Clinical trial NCT05047523
Conditions: Wilson Disease
Keywords: Wilson Disease Pediatric
Sponsor: Alexion Pharmaceuticals, Inc.
Start date: 2021-09-13; Completion date: 2023-06-26
Enrollment: 40 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is being conducted to evaluate the efficacy, safety, pharmacokinetics (PK), and pharmacodynamics of ALXN1840 versus standard of care in pediatric participants with Wilson disease (WD).

Detailed description:
Participants who complete the 48 weeks of treatment in Period 1 will have the option to receive ALXN1840 for 24 weeks in Period 2 (open-label extension).

Safety will be monitored throughout the study.

Arms: arm 1: ALXN1840 will be administered at one of two starting doses, with incremental dose increases permitted. arm 2: Participants will receive their current therapy or initiate Standard of Care therapy.
Interventions: intervention 1: ALXN1840 intervention 2: Standard of Care
Intervention descriptions: intervention 1: Administered as an oral tablet. intervention 2: Depending on the site/region, participants randomized to receive Standard of Care treatment will receive trientine, penicillamine, zinc, or a combination of these medicines, administered according to standard regimens.

Protocol documents:
Prot_000.pdf: 
Protocol Amendment 3 (Global) 
08 Mar2022 
TITLE PAGE 
Protocol Title: 
ALXN1840-WD-302 
A multicenter, randomized, controlled, open-label, rater-blinded study to evaluate efficacy, 
safety, pharmacokinetics, and pharmacodynamics of ALXNl 840 versus standard of care in 
pediatric participants with Wilson disease 
Protocol Number: ALXN1840-WD-302 
Amendment Number: 3 (Global) 
Compound: ALXN1840 (formerly known as ATN-224 and WTX101) or bis-choline 
tetrathiomolybdate (tiomolibdic acid, tiomolibdate choline) 
Study Phase: 3 
Short Title: Phase 3, open-label study of ALXNl 840 versus standard of care in pediatric 
participants with Wilson disease 
Sponsor Name: Alexion Pharmaceuticals, Inc. 
Legal Registered Address: 
121 Seaport Boulevard 
Boston, MA 02210 
USA 
Regulatory Agency ldentifier.Number(s): IND 119006, EudraCT 2021-001015-82 
Release Date: 
Amendment 3 (Global) 
Amendment 2 (Germany) 
Amendment 1.1 (UK) 
Amendment 1 (UK) 
Ori2inal Protocol 
Sponsor Signatory: 
08 Mar 2022 
08 Nov 2021 
30 Sep 2021 
07 Jul 2021 
15 Mar 2021 
09 Mr;vr 20 22 
Date 
Medical Monitor Name and Contact Information can be found in the Study Contact List. 
Page 1 ofl08 
Alexion Confidential 
NCT05047523


Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
INVESTIGATOR’S AGREEMENT 
I have read the study protocol and agree to conduct the study in accordance with this protocol 
amendment 3 (Global), 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 
Page 2 of 108 
Alexion Confidential 


Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
PROTOCOL AMENDMENT SUMMARY OF CHANGES 
Amendment 3 (Global) (08 Mar 2022) 
This substantial amendment is considered to impact the scientific value of the study 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, the US Food and Drug Administration’s (FDA) regulation at 
21 CFR part 312.30(b), and any applicable local regulations.  
Rationale for the Amendment: 
The main reason for this amendment is to reduce the maximum daily dose of ALXN1840 from 
60 mg for adolescent participants and 30 mg for pediatric participants to 15 mg for all 
participants in this study. The decision to reduce the maximum daily dose was made based on 
results from the Primary Evaluation Period of the ongoing Phase 3 study WTX101-301. 
In addition, changes that were made in the following country-specific protocol amendments and 
Administrative Change Letters have also been incorporated into this global amendment. 
•
Administrative Change Letter 1 (dated 09 Jun 2021): to change the guidance on blood
volume and to make some minor clarifications and corrections.
•
Protocol Amendment 1.1 (UK) (30 Sep 2021): the main change was to specify
permitted gastrostomy devices in inclusion criterion #5, as requested by the UK
Medicines and Healthcare products Regulatory Agency (MHRA).
•
Administrative Change Letter 2 (dated 17 Sep 2021): the main change was to clarify
when randomization would occur, so as to enable sites to perform randomization up
to the start of Day 1 procedures, rather than just on Day -1.
•
Administrative Change Letter 3 (dated 29 Oct 2021): to clarify that post-dose
collection of PK/PD/biomarker samples is required for participants randomized to
either ALXN1840 or SoC.
•
Protocol Amendment 2 (Germany) (08 Nov 2021): changes were made in response to
a request from the Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM;
German Federal Institute for Drugs and Medical Devices) to revise the time
specification for reporting an SAE by the Investigator to Alexion to “immediately”
instead of “within 24 hours” and to include text on the potential risk and mitigation
strategies for pediatric participants. These changes are included in a new section for
country-specific changes (Section 10.11).
•
Administrative Change Letter 4 (dated 15 Dec 2021): to clarify the distribution of
participants among strata, because the distribution (ie, the number of participants in
each stratum) is a goal, and is not intended to be prescriptive.
Minor administrative changes were also made for consistency and clarity. 
Changes from the original protocol are summarized in the table below. 
Page 3 of 108 
Alexion Confidential 


Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
Section # and Name 
Description of Change 
Brief rationale and/or 
clarifications 
1.1 Synopsis 
2.1 Study Rationale 
4.3 Justification for Dose 
Removal of term “standard” from “standard 
treatment” for WD from the protocol. 
This change was made for 
consistency and to avoid confusion 
between ‘standard treatment’ and 
‘SoC’. 
1.1 Synopsis 
3 Objectives and 
Endpoints 
Revisions to PK endpoints: 
•
terminal elimination half-life; (t1/2)
removed
•
Ctrough added
Revision to text as follows: 
•
Derived population secondary PK
parameters such as revised to note
that derived secondary PK
parameters such as CL/F and Vd/F
(as appropriate)
t1/2 removed as not enough time 
points to calculate.  
Addition of Ctrough, because there will 
be enough data to calculate this 
parameter. 
Revision of wording, because there 
may not be enough time points to 
calculate secondary PK parameters. 
1.1 Synopsis 
1.2 Schema, Figure 1 
4.1 Overall Design 
Addition of “a minimum of” to the number 
of participants in each stratum. 
To clarify the distribution of 
participants among cohorts, because 
the distribution of the strata (ie, the 
number of participants) was an 
approximation and was not intended 
to be prescriptive. It was intended 
that a minimum of 6 participants 
should be included in each stratum 
(N = 24) and the remaining 24 
participants can come from any of 
the strata in any combination. 
1.1 Synopsis 
1.3 Schedule of 
Activities, Table 1 
4.1 Overall Design 
4.2 Scientific Rationale 
for Study Design 
8.6 Pharmacodynamics 
Clarification in footnote l that PK, measured 
by plasma total molybdenum and PUF 
molybdenum, and PD, measured by plasma 
total copper and LBC, will be determined 
for all participants. 
To clarify the post-dose collection of 
PK/PD/biomarker samples for 
participants randomized to either 
ALXN1840 or SoC. 
1.1 Synopsis 
2.3.1 Risk Assessment 
4.1 Study Design 
4.3 Justification for Dose 
6.1 Study Interventions 
Administered, Table 5 
6.1.1 Dose Modification 
for ALXN1840 
6.6.1 Dose Modification 
for ALN1840, Table 5 
8.4 Treatment of 
Overdose 
10.8.1 Participants aged 
12 to < 18 years 
Removal of text relating to dose increases 
from 15 mg/day to a maximum of 60 
mg/day.  
Text revised, as appropriate, to state that the 
maximum permitted daily dose is 15 mg. 
It has been decided to limit the 
maximum dose to 15 mg/day, based 
on Primary Evaluation Period data 
from the ongoing Study WTX101-
301. 
Page 4 of 108 
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Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
Section # and Name 
Description of Change 
Brief rationale and/or 
clarifications 
1.1 Synopsis 
The following text on individualized doses 
for participants aged 3 to < 12 years has 
been removed.  
•
Individualized doses ranging from
2.5 mg/day to 30 mg/day are
allowed.
The preceding and subsequent text in 
the section adequately covers the 
range of dosing options. 
1.2 Study Schema, Figure 
1 
1.3 Schedule of 
Activities, Table 1 
Screening period changed from Day -28 to 
Day -2 to Day -28 to Day -1, with 
randomization to occur before Day 1 
procedures begin. 
To enable sites to perform 
randomization up to the start of Day 
1 procedures, rather than just on Day 
-1.
1.3 Schedule of 
Activities, Table 1 
Addition of text to note stating that 
participants who are randomized to 
ALXN1840 in Period 1 do not need to 
attend visits at Weeks 4, 6, 8, and 18 in 
Period 2. 
