges. 
This summary of normal range category changes illustrates the number and percentage of participants 
who fall into specified categories (Decrease to Low, Change to Normal or No Change, Increase to High) 
by comparing the baseline normal range category to the planned time normal range category and the 
worst-case normal range category. The worst-case post-baseline row will be used to summarize the 
participants’ overall worst-case normal range category change. The determination of the worst-case takes 
into account both planned and unscheduled assessments. Only laboratory tests which cannot be graded 
per CTCAE v. 5.0 specified criteria will be included.  
Participants with missing baseline value are to be assumed to have normal baseline value. Worst-case 
can be either High or Low. If a participant has a Decrease to Low and an Increase to High during the 
same time interval, then the participant is counted in both the ‘Decrease to Low’ and ‘Increase to High’ 
categories. If a participant was high at baseline and decreases to Low during the time interval, then the 
participant is counted in the ‘Decrease to Low’ category. Likewise, if a participant was Low at baseline 
and increases to High during the time interval, then the participant is counted in the ‘Increase to High’ 
category. Participants are only counted in the ‘Change to Normal or No Change’ category if they are: 
• 
Normal at baseline and have no normal range High and no normal range Low values during the 
time interval 
• 
High at baseline and do not change to Low during the time interval 
• 
Low at baseline and do not change to High during the time interval  Shift tables by treatment will 
be produced for these laboratory parameters. These tables will summarize the number of 
participants with each baseline grade relative to the reference ranges and changes to the worst 
highest grade assessed post-dose during the study. 
All events of ALT ≥ 3 × upper limit of normal (ULN) and bilirubin ≥ 2 ×ULN (> 35% direct bilirubin) or ALT 
≥ 3 × ULN and international normalized ratio (INR) > 1.5, if INR measured which may indicate severe liver 
injury (possible Hy’s Law), must be reported as an SAE. Liver function results will be presented in a 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Alexion Pharmaceuticals, Inc.; Protocol No.: ALXN1840-HV-109 
SAP Version: 1.0 11-Mar-2021 
 
 
This document is confidential. 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
 
Page 31 of 35 
summary table and eDISH (evaluation of drug-induced serious hepatotoxicity) plots. 
All laboratory results, as well as CTCAE grades will be included in data listings. Abnormal results for 
hematology,  clinical chemistry, urinalysis and coagulation will be listed separately. Laboratory results for 
serology, pregnancy tests, FSH, urine drug screen, alcohol breath test, serum Ceruloplasmin and serum 
copper will be listed only. 
 
Vital Signs  
Systolic blood pressure (mmHg), diastolic blood pressure (mmHg), heart rate (bpm), respiratory rate 
(breaths per minute) and temperature (degree Celsius) will be measured at Screening, Day 1 (Pre-dose, 
6 hours, 12 hours), Day 2, Day 5, Day 11 of each treatment period and EOS/ET. 
If vital sign results are abnormal, 2 additional readings will be taken. The mean of the 3 replicates will be 
recorded in the case report form (CRF) and used for the analysis.   
Actual values and changes from baseline in vital sign measurements will be summarized by treatment. 
Note temperature will be reported in centigrade. Any conversions required will be as follows: 
Temperature (in °C) = 5/9 (Temperature [in °F]-32). 
All vital signs will be provided in data listings. 
 
ECG 
The ECG parameters include heart rate, PR, RR, QRS, QT, and corrected QTcF intervals.  
12-lead ECGs in triplicate will be taken at Screening and on Day 1, 0.5 hours pre-dose and at 6 hours 
post-dose on Day 1 of the first dosing period and Day 1 of the Dose-Proportionality Extension Period. 12-
lead ECGs should be measured after a minimum of 5 minutes in supine position. The average of the 
triplicate ECG readings at the time points collected will be calculated and used in the analyses.  
Actual values and change from baseline of these average ECGs will be summarized by treatment.  
All ECG parameters, including all single ECG measurements, but also the mean value and overall ECG 
evaluation will be provided in data listings. 
 
Physical Examination 
A full physical examination will be performed at Screening and on Day -1 of the 2 dosing periods. A 
symptom-driven physical examination of relevant body systems may be performed at other times, at the 
Investigator’s discretion.  
Physical examination data will be listed. 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Alexion Pharmaceuticals, Inc.; Protocol No.: ALXN1840-HV-109 
SAP Version: 1.0 11-Mar-2021 
 
 
This document is confidential. 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
 
Page 32 of 35 
 
Interim Analyses 
An interim analysis is planned after completion of the Two-way Crossover Periods of the study (Group 2 
discharged after completing Period 2) and after the bioassay results for plasma total and PUF Mo and Cu 
results become available. 
The interim analysis will capture all PK, PD, and safety data and provide comparative relative 
bioavailability data of the 2 treatments to decide on safe and appropriate dosing with the 1.25 mg EC 
mini-tablets in the planned Study ALXN1840-WD-302 in pediatric patients with WD. 
  


Statistical Analysis Plan for Interventional Studies 
Sponsor: Alexion Pharmaceuticals, Inc.; Protocol No.: ALXN1840-HV-109 
SAP Version: 1.0 11-Mar-2021 
 
 
This document is confidential. 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
 
Page 33 of 35 
 
Changes from Analysis Planned in Protocol 
Not Applicable. 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Alexion Pharmaceuticals, Inc.; Protocol No.: ALXN1840-HV-109 
SAP Version: 1.0 11-Mar-2021 
 
 
This document is confidential. 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
 
Page 34 of 35 
 
Reference List 
• 
EMA. Committee for medicinal products for human use (CHMP): Guideline on the Investigation of 
Bioequivalence (CPMP/EWP/QWP/1401/98 Rev. 1). Available from: 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/01/WC50007
0039.pdf. 2010. 
• 
Newlands A. Statistics and Pharmacokinetics in Clinical Pharmacology Studies. SAS Conference 
Proceedings: Pharmaceutical Users Software Exchange; Dublin, Ireland, 2006. 
• 
Smith BP, Vandenhende FR, DeSante KA, et al. Confidence interval criteria for assessment of 
dose proportionality. Pharm Res. 2000;17(10):1278-1283. 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Alexion Pharmaceuticals, Inc.; Protocol No.: ALXN1840-HV-109 
SAP Version: 1.0 11-Mar-2021 
 
 
This document is confidential. 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
 
Page 35 of 35 
 
Quality Control 
SAS programs are developed to produce output such as analysis data sets, summary tables, data 
listings, figures or statistical analyses. An overview of the development of programs is detailed in Syneos 
Health Developing Statistical Programs SOP (3907) . 
Syneos Health Developing Statistical Programs SOP (3907), Conducting the Transfer of Biostatistical 
Deliverables SOP (3908) and the SAS Programming and Vaidation Plan describes the quality control 
procedures that are performed for all SAS programs and output. Quality control is defined here as the 
operational techniques and activities undertaken to verify that the SAS programs produce the output by 
checking for their logic, efficiency and commenting and by review of the produced output.  
Syneos Health SOP Pharmacokinetic and Related Data Analysis (3913) describes the process for the 
interaction between the Biostatistics and Pharmacokinetics departments for the analysis of 
pharmacokinetic and pharmacodynamic data.