Conditions: Healthy
Keywords: ALXN1840 Enteric-coated tablet Pharmacokinetics Pharmacodynamics Healthy
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 48
Healthy volunteers: yes

Brief summary:
To assess the relative bioavailability of ALXN1840 administered orally as a single enteric-coated (EC) tablet (reference, Treatment A) versus three EC tablets (test, Treatment B).

Detailed description:

Arms:
arm 1: Participants received ALXN1840 once in each Period as a single oral dose under fasted conditions as follows:

Period 1: ALXN1840 as a single EC tablet (Treatment A, reference). Period 2: ALXN1840 as three EC tablets (Treatment B, test).

Participants were discharged following the 240-hour post-dose procedures (approximately 10 days after dosing in each period) unless it was medically necessary to extend the confinement.

There was a washout period of at least 14 days between each ALXN1840 dosing. arm 2: Participants received ALXN1840 once in each Period as a single oral dose under fasted conditions as follows:

Period 1: ALXN1840 as three EC tablets (Treatment B, test). Period 2: ALXN1840 as a single EC tablet (Treatment A, reference).

Participants were discharged following the 240-hour post-dose procedures (approximately 10 days after dosing in each period) unless it was medically necessary to extend the confinement.

There was a washout period of at least 14 days between each ALXN1840 dosing.

Interventions: intervention 1: ALXN1840
Intervention descriptions: intervention 1: Participants received ALXN1840 at Hour 0 on Day 1 of the dosing period.

Protocol document:
Prot_000.pdf: 
A Phase 1, Randomized, 2-Period, 2-Way Cross-over Study 
to Assess the Single-Dose Pharmacokinetics of ALXN1840 
Enteric-Coated Tablets at 2 Dose Strengths in Healthy Adult 
Subjects 
Unique Protocol ID: 
NCT Number: 
EudraCT Number: 
  Date of Protocol: 
ALXN1840-HV-104 
NCT05303324 
2019-000516-28 
  09 April 2019 


Protocol 
 
ALXN1840-HV-104 Amendment 1 
Page 1 of 58 
 
Alexion Confidential 
 
 
TITLE PAGE 
Protocol Title: 
A Phase 1, Randomized, Open-Label, 2-Way Crossover Study to 
Assess the Single-Dose Pharmacokinetics of ALXN1840 
Enteric-Coated Tablets at 2 Dose Strengths in Healthy Adult 
Subjects  
Protocol Number: 
ALXN1840-HV-104  
Compound Number: 
ALXN1840  
USAN/INN: 
bis-choline tetrathiomolybdate  
Amendment Number: 
1 
Short Title: 
Pharmacokinetic Study of Oral ALXN1840 at 2 Dose Strengths in 
Healthy Adult Subjects   
Sponsor Name 
Alexion Pharmaceuticals, Inc. (Alexion)  
Legal Registered 
Address: 
121 Seaport Blvd.  
Boston, MA 02210 
USA  
Regulatory Agency 
Identifying Numbers: 
IND 119006 
EudraCT: 2019-000516-28  
Approval Date: 
 
Original Protocol 
01 Mar 2019 
Amendment 1 
09 Apr 2019 


Protocol 
ALXN1840-HV-104 Amendment 1 
Sponsor Signatory: 
9-Apr-2019 
Date 
Medical Monitor Name and Contact Information   
100 College Street 
New Haven, CT 06510 
USA  
Telephone: 
  
24-hour Emergency Contact: 
Page 2 of 58 
Alexion Confidential 
PPD
PPD
PPD


Protocol 
 
ALXN1840-HV-104 Amendment 1 
Page 3 of 58 
 
Alexion Confidential 
 
INVESTIGATOR’S AGREEMENT  
I have read the ALXN1840-HV-104 study protocol amendment 1 and agree to conduct the study 
in accordance with this protocol, 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 
 
ALXN1840-HV-104 Amendment 1 
Page 4 of 58 
 
Alexion Confidential 
 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
DOCUMENT HISTORY 
Document 
Date 
Original Document 
01 Mar 2019 
Amendment 1 
09 Apr 2019 
 
Amendment 1 (09 Apr 2019)  
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union.  
Overall Rationale for the Amendment: 
The protocol is being amended to align with changes that have been made by the UK Medicines 
and Healthcare products Regulatory Agency regarding adverse events. 
 
Section # and Name 
Description of Change 
Brief rationale and/or clarifications 
Substantial Revisions 
Section 6.6 Study Drug 
Stopping Rules 
Change in study drug stopping 
rules in relation to adverse 
reactions 
To align with the latest recommendations by 
the UK Medicines and Healthcare products 
Regulatory Agency regarding adverse 
reactions 
Non-substantial Revisions 
Section 8.2.1 Physical 
Examination 
Change to details of assessments 
of height, weight, and body mass 
index 
To correct the text so that it aligns with the 
Schedule of Activities 
Section 10.4 Recording and 
Follow-Up of AEs and/or SAEs 
To remove the final bullet point, 
which states the following: 
• Any female subject who 
becomes pregnant while 
participating in the study may 
not be withdrawn from the 
study. 
To correct a typographical error that was 
contradicting text in Section 2.3.2.1 that in 
the event of a pregnancy in a study subject, 
the subject will be discontinued from study 
drug. 
 
 


Protocol 
 
ALXN1840-HV-104 Amendment 1 
Page 5 of 58 
 
Alexion Confidential 
 
TABLE OF CONTENTS 
INVESTIGATOR’S AGREEMENT ...............................................................................................3 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ............................................4 
1. 
PROTOCOL SUMMARY ..........................................................................................10 
1.1. 
Synopsis ......................................................................................................................10 
1.2. 
Schema ........................................................................................................................13 
1.3. 
Schedule of Activities .................................................................................................14 
2. 
INTRODUCTION ......................................................................................................17 
2.1. 
Study Rationale ...........................................................................................................17 
2.2. 
Background .................................................................................................................17 
2.3. 
Benefit/Risk Assessment ............................................................................................20 
2.3.1. 
Identified Risks ...........................................................................................................20 
2.3.2. 
Potential Risks ............................................................................................................21 
2.3.2.1. 
Pregnancy Exposure ...................................................................................................21 
3. 
OBJECTIVES AND ENDPOINTS ............................................................................22 
4. 
STUDY DESIGN .......................................................................................................23 
4.1. 
Overall Design ............................................................................................................23 
4.2. 
Scientific Rationale for Study Design ........................................................................24 
4.3. 
Justification for Dose ..................................................................................................24 
4.4. 
End of Study Definition ..............................................................................................25 
5. 
STUDY POPULATION .............................................................................................26 
5.1. 
Inclusion Criteria ........................................................................................................26 
5.2. 
Exclusion Criteria .......................................................................................................27 
5.3. 
Lifestyle Considerations .............................................................................................28 
5.3.1. 
Meals and Dietary Restrictions ...................................................................................28 
5.3.2. 
Caffeine, Alcohol, and Tobacco .................................................................................29 
5.3.3. 
Physical Activity .........................................................................................................29 
5.4. 
Screen Failures and Replacements .............................................................................29 
5.4.1. 
Criteria for Study Termination ...................................................................................29 
6. 
STUDY DRUG ...........................................................................................................30 
6.1. 
Study Drug Administered ...........................................................................................30 
6.2. 
Packaging and labelling of IMPs ................................................................................30 


Protocol 
 
ALXN1840-HV-104 Amendment 1 
Page 6 of 58 
 
Alexion Confidential 
 
6.3. 
Preparation/Handling/Storage/Accountability ............................................................30 
6.4. 
Measures to Minimize Bias: Randomization and Blinding ........................................31 
6.5. 
Study Drug Compliance .............................................................................................31 
6.6. 
Study Drug Stopping Rules ........................................................................................31 
6.6.1. 
Adverse Reaction Rules ..............................................................................................31 
6.6.1.1. 
General Adverse Reaction rules .................................................................................31 
6.7. 
Concomitant Therapy .................................................................................................33 
6.8. 
Contraception Guidance .............................................................................................33 
6.9. 
Intervention after the End of the Study .......................................................................34 
7. 
DISCONTINUATION OF STUDY DRUG AND SUBJECT 
WITHDRAWAL ........................................................................................................35 
7.1. 
Discontinuation of Study Drug ...................................................................................35 
7.2. 
Subject Withdrawal From the Study ...........................................................................35 
7.3. 
Lost to Follow Up .......................................................................................................35 
8. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................36 
8.1. 
Efficacy Assessments .................................................................................................36 
8.2. 
Safety Assessments .....................................................................................................36 
8.2.1. 
Physical Examination .................................................................................................36 
8.2.2. 
Vital Signs ..................................................................................................................36 
8.2.3. 
Electrocardiograms .....................................................................................................37 
8.2.3.1. 
Recording of 12-Lead ECGs ......................................................................................37 
8.2.3.2. 
Safety Review of 12-Lead ECGs ................................................................................37 
8.2.4. 
Clinical Safety Laboratory Assessments ....................................................................37 
8.2.5. 
Drug and Alcohol Screen ............................................................................................38 
8.2.6. 
Pregnancy Testing ......................................................................................................38 
8.3. 
Adverse Events and Serious Adverse Events .............................................................38 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE Information .......................38 
8.3.2. 
Method of Detecting AEs and SAEs ..........................................................................39 
8.3.3. 
Follow-up of AEs and SAEs .......................................................................................39 
8.3.4. 
Regulatory Reporting Requirements for SAEs ...........................................................39 
8.3.5. 
Pregnancy ...................................................................................................................40 
8.4. 
Safety Review Committee ..........................................................................................40 
8.5. 
Treatment of Overdose ...............................................................................................40 


Protocol 
 
ALXN1840-HV-104 Amendment 1 
Page 7 of 58 
 
Alexion Confidential 
 
8.6. 
Pharmacokinetics ........................................................................................................40 
8.7. 
Pharmacodynamics .....................................................................................................40 
8.8. 
Genetics ......................................................................................................................41 
8.9. 
Biomarkers ..................................................................................................................41 
9. 
STATISTICAL CONSIDERATIONS .......................................................................42 
9.1. 
Statistical Hypotheses .................................................................................................42 
9.2. 
Sample Size Determination ........................................................................................42 
9.3. 
Populations for Analyses ............................................................................................42 
9.4. 
Statistical Analyses .....................................................................................................42 
9.4.1. 
Efficacy Analyses .......................................................................................................43 
9.4.2. 
Safety Analyses ..........................................................................................................43 
9.4.3. 
Other Analyses ............................................................................................................43 
9.4.3.1. 
Pharmacokinetic Analyses ..........................................................................................43 
9.5. 
Interim Analyses .........................................................................................................44 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ..................................................................................................45 
10.1. 
Regulatory, Ethical, and Study Oversight Considerations .........................................45 
10.1.1. 
Regulatory and Ethical Considerations ......................................................................45 
10.1.2. 
Financial Disclosure ...................................................................................................45 
10.1.3. 
Informed Consent Process ..........................................................................................45 
10.1.4. 
Data Protection ...........................................................................................................46 
10.1.5. 
Dissemination of Clinical Study Data ........................................................................46 
10.1.6. 
Data Quality Assurance ..............................................................................................46 
10.1.7. 
Source Documents ......................................................................................................47 
10.1.8. 
Study and Site Closure ................................................................................................47 
10.1.9. 
Publication Policy .......................................................................................................48 
10.2. 
Clinical Laboratory Tests ...........................................................................................49 
10.3. 
Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ...........................................................................................50 
10.3.1. 
Adverse Event Definition ...........................................................................................50 
10.3.2. 
Adverse Reaction Definition ......................................................................................50 
10.3.3. 
Serious Adverse Event Definition ..............................................................................51 
10.3.4. 
Suspected Unexpected Serious Adverse Reactions ....................................................51 


Protocol 
 
ALXN1840-HV-104 Amendment 1 
Page 8 of 58 
 
Alexion Confidential 
 
10.3.5. 
Recording and Follow-Up of AEs and/or SAEs .........................................................52 
10.3.6. 
Reporting of Serious Adverse Events .........................................................................53 
10.4. 
Contraceptive Guidance and Collection of Pregnancy Information ...........................54 
10.5. 
Abbreviations ..............................................................................................................56 
11. 
REFERENCES ...........................................................................................................58 


Protocol 
 
ALXN1840-HV-104 Amendment 1 
Page 9 of 58 
 
Alexion Confidential 
 
LIST OF TABLES 
Table 1: 
Schedule of Study Visits and Assessments – Screening Through End of 
Study ...........................................................................................................................14 
Table 2: 
Schedule of Study Visits and Assessments – Continued ............................................16 
Table 3: 
Total Molybdenum Pharmacokinetic Parameters From Study WTX101-101 ...........18 
Table 4: 
Total Mo PK Parameters From Study WTX101-102 .................................................19 
Table 5: 
Study ALXN1840-HV-104 Objectives and Endpoints ..............................................22 
Table 6: 
Study Drug Dosing Sequences ...................................................................................23 
Table 7: 
Study Drug Dosing .....................................................................................................24 
Table 8: 
Study Drug Administered ...........................................................................................30 
Table 9: 
Study ALXN1840-HV-104 Analysis Sets ..................................................................42 
Table 10: Protocol-Required Safety Laboratory Assessments ...................................................49 
Table 11: List of Abbreviations and Definitions of Terms .........................................................56 
 
LIST OF FIGURES 
Figure 1: 
Study ALXN1840-HV-104 Schematic .......................................................................13 
 
 


Protocol 
 
ALXN1840-HV-104 Amendment 1 
Page 10 of 58 
 
Alexion Confidential 
 
1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Protocol Title: A Phase 1, Randomized, Open-Label, 2-Way Crossover Study to Assess the 
Single-Dose Pharmacokinetics of ALXN1840 Enteric-Coated Tablets at 2 Dose Strengths in 
Healthy Adult Subjects.  
Short Title: Pharmacokinetic Study of Oral ALXN1840 at 2 Dose Strengths in Healthy Adult 
Subjects.  
Rationale: 
The 5 mg ALXN1840 dose has been manufactured and selected to be tested in this study to 
support dosing in pediatric patients with Wilson disease (WD), in whom a lower starting dose 
than the starting dose for adult patients may be warranted.  
The 15 mg enteric-coated (EC) tablet formulation is the current one being tested in the on-going 
Phase 3 Study WTX101-301. The 5 mg EC tablet formulation is new and has not been tested in 
humans. The per-period 15 mg ALXN1840 total dose selected for this study in healthy subjects 
is within the dose range demonstrated to be safe in healthy subjects and has demonstrated a 
favorable safety profile and treatment effects in patients with WD. Oral doses of 60 mg 
ALXN1840 in non-coated capsules or EC tablets (30 mg formulation), were tested in previous 
3-period crossover bioavailability studies conducted in healthy male and female volunteers 
(Studies WTX101-101 and WTX101-102), and were considered to have a favorable safety 
profile and to be well tolerated. ALXN1840 doses of 15 to 120 mg/day (15 mg EC tablets or 
30 mg capsules) have been tested in the Phase 2 Study WTX101-201 in patients with WD, with 
a favorable safety profile. In the on-going Phase 3 Study WTX101-301, patients are to start with 
a dose of 15 mg/day, followed by individualized dose titrations ranging from 15 mg/every other 
day and up to 60 mg/day. In summary, to date, 15 to 60 mg/day single or repeated daily doses 
have shown to have favorable safety profiles and to be well tolerated throughout the Phase 1 to 
Phase 3 clinical studies, in both healthy subjects and patients with WD.  
 


Protocol 
 
ALXN1840-HV-104 Amendment 1 
Page 11 of 58 
 
Alexion Confidential 
 
Objectives and Endpoints  
Objectives 
Endpoints 
Primary 
• 
To assess the relative bioavailability of ALXN1840 
administered orally as 3 × 5 mg EC tablets (test) 
versus 1 × 15 mg EC tablet (reference) 
• 
PK parameters for plasma total Mo (Cmax, 
AUCt, and AUC∞) 
Secondary 
• 
To assess the overall safety and tolerability of 
ALXN1840 
• 
Safety assessed by incidence of TEAEs 
and TESAEs, physical examination, vital 
signs measurements, clinical laboratory 
and 12-lead ECG results 
Exploratory 
• 
Relationships between CL/F and body size — body 
weight (kg) and body mass index (BMI, kg/m²) 
• 
CL/F, body weight, and body mass index 
• 
To explore PD and biomarkers of 15 mg 
ALXN1840 among the following dosing regimens: 
either as a single 15 mg EC tablet (Treatment A) or 
3 EC tablets of 5 mg (Treatment B) 
• 
Absolute and percent changes of plasma 
copper levels (total Cu, Cp, CpC and NCC) 
• 
The NCC level will be corrected for the 
amount of Cu bound to the TPC 
(NCCcorrected) 
Abbreviations: AUC∞ =  area under the plasma concentration versus time curve from zero 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 = clearance/bioavailability; Cmax = maximum observed concentration; Cp = ceruloplasmin; 
CpC = ceruloplasmin-bound copper; Cu = copper; EC = enteric-coated; Mo = molybdenum; 
ECG = electrocardiogram; NCC = non-ceruloplasmin-bound copper; NCCcorrected = NCC level corrected for the 
amount of Cu bound to the TPC; PD = pharmacodynamic(s); PK = pharmacokinetic(s); 
TEAE = treatment-emergent adverse events; TESAE = treatment-emergent serious adverse event; 
TPC = Cu-tetrathiomolybdate-albumin tripartite complex formed after ALXN1840 administration. 
Overall Design: 
This is a single-center, randomized, open-label, 2-way crossover study to assess the single-dose 
pharmacokinetics (PK) of ALXN1840 EC tablets at 2 dose strengths in healthy male and female 
adult subjects under fasting conditions. Pharmacokinetic parameters will be calculated based on 
the measurement of plasma total molybdenum (Mo) concentration. A total of 48 healthy, adult 
participants (20-28 male and 20-28 female) who complete the study screening assessments and 
meet all eligibility criteria will be enrolled to allow for a minimum of 40 subjects to complete the 
study (20-24 subjects in each sequence, 10-14 of each sex in each sequence).   
The study has a Screening Period (Days -28 to -2), 2 Dosing Periods (Day -1 to Day 11 each), 
and an end-of-study (EOS) visit 14 days (+ 2 days) post final dose. After completing the 
Screening Period, enrolled subjects will be admitted to an inpatient facility (Clinical Research 
Unit [CRU]) on Day -1 for dosing on Day 1 in Dosing Period 1. Subjects will be readmitted to 
the CRU for Dosing Period 2 following a minimum of 14 days after the previous dose. 
In each Dosing Period, subjects will receive 1 of the 2 treatments as outlined below:  
Treatment A (reference) 
1 × 15 mg ALXN1840 EC tablet 
Treatment B (test) 
3 × 5 mg ALXN1840 EC tablets 
Abbreviation: EC = enteric-coated. 


Protocol 
 
ALXN1840-HV-104 Amendment 1 
Page 12 of 58 
 
Alexion Confidential 
 
Subjects will return to the CRU 14 days (+2 days) after the final dose of study drug for the EOS 
visit with follow-up procedures, and to determine if any adverse event (AE) has occurred since 
the last study visit. If subjects withdraw from the study early, they will be seen and assessed by 
the Investigator, whenever possible, to undergo the procedures associated with the EOS visit. 
Subjects may be replaced at the discretion of the Sponsor.  
The study will be conducted at a single site in the UK. 
Number of Subjects:  
A total of 48 subjects will be enrolled (20-28 male subjects and 20-28 female subjects) to ensure 
a minimum sample size of 40 subjects (20-24 subjects in each sequence, 10-14 of each sex in 
each sequence) complete the study. 
Intervention Groups and Duration: 
Each subject will receive both treatments in 1 of the 2 sequences as defined in the table below 
according to the study drug dosing regimen outlined above, where the single 15 mg EC tablet 
(Treatment A) is the "reference" dose and the 3 EC tablets of 5 mg (Treatment B) are the "test" 
dose. 
Sequence 
Number 
Treatment Sequence 
Malea 
Femalea 
Total 
Period 1 
Period 2 
1 
A 
B 
10-14 
10-14 
24 
2 
B 
A 
10-14 
10-14 
24 
Total 
20-28 
20-28 
48 
a In an effort to achieve balance between males and females in each sequence, there will be no less than 20 and no 
more than 28 of either sex (ie, a maximum split in either direction of approximately 60%:40%). 
The planned study duration is approximately 70 days; up to 27 days for screening, approximately 
29 days for dosing and follow-up, and an interval of at least 14 days between the 2 Dosing 
Periods.  
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 
 
ALXN1840-HV-104 Amendment 1 
Page 13 of 58 
 
Alexion Confidential 
 
Statistical Analyses: 
The primary objective of this study is to assess the relative bioavailability of 3 × 5 mg EC 
tablets (test) versus 1 × 15 mg EC tablet (reference). Although there will be no formal 
bioequivalence test, the framework of 2 one-sided tests, with limits of 0.8 and 1.25, can be 
applied to assess the adequacy of the sample size. A post-hoc analysis of a previous 
bioavailability study (Study WTX101-102) found a within-subjects coefficient of variation (CV) 
of 0.34. For data from a two-period cross-over design, a total sample size of 40 subjects achieves 
81% power at a 5% significance level when the true ratio of the means is 1, and the coefficient of 
variation is 0.34.  
1.2. 
Schema 
Figure 1: 
Study ALXN1840-HV-104 Schematic  
 
 
* 
Subjects will leave the Clinical Research Unit on Day 11 of Dosing Period 1 and will be readmitted following a 
minimum of 14 days after the dose of study drug for Dosing Period 2.  
** EOS visit to be performed 14 days (+2 days) after the final dose of study drug. 
Abbreviations: EOS = end of study, PD = pharmacodynamics; PK = pharmacokinetics. 
Day           -1             1
2            3            4             5             6              7             8              9           10          11             12  
14 + 2
Screening
Days -28 to -2
ALXN1840
Administration*
EOS Visit**
Inpatient stay at the Clinical Research Unit
Safety and Tolerability
PK/PD
Dosing Periods 1 and 2


Protocol 
 
ALXN1840-HV-104 
Page 14 of 58 
 
Alexion Confidential 
 
1.3. 
Schedule of Activities 
Table 1: 
Schedule of Study Visits and Assessments – Screening Through End of Study  
 Screeninga 
Study Days in Each Dosing Periodb 
EOS or 
ETc 
Dosing Period 1: Days/Hours → -28 to -2 
-1d 
1 
2/24 
3/48 
4/72 
5/96 
6/120 7/144 
8/168 
9/192 10/216 11/240 
14 + 2 
Dosing Period 2: Days/Hours → 
 
 
1 
2/24 
3/48 
4/72 
5/96 
6/120 7/144 
8/168 
9/192 10/216 11/240 
 
Informed consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteriad 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
xe 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examinationf 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
x 
Height, weight, and BMI 
x 
 
 
 
 
 
 
 
 
 
 
 
 
x 
12-Lead ECGg 
x 
 
xh 
x 
 
 
x 
 
 
 
 
 
 
x 
Vital signs (heart rate, BP, RR & T)i 
xg 
 
xh 
x 
 
 
x 
 
 
 
 
 
 
x 
Hematology, chemistry, urinalysis, 
and coagulationh 
x 
 
xh 
x 
 
 
x 
 
 
 
 
xj 
 
x 
Serum Cp and Cu 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy test (females only)k 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
x 
FSH (postmenopausal females only) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol breath test and urine drug 
screen 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
HIV antibody/hepatitis B and C screen 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE monitoring 
 
Concomitant medications 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Study drug administrationl 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
Plasma PK/PD biomarker samplesm 
 
 
xh 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Inpatient stay in the CRU 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Outpatient visits 
x 
 
 
 
 
 
 
 
 
 
 
 
 
x 
a Within 28 days prior to Day -2 of the first dose of study drug in Dosing Period 1. Note that Screening only occurs once. 
b After completion of Dosing Period 1, subjects 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.  
c Subjects will return to the CRU 14 days (+2 days) following the final dose of study drug in Dosing Period 2 for an EOS evaluation. In the event of ET, the 
procedures listed at the EOS are performed prior to subject discharge.  


Protocol 
 
ALXN1840-HV-104 
Page 15 of 58 
 
Alexion Confidential 
 
d 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 patient is 
able to continue in the study.  
e Randomization is to occur after the subject has met all inclusion and no exclusion criteria on Day -1 in Dosing Period 1 
f 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.  
g 12-lead ECG in triplicate will be taken 0.5 hours pre-dose, at 4 hours post-dose (before lunch) on Days 1, Day 2 and Day 5 (see Table 2), and at EOS for each 
Dosing Period. 12-lead ECG in triplicate will be conducted before PK/PD/biomarker blood sampling if these 2 events occur at the same time. 
h See Table 2 for details  
i At screening, supine and standing (orthostatic) blood pressures will be performed to exclude volunteers with orthostatic hypotension. Standing blood pressure 
will be measured after subjects have been standing for 1 minute.  
j Samples for urinalysis and coagulation will not be obtained on Day 10. 
k Serum pregnancy test is not required if the subject is confirmed to be post-menopausal.   
l Study drug dosing will occur with the subject being in a fasted state.  
m Blood samples for the measurement of plasma total Mo (PK) and total Cu, Cp, CpC, and NCC/NCCcorrected (PD)  
Abbreviations: AE = adverse event; BMI = body mass index; BP = blood pressure; Cp = ceruloplasmin; CpC = ceruloplasmin-bound copper; CRU = Clinical 
Research Unit; Cu = copper; EOS/ET = End of Study or Early Termination; FSH = follicle stimulating hormone; Mo = molybdenum; NCC = non-
ceruloplasmin-bound copper; NCCcorrected = NCC level corrected for the amount of Cu bound to the Cu-tetrathiomolybdate-albumin tripartite complex formed 
after ALXN1840 administration; PK = pharmacokinetics; RR = respiration rate; T = temperature. 
 


Protocol 
 
ALXN1840-HV-104 
Page 16 of 58 
 
Alexion Confidential 
 
Table 2: 
Schedule of Study Visits and Assessments – Continued 
Study Day 
Time 
(hour) 
PK/PD/Biomarker 
Samples 
Vital Signs 
Hematology, Chemistry, 
Urinalysis, and Coagulation 
12-lead ECGa 
D1 
-2 
 
 
 
 
-1 
 
 
 
 
-0.5 
X 
X 
X  
X 
0b 
 
 
 
 
1 
X 
X 
 
 
2 
X 
 
 
 
3 
X 
 
 
 
4 
X 
X 
X 
Xc 
5 
X 
 
 
 
6 
X 
 
 
 
8 
X 
X 
 
 
12 
X 
X 
 
 
D2 
24 
X 
X 
X 
X 
D3 
48 
X 
 
 
 
D4 
72 
X 
 
 
 
D5 
96 
X 
X 
X 
X 
D6 
120 
X 
 
 
 
D7 
144 
X 
 
 
 
D8 
168 
X 
 
 
 
D9 
192 
X 
 
 
 
D10 
216 
X 
 
Xd 
 
D11 
240 
X 
 
 
 
a 12-lead ECG in triplicate will be conducted before PK/PD/biomarker blood sampling if these 2 events occur at the same time. 
b Hour 0 corresponds to the time of ALXN1840 administration. Unless stated otherwise, times listed are in relation to ALXN1840 dosing. 
c 12-lead ECG in triplicate will be performed 4 hours post-dose (before lunch). 
d On Day 10, only chemistry, hematology, and non-fasting safety blood samples will be obtained. Samples for urinalysis and coagulation will not be obtained. 
Abbreviations: D = day; PD = pharmacodynamic(s); PK = pharmacokinetic(s). 
 
 


Protocol 
 
ALXN1840-HV-104 
Page 17 of 58 
 
Alexion Confidential 
 
2. 
INTRODUCTION 
2.1. 
Study Rationale 
This study will assess the pharmacokinetics (PK) and safety of ALXN1840 EC tablets in healthy 
adult subjects at 2 dose strengths.  
2.2. 
Background 
ALXN1840 (bis-choline tetrathiomolybdate; formerly known as WTX101) is a novel, 
first-in-class, copper (Cu)-protein binding agent in development for the treatment of WD. 
ALXN1840 is targeted to address the following unmet medical needs: 
• Rapid and sustained control of Cu and clinical symptoms of WD through the rapid 
formation of irreversible Cu-tetrathiomolybdate-protein complexes, leading to rapid 
Cu control without mobilizing free Cu that could cause tissue toxicity, including 
neurological deterioration that has been reported at the initiation of treatment with 
chelators. This hypothesis is supported by results from Study WTX101-201 in 
patients with WD (Weiss, 2017).  
• Improved compliance over current chelator therapy through improved tolerability and 
the convenience of a simplified dosing regimen (once daily [QD]) compared to current 
therapeutic options (multiple daily dosing).  
ALXN1840 has been selected for development in WD due to its improved stability properties 
over ammonium tetrathiomolybdate, which has previously been studied in 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.   
Two Phase 1 healthy subject studies (WTX101-101 and WTX101-102, N = 18 for each study) to 
assess the PK of ALXN1840 have been completed. Total plasma molybdenum (Mo) 
concentrations were used as a surrogate PK measure for tetrathiomolybdate.   
Study WTX101-101 evaluated the relative exposure of 60 mg ALXN1840 (2 × 30 mg uncoated 
capsules [UCs]) without and with co-administration of a long-acting proton pump inhibitor (PPI) 
under fasted conditions, the latter also under fed conditions. Based on total plasma Mo, 
administration of the UC + PPI under fasted conditions resulted in a 30% increase in exposure 
compared to the UC alone. Administration of the UC + PPI fed resulted in a 22% decrease in 
exposure compared to the UC + PPI fasted. There was a decrease in the between-subject 
variability when the UC was administered with a PPI. The mean terminal elimination half-life 
(t½) for total Mo was similar for all 3 treatments, with an overall mean of approximately 
51 hours, or slightly over 2 days (Table 3).   
 


Protocol 
 
ALXN1840-HV-104 
Page 18 of 58 
 
Alexion Confidential 
 
Table 3: 
Total Molybdenum Pharmacokinetic Parameters From Study WTX101-101  
Parametera 
Treatment 
UC Fasted 
UC + PPI Fasted 
UC + PPI Fed 
Cmax (ng/mL) 
331 ± 122 (18) 
401 ± 78.3 (18) 
385 ± 71.3 (18) 
tmax (h) 
4.48 (18) [1.08 – 10.0] 
4.48 (18) [2.98 – 6.02] 
5.99 (18) [3.48 – 8.02] 
AUC(0-t) (h*ng/mL) 
14,600 ± 7,023 (18) 
18,537 ± 4,303 (18) 
14,536 ± 3,663 (18) 
AUC∞ (h*ng/mL) 
16,435 ± 7,126 (17) 
19,862 ± 4,665 (18) 
15,603 ± 3,921 (18) 
z (1/h) 
0.0137 ± 0.0035 (17) 
0.0140 ± 0.0019 (18) 
0.0142 ± 0.0031 (18) 
t½ (h) 
53.1 ± 11.6 (17) 
50.6 ± 7.46 (18) 
50.7 ± 9.05 (18) 
CL/F (L/h) 
1.01 ± 0.54 (17) 
0.72 ± 0.21 (18) 
0.94 ± 0.38 (18) 
Vz/F (L) 
75.0 ± 38.9 (17) 
52.1 ± 17.4 (18) 
65.6 ± 17.1 (18) 
a Arithmetic mean ± standard deviation (n) except for tmax for which the median (n) [range] is reported. 
Abbreviations: AUC∞ = area under the plasma concentration versus time curve with the last concentration 
extrapolated based on the z; AUC(0-t) = area under the plasma concentration versus time curve to the last 
measurable concentration; CL/F = Clearance/bioavailability; Cmax = maximum observed concentration; 
z = elimination rate constant; PPI = proton pump inhibitor; t½ = terminal elimination half-life; tmax = time to 
maximum concentration; UC = uncoated capsule; Vz/F = apparent volume of distribution. 
A total of 18 subjects were enrolled in Study WTX101-101, completed the study, and were 
included in the safety analysis. There were no deaths, serious adverse events (SAEs), or 
discontinuations due to adverse event (AEs) in the study. Overall, a total of 39 AEs were 
experienced by 12 (67%) subjects in this study. The percentages of subjects reporting AEs were 
similar following each of the 3 study treatments. Of the 39 AEs reported during the study, 38 
AEs were mild (Grade 1) and 1 AE was moderate (Grade 2) in severity. One subject experienced 
2 laboratory AEs of decreased hematocrit and decreased hemoglobin which were considered 
possibly related to study drug by the Investigator; however, both of these laboratory AEs were 
reported prior to dosing with ALXN1840 administration. Headache, contact dermatitis and sinus 
congestion were the most common AEs reported during the study and were reported by 
3 to 6 (17% to 33%) subjects each. There was 1 AE considered by the Investigator to be likely 
related to study drug (headache) and 10 AEs considered to be possibly related to study drug; all 
other AEs were considered by the Investigator to be unlikely related or unrelated to study drug. 
There were no clinically important trends in the laboratory, vital signs, ECG, or physical 
examination assessments in the study.  
Study WTX101-102 evaluated the relative exposure of ALXN1840 from an enteric-coated (EC) 
tablet under fed and fasting conditions compared to the current non-coated capsule (also referred 
to as UC) administered with a PPI (under fasting conditions) in order to confirm the in vivo 
performance characteristics, including the absorption profile, and food effect of the EC tablet in 
humans. There was a slight decrease in the plasma concentrations of total Mo after 
administration of the EC tablet fasted compared to the UC + PPI fasted. Similar trends were 
observed with respect to maximum observed concentration (Cmax), area under the plasma 
concentration versus time curve (AUC) to the last measurable concentration (AUC[0-t]), and AUC 
with the last concentration extrapolated based on the elimination rate constant (z) (AUC[inf]). 


Protocol 
 
ALXN1840-HV-104 
Page 19 of 58 
 
Alexion Confidential 
 
Nevertheless, examination of the individual subject data indicated that while a similar pattern 
was observed with some of the individual subjects, the majority of the subjects had a total Mo 
concentration-time profile that was comparable for the EC tablet and UC + PPI when both were 
administered under fasted conditions. However, administration of the EC tablet fed resulted in a 
60% to 75% decrease in absorption which was consistent among the majority of subjects. The 
mean t½ was essentially the same for all 3 treatments, with an overall mean of approximately 
48 hours or 2 days (Table 4).  
Table 4: 
Total Mo PK Parameters From Study WTX101-102  
Parametera 
Treatment 
EC Tablet Fasted 
EC Tablet Fed 
UC + PPI Fasted 
Tlag (h) 
2.00 (4) 
3.00 (6) 
---b 
Cmax (ng/mL) 
376 ± 98.0 (18) 
187 ± 118 (17) 
442 ± 69.6 (18) 
tmax (h) 
4.54 (18) [3.00 – 9.53] 
4.55 (17) [3.52 – 9.51] 
4.50 (18) [2.99 – 10.0] 
AUC(o-t) (h*ng/mL) 
16,026 ± 5,635 (18) 
5,740 ± 4,681 (17) 
19,809 ± 3,509 (18) 
AUC∞ (h*ng/mL) 
17,258 ± 5,955 (18) 
6,973 ± 5,065 (15) 
21,047 ± 4,022 (17) 
z (1/h) 
0.0149 ± 0.0023 (18) 
0.0258 ± 0.0303 (15) 
0.0145 ± 0.0014 (17) 
t½ (h) 
51.0 ± 8.87 (18) 
43.5 ± 20.9 (15) 
48.2 ± 4.86 (17) 
CL/F (L/h) 
0.92 ± 0.51 (18) 
6.34 ± 11.9 (15) 
0.66 ± 0.13 (17) 
Vz/F (L) 
66.6 ± 34.0 (18) 
175 ± 98.1 (15) 
45.2 ± 8.31 (17) 
a  Arithmetic mean ± standard deviation (N) except for tmax for which the median (N) [Range] is reported.  
b  Parameter could not be estimated for any subject for this treatment. 
Abbreviations: AUC∞ = area under the plasma concentration versus time curve with the last concentration 
extrapolated based on the z; AUC(0-t) = area under the plasma concentration versus time curve to the last 
measurable concentration; CL/F = clearance/bioavailability; Cmax = maximum observed concentration; 
EC = enteric-coated; z = elimination rate constant; PK = pharmacokinetic(s); PPI = proton pump inhibitor; 
t½ = terminal elimination half-life; Tlag = lag time; tmax = time to maximum concentration; UC = uncoated capsule; 
Vz/F = apparent volume of distribution. 
A total of 18 subjects were enrolled, completed the study, and were included in the safety 
analysis. There were no deaths, SAEs, or discontinuation due to AEs in this study. Overall, a 
total of 21 AEs were reported by 7 (39%) subjects in this study. The percentages of subjects 
reporting AEs following ALXN1840 dosing were similar following each of the 3 study 
treatments. All AEs reported in the study were mild (Grade 1) in severity. Diarrhea, headache, 
and nasal congestion were the most frequently reported AEs in this study and were each reported 
by 2 (11%) subjects. There was 1 AE considered by the Investigator to be probably related to 
study drug (nausea) and 5 AEs considered to be possibly related to study drug (4 events of 
diarrhea and 1 event of nausea); all other AEs were considered to be unrelated to the study drugs. 
There were no clinically important trends in the laboratory, vital sign, ECG, or physical 
examination assessments in this study.  
There were no apparent relationships between clearance/bioavailability (CL/F) and body size 
(weight, body mass index) in either Study WTX101-101 or Study WTX101-102, suggesting that 
a fixed dose, rather than a dose based on body size (ie, mg/kg or mg/m²) may be appropriate for 
ALXN1840.  
ALXN1840 has been evaluated in 28 patients with WD in the Phase 2 Study WTX101-201. Final 
results from the main 24-week study showed that ALXN1840 monotherapy reduced mean serum 
non-ceruloplasmin-bound Cu by 72% at Week 24 compared with baseline. ALXN1840 treatment 
also resulted in significant improvements in neurological status and disability measured as a 


Protocol 
 
ALXN1840-HV-104 
Page 20 of 58 
 
Alexion Confidential 
 
change from baseline in Unified WD Rating Scale (UWDRS) Part III and Part II, respectively. In 
addition, liver status, as measured by the Modified Nazer Score and model for end-stage liver 
disease (MELD), was stabilized or improved in the majority of patients. Treatment with 
ALXN1840 was generally well-tolerated, with most reported AEs being mild (Grade 1) to 
moderate (Grade 2). Reversible liver function test elevations were observed in 39% of patients; 
these elevations were mild to moderate, asymptomatic, were associated with no notable increases 
in bilirubin (ie, no documented case of Hy’s Law), and normalized with dose reduction or 
treatment interruption. No paradoxical neurological worsening was observed upon treatment 
initiation with ALXN1840 (Weiss, 2017). All subjects who completed the 24-week Dosing 
Period were enrolled in a 36-month Extension Phase. Preliminary available follow-up data at 
48 weeks from the ongoing 36-month Extension Phase of the study were consistent with the 
24-week Dosing Period results. No clear dose-proportionality was observed in 
Study WTX101-201. This result may have been due to the small sample size and relatively high 
inter-subject variability.   
In a previous oncology study (PH1/097) with 18 patients with solid tumors, 90 mg to 210 mg of 
ALXN1840 co-administered with PPI showed a dose-related increase of exposure  
(Lowndes, 2008).  
In total, tetrathiomolybdate has been evaluated in nearly 600 patients in studies of WD, 
oncology, macular degeneration, and primary biliary cirrhosis indications using either the 
ammonium or the bis-choline tetrathiomolybdate salt forms, and in 36 healthy volunteers in 
Phase 1 studies. ALXN1840 has been generally well-tolerated, and the most frequently reported 
drug-related AEs were changes in hematological parameters, fatigue, sulphur eructations, and 
other gastrointestinal (GI) symptoms. Aminotransferase elevations were much less common in 
subjects without WD compared with patients with WD; however, it should be noted that in the 
oncology program, which constitutes the majority of subjects without WD, causality of 
tetrathiomolybdate for these elevations was difficult to establish due to underlying disease. 
Detailed descriptions of the chemistry, pharmacology, efficacy, and safety of ALXN1840 are 
provided in the Investigator’s Brochure (IB).  
2.3. 
Benefit/Risk Assessment 
This is a healthy volunteer study and there is no direct benefit to study subjects. Identified and 
potential risks are described below.   
More information about the known and expected benefits and risks and reasonably expected AEs 
with ALXN1840 may be found in the current edition of the IB.  
2.3.1. 
Identified Risks 
Many of the potential risks of ALXN1840 to patients with WD are not relevant to healthy 
volunteers; therefore, only those expected to be relevant risks for healthy subjects are discussed 
in this section.  
In patients with WD, who received multiple daily doses of ALXN1840, the most commonly 
experienced potential drug effects were increased alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), gamma glutamyltransferase (without increased bilirubin). Increases 


Protocol 
 
ALXN1840-HV-104 
Page 21 of 58 
 
Alexion Confidential 
 
occurred 4-10 weeks after daily dosing at 30 mg/day or higher. All were asymptomatic. Liver 
function tests normalized within 1-2 weeks of dose adjustments/treatment interruption.  
Three patients with ALT increases of between 14.3 times and 29.3 times from baseline 
discontinued treatment. The second highest ALT (615 IU/L) concentration occurred in a patient 
who had initially received 120 mg/day of ALXN1840. The highest ALT (1341 IU/L) 
concentration occurred in a patient who had ALT elevations with previous penicillamine 
treatment. None of these 3 patients had a notable bilirubin increase, and all abnormal liver tests 
were reversible.  
Other side effects observed with ALXN1840 with potential significance for the participating 
healthy subjects were thrombocytopenia, neutropenia, and anemia. In all cases, treated patients 
recovered after dose reduction.  
All potential drug effects were reversible and only experienced after several weeks of daily 
dosing in patients with WD. The healthy volunteers in this study will receive 2 single doses of 
ALXN1840, a minimum of 14 days apart, which will also reduce the risk of adverse effects. The 
doses they will receive (as well as higher doses) have already been extensively tested in patients 
with WD.  
Subjects will be closely monitored and remain in the CRU for a minimum of 10 days following 
each single dose administration. Safety blood samples will be taken at Screening and Day -1, 
Day 1 (4 hours post-dose), Day 2 (24 hours post-dose), Day 5 (96 hours post-dose), and Day 10 
(216 hours post-dose), prior to discharge from the CRU, as well as at the EOS or Early 
Termination (ET) visit (if applicable).   
2.3.2. 
Potential Risks 
2.3.2.1. 
Pregnancy Exposure 
No studies of ALXN1840 have been conducted in pregnant women. Pregnant or breastfeeding 
subjects will be excluded from the clinical study. To avoid pregnancy, appropriate precautions 
will be taken for subjects of childbearing potential as required in Section 6.8. In the event of a 
pregnancy in a study subject, the subject will be discontinued from study drug (Section 7) and 
followed up in accordance with Section 10.4.  


Protocol 
 
ALXN1840-HV-104 
Page 22 of 58 
 
Alexion Confidential 
 
3. 
OBJECTIVES AND ENDPOINTS 
The study objectives and corresponding endpoints are presented in Table 5. 
Table 5: 
Study ALXN1840-HV-104 Objectives and Endpoints  
Objectives 
Endpoints 
Primary 
• 
To assess the relative bioavailability of ALXN1840 
administered orally as 3 × 5 mg EC tablets (test) 
versus 1 × 15 mg EC tablet (reference) 
• 
PK parameters for plasma total Mo (Cmax, AUCt, 
and AUC∞) 
Secondary 
• 
To assess the overall safety and tolerability of 
ALXN1840 
• 
Safety assessed by incidence of TEAEs and 
TESAEs, physical examination, vital signs 
measurements, clinical laboratory, and 12-lead ECG 
results 
Exploratory 
• 
Relationships between CL/F and body size — body 
weight (kg) and body mass index (BMI, kg/m²) 
• 
CL/F, body weight, and body mass index 
• 
To explore PD and biomarkers of 15 mg 
ALXN1840 among the following dosing regimens: 
either as a single 15 mg EC tablet (Treatment A) or 
3 EC tablets of 5 mg (Treatment B) 
• 
Absolute and percent changes of plasma copper 
levels (total Cu, Cp, CpC and NCC) 
• 
The NCC level will be corrected for the amount of 
Cu bound to the TPC (NCCcorrected) 
Abbreviations: AUC∞ = area under the plasma concentration versus time curve from zero 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 = clearance/bioavailability; Cmax = maximum observed concentration; Cp = ceruloplasmin; 
CpC = ceruloplasmin-bound copper; Cu = copper; EC = enteric-coated; Mo = molybdenum; NCC = non-
ceruloplasmin-bound copper; NCCcorrected = NCC level corrected for the amount of Cu bound to the TPC; 
PD = pharmacodynamic(s); PK = pharmacokinetic(s); TEAE = treatment-emergent adverse events; 
TESAE = treatment-emergent serious adverse event; TPC = Cu-tetrathiomolybdate-albumin tripartite complex 
formed after ALXN1840 administration. 


Protocol 
 
ALXN1840-HV-104 
Page 23 of 58 
 
Alexion Confidential 
 
4. 
STUDY DESIGN 
4.1. 
Overall Design 
This is a single-center, randomized, open-label, 2-way crossover study to assess the single-dose 
PK of ALXN1840 EC tablets at 2 dose strengths healthy male and female adult subjects under 
fasting conditions. Pharmacokinetic parameters will be calculated based on the measurement of 
plasma total Mo concentration. A total of 48 healthy, adult participants (20-28 males and 
20-28 females) who complete the study screening assessments and meet all eligibility criteria 
will be enrolled to allow for a minimum of 40 subjects to complete the study (20-24 subjects in 
each sequence, 10-14 of each sex in each sequence).   
The study has a Screening Period (Days -28 to -2), 2 Dosing Periods (Day -1 to Day 11 each), 
and an end-of-study (EOS) visit 14 days (+ 2 days post final dose). After completing the 
Screening Period, enrolled subjects will be admitted to an inpatient facility (Clinical Research 
Unit [CRU]) on Day -1 for dosing on Day 1 in Dosing Period 1. Subjects will be readmitted to 
the CRU for Dosing Period 2 following a minimum of 14 days after the previous dose. 
Subjects will be randomized to 1 of the 2 treatment sequences, where the single 15 mg EC tablet 
(Treatment A) is the "reference" dose and the 3 EC tablets of 5 mg (Treatment B) are the "test" 
dose, as defined in Table 6.   
Table 6: 
Study Drug Dosing Sequences 
Sequence 
Number 
Treatment Sequence 
Malea 
Femalea 
Total 
Period 1 
Period 2 
1 
A 
B 
10-14 
10-14 
24 
2 
B 
A 
10-14 
10-14 
24 
Total 
20-28 
20-28 
48 
a In an effort to achieve balance between males and females in each sequence, there will be no less than 20 and no 
more than 28 of either sex (ie, a maximum split in either direction of approximately 60%:40%). 
After completing the screening phase, enrolled subjects will be admitted to an inpatient facility 
(CRU) on Day -1 for dosing on Day 1. During Days 1 to 11 of each Dosing Period, subjects will 
remain at the CRU and have samples obtained for PK/pharmacodynamic (PD) biomarkers as 
well as safety evaluations performed according to the Schedule of Activities (Table 1 and 
Table 2). Subjects will be discharged 10 days after dosing within each Dosing Period (ie, on 
Day 11) following the 240-hour post-dose procedures, unless it is medically necessary to extend 
the confinement. Subjects will return to the CRU for Dosing Period 2 following a minimum of 
14 days between the 2 Dosing Periods.  
In each Dosing Period, subjects will receive 1 of the 2 treatments as outlined in Table 7.  


Protocol 
 
ALXN1840-HV-104 
Page 24 of 58 
 
Alexion Confidential 
 
Table 7: 
Study Drug Dosing  
Treatment A (reference) 
1 × 15 mg ALXN1840 EC tablet 
Treatment B (test) 
3 × 5 mg ALXN1840 EC tablets 
Abbreviation: EC = enteric-coated. 
Subjects will return to the CRU 14 days (+ 2 days) after the final dose of study drug for the EOS 
visit with follow-up procedures, and to determine if any AE has occurred since the last study 
visit. If subjects withdraw from the study early, they will be seen and assessed by the 
Investigator, whenever possible, to undergo the procedures associated with the EOS visit. 
Subjects may be replaced at the discretion of the Sponsor.  
The planned study duration is approximately 70 days; up to 27 days for screening, approximately 
29 days for dosing and follow-up, and an interval of at least 14 days between the 2 Dosing 
Periods.  
The study will be conducted at a single site in the UK.  
A Safety Review Committee may be used to evaluate the study data for subject safety and make 
recommendations on dose modification or termination of the study. 
4.2. 
Scientific Rationale for Study Design  
• This study is being conducted in healthy subjects and not patients with WD 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 typical Phase 1 
clinical pharmacology studies for assessing the medication of interest and to 
minimize assignment bias. 
• A 2-way crossover study design was adopted to control the variability within and 
between subjects.  
• The interval between the 2 ALXN1840 Dosing Periods will be at least 14 days, based 
on the estimated mean half-life for ALXN1840 of approximately 2 days previously 
reported in the bioavailability Studies WTX101-101 and WTX101-102, where 
healthy subjects took oral dose at 60 mg. Therefore, the 14-day interval between 
Dosing Periods is considered sufficient to eliminate, on average, approximately more 
than 99.2% of the plasma total Mo before the next dose is administered. The 14-day 
interval after Period 2 dosing will also assure that the subjects will have virtually all 
the ALXN1840 eliminated at the EOS.  
4.3. 
Justification for Dose 
The 5 mg ALXN1840 dose has been manufactured and selected to be tested in this study to 
support dosing in pediatric patients with WD, in whom a lower starting dose may be warranted. 
The 15 mg EC tablet formulation is the current formulation being tested in the on-going Phase 3 
Study WTX101-301. The 5 mg EC tablet formulation is new and has not been tested in humans. 


Protocol 
 
ALXN1840-HV-104 
Page 25 of 58 
 
Alexion Confidential 
 
The per-period 15 mg ALXN1840 total dose selected for this study in healthy subjects is within 
the dose range demonstrated to be safe in healthy subjects and has demonstrated a favorable 
safety profile and treatment effects in patients with WD. Oral doses of 60 mg ALXN1840 in 
non-coated capsules or EC tablets (30 mg formulation), were tested in previous 3-period 
crossover bioavailability studies conducted in healthy male and female volunteers (Studies 
WTX101-101 and WTX101-102), and were considered to have a favorable safety profile and to 
be well tolerated. The 15 to 60 mg/day dose range has also been demonstrated to be efficacious 
with a favorable safety profile in treating patients with WD in the Phase 2 Study WTX101-201 
(Weiss, 2017).  
In summary, to date, 15 to 60 mg/day single or repeated daily doses have shown to have 
favorable safety profiles and to be well tolerated throughout the Phase 1 to Phase 3 clinical 
studies, in both healthy subjects and patients with WD.  
4.4. 
End of Study Definition 
A subject will be considered to have completed the study if the subject has completed all periods 
of the study including the EOS visit.  
Measurement of the primary endpoint will be completed after the last visit of the last subject in 
the study. The end of the study is defined as the last visit for the last subject.  


Protocol 
 
ALXN1840-HV-104 
Page 26 of 58 
 
Alexion Confidential 
 
5. 
STUDY POPULATION 
The study population will consist of adult healthy volunteers who meet study enrollment criteria. 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted.  
5.1. 
Inclusion Criteria 
Subjects will be eligible to be included in the study only if all of the following criteria apply: 
Age/Sex 
1. Male or female subject must be 18 to 45 years of age, inclusive, at the time of signing the 
informed consent.   
Weight 
2. Body weight ≤ 100 kg and body mass index within the range 18 – 25 kg/m2, inclusive, at 
screening.   
Pregnancy  
3. Negative serum pregnancy test at screening and Day-1 for all women of childbearing 
potential.   
Contraception 
4. Female subjects of childbearing potential, if heterosexually active, and male subjects, if 
heterosexually active and with a female spouse or partner of childbearing potential or a 
pregnant or breastfeeding spouse or partner, must be willing to follow protocol-specified 
contraception guidance starting at least one menstrual cycle before first study drug 
administration and continuing for up to 3 months after the end of systemic exposure of 
the study drug (ie, 3 months after EOS visit) (described in Section 6.8).  
Other Inclusion Criteria 
5. Adequate venous access in the left or right arm to allow collection of a number of blood 
samples.  
6. Willing and able to fast per the study requirements.   
7. Satisfactory medical assessment with no clinically significant or relevant abnormalities as 
determined by medical history, physical examination, vital signs, 12-lead ECG, and 
clinical laboratory evaluation (hematology, biochemistry, coagulation, and urinalysis) 
that are reasonably likely to interfere with the subject's participation in or ability to 
complete the study, or to potentially confound interpretation of study results, as assessed 
by the Investigator.   


Protocol 
 
ALXN1840-HV-104 
Page 27 of 58 
 
Alexion Confidential 
 
Informed Consent 
8. Willing and able to give written informed consent as described in Section 10.1.3, which 
includes compliance with the requirements listed in the informed consent form (ICF) and 
in this protocol.   
5.2. 
Exclusion Criteria  
Subjects are excluded from the study if any of the following criteria apply: 
Medical Conditions 
1. Current or recurrent/chronic disease (eg, cardiovascular, hematological, neurological, 
endocrine, immunological, rheumatological, renal, hepatic or GI or other conditions) that 
or could affect clinical assessments or clinical laboratory evaluations.  
2. Current or relevant history of physical or psychiatric illness that are not stable or may 
require a change in treatment, use of prohibited therapies during the study or make the 
subject unlikely to fully comply with the requirements of the study or complete the study, 
or any condition that presents undue risk from the study drug or study procedures.  
3. Any other significant disease or disorder which, in the opinion of the Investigator, may 
put the subject at risk.  
4. History of malignancy with the exception of a nonmelanoma skin cancer or carcinoma 
in-situ of the cervix that has been treated with no evidence of recurrence within 5 years.  
5. Positive test for hepatitis B surface antigen (HBsAg) or HIV antibody at screening.  
6. Acute or chronic hepatitis C virus infection (evidenced by detection of hepatitis C virus 
(HCV) antibody and confirmed by detection of HCV RNA.  
7. 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 
8. Use of prescription medications (excluding oral contraceptives) within 14 days prior to 
dosing on Day 1, except with prior approval of the Sponsor.  
9. Use of nonprescription/ over-the-counter medications, including herbal remedies and 
supplements, within 7 days prior to dosing on Day 1.  
Prior/Concurrent Clinical Study Experience 
10. Participation (ie, last protocol-required study visit) in a clinical study within 90 days 
before initiation of dosing on Day 1.  
Diagnostic Assessments 
11. Supine blood pressure  90/60 mmHg or  140/90 mmHg at screening.  
12. Serum ceruloplasmin (Cp) value outside of the normal range at screening.  
13. Serum total Cu value outside of the normal range at screening.  
14. Hemoglobin level below the lower limit of normal at screening. 


Protocol 
 
ALXN1840-HV-104 
Page 28 of 58 
 
Alexion Confidential 
 
15. Serum creatinine > upper limit of normal (ULN) of the reference range of the testing 
laboratory at screening or on Day -1.  
16. Alanine aminotransferase, AST, or total bilirubin outside of normal reference range of the 
testing laboratory at screening.  
17. Any clinically significant abnormal hematological parameters (per the Investigator’s 
discretion). 
18. Donated or lost 400 mL blood or more within the last 16 weeks preceding the first day of 
dosing. 
Other Exclusion Criteria 
19. Female subjects who are breastfeeding.   
20. Prior exposure to ALXN1840.  
21. Major surgery or hospitalization within 90 days prior to dosing on Day 1.  
22. Use of tobacco in any form (e.g. smoking or chewing) or other nicotine-containing 
products in any form (e.g. gum, patch, electronic cigarettes) 6 months prior to the planned 
first day of dosing (Section 5.3.2).   
23. History of illicit drug abuse, history of significant alcohol abuse within 1 year prior to the 
screening visit, or clinical evidence of substance and/or alcohol abuse within the 2 years 
before screening. Alcohol abuse is defined as regular weekly intake of more than 14 units 
(for both males and females), using the following NHS alcohol tracker 
http://www.nhs.uk/Tools/Pages/drinks-tracker.aspx.  
24. Positive urine drug toxicology screen at screening or on Day -1.   
25. Alcohol consumption within 48 hours prior to study drug administration or positive 
alcohol breath test at screening or on Day -1.   
5.3. 
Lifestyle Considerations 
5.3.1. 
Meals and Dietary Restrictions 
• Subjects are required to abstain from ingesting food containing poppy seeds within 
24 hours prior to admission.  
• Subjects will receive standardized meals and snacks scheduled at the same time in 
each period of the study. No outside food or drink is permitted at the inpatient 
facility. All meals and snacks will be provided.  
• Subjects will be administered the dose of ALXN1840 following an overnight fast of 
at least 10 hours. No food will be allowed for at least 4 hours post-dose. Water can be 
allowed as desired except for 1 hour before and after drug administration.  


Protocol 
 
ALXN1840-HV-104 
Page 29 of 58 
 
Alexion Confidential 
 
5.3.2. 
Caffeine, Alcohol, and Tobacco 
 Subjects will be required to abstain from: 
• Ingesting caffeine- or xanthine-containing products (eg, coffee, tea, cola drinks, and 
chocolate) 24 hours before admission through discharge from the inpatient facility, 
and 24 hours before each study outpatient/follow-up visit.  
• Ingesting alcohol 48 hours before admission through discharge from the inpatient 
facility, and 48 hours before each study outpatient/follow-up visit.     
• Using tobacco in any form (e.g. smoking or chewing) or other nicotine-containing 
products in any form (e.g. gum, patch, electronic cigarettes) 6 months prior to the 
planned first day dosing through to the EOS visit.   
5.3.3. 
Physical Activity 
Subjects will be required to abstain from strenuous physical activity 48 hours prior to blood 
draws for clinical safety laboratory testing. Subjects should not start new physical training 
activities during the study until study completion (last visit).   
5.4. 
Screen Failures and Replacements 
Screen failures are defined as subjects who signed consent to take part in the study but were not 
randomized. A minimal set of screen failure information is required to ensure transparent 
reporting of screen failure subjects to meet the Consolidated Standards of Reporting Trials 
(CONSORT; Schulz, 2010) publishing requirements and to respond to queries from regulatory 
authorities.  
Rescreening is not permitted where the cause is not deemed to be temporary. Subjects who 
initially failed due to temporary non-medically significant issues (eg, screening occurs outside 
the planned window) are eligible for rescreening one the cause has resolved. 
Minimal information including ICF process and reason for screen failure will be source data 
reviewed. All subjects will be listed in the Screening progress report, and screen failure subjects 
will be reviewed by the clinical research associate 
5.4.1. 
Criteria for Study Termination  
The Investigator, competent authority, or Alexion may terminate the study for reasonable cause. 
Conditions that warrant termination of the study include, but are not limited to, the following: 
• Discovery of an unexpected, serious, or unacceptable risk to subjects enrolled in the 
study. 
• Decision on the part of Alexion to suspend or discontinue testing, evaluation, or 
development of the study drug. 
• Failure of the Investigator to comply with the approved protocol, pertinent guidelines, 
and/or regulations. 
• Submission of knowingly false information from the Investigator to Alexion and/or 
regulatory authorities. 


Protocol 
 
ALXN1840-HV-104 
Page 30 of 58 
 
Alexion Confidential 
 
6. 
STUDY DRUG  
Study drug is defined as any investigational drug product(s), marketed product(s), or placebo, 
intended to be administered to a subject according to the protocol. ALXN1840 (bis choline 
tetrathiomolybdate), administered orally, is the only drug investigated in this study. 
6.1. 
Study Drug Administered 
The study drug composition and doses to be administered in this study are presented in Table 8.   
Table 8: 
Study Drug Administered  
Study Intervention Name: 
ALXN1840 (formerly WTX101)  
Dosage formulation: 
EC tablets (containing either 15 mg ALXN1840 or 5 mg 
ALXN1840) 
Unit dose strength(s)/Dosage level(s): 
15 mg ALXN1840 EC tablet (Treatment A) 
5 mg ALXN1840 EC tablet (Treatment B) 
Route of Administration  
Oral  
Dosing instructions: 
 
Additional instructions are provided in the 
pharmacy manual. 
Study drug will be administered as outlined in Table 6. 
All study medications will be taken with approximately 240 mL of 
water.  
Subjects will be instructed not to crush, split, or chew the study 
medication.  
Packaging and Labeling 
Additional instructions are provided in the 
pharmacy manual. 
ALXN1840 will be provided in bulk blisters with each tablet 
situated in one transparent thermoform cavity. Each blister will be 
labeled per country requirement. 
Manufacturer 
Catalent, Inc. 
Abbreviation: EC = enteric-coated. 
Source: ALXN1840 Investigator’s Brochure 
The blistered study drug will be supplied to the Investigator's site as bulk blistered inventory. 
The site's pharmacy will repackage the supplies into individual, labelled subject doses and 
perform Qualified Person certification of the repackaged product.  
6.2. 
Packaging and labelling of IMPs 
The labelling of the study drugs will be in compliance with Good Manufacturing Practice (GMP) 
specifications, as described in The Rules Governing Medicinal Products in the European Union, 
Volume 4, Annex 13, Investigational Medicinal Products, and any other or local applicable 
regulations.  
Sample label(s) will be submitted to the UK health authorities according to the submission 
requirements.  
6.3. 
Preparation/Handling/Storage/Accountability 
• The Investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit and storage for all study drug received and any 
discrepancies will be reported and resolved prior to use of the study drug.  


Protocol 
 
ALXN1840-HV-104 
Page 31 of 58 
 
Alexion Confidential 
 
• Only subjects enrolled in the study may receive study drug and only authorized site 
staff may supply or administer study drug. All study drug 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.  
• The Investigator, or qualified designee, is responsible for study drug accountability, 
reconciliation, and record maintenance (ie, receipt, reconciliation, and final 
disposition records).  
Additional instructions are provided in the pharmacy manual.   
6.4. 
Measures to Minimize Bias: Randomization and Blinding 
This is an open-label study where, in order to minimize selection bias in treatment assignment, 
subjects will be randomized to 2 treatment sequences.   
Eligible subjects who meet all inclusion and no exclusion criteria will be assigned unique 
numbers for enrollment. Study subject numbers will not be reallocated once assigned.  
In an effort to achieve balance between the number of males and females in the 2 sequences, the 
maximum split in either direction will be approximately 60%:40% (10-14 of each sex in each 
sequence).  
6.5. 
Study Drug Compliance 
Study drug will be administered to subjects in a controlled setting under the supervision of the 
Investigator, or designee, thereby ensuring compliance with study drug administration. Study 
center personnel will ensure that all subjects are adequately informed about the specific study 
drug dosing regimen required for compliance with the study protocol. 
6.6. 
Study Drug Stopping Rules 
6.6.1. 
Adverse Reaction Rules 
An adverse reaction is any TEAE that is considered related to the study medication (for a full 
definition of related TEAEs, see Section 10.3.5). 
Any TEAEs or TESAEs that are not considered related to study drug do not constitute adverse 
reactions or serious adverse reactions and, therefore, these rules do not apply. 
6.6.1.1. 
General Adverse Reaction rules 
The general adverse reaction rules refer to all adverse reactions, excluding those relating to the 
liver and hematology and QT interval prolongation. The CTCAE may not give clear enough 
guidance, and grading may not be appropriate for this study in healthy volunteers; therefore, 
special study-specific rules have been created. 
Individual Adverse Reaction Rules 
An individual subject will not receive the dose of ALXN1840 in the subsequent period, if either 
of the following occurs: 


Protocol 
 
ALXN1840-HV-104 
Page 32 of 58 
 
Alexion Confidential 
 
• Subject experiences any CTCAE Grade 3 (or higher) adverse reaction, or a serious 
adverse reaction, irrespective of severity/CTCAE grade.  
• Subject experiences any CTCAE Grade 1 or 2 adverse reaction considered to be 
related to study drug that is considered a safety concern by the Safety Review 
Committee.  
Group Adverse Reaction Rules 
Dosing will be suspended for all subjects, or potentially only in an affected cohort, if either of 
the following occurs:  
• One subject (among any of the 48 total subjects) experiences a non-serious, severe 
(CTCAE Grade 3) adverse reaction.  
• One subject experiences a serious adverse reaction, irrespective of severity/CTCAE 
grade.  
In the event of suspension of dosing, continuation of the study will require a protocol amendment 
that has been approved by the MHRA and ethics committee.  
Special individual Adverse Reaction Rules 
Dosing in an individual subject will be suspended if they experience any of the following: 
• Liver function test elevation  
 ALT or AST value > 3 × ULN together with bilirubin increase >2 × ULN. 
 ALT or AST value > 8 × ULN. 
 ALT or AST value > 3 × ULN, and symptomatic. 
• Hematology  
 Hemoglobin reduction to an absolute value of 8g/dL (80g/L) or lower. 
 Platelet count reduction of > 50% from baseline or absolute value < 80.000/mm3 
(Day -1 blood samples). 
• QT interval prolongation  
 A prolongation of the uncorrected QT interval of > 500ms (using consistent, 
technically valid triplicate ECG). 
Special group AR rules 
If 1 subject fulfils the special individual adverse reaction rules, and this could be reasonably 
attributed to study drug, a Safety Review Committee meeting will be arranged and, if necessary, 
dosing for all subjects will be temporarily suspended until the Safety Review Committee meets. 
At this meeting, a decision will be made regarding the continuation of dosing in the remaining 
subjects. 


Protocol 
 
ALXN1840-HV-104 
Page 33 of 58 
 
Alexion Confidential 
 
If it is then confirmed that 1 subject fulfils Hy’s Law criteria, dosing will be suspended in all 
subjects and can only continue with a substantial amendment to the protocol that has been 
approved by the MHRA and ethics committee. 
If 2 or more subjects fulfil any of the other special individual adverse reaction rules, dosing will 
be suspended in all subjects and can only continue if the Safety Review Committee decides that 
dosing can continue, and a substantial amendment is made to the protocol that is approved by the 
MHRA and ethics committee. 
Details of the Safety Review Committee are provided in Section 8.4. 
6.7. 
Concomitant Therapy 
• Subjects must abstain from taking prescription drugs within 14 days prior to dosing 
on Day 1 and nonprescription drugs/ over-the-counter medications (including 
vitamins and dietary or herbal supplements) within 7 days prior to dosing on Day 1 
until completion of the follow-up visit, unless, in the opinion of the Investigator and 
the Sponsor, the medication will not interfere with the study.   
• As per the ALXN1840 IB, in this study, investigators should use caution in the co-
administration of drugs known to be substrates of CYP2C9 and CYP2B6. Common 
substrates of CYP2C9 include ibuprofen, which is permitted in this study. Therefore, 
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 
• Topical skin products without significant systemic absorption are permitted for use 
during the study at the Investigator’s discretion.   
• Other concomitant medication may be considered on a case-by-case basis by the 
Investigator in consultation with the medical monitor if required.   
• Concomitant procedures are not allowed unless medically indicated and/or permitted 
by the Sponsor or the Investigator or delegate.  
6.8. 
Contraception Guidance 
Female subjects who are documented as being of non-childbearing potential as defined in 
Section 10.4 are exempt from contraception requirements.  
Female subjects of childbearing potential, if heterosexually active, must use highly effective 
contraception as defined below, starting at least one menstrual cycle before first study drug 
administration and continuing for up to 3 months after the end of systemic exposure of the study 
drug (i.e. 3 months after EOS visit).   
Highly effective contraceptive methods for females are as follows:   
• Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation as follows:   
 Oral  
 Intravaginal  


Protocol 
 
ALXN1840-HV-104 
Page 34 of 58 
 
Alexion Confidential 
 
 Transdermal  
• Progestogen-only hormonal contraception associated with inhibition of ovulation as 
follows:   
 Oral  
 Injectable  
 Implantable  
• Intrauterine device (IUD) 
• Intrauterine hormone-releasing system (IUS) 
• Bilateral tubal occlusion 
• Male partner vasectomized (with documented evidence of azoospermia if possible) 
• Abstinence (N.B. 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 treatments. The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the clinical study and the preferred and usual 
lifestyle of the subject).   
Male subjects, 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 drug (ie, 3 months after EOS visit). Barrier contraception is required even 
with documented medical assessment of surgical success of a vasectomy. Female spouses or 
partners of male subjects who are of childbearing potential must use highly effective 
contraception as defined above, starting at least 1 menstrual cycle before (the male subject’s) 
first study drug administration and continuing until at least 3 months after the end of their male 
partner’s systemic exposure to the study drug (ie, 3 months after EOS visit). Male subjects must 
not donate sperm and female subjects must not donate ova for at least 3 months after the end of 
systemic exposure of the study drug (ie, 3 months after EOS visit).  
For male subjects 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.  
6.9. 
Intervention after the End of the Study 
This is a healthy volunteer study and no follow-up intervention is planned.   


Protocol 
 
ALXN1840-HV-104 
Page 35 of 58 
 
Alexion Confidential 
 
7. 
DISCONTINUATION OF STUDY DRUG AND SUBJECT 
WITHDRAWAL 
7.1. 
Discontinuation of Study Drug 
Subjects who discontinue study drug, for any reason, should undergo all scheduled safety, PK 
and PD evaluations as specified in the Schedule of Activities (Table 1 and Table 2) in relation to 
the last dose they received. 
If a subject withdraws consent and is unwilling to attend all scheduled procedures, then all 
attempts will be made to encourage them to attend for the EOS visit. 
7.2. 
Subject Withdrawal From the Study  
A subject 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. 
If the subject withdraws consent for disclosure of future information, the Sponsor may retain and 
continue to use any data collected before such a withdrawal of consent. 
Data to be collected at the time of study discontinuation and follow-up and for any further 
evaluations that need to be completed are specified in the Schedule of Activities (Table 1 and 
Table 2). 
7.3. 
Lost to Follow Up  
A subject 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 subject fails to return to the clinic for a required study 
visit:   
• The site must attempt to contact the subject and leave a message on their primary 
contact number (if not answered), explaining the reason and need to attend visits. If 
not answered, the site will send an SMS to this number asking the volunteer to 
contact the site urgently.   
• In parallel, the site will send an e-mail to the subject requesting the subject to attend 
the study visit. If no e-mail address is available, the site will send a written letter to 
the subject’s primary address with the same information. These contact attempts must 
be documented in the subject’s medical record.   
• Should the subject continue to be unreachable, he/she will be considered to have 
withdrawn from the study.   


Protocol 
 
ALXN1840-HV-104 
Page 36 of 58 
 
Alexion Confidential 
 
8. 
STUDY ASSESSMENTS AND PROCEDURES 
Study procedures and their timing are summarized in the Schedule of Activities (Table 1 and 
Table 2).  
• Protocol waivers or exemptions are not allowed.  
• Immediate safety concerns should be discussed with the Sponsor’s medical monitor 
immediately upon occurrence or awareness to determine if the subject should 
continue or discontinue study intervention.  
• Adherence to the study design requirements, including those specified in the Schedule 
of Activities, is essential and required for study conduct.   
• All screening evaluations must be completed and reviewed to confirm that potential 
subjects meet all eligibility criteria. The Investigator will maintain a screening log to 
record details of all subjects screened and to confirm eligibility or record reasons for 
screening failure, as applicable.   
• Procedures conducted as part of the subject’s routine clinical management (eg, blood 
count) and obtained before signing of the ICF may be utilized for screening or 
baseline purposes provided the procedures met the protocol-specified criteria and 
were performed within the time frame defined in the Schedule of Activities.   
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 presented in the Schedule of Activities 
(Table 1 and Table 2).  
8.2.1. 
Physical Examination  
A full physical examination will be performed at screening and at the beginning of each Dosing 
Period admission. A symptom-driven physical examination will be performed at the EOS visit 
and may be performed at other times, at the Investigator’s discretion.  
Each examination will include the following assessments: general appearance; skin; head, ears, 
eyes, nose, and throat; neck; lymph nodes; chest; heart; abdominal cavity; limbs; central nervous 
system; and musculoskeletal system.   
Height and weight will also be measured and recorded at screening and the EOS visit. Body 
mass index will be calculated and recorded at screening and the EOS visit.   
8.2.2. 
Vital Signs 
Vital sign measurements will be taken after the subject has been resting in the supine position for 
at least 5 minutes and will include temperature (°C; tympanic), respiratory rate (RR), supine 
blood pressure, and heart rate. Orthostatic (standing) blood pressure will only be measured at 


Protocol 
 
ALXN1840-HV-104 
Page 37 of 58 
 
Alexion Confidential 
 
screening, after volunteers have been standing for 1 minute. The timing of vital sign 
measurements is described in the Schedule of Activities (Table 1 and Table 2). Out of range 
blood pressure or heart rate measurements will be repeated at the Investigator’s discretion. 
Confirmed, clinically significant vital sign measurements will be recorded as TEAEs. 
8.2.3. 
Electrocardiograms  
8.2.3.1. 
Recording of 12-Lead ECGs 
A triplicate 12-lead ECG will be obtained using a GE Marquette MAC1200® / MAC1200ST® 
recorder connected via a fixed network connection to the MUSE® Cardiology Information 
System (MUSE) after the subject has been resting for at least 10 minutes. 12-lead ECGs will be 
conducted before PK/PD/biomarker blood sampling if these 2 events occur at the same time. The 
timing of 12-lead ECGs is described in the Schedule of Activities (Table 1 and Table 2).   
12-lead ECGs recorded during screening will be stored electronically on the MUSE information 
system. Only ECGs recorded electronically will be valid ECGs for any purpose other than safety 
assessment. ECG printouts may be filed in the subject’s case report form (CRF) for medical 
safety reviews. 
Each 12-lead ECG recorder will be set up to the required technical specifications and containing 
the information required to identify the records. Each ECG recording will be clearly identified 
(Subject ID, visit date, and the actual times of ECG recordings).   
12-lead ECG recordings will be made after the subjects have been resting in a supine position for 
at least 10 minutes. The subjects will avoid postural changes during the ECG recordings and 
clinical staff will ensure that subjects are awake during the ECG recording.   
At each time point, the 12-lead ECG will be recorded in triplicate, to reduce variance and 
improve the precision of measurement. The triplicates will be performed at approximately 
1-minute intervals. Each ECG recording (trace) will last 10 seconds. Repeat ECGs will be 
performed until at least three 10-second ECG records per scheduled time-point meet the quality 
criteria set out in the Study Operations Manual and the applicable Standard Operating Procedure 
to enable reading and analyzing at least 5 complexes per derivation.  
8.2.3.2. 
Safety Review of 12-Lead ECGs 
All recorded 12-lead ECGs will be reviewed by the Investigator, or qualified designee, and the 
review findings will be documented in the CRF. If a subject shows an abnormal ECG, additional 
safety recordings (including the use of 5- or 12-lead Holter equipment) may be made and the 
abnormality be followed to resolution, if required.   
8.2.4. 
Clinical Safety Laboratory Assessments 
All protocol-required laboratory assessments, as defined in Section 10.2, must be conducted in 
accordance with the Schedule of Activities (Table 1 and Table 2) and the laboratory 
manual. Clinical and laboratory assessments will be performed by a local laboratory to assess 
safety of ALXN1840. Laboratory assessments will include full liver safety tests, creatinine, and 
calculation of creatinine clearance.  


Protocol 
 
ALXN1840-HV-104 
Page 38 of 58 
 
Alexion Confidential 
 
• The Investigator must review the laboratory report, document this review, and record 
all clinically relevant changes occurring during the study in the AE section of the 
CRF. The laboratory reports must be filed with the source documents.   
• All laboratory tests with values considered clinically significantly abnormal during 
participation in the study will 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 the 
Sponsor’s medical monitor should be notified.   
 If laboratory values from non-protocol-specified laboratory assessments 
performed at the institution’s local laboratory require a change in subject 
management or are considered clinically significant by the Investigator (eg, SAE 
or AE or dose modification), then the results must be recorded in the CRF.   
• The maximum amount of blood to be collected from each subject over the duration of 
the study, including any extra assessments that may be required, will not exceed 
500 mL. Repeat or unscheduled samples may be obtained for safety and/or eligibility 
reasons or if there are any technical issues with the samples. Please refer to the 
laboratory manual for specific details regarding plasma sampling volumes.  
8.2.5. 
Drug and Alcohol Screen 
A urine sample for drug screen will be analyzed for the substances listed in Section 10.2. Timing 
of urine drug and alcohol breath tests is specified in the Schedule of Activities (Table 1 and 
Table 2). 
8.2.6. 
Pregnancy Testing 
Pregnancy testing will be performed in serum for all female subjects at the time points specified 
in the Schedule of Activities (Table 1 and Table 2).  
8.3. 
Adverse Events and Serious Adverse Events  
The definitions of an AE or SAE and specific reporting requirements are located in Section 10.3. 
Adverse events will be reported to the Investigator or qualified designee by the subject (or, when 
appropriate, by a caregiver, surrogate, or the subject’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 drug or study procedures, or that caused 
the subject to discontinue the study drug (see Section 7).   
8.3.1. 
Time Period and Frequency for Collecting AE and SAE Information   
All AEs and SAEs will be collected from signing of the informed consent form (ICF) until the 
EOS visit. 


Protocol 
 
ALXN1840-HV-104 
Page 39 of 58 
 
Alexion Confidential 
 
Medical occurrences that begin before the first dose of study drug and after obtaining informed 
consent will be recorded on the CRF and will be considered as medical history. 
All SAEs will be recorded and reported to the Sponsor, or designee, within 24 hours, as indicated 
in Section 10.3. The Investigator will submit updated SAE data to the Sponsor within 24 hours of 
the data being available. 
Investigators are not obligated to actively seek AEs or SAEs after the conclusion of study 
participation (i.e., after EOS visit). 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports to the Sponsor are provided in 
Section 10.3. 
8.3.2. 
Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the subject 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 each subject at 
subsequent visits/contacts. All SAEs will be followed until resolution, stabilization, the event is 
otherwise explained, or the subject is lost to follow-up (as defined in Section 10.3). Further 
information on follow-up procedures is provided in Section 10.3.  
8.3.4. 
Regulatory Reporting Requirements for SAEs  
• Prompt notification by the Investigator to the Sponsor of a SAE is essential so that 
legal obligations and ethical responsibilities towards the safety of subjects and the 
safety of a study intervention under clinical investigation are met.  
• The Sponsor 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. The Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Independent Ethics Committee 
(IEC), and Investigators. 
• Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and the Sponsor’s 
policy and forwarded to Investigators as necessary. 
• An Investigator who receives a safety report describing a SAE or other specific safety 
information (eg, summary or listing of SAEs) from the Sponsor will review and then 
file it along with the IB and will notify the IEC, if appropriate according to local 
requirements. 


Protocol 
 
ALXN1840-HV-104 
Page 40 of 58 
 
Alexion Confidential 
 
8.3.5. 
Pregnancy  
• Incidence of all pregnancies in female subjects and if indicated female sexual partners 
of male subjects will be collected after the administration of study drug and for at 
least 3 months after the EOS visit thereafter.   
• Complications of abnormal pregnancy outcomes (eg, spontaneous abortion, fetal 
death, stillbirth, congenital anomalies, and ectopic pregnancy) are AEs and may meet 
the criteria for SAEs (Section 10.3).   
• If a pregnancy is reported, the Investigator should inform the Sponsor, or designee, 
within 24 hours of learning of the pregnancy. Specific pregnancy information to be 
collected is outlined in Section 10.3.6.  
8.4. 
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 (see Section 6.6). 
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.   
8.5. 
Treatment of Overdose 
No cases of overdose have been reported during ALXN1840 clinical studies. Study drug will be 
administered and monitored by site personnel.  
8.6. 
Pharmacokinetics  
Whole blood samples will be collected for the measurement of plasma total Mo (PK) over time 
as specified in the Schedule of Activities (Table 1 and Table 2). Additional samples may be 
collected during the study if warranted and agreed upon between the Investigator and the 
Sponsor. The actual date and time (24-hour clock time) of each sample will be recorded. Other 
PK concentration measurements including, but not limited to, that of plasma ultrafiltrate (PUF) 
Mo may be conducted.  
Additional samples may be collected during the study if warranted and agreed upon between the 
Investigator and Alexion. Details including further handling and processing instructions and 
sampling-time windows will be provided in the study laboratory manual.   
8.7. 
Pharmacodynamics 
After study drug administration, plasma samples will be collected for the measurement of plasma 
total Cu and non-ceruloplasmin-bound copper (NCC) over time as specified in the Schedule of 
Activities (Table 1 and Table 2). Calculations will also be performed for NCC and corrected 
NCC (NCCcorrected), the latter of which is non-Cp-bound and non-Mo-albumin-bound Cu. 


Protocol 
 
ALXN1840-HV-104 
Page 41 of 58 
 
Alexion Confidential 
 
Detailed calculation formulae will be provided in the statistical analysis plan (SAP). The actual 
date and time (24-hour clock time) of each sample will be recorded.   
Additional samples may be collected during the study if warranted and agreed upon between the 
Investigator and the Sponsor. Details including further handling and processing instructions and 
sampling-time windows will be provided in the study laboratory manual.  
8.8. 
Genetics 
Genetics will not be evaluated in this study.  
8.9. 
Biomarkers  
After study drug administration, whole blood samples will be collected for the measurement of 
plasma Cp and ceruloplasmin-bound copper (CpC) as biomarkers as specified in the Schedule of 
Activities (Table 1 and Table 2). Analyses of other biomarker data including, but not limited to, 
those of PUF Cu may be conducted. 
The actual date and time (24-hour clock time) of each sample will be recorded. Additional 
samples may be collected during the study if warranted and agreed upon between the 
Investigator and the Sponsor. Details including further handling and processing instructions and 
sampling-time windows will be provided in the study laboratory manual. 


Protocol 
 
ALXN1840-HV-104 
Page 42 of 58 
 
Alexion Confidential 
 
9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Statistical Hypotheses 
Not applicable. 
9.2. 
Sample Size Determination  
The study sample size is not based on hypothesis testing with statistical considerations. A sample 
size of 40-48 subjects (20-24 subjects in each sequence; 10-14 male and female subjects in each 
sequence, with a maximum split in either direction of approximately 60%:40%) has been 
selected based on practicality and convention for this type of study. Considering potential for 
subject drop-out of the study, a total of 48 subjects will be enrolled with 20-28 male subjects and 
20-28 female subjects.   
The primary objective of this study is to assess the relative bioavailability of 3 × 5 mg EC tablets 
(Treatment B, test) versus 1 × 15 mg EC tablet (Treatment A, reference). Although there will be 
no formal bioequivalence test, the framework of 2 one-sided tests, with limits of 0.8 and 1.25, 
can be applied to assess the adequacy of the sample size. A post-hoc analysis of a previous 
bioavailability study (WTX101-102) found a within-subjects coefficient of variation (CV) of 
0.34. For data from a two-period cross-over design, a total sample size of 40 subjects achieves 
81% power at a 5% significance level when the true ratio of the means is 1, and the coefficient of 
variation is 0.34.  
9.3. 
Populations for Analyses 
The analysis sets are defined in Table 9. 
Table 9: 
Study ALXN1840-HV-104 Analysis Sets  
Population 
Description 
Enrolled  
All subjects who sign the ICF 
Safety Set 
All subjects who receive at least 1 dose of study drug 
Pharmacokinetic 
All subjects who have sufficient plasma samples to enable the calculation of PK 
parameters 
Pharmacodynamic 
All subjects who have sufficient plasma samples which will enable the 
evaluation of the PD effects 
Abbreviations: ICF = informed consent form; PD = pharmacodynamic; PK = pharmacokinetic. 
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. Descriptive statistics for PK 
parameters will include number of observations, arithmetic mean, SD, arithmetic coefficient of 
variation (%CV), median, minimum, maximum, geometric mean and geometric %CV. 
Categorical variables will be summarized using percentages and frequency counts. Descriptive 
statistics and percentages and frequency counts will be summarized by sex, treatment, period, 
and sequence, where appropriate.  
All statistical analyses will be conducted using SAS® for Windows® Version 9.3 or higher. 


Protocol 
 
ALXN1840-HV-104 
Page 43 of 58 
 
Alexion Confidential 
 
An SAP will be developed and finalized before data cutoff/database lock and will further 
describe the subject 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.  
9.4.1. 
Efficacy Analyses 
No efficacy analyses will be performed for this study.  
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 (SOC) and Preferred Term for each treatment and 
overall, by relationship to study drug. Adverse events will also be summarized by treatment and 
overall by severity. Serious AEs and AEs resulting in withdrawal from the study will be listed. 
Subjects having multiple AEs within a category (eg, overall, SOC, Preferred Term) will be 
counted once in that category. For severity tables, a subject’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 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 subjects 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 each treatment.   
All concomitant medications will be coded and summarized using the WHO Drug Dictionary.  
9.4.3. 
Other Analyses  
9.4.3.1. 
Pharmacokinetic Analyses  
Individual ALXN1840 PK, assessed as plasma total Mo concentration-time data will be listed, 
plotted, and summarized with descriptive statistics, with mean PK data plotted. The following 
plasma total Mo PK parameters will be derived for individual subjects and summarized with 
descriptive statistics: Cmax in plasma, time to maximum concentration (tmax) in plasma, area under 
the plasma concentration versus time curve from time 0 to the last quantifiable concentration 
(AUCt), area under the plasma concentration versus time curve from time 0 (dosing) to infinity 
(AUC∞), apparent terminal-phase elimination rate constant (λz), t½, CL/F, apparent volume of 
distribution (Vd/F), and relative bioavailability (Frel) between test and reference treatments. 


Protocol 
 
ALXN1840-HV-104 
Page 44 of 58 
 
Alexion Confidential 
 
Analyses of other PK data including, but not limited to those, of PUF Mo may be conducted. PK 
parameters will be calculated using Phoenix® WinNonlin®. 
Detailed PK analyses will be described in the PK/PD data analysis plan (DAP), which will be 
finalized before database lock. 
9.4.3.1.1. Bioavailability Analysis  
The PK parameters for total Mo (Cmax, AUCt, and AUC∞) will be evaluated using an Analysis of 
Variance (ANOVA) statistical model with Dosing Period, treatment, and sequence as the fixed 
effects, and subject as a random effect, using the natural logarithms of the data. Confidence 
intervals (90%) will be constructed for the least squares geometric mean ratios (GMR) for the 
3 × 5 mg ALXN1840 versus 1 × 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-subject coefficient of variation 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% confidence intervals of Cmax, AUCt, and AUC∞ will be reported for each treatment. 
Detailed PK analyses will be described in the PK/PD DAP finalized before database lock.  
9.4.3.1.2. Pharmacodynamic and Biomarker Analyses  
Individual ALXN1840 PD and biomarkers, assessed as plasma total Cu (PD), NCC (PD), 
NCCcorrected (PD), Cp (biomarker), and CpC (biomarker) concentration-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 PD and biomarker concentration-time 
data. Analyses of other biomarker data including, but not limited to, those of PUF Cu may be 
conducted. 
Detailed PD analyses will be described in the PK/PD DAP finalized before database lock.  
9.5. 
Interim Analyses  
No interim analyses are planned for this study. 


Protocol 
 
ALXN1840-HV-104 
Page 45 of 58 
 
Alexion Confidential 
 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1. 
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 International Ethical Guidelines 
 Applicable ICH of Technical Requirements for Pharmaceuticals for Human Use 
GCP Guidelines 
 Applicable laws and regulations 
• The protocol, protocol amendments, ICF, IB, and other relevant documents (eg, 
advertisements) must be submitted to an IEC by the Investigator and reviewed and 
approved by the IEC before the study is initiated.  
• Any substantial amendments to the protocol will require IEC approval before 
implementation of changes made to the study design, except for changes necessary to 
eliminate an immediate hazard to study subjects.  
• The Investigator will be responsible for the following: 
 Providing written summaries of the status of the study to the IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IEC. 
 Notifying the IEC of SAEs or other significant safety findings as required by IEC 
procedures. 
 Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IEC, 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 the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor 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.   
10.1.3. 
Informed Consent Process  
• The Investigator or his/her representative will explain the nature of the study to the 
subject and answer all questions regarding the study.  


Protocol 
 
ALXN1840-HV-104 
Page 46 of 58 
 
Alexion Confidential 
 
• Subjects must be informed that their participation is voluntary. Subjects will be 
required to sign a statement of informed consent that meets the requirements of 
21 CFR 50, local regulations, ICH guidelines, Health Insurance Portability and 
Accountability Act (HIPAA) requirements, where applicable, and the IEC or study 
center.  
• The medical record must include a statement that written informed consent was 
obtained before the subject was enrolled in the study and the date the written consent 
was obtained. The authorized person obtaining the informed consent must also sign 
the ICF. 
• Subjects must be re-consented to the most current version of the ICF(s) during their 
participation in the study.  
• A copy of the ICF(s) must be provided to the subject. The Investigator must retain the 
original version of the signed ICF(s). 
10.1.4. 
Data Protection  
• Subjects will be assigned a unique identifier. Any subject records or datasets that are 
transferred to the Sponsor will contain the identifier only; subject names or any 
information which would make the subject identifiable will not be transferred. 
• The subject must be informed that his/her personal study-related data will be used by 
the Sponsor in accordance with local data protection law. The level of disclosure must 
also be explained to the subject. 
• The subject must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
Sponsor, by appropriate IEC members, and by inspectors from regulatory authorities. 
10.1.5. 
Dissemination of Clinical Study Data  
Study-related information and study results may be posted on the US National Institutes of 
Health website www.clinicaltrials.gov, the EU website www.clinicaltrialsregister.eu/, or other 
publically accessible websites as appropriate and in accordance with local regulations. 
10.1.6. 
Data Quality Assurance  
• All subject data relating to the study will be recorded on printed or electronic CRF 
unless transmitted to the Sponsor 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, IEC review, and 
regulatory agency inspections and provide direct access to source data documents.  
• The Sponsor, or designee, is responsible for the data management of this study 
including quality checking of the data.  


Protocol 
 
ALXN1840-HV-104 
Page 47 of 58 
 
Alexion Confidential 
 
• 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 subjects 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. Study monitors will communicate with investigative sites on 
a regular basis regarding study protocol deviations. All protocol deviations will be 
appropriately documented by the Investigator or designee, and study monitors. 
• Records and documents, including signed ICFs, pertaining to the conduct of this 
study must be retained by the Investigator for a minimum of 25 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 the Sponsor. No records may be transferred to another location or party 
without written notification to the Sponsor. Unless otherwise specified, procedures, 
data collection, and evaluation will be conducted as per the study center’s standard 
operating procedures. 
10.1.7. 
Source Documents  
• Source documents provide evidence for the existence of the subject and substantiate 
the integrity of the data collected. The Investigator or designee will prepare and 
maintain adequate and accurate source documents (medical records, ECG readings, 
AE and concomitant medication reporting, raw data collection forms) designed to 
record all observations and other pertinent data for each subject. Source documents 
are filed at the Investigator’s site. 
• Data entered in the CRF 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. 
10.1.8. 
Study and Site Closure  
The Sponsor, or designee, reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected 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 the Sponsor or Investigator may include but are 
not limited to: 
• Failure of the Investigator to comply with the protocol, the requirements of the IEC or 
local health authorities, the Sponsor's procedures, or GCP guidelines 
• Inadequate recruitment of subjects by the Investigator 
• Discontinuation of further study drug development 


Protocol 
 
ALXN1840-HV-104 
Page 48 of 58 
 
Alexion Confidential 
 
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 
 
ALXN1840-HV-104 
Page 49 of 58 
 
Alexion Confidential 
 
10.2. 
Clinical Laboratory Tests   
The tests detailed in Table 10 will be performed by the local laboratory.  
• Protocol-specific requirements for inclusion or exclusion of subjects 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 (“CS”) or not clinically significant (“NCS”). 
Table 10: 
Protocol-Required Safety Laboratory Assessments  
Laboratory 
Assessments 
Parameters 
Hematology 
Platelet count  
RBC count 
Hemoglobin 
Hematocrit 
RBC indices: 
Mean corpuscular volume 
Mean corpuscular 
hemoglobin 
% Reticulocytes 
WBC count with differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
Clinical 
chemistry 
BUN 
Chloride  
Potassium 
Bicarbonate  
Sodium  
Glucose 
AST 
ALT 
Alkaline phosphatase, 
Gamma glutamyltransferase 
HbA1C (Screening only) 
Urea 
Total and direct bilirubin 
Total protein 
Albumin 
Creatinine 
Creatine phosphokinase 
Coagulation 
International normalized ratio, partial thromboplastin time, prothrombin time 
Routine 
urinalysis 
Specific gravity, pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, 
leukocyte esterase 
 
Microscopic examination (if any leucocytes, more than a trace protein, nitrites, and blood [if 
not menstruating] are abnormal) 
Other screening 
tests 
• 
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]) 
• 
Cp and Cu concentrations in serum     
• 
HIV-1 and HIV-2 antibodies, HBsAg, anti-HBC IgG + IgM (if IgG positive), and 
anti-HCV with confirmation by HCV RNA  
• 
Serum hCG pregnancy test (as needed for women of childbearing potential) 
• 
FSH (postmenopausal females only) 
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; 
Cp = ceruloplasmin; Cu = copper; FSH = follicle stimulating hormone; HBsAg = hepatitis B surface antigen; 
hCG = human chorionic gonadotropin; HCV = hepatitis C virus; RBC = red blood cells; WBC = white blood cells. 
 


Protocol 
 
ALXN1840-HV-104 
Page 50 of 58 
 
Alexion Confidential 
 
10.3. 
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting  
10.3.1. 
Adverse Event Definition 
Adverse Event Definition 
• 
An AE is any untoward medical occurrence in a patient or clinical study subject, temporally associated with 
the use of study intervention, whether or not considered related to the study intervention. 
• 
NOTE: An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease (new or exacerbated) temporally associated with the use of study intervention. 
 
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 (ie, not related to progression of 
underlying disease). 
• 
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   
• 
Any clinically significant abnormal laboratory findings or other abnormal safety assessments which are 
associated with the underlying disease, unless judged by the Investigator to be more severe than expected for 
the subject’s condition. 
• 
The disease/disorder being studied or expected progression, signs, or symptoms of the disease/disorder being 
studied, unless more severe than expected for the subject’s condition. 
• 
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 (social and/or convenience admission to a 
hospital). 
• 
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. 
10.3.2. 
Adverse Reaction Definition 
Adverse Reaction Definition   
• 
An adverse reaction is any TEAE that is considered related to the study medication (for a full definition of 
related TEAEs, see Section 10.3.5) 
 


Protocol 
 
ALXN1840-HV-104 
Page 51 of 58 
 
Alexion Confidential 
 
10.3.3. 
Serious Adverse Event Definition  
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (eg, hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease).  
A serious adverse event 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 subject 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 were more 
severe. 
3. Requires inpatient hospitalization or prolongation of existing hospitalization  
In general, hospitalization signifies that the subject 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 subject 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. 
10.3.4. 
Suspected Unexpected Serious Adverse Reactions  
Suspected Unexpected Serious Adverse Reactions Definition  
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed in the IB and that 
the Investigator identifies as related to study drug or procedure. The US 21CFR312.32 and EU Clinical Trial 
Directive 2001/20/EC and the associated detailed guidance documents or national regulatory requirements in 
participating countries require the reporting of SUSARs. The Sponsor has procedures that will be followed for the 
recording and expedited reporting of SUSARs that are consistent with global regulations and the associated 
detailed guidance documents. Suspected unexpected serious adverse reactions will be reported to the national 
competent authority and IECs where applicable. 
 


Protocol 
 
ALXN1840-HV-104 
Page 52 of 58 
 
Alexion Confidential 
 
10.3.5. 
Recording and Follow-Up of AEs and/or SAEs  
Adverse Event and Serious Adverse Event Recording  
• 
When an AE or 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 or SAE information in the CRF. 
• 
It is not acceptable for the Investigator to send photocopies of the subject’s medical records to the Sponsor or 
designee 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 the Sponsor or 
designee. In this case, all subject identifiers, with the exception of the subject number, will be redacted on the 
copies of the medical records before submission. 
• 
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. 
Assessment of Event Severity  
The Investigator will make an assessment of intensity for each AE and SAE reported during the study and assign it 
to 1 of the following categories from CTCAE v5.0, published 27 Nov 2017. Each CTCAE term is a Lowest Level 
Term per MedDRA. Each Lowest Level Term will be coded to a MedDRA Preferred Term: 
 
1. Grade 1: Mild (asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not 
indicated) 
2. Grade 2: Moderate (minimal, local or noninvasive intervention indicated; limiting age-appropriate 
instrumental activities of daily living [ADL]) 
3. Grade 3: Severe (severe or medically significant, but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care ADL) 
4. Grade 4: Life-threatening consequences; urgent intervention indicated 
5. Grade 5: Death related to AE 
Any change in the severity of an AE should be documented based on specific guidelines in the CRF Completion 
Guidelines. 
Severity and seriousness must be differentiated: severity describes the intensity of an AE, while the term 
seriousness refers to an AE that has met specific criteria for an SAE as described above. 
Causality Assessment  
• 
An Investigator causality assessment (not related or related) must be provided for all AEs, both serious and 
nonserious based upon the Investigator’s medical judgement and the observed symptoms associated with the 
event. This assessment must be recorded in the CRF and any additional forms as appropriate. 
• 
Causality Assessment Descriptions 
 
Not related: This relationship suggests that there is no causal association between the study drug and the 
reported event. 
 
Related: This relationship suggests that there is causal association between the study drug and the reported 
event.  
 
 


Protocol 
 
ALXN1840-HV-104 
Page 53 of 58 
 
Alexion Confidential 
 
Follow-up of Adverse Events and Serious Adverse Events  
• 
The Investigator is obligated to perform or arrange for the conduct of supplemental measurements and/or 
evaluations as medically indicated or as requested by the Sponsor or designee 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 subject dies during participation in the study or during a recognized follow-up period, the Investigator 
will provide the Sponsor or designee with a copy of any postmortem findings including histopathology. 
• 
New or updated information will be recorded in the originally completed CRF. 
• 
The Investigator will submit any updated SAE data to the Sponsor or designee within 24 hours of receipt of 
the updated information. 
 
10.3.6. 
Reporting of Serious Adverse Events  
Serious Adverse Event Reporting to the Sponsor or Designee via Paper Case Report Form  
•  All AEs must be assessed by the Investigator to determine if they meet criteria for an SAE. All SAEs must be 
reported to the Sponsor or designee immediately, or within 24 hours of the Investigator and/or study site staff 
becoming aware of the event, regardless of the presumed relationship to the study drug. 
•  The Investigator must complete, sign, and date the SAE pages, verify the accuracy of the information 
recorded on the SAE pages with the corresponding source documents, and send a copy via email or facsimile 
to the contact information provided below: 
 Email: 
 
 Facsimile: 
 
•  Additional follow-up information, if required or available, should be entered into the CRF and sent to the 
Sponsor within 24 hours of the Investigator or study site staff becoming aware of this additional information 
via the reporting process outlined above. These reporting timelines need to be followed for all initial SAE 
cases and follow-up versions of the initial cases. 
•  For all SAEs, the Investigator must provide the following: 
 Appropriate and requested follow-up information in the time frame detailed above 
 Causality of the serious event(s) 
 Outcome of the serious event(s) 
 Medical records and laboratory/diagnostic information 
• 
If applicable, additional information such as relevant medical records should be submitted to the Sponsor via 
the email address or facsimile number noted above. 
• 
All forms and follow-up information submitted to the Sponsor (eg, discharge summary) should be kept in 
the appropriate section of the study file. 
 
PPD
PPD


Protocol 
 
ALXN1840-HV-104 
Page 54 of 58 
 
Alexion Confidential 
 
10.4. 
Contraceptive Guidance and Collection of Pregnancy Information 
Definitions 
Woman of Childbearing Potential   
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below). 
Women in the Following Categories are Not Considered Women of Childbearing Potential  
1. Premenopausal female with 1 of the following: 
• Documented hysterectomy 
• Documented bilateral salpingectomy 
• Documented bilateral oophorectomy 
• Note: Documentation can come from the site personnel’s review of the subject’s 
medical records, medical examination, or medical history interview. 
2. Postmenopausal female 
• A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle stimulating hormone (FSH) level in the 
postmenopausal range, as per local laboratory reference ranges, will be used to 
confirm a postmenopausal state in women not using hormonal contraception or 
hormonal replacement therapy (HRT). However, in the absence of 12 months of 
amenorrhea, a single FSH measurement is insufficient.  
• Female subjects on HRT and whose menopausal status is in doubt will be required to 
use one of the non-estrogen hormonal highly effective contraception methods if they 
wish to continue their HRT during the study. Otherwise, they must discontinue HRT 
to allow confirmation of postmenopausal status before study enrollment. 
Pregnancy Testing  
• Women of childbearing potential should only be included after a negative serum 
pregnancy test. Additional pregnancy testing should be performed per the time points 
specified in the Schedule of Activities (Table 1 and Table 2). 
Collection of Pregnancy Information   
• Pregnancy data will be collected during this study for all subjects and a female 
spouse/partner of male subjects. Exposure during pregnancy (also referred to as 
exposure in utero) can be the result of either maternal exposure or transmission of 
drug product via semen following paternal exposure.   
• If a female subject participating in this study or a male subject’s female sexual partner 
of childbearing potential becomes or is found to be pregnant while being treated or 
exposed to study drug, the Investigator must submit the “Pregnancy Reporting and 
Outcome/Breast Feeding Form” to the Sponsor or designee via the same method as 
SAE reporting. (Section 10.3). When the outcome of the pregnancy becomes known, 


Protocol 
 
ALXN1840-HV-104 
Page 55 of 58 
 
Alexion Confidential 
 
the form should be updated and submitted to the Sponsor’s Global Drug Safety 
(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 Reporting and Outcome Form/Breastfeeding” form) and 
any AEs experienced by the infant must be reported to the Sponsor’s GDS or 
designee via facsimile or email (Section 10.3).  
• A pregnancy in itself is not regarded as an AE unless there is a suspicion that the 
study drug 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). Elective abortions 
without complications should not be reported as AEs (Section 8.3.5).  
 


Protocol 
 
ALXN1840-HV-104 
Page 56 of 58 
 
Alexion Confidential 
 
10.5. 
Abbreviations 
A list of abbreviations and terms are used in this study protocol is provided in Table 11. 
Table 11: 
List of Abbreviations and Definitions of Terms  
Abbreviation 
Definition 
z 
apparent terminal-phase elimination rate constant  
%CV 
arithmetic coefficient of variation  
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  
CL/F 
clearance/bioavailability   
Cmax 
maximum observed concentration  
CONSORT 
Consolidated Standards of Reporting Trials  
Cp 
ceruloplasmin  
CpC 
ceruloplasmin-bound copper  
CRF 
case report form  
CRU 
clinical research unit  
CTCAE 
Common Terminology Criteria for Adverse Events  
Cu 
copper  
CV 
coefficient of variation  
DAP 
data analysis plan  
EC 
enteric-coated  
EOS 
End of Study  
ET 
Early Termination 
FSH 
follicle-stimulating hormone  
GCP  
Good Clinical Practice   
GI 
gastrointestinal  
GDS 
Global Drug Safety  
HBsAg 
hepatitis B surface antigen 
HCV 
hepatitis C virus  
HIPAA 
Health Insurance Portability and Accountability Act  
IB 
Investigator’s Brochure  
ICF 
informed consent form  
IEC 
Independent Ethics Committee  
MELD 
model for end-stage liver disease  


Protocol 
 
ALXN1840-HV-104 
Page 57 of 58 
 
Alexion Confidential 
 
 
Mo 
molybdenum  
NCC 
non-ceruloplasmin-bound copper  
NCCcorrected 
corrected NCC 
PD 
pharmacodynamic(s)  
PK 
pharmacokinetic(s)  
PPI 
proton pump inhibitor  
PUF 
plasma ultrafiltrate  
QT 
interval between the start of the Q wave and the end of the T wave in an ECG  
QTcF 
QT interval corrected using the Fridericia’s formula  
RR 
respiratory rate  
SAE 
serious adverse event  
SAP 
Statistical Analysis Plan  
TEAE 
treatment-emergent adverse event  
TESAE 
treatment-emergent serious adverse event  
t½ 
terminal elimination half-life  
tmax 
time to maximum concentration  
TPC 
Cu-tetrathiomolybdate-albumin tripartite complex formed after ALXN1840 
administration 
UC 
uncoated capsules  
ULN 
upper limit of normal 
UWDRS 
Unified WD Rating Scale  
Vd/F 
apparent volume of distribution  
WD 
Wilson disease  


Protocol 
 
ALXN1840-HV-104 
Page 58 of 58 
 
Alexion Confidential 
 
11. 
REFERENCES 
Lowndes SA, Adams A, Timms A, et al. Phase I study of copper-binding agent ATN-224 in 
patients with advanced solid tumors. Clin Cancer Res. 2008;14(22):7526-7534. 
Schulz KF, Altman DG, Moher D. CONSORT 2010 statement: updated guidelines for reporting 
parallel group randomized trials. Ann Intern Med. 2010;152(11):726-732. 
Weiss KH, Askari FK, 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-Way Cross-over Study 
to Assess the Single-Dose Pharmacokinetics of ALXN1840 
Enteric-Coated Tablets at 2 Dose Strengths in Healthy Adult 
Subjects 
Unique Protocol ID: 
NCT Number: 
EudraCT Number:  
  Date of SAP:         
ALXN1840-HV-104 
NCT05303324 
2019-000516-28 
 11 November 2019 


PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


Statistical Analysis Plan 
 
 
 
C18054 ALXN1840-HV-104 SAP Final 1.0 11Nov2019Page 2 of 20 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
Abbreviation  
Explanation  
AE  
Adverse Event  
ANOVA 
Analysis of Variance 
ATC 
Anatomical Therapeutic Chemical 
AUC 
Area under the Plasma Concentration Time Curve 
AUCextr 
The percentage of AUC∞ extrapolated 
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 Time Zero Extrapolated to Infinity 
BDRM 
Blind Data Review Meeting 
BLQ 
Below the Level of Quantification 
BMI 
Body Mass Index 
CL/F 
Clearance/Bioavailability 
Cmax  
Maximum Observed Plasma Concentration  
Cp 
Ceruloplasmin 
CpC 
Ceruloplasmin-bound copper 
CSR 
Clinical Study Report 
CRU 
Clinical Research Unit 
CTCAE 
Common Terminology Criteria for Adverse Events 
Cu 
Copper 
CV 
Coefficient of Variation 
EC 
Enteric-Coated 
ECG  
Electrocardiogram  
EOS 
End of Study 
ET 
Early Termination 
Frel 
Relative Bioavailability 
GMR 
Geometric Mean Ratio 
ICF 
Informed Consent Form 
λz  
Apparent Terminal-Phase Elimination Rate Constant  
MedDRA 
Medical Dictionary for Regulatory Activities 
Mo 
Molybdenum 
NCC 
Non-Ceruloplasmin-Bound Copper 
NCCcorrected 
Corrected NCC 
PD  
Pharmacodynamic(s)  
PDF 
Portable Document Format 
PK  
Pharmacokinetic(s)  
PUF 
Plasma Ultrafiltrate 


Statistical Analysis Plan 
 
 
 
C18054 ALXN1840-HV-104 SAP Final 1.0 11Nov2019Page 3 of 20 
QT 
Interval between the start of the Q wave and the end of 
the T wave in an ECG 
QTcF  
QT interval corrected using Fridericia’s formula  
RPL 
Richmond Pharmacology Ltd 
RTF 
Rich Text Format 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis Software 
SD 
Standard Deviation 
SOC 
System Organ Class 
TEAE 
Treatment-Emergent Adverse Event 
TESAE 
Serious Treatment-Emergent Adverse Event 
t½ 
Terminal Elimination Half-Life  
TFLs 
Tables, Figures and Listings 
Tmax  
Time to Maximum Observed Plasma Concentration  
TPC 
Cu-Tetrathiomolybdate-Albumin Tripartite Complex 
Formed after ALXN1840 Administration 
Vd/F 
Apparent Volume of Distribution  
WHO-DD 
World Health Organization Drug Dictionary 
 
 
 


Statistical Analysis Plan 
 
 
 
C18054 ALXN1840-HV-104 SAP Final 1.0 11Nov2019Page 4 of 20 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................. 2 
1. INTRODUCTION ..................................................................................... 6 
2. STUDY OBJECTIVES AND ENDPOINTS ....................................................... 6 
2.1 Study objectives ................................................................................ 6 
2.2 Endpoints ......................................................................................... 6 
3. STUDY DESIGN ...................................................................................... 7 
3.1 Overall Design ................................................................................... 7 
3.2 Duration of Study .............................................................................. 8 
3.3 Sample size ...................................................................................... 9 
3.4 Randomization and Blinding ................................................................ 9 
4. STATISTICAL ANALYSES ....................................................................... 10 
4.1 Interim Analysis .............................................................................. 11 
4.2 Analysis Populations ......................................................................... 11 
4.3 Subject Disposition .......................................................................... 12 
4.4 Demographic Characteristics ............................................................. 12 
4.5 Baseline and Other Safety Characteristics ........................................... 12 
4.6 Inclusion and Exclusion Criteria ......................................................... 12 
4.7 Protocol Deviations .......................................................................... 12 
4.8 Medical History ................................................................................ 12 
4.9 Study Drug Administration and Meals ................................................. 13 
4.10 Prior and Concomitant Medications ................................................... 13 
4.11 Safety Analyses ............................................................................. 13 
4.11.1 Adverse Events ........................................................................ 14 
4.11.2 Laboratory Data ....................................................................... 14 
4.11.3 Electrocardiograms ................................................................... 15 
4.11.4 Vital Signs ............................................................................... 16 
4.11.5 Physical Examination ................................................................ 16 
4.12 Pharmacokinetic Analyses ............................................................... 16 
4.12.1 Values Below the Limit of Quantification and Missing Values .......... 16 
4.12.2 Pharmacokinetic Parameters ...................................................... 17 
4.12.3 Bioavailability Analysis .............................................................. 18 


Statistical Analysis Plan 
 
 
 
C18054 ALXN1840-HV-104 SAP Final 1.0 11Nov2019Page 5 of 20 
4.12.4 CL/F and Body Size ................................................................... 19 
4.13 Pharmacodynamic and Biomarker Analyses ....................................... 19 
4.14 Methods for Withdrawals, Missing Data and Outliers ........................... 20 
 


Statistical Analysis Plan 
 
 
 
C18054 ALXN1840-HV-104 SAP Final 1.0 11Nov2019Page 6 of 20 
   
1. INTRODUCTION 
The purpose of this Statistical Analysis Plan (SAP) is to define the variables and 
analysis methodology to address the study objectives. 
The protocol dated 09 Apr 2019, Amendment 1, was used in the preparation of 
this SAP. 
Pharmacokinetic (PK) parameters calculations and statistical analyses will be the 
responsibility of Richmond Pharmacology Ltd (RPL). Tables, figures, and listings 
(TFLs) will be produced using Statistical Analysis Software (SAS), Version 9.3 or 
higher. 
 
2. STUDY OBJECTIVES AND ENDPOINTS 
 
2.1 Study objectives 
The objectives of this study are: 
Primary 
x 
To assess the relative bioavailability of ALXN1840 administered orally as      
3 × 5 mg enteric-coated (EC) tablets (test) versus 1 × 15 mg EC tablet 
(reference). 
Secondary 
x 
To assess the overall safety and tolerability of ALXN1840. 
Exploratory 
x 
Relationships between Clearance/bioavailability (CL/F) and body size, 
body weight (kg) and body mass index (BMI kg/m²). 
x 
To explore pharmacodynamics (PD) and biomarkers of 15 mg ALXN1840 
among the following dosing regimens: either as a single 15 mg EC tablet 
(Treatment A) or 3 EC tablets of 5 mg (Treatment B). 
 
2.2 Endpoints 
Primary 
x 
PK parameters for plasma total molybdenum (Mo) including the maximum 
observed plasma concentration (Cmax), the area under the plasma 
concentration versus time curve from zero to the last quantifiable 
concentration (AUCt), and extrapolated to infinity (AUC∞). 


Statistical Analysis Plan 
 
 
 
C18054 ALXN1840-HV-104 SAP Final 1.0 11Nov2019Page 7 of 20 
    
Secondary 
x 
Safety assessed by incidence of treatment emergent adverse events 
(TEAEs) and serious TEAEs (TESAEs), physical examination, vital signs 
measurements, clinical laboratory, and 12-lead electrocardiogram (ECG) 
results. 
 
Exploratory 
x 
CL/F, body weight, and body mass index. 
x 
Absolute and percent changes of plasma copper (Cu) levels including total 
Cu, ceruloplasmin (Cp), ceruloplasmin-bound copper (CpC) and non-
ceruloplasmin-bound copper (NCC). 
x 
The NCC level will be corrected for the amount of Cu bound to the TPC 
resulting in corrected NCC (NCCcorrected). 
 
3. STUDY DESIGN 
This is a single-center, randomized, open-label, 2-way crossover study to assess 
the single-dose pharmacokinetics (PK) of ALXN1840 EC tablets at 2 dose 
strengths in healthy male and female adult subjects under fasting conditions. 
Pharmacokinetic parameters will be calculated based on the measurement of 
plasma total Mo concentration. A total of 48 healthy, adult participants (20-28 
male and 20-28 female) who complete the study screening assessments and 
meet all eligibility criteria will be enrolled to allow for a minimum of 40 subjects 
to complete the study (20-24 subjects in each sequence, 10-14 of each sex in 
each sequence).  
 
3.1 Overall Design 
The study has a Screening Period (Days -28 to -2), 2 Dosing Periods (Day -1 to 
Day 11 each) and an end-of-study (EOS) visit 14 days (+2 days) post final dose. 
After completing the Screening Period, enrolled subjects will be admitted to an 
inpatient facility (Clinical Research Unit [CRU]) on Day -1 for dosing on Day 1 in 
Dosing Period 1. Subjects will be readmitted to the CRU for Dosing Period 2 
following a minimum of 14 days after the previous dose. In each Dosing Period, 
subjects will receive 1 of the 2 treatments as illustrated below: 
 
Treatment A (reference) 
1 x 15 mg ALXN1840 EC tablet 
Treatment B (test) 
3 x 5 mg ALXN1840 EC tablets 


Statistical Analysis Plan 
 
 
 
C18054 ALXN1840-HV-104 SAP Final 1.0 11Nov2019Page 8 of 20 
Table 1: Treatments 
Subjects will return to the CRU 14 days (+2 days) after the final dose of study 
drug for the EOS visit with follow-up procedures, and to determine if any 
adverse event (AE) has occurred since the last study visit. If subjects withdraw 
from the study early, they will be seen and assessed by the Investigator, 
whenever possible, to undergo the procedures associated with the EOS visit. 
Subjects may be replaced at the discretion of the Sponsor. 
A total of 48 subjects will be enrolled (20-28 male subjects and 20-28 female 
subjects) to ensure a minimum sample size of 40 subjects (20-24 subjects in 
each sequence, 10-14 of each sex in each sequence) complete the study. 
 
Each subject will receive both treatments in 1 of the 2 sequences as defined in 
the table below according to the study drug dosing regimen outlined above, 
where the single 15 mg EC tablet (Treatment A) is the "reference" dose and the 
3 EC tablets of 5 mg (Treatment B) are the "test" dose. 
 
Sequence 
Number 
Treatment Sequence 
Male  
Female 
Total 
Period 1 
Period 2 
1 
A 
B 
10-14 
10-14 
24 
2 
B 
A 
10-14 
10-14 
24 
Total 
20-28 
20-28 
48 
Table 2: Treatment Sequence 
 
3.2 Duration of Study 
The planned study duration is approximately 70 days; up to 27 days for 
screening, approximately 29 days for dosing and follow-up, and an interval of at 
least 14 days between the 2 Dosing Periods. 
 


Statistical Analysis Plan 
 
 
 
C18054 ALXN1840-HV-104 SAP Final 1.0 11Nov2019Page 9 of 20 
 
Figure 1: Study ALXN1840 Schematic 
* Subjects will leave the Clinical Research Unit on Day 11 of Dosing Period 1 and will be readmitted following a 
minimum of 14 days after the dose of study drug for Dosing Period 2. 
** EOS visit to be performed 14 days (+2 days) after the final dose of study drug. 
Abbreviations: EOS = end of study, PD = pharmacodynamics; PK = pharmacokinetics. 
 
 
3.3 Sample size 
The study sample size is not based on hypothesis testing with statistical 
considerations. A sample size of 40-48 subjects (20-24 subjects in each 
sequence; 10-14 male and female subjects in each sequence, with a maximum 
split in either direction of approximately 60%:40%) has been selected based on 
practicality and convention for this type of study. Considering potential for 
subject drop-out of the study, a total of 48 subjects will be enrolled with 20-28 
male subjects and 20-28 female subjects. 
 
3.4 Randomization and Blinding 
This is an open-label study where, in order to minimize selection bias in 
treatment assignment, subjects will be randomized to 2 treatment sequences. 
x 
Eligible subjects who meet all inclusion and no exclusion criteria will be 
assigned unique numbers for enrollment.  
x 
Study subject numbers will not be reallocated once assigned.  
x 
To achieve balance between the number of males and females in the 2 
treatments sequence the maximum split in either direction will be 
approximately 60%:40% (10-14 of each sex in each sequence). 
x 
Subjects randomized to Treatment A will receive 1 × 15 mg ALXN1840 EC 
tablet, whilst subjects randomized to Treatment B will receive 3 x 5 mg 
ALXN1840 EC tablets. 
 


Statistical Analysis Plan 
 
 
 
C18054 ALXN1840-HV-104 SAP Final 1.0 11Nov2019Page 10 of 20 
4. STATISTICAL ANALYSES 
In general, descriptive statistics for continuous variables will include number of 
non-missing values (n), arithmetic mean, standard deviation (SD), median, 
minimum, and maximum.  
Descriptive statistics for PK parameters will include number of non-missing 
observations (n), arithmetic mean, SD, arithmetic coefficient of variation (CV), 
geometric mean, geometric CV, median, minimum and maximum.  
Categorical variables will be summarized using frequency counts and 
percentages.  
For all tables, except PK parameter tables, descriptive statistics for minimum 
and maximum will be presented with the same decimal digits as the original 
data, and with 1 more decimal place than the original data for mean and 
median; SD will be reported with 2 more decimal places than the original data. 
Descriptive statistics and percentages and frequency counts will be summarized 
by sex, treatment, period and sequence, where appropriate. 
PK parameters will be presented as follows in the listing: Cmax and time to 
maximum observed plasma concentration (Tmax) will be presented as given in 
the raw data; AUCt, AUC∞, the apparent terminal-phase elimination rate 
constant (λz), the terminal elimination half-life (t1/2), CL/F, and the apparent 
volume of distribution (Vd/F) will be presented with 3 decimal places. Descriptive 
statistics for PK parameters will be presented with decimal places as appropriate 
for the parameter and treatment.  
The analyses will be presented by treatment, sex, period and sequence where 
appropriate. All collected data will be presented in by-subject listings. Listings 
will be ordered by treatment sequence and subject number and will include all 
randomized subjects.  
Baseline will be defined as the last non-missing value among assessments 
recorded prior to first administration of study drug per period, where 
unscheduled assessment at the respective scheduled study are also taken into 
account. Changes from baseline values will be calculated as the post-baseline 
assessment value minus the baseline value per period. In general, only observed 
values from scheduled time points will be used to create summary tables, with 
the exception of unscheduled assessments on the respective study day. It is 
assumed that unscheduled assessments on scheduled study days are repetitions 
of potentially invalid scheduled assessments, and thus those unscheduled 
assessments will replace the respective scheduled assessments for summary 
tables and further statistical analyses.  
Early Termination (ET) visits will be recoded to ET visits where necessary and 
reported as ET.  


Statistical Analysis Plan 
 
 
 
C18054 ALXN1840-HV-104 SAP Final 1.0 11Nov2019Page 11 of 20 
Deviations from the planned analyses will be described in the final clinical study 
report (CSR).  
Page layout of the TFLs will be in landscape mode and will be provided as RTF 
files in Microsoft Word. Final TFLs will additionally be created in bookmarked 
portable document format (PDF). Further details of page layout will be provided 
in the TFL shell document.  
All statistical analyses will be conducted using SAS® for Windows® Version 9.3 
or higher.  
4.1 Interim Analysis  
No interim analyses are planned for this study. 
4.2 Analysis Populations 
Inclusion and exclusion from each analysis population will be decided at the 
Blind Data Review Meeting (BDRM) prior to database lock. Further exclusions 
may be made from PK and PD populations based on the plasma concentration 
data. 
Randomized Population 
The randomized population consists of all enrolled subjects who sign the 
informed consent form (ICF), and randomised in the study, regardless of 
whether subjects received a dose of study drug. Subjects who prematurely 
withdraw from the study for any reason and for whom an assessment is not 
performed will still be included in the randomized population. Subjects will be 
summarized according to their randomized treatment group. 
Safety Population  
The safety population will consist of all subjects who receive at least 1 dose of 
the study drug. 
PK Population  
The PK population will consist of all subjects who have sufficient plasma samples 
data to enable the calculation of at least one of the following PK parameters: 
Cmax, AUCt or AUC∞ for plasma total Mo under both treatments, A and B. 
Subjects who did not receive the full dose of study drug will be excluded from 
the PK population. 
PD Population  
The PD population will consist of all subjects who have sufficient plasma samples 
which will enable the evaluation of the PD effects, that is for whom at least one 
absolute and percentage change of plasma copper levels in terms of either Cu, 
Cp, CpC or NCC is available under both treatments, A and B.  
 


Statistical Analysis Plan 
 
 
 
C18054 ALXN1840-HV-104 SAP Final 1.0 11Nov2019Page 12 of 20 
4.3 Subject Disposition 
All subjects enrolled will be included in the summary of subject disposition. This 
will present the overall number of subjects screened and by treatment sequence 
and overall the frequency and percentage of subjects randomized and treated, 
and who completed or discontinued from the study, along with reason for 
discontinuation. Furthermore, the number and percentage of subjects in each 
analysis population will be tabulated. Discontinued subjects will be listed. 
Subject assignment to analysis populations will be listed. Screen Failures will not 
be listed or included in summary tables. 
 
4.4 Demographic Characteristics 
Individual subject demographics (including age, sex, race and ethnicity), body 
measurement data (height, body weight and body mass index) at screening and 
menstruation information (regular cycle, first day of last cycle, average cycle 
length) will be listed and summarized (excluding menstruation information) by 
each treatment sequence and overall for the safety population. If the remaining 
analysis populations are different from the safety population by more than 5%, 
separate demographic tables will be produced. Height will be measured in 
centimetres and weight in kilograms. Body mass index will be given in kg/m2. 
 
4.5 Baseline and Other Safety Characteristics 
Data collected from virus serology, serum pregnancy test, alcohol breath test 
and urine drug screen will be listed by subject. 
 
4.6 Inclusion and Exclusion Criteria 
The inclusion and exclusion criteria will be listed together with the overall 
eligibility for each subject and the frequency of failed inclusion or exclusion 
criteria will be summarized. 
 
4.7 Protocol Deviations 
The final review of protocol deviations will be performed prior to database lock. 
The protocol deviations will be listed and summarized by treatment sequence. 
 
4.8 Medical History 
Medical history data will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) dictionary Version 21.0 (or higher). Medical and surgical 
history data will be listed individually and summarized by treatment sequence.  


Statistical Analysis Plan 
 
 
 
C18054 ALXN1840-HV-104 SAP Final 1.0 11Nov2019Page 13 of 20 
 
4.9 Study Drug Administration and Meals 
As per protocol, study drug dosing will occur with the subject being in a fasted 
state. 
Study drug administration data will be listed individually. 
Meal (breakfast, lunch, dinner, snacks) times and consumption grade will be 
listed. 
4.10 Prior and Concomitant Medications 
All prior and concomitant medications will be coded using the World Health 
Organization Drug Dictionary version June 1, 2018 or higher and will be listed 
individually.  
Prior medications are defined as those for which the end date and time is prior to 
the date, and time of first study drug administration.  
Concomitant medications are defined as those either with start date and time on 
or after the date and time of first study drug administration, or those with start 
date and time prior to the first study drug administration and continuing at the 
time of first dose of study drug administration.  
 If medication/therapy dates or times are incomplete and it is not clear whether 
the medication/therapy was concomitant, it will be assumed to be concomitant. 
All prior and concomitant medications/therapies will be listed by subject using 
reported name, anatomical therapeutic chemical (ATC) Term and World Health 
Organization drug dictionary (WHO-DD) Preferred Name, indication, dose, dose 
unit, frequency, route of administration, start date and end date or ‘ongoing’ flag 
and duration of use. Concomitant medications will be flagged.  
The number and percentage of subjects with concomitant medication/therapy 
will be summarised overall and by WHO-DD Preferred Name and ATC Term using 
the safety population. Prior medication will be summarized in the same way as 
concomitant medication. 
Non-pharmacologic therapies and procedures will be listed separately. 
 
4.11 Safety Analyses 
All safety analyses will be performed on the safety population.  
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. 
 


Statistical Analysis Plan 
 
 
 
C18054 ALXN1840-HV-104 SAP Final 1.0 11Nov2019Page 14 of 20 
4.11.1 Adverse Events 
A Treatment Emergent Adverse Event (TEAE) is any adverse event that 
commences after the start of administration of study drug. TEAEs will further be 
classified by the Period in which they commenced. A TEAE will be classified as 
Period 1 if the AE start date/time is on or after the date and time of drug 
administration in Period 1, and Period 2 if the AE start date/time is on or after 
the date and time of drug administration in Period 2. 
The incidence of TEAEs (after dosing) will be summarized using the safety 
population.  
The MedDRA dictionary Version 21.0 (or higher) will be used to classify all AEs 
reported during the study by System Organ Class (SOC) and Preferred Term.  
A summary of TEAEs including the incidence of subjects who experienced TEAEs 
(number and percentage of subjects) and incidence of TEAEs (number of events) 
will be presented for each period, treatment and overall, by toxicity and by 
relationship to study drug.  
TEAEs and serious TEAEs will be summarized by SOC and Preferred Term for 
each period and treatment and overall, and by relationship to study drug and by 
toxicity.  
Subjects having multiple AEs within a category (e.g., overall, SOC and Preferred 
Term) will be counted once in that category.  
For toxicity tables, a subject's worst toxicity event within a category will be 
counted. For relationship tables, a subject's event with greatest relationship to 
study drug within a category will be counted.  
In each table, SOC and Preferred Term will be presented in descending order of 
overall incidence rate (alphabetical order will be used in case of equal rates).  
All adverse events will be listed. Serious TEAEs and AEs resulting in withdrawal 
from the study will be listed separately. 
Adverse events during screening will be summarized by treatment sequence and 
overall. 
4.11.2 Laboratory Data 
Clinical laboratory parameters (including blood chemistry, haematology, 
coagulation, urinalysis and other laboratory results) will be listed and abnormal 
parameters will be flagged as high (H) or low (L) according to reference ranges. 
Absolute (observed) values and changes from baseline (continuous variables) 
will be summarized for each parameter and scheduled time point by treatment. 
The last lab value will be used for summary analysis if repeated measurements 
are made at any time point.  


Statistical Analysis Plan 
 
 
 
C18054 ALXN1840-HV-104 SAP Final 1.0 11Nov2019Page 15 of 20 
For summary statistics, a lab value with “<” will be replaced with a numeric 
value by removing the “<” sign. In the listings, the values will be displayed as 
originally reported by the laboratory.  
Laboratory parameter values will be graded according to the Common 
Terminology Criteria for Adverse Events (CTCAE) and summarized by CTCAE 
grade. Non-protocol parameters will only be listed, in a separate listing, if 
required. Shift tables by treatment will be produced for all other laboratory 
parameters. These tables will summarize the number of subjects with each 
baseline grade relative to the normal ranges and changes to the worst highest 
grade assessed post-dose during the study. Similarly, shift tables from baseline 
based on NCI toxicity grade will be created. 
As per the study protocol, any laboratory tests with values considered clinically 
significantly abnormal are to be repeated until the values return to normal or 
baseline or are no longer considered clinically significant by the Investigator or 
medical monitor. For all summary analyses, only the last available of all 
repeated measurements is to be used. 
 
4.11.3 Electrocardiograms 
ECG parameters will be measured at the time points specified in the study 
protocol and will at least include heart rate, PR interval, RR interval, QRS 
duration, interval between the start of the Q wave and the end of the T wave in 
an ECG (QT), and corrected QT interval corrected using Fridericia’s formula 
(QTcF), where QTcF=QT/RR^1/3. The variables will be listed individually.  
Three or more replicate measurements are taken at each protocol time point and 
the arithmetic mean of the evaluable/available measurements will be taken as 
the measurement to be used for summary statistics. Arithmetic mean values will 
also be included into the listings.  
For ECG variables, the change from baseline will be derived using the arithmetic 
mean value of each time-point triplicate minus the arithmetic mean of baseline 
triplicate values per period.  
Mean absolute (observed) values and corresponding changes from baseline in 
the ECG variables will be summarized by treatment and time point.  
An outlier analysis will be performed on mean values that will summarize the 
frequency and percentage of subjects who meet any of the following outlier 
criteria at each visit by treatment: 
• QT, QTcF interval > 450 msec to ≤ 480 msec 
• QT, QTcF interval > 480 msec to ≤ 500 msec 
• QT, QTcF interval > 500 msec 


Statistical Analysis Plan 
 
 
 
C18054 ALXN1840-HV-104 SAP Final 1.0 11Nov2019Page 16 of 20 
• QT, QTcF interval increases from baseline > 30 msec to ≤ 60 msec 
• QT, QTcF interval increases from baseline > 60 msec 
As per the clinical study protocol, recorded ECGs will be reviewed by the 
Investigator, or qualified designee, and abnormal ECGs may be followed by 
additional safety recordings. For summary analyses, the additional safety ECGs 
will be used only, and will replace the initial ECGs that were reviewed as 
abnormal. 
 
4.11.4 Vital Signs 
Vital signs data (systolic and diastolic blood pressure, heart rate, temperature, 
respiration rate, and if available orthostatic drop calculated as standing minus 
supine value) will be listed for individual subjects.  
Summary statistics of absolute (observed) values and changes from baseline will 
be calculated for each parameter and scheduled time point by treatment. 
As per the study protocol, out of range blood pressure or heart rate 
measurements are to be repeated by the Investigator’s discretion, and for 
summary statistics any such repeated measurement is to be used instead of the 
initial out of range measurement. 
 
4.11.5 Physical Examination 
Physical examination data will be listed individually and abnormal findings will be 
summarized by period and treatment. 
 
4.12 Pharmacokinetic Analyses 
All plasma concentration data will be listed for each individual subject and 
summarized 
at 
each 
time 
point 
by 
treatment. 
Individual 
and 
mean 
concentrations versus nominal time on linear and semi-log scales will be 
presented graphically by treatment 
The PK population will be used to present the summary of PK parameters. 
 
4.12.1 Values Below the Limit of Quantification and Missing Values  
If a Below the Limit of Quantification (BLQ) value occurs in a profile before the 
first measurable concentration within period, it will be assigned a value of zero 
concentration. If a BLQ value occurs after a measurable concentration in a 
profile and is followed by a value above the lower limit of quantification, then the 
BLQ value will be omitted following visual inspection of the plasma concentration 
versus time profile to assess the appropriateness of this assignment. If a BLQ 


Statistical Analysis Plan 
 
 
 
C18054 ALXN1840-HV-104 SAP Final 1.0 11Nov2019Page 17 of 20 
value occurs at the end of a collection profile (after the last quantifiable 
concentration), the value will be treated as missing data. If 2 BLQ values occur 
in succession, the profile will be deemed to have terminated at the first BLQ 
value and any subsequent concentrations will be omitted from PK calculations 
following visual inspection of the plasma concentration versus time profile to 
assess the appropriateness of this assignment. 
Samples with no reportable value due to a bioanalytical issue or missing samples 
will be set to missing, and will not be included in the PK calculations. If a subject 
vomited following dose administration, then their profile will be examined to 
determine the impact of this on PK parameter estimation.  
When calculating the mean or median value for a concentration at a given time 
point, all BLQ values will be set to zero except when an individual BLQ falls 
between 2 quantifiable values, in which case it will be omitted. 
For tabulation, graphical representation, and calculation purposes, all samples 
with no reportable value (or missing samples) observed after dosing will be set 
to missing. 
 
4.12.2 Pharmacokinetic Parameters 
The plasma total Mo PK parameters will be summarized with descriptive 
statistics.  
Analyses of other PK data including, but not limited to those, of PUF Mo may be 
conducted. PK parameters will be calculated using Phoenix® WinNonlin®.  
The following PK parameters will be derived for each subject: 
x 
Cmax [ng/mL]: Maximum observed plasma concentration 
o for multiple peaks, the highest post-dose concentration will be 
reported as Cmax 
x 
Tmax [h]: Time to maximum observed plasma concentration 
o in case that multiple peaks are of equal magnitude, the earliest 
Tmax will be reported 
x 
AUCt [h*ng/mL]: Area under the plasma concentration versus time 
curve from time zero (dosing) to the last quantifiable concentration 
x 
AUC∞ [h*ng/mL]: Area under the plasma concentration versus time 
curve from time zero (dosing) extrapolated to infinity 
x 
AUCextr (%): The percentage of AUC∞ extrapolated 
o Subjects with an AUCext > 20% will be flagged, and parameters 
that are dependent on AUC∞ will also be flagged (AUC∞, AUC∞ _n, 
CL/F, Vd/F and Frel) 
x 
λz [1/h]: Apparent terminal-phase elimination rate constant 


Statistical Analysis Plan 
 
 
 
C18054 ALXN1840-HV-104 SAP Final 1.0 11Nov2019Page 18 of 20 
o only those data points that are judged to describe the terminal log-
linear decline will be used in the regression. 
o A minimum number of 3 data points in the terminal phase will be 
used in calculating λz, with the line of regression starting at any 
post-Cmax data point (Cmax should not be part of the regression 
slope). 
x 
t½ [h]: Terminal elimination half-life 
o Calculated as ln(2) / λz 
x 
CL/F [L/h]: Apparent total clearance 
o Calculated as dose / AUC∞. 
x 
Vd/F [L]: Apparent volume of distribution during terminal phase 
o Calculated as dose / (λz*AUC∞) 
x 
Relative Bioavailability (Frel): defined as the ratio of the geometric 
means of PK parameter (Cmax, AUCt and AUC∞) for the test (= treatment 
B = 3 x 5 mg ALXN1840 EC tablets) over the reference (= treatment A = 
1 x 15 mg ALXN1840 EC tablet) treatment, for details see section 4.12.3  
PK parameters will be listed for each individual subject and summarized by 
period and treatment. Descriptive statistics for PK parameters will include 
number of observations (n), arithmetic mean (Mean), SD, arithmetic coefficient 
CV, geometric mean, geometric CV, median, minimum and maximum. 
Some PK parameters may not be calculated for all or some subjects if the 
concentration data are not deemed to be amenable to evaluation. Explanations 
for PK parameters that could not be estimated will be provided in the CSR. 
Additional PK parameters may be calculated, as appropriate. 
 
4.12.3 Bioavailability Analysis 
The PK parameters for total Plasma and Plasma Ultrafiltrate Mo (Cmax, AUCt, and 
AUC∞) will be evaluated using an Analysis of Variance (ANOVA) statistical model 
with dosing period, treatment, and sequence as the fixed effects, and subject as 
a random effect, using the natural logarithms of the data. Confidence intervals 
(90%) will be constructed for the least squares geometric mean ratios (GMR) for 
the 3 × 5 mg ALXN1840 (test) versus  1 × 15 mg ALXN1840 (reference) 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-subject coefficient of variation 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% confidence intervals of Cmax, AUCt, and 
AUC∞ will be reported for each treatment.  
 


Statistical Analysis Plan 
 
 
 
C18054 ALXN1840-HV-104 SAP Final 1.0 11Nov2019Page 19 of 20 
4.12.4 CL/F and Body Size 
Relationships between CL/F and body size (body weight [kg] and BMI [kg/m²]) 
will be evaluated graphically for the two treatment sequences and with combined 
data. If suggested by the graphs, regression models may be fit to the data. 
 
4.13 Pharmacodynamic and Biomarker Analyses 
Individual ALXN1840 PD and biomarkers, assessed as plasma total Cu (PD), NCC 
(PD), NCCcorrected (PD), Cp (biomarker), and CpC (biomarker) concentration-time 
data (including measured, absolute and percent changes from baseline) will be 
listed and summarized at each time point by treatment with descriptive 
statistics.  
NCC is calculated by subtracting the amount of Cu bound to ceruloplasmin from 
the total plasma Cu level:  
ܰܥܥሾɊ݉݋݈Ȁܮሿൌܶ݋ݐ݈ܽ݌݈ܽݏ݉ܽܥݑሾɊ݃Ȁܮሿെሺ͵Ǥͳͷ כ ܿ݁ݎݑ݈݋݌݈ܽݏ݉݅݊ሾ݉݃Ȁܮሿሻ
͸͵ǤͷሾɊ݃ȀɊ݉݋݈ሿ
 
For subjects dosed with ALXN1840, there is also Cu bound in the 
tetrathiomolybdate-Cu-albumin tripartite complex which is addressed by the 
NCC correction method:  
ܰܥܥ௖௢௥௥௘௖௧௘ௗൌ൫ξܰܥܥെͲǤͻͻ͵ξܯ݋൯
ଶ 
In the calculation of NCC and NCCcorrected, the following adjustments will be 
made: 
x 
Copper values < lower limit of quantification (LLOQ) are set to missing 
and NCC will not be derived;  
x 
Ceruloplasmin <LLOQ are set to 0; 
x 
Molybdenum <LLOQ are set to 0; 
x 
Negative NCC values are not utilized and NCCcorrected will not be 
derived;  
x 
NCCcorrected will be set to 0 when 0.993√Mo > √NCC. 
  
 Individual subject data (and change from baseline) of plasma Cp and copper 
levels (total Cu, Cp, CpC and NCCcorrected) will be presented graphically for 
each period and treatment. Mean plots (for measured and change from baseline 
value) by period and treatment will be presented (separately for PD and 
biomarker parameters) and over time by period.  
Analyses of other biomarker data including, but not limited to, those of PUF Cu 
may be conducted. 


Statistical Analysis Plan 
 
 
 
C18054 ALXN1840-HV-104 SAP Final 1.0 11Nov2019Page 20 of 20 
 
4.14 Methods for Withdrawals, Missing Data and Outliers 
The individual plasma concentration data and the actual timing of study drug 
administration and blood sampling will be used throughout the analyses. If there 
is any doubt about the actual time at which a sample was taken, then the 
scheduled time will be used. For PK data analysis, please see Section 4.12.1 
regarding the handling of missing and below level of quantification (BLQ) values.  
For PD data analysis, there will be no imputation for missing values.  
If medication dates are incomplete and it is not clear whether the medication 
was concomitant, it will be assumed to be concomitant.  
AEs with unknown start date/time will be assumed to be treatment-emergent 
unless the end date/time is known to be before the first administration of study 
drug. Otherwise missing or partial dates will be listed as such.  
There will be no further imputation of missing data (i.e., subjects who 
prematurely discontinue from the study will not be included in summary 
statistics or analyses beyond the time of discontinuation).  
Depending on the extent of missing values, the appropriateness of the methods 
described for handling missing data may be reassessed prior to database lock (to 
examine the sensitivity of results to handling of missing data). 


Certificate Of Completion
Envelope Id: 
Status: Completed
Subject: Please DocuSign: C18054 ALXN1840-HV-104 SAP Final 1.0 11Nov2019_signed.pdf
Source Envelope: 
Document Pages: 20
Signatures: 2
Envelope Originator: 
Certificate Pages: 2
Initials: 0
AutoNav: Enabled
EnvelopeId Stamping: Disabled
Time Zone: (UTC-05:00) Eastern Time (US & Canada)
100 College St.
New Haven, CT  06510
IP Address: 
Record Tracking
Status: Original
             19-Nov-2019 | 12:54
Holder:
            
Location: DocuSign
Signer Events
Signature
Timestamp
Alexion Pharmaceuticals Inc.
Security Level: Email, Account Authentication 
(Required), Digital Certificate
Signature Provider Details: 
      Signature Type: Alexion Pharmaceuticals, Inc. 
(Regulated) (Client ID: 
      Signature Issuer: Alexion Pharmaceuticals Issue 
2 CA
Signature Adoption: Pre-selected Style
Signature ID: 
Using IP Address: 
Signature Provider Location: 
https://dswebapp.alexion.com/takepen/signenvelope
With Signing Authentication via DocuSign password
With Signing Reasons (on each tab): 
   I approve this document
Sent: 19-Nov-2019 | 13:00
Viewed: 19-Nov-2019 | 13:20 
Signed: 19-Nov-2019 | 13:21
Electronic Record and Signature Disclosure: 
      Not Offered via DocuSign
Alexion Pharmaceuticals, Inc. (Regulated)
Security Level: Email, Account Authentication 
(Required), Digital Certificate
Signature Provider Details: 
      Signature Type: Alexion Pharmaceuticals, Inc. 
(Regulated) (Client ID: 
      Signature Issuer: Alexion Pharmaceuticals Issue 
2 CA
Signature Adoption: Pre-selected Style
Signature ID: 
Using IP Address: 
Signature Provider Location: 
https://dswebapp.alexion.com/takepen/signenvelope
With Signing Authentication via DocuSign password
With Signing Reasons (on each tab): 
   I approve this document
Sent: 19-Nov-2019 | 13:00
Viewed: 19-Nov-2019 | 13:06 
Signed: 21-Nov-2019 | 08:33
Electronic Record and Signature Disclosure: 
      Not Offered via DocuSign
In Person Signer Events
Signature
Timestamp
Editor Delivery Events
Status
Timestamp
Agent Delivery Events
Status
Timestamp
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


Intermediary Delivery Events
Status
Timestamp
Certified Delivery Events
Status
Timestamp
Carbon Copy Events
Status
Timestamp
Witness Events
Signature
Timestamp
Notary Events
Signature
Timestamp
Envelope Summary Events
Status
Timestamps
Envelope Sent
Hashed/Encrypted
19-Nov-2019 | 13:00
Certified Delivered
Security Checked
19-Nov-2019 | 13:20
Signing Complete
Security Checked
21-Nov-2019 | 08:33
Completed
Security Checked
21-Nov-2019 | 08:33
Payment Events
Status
Timestamps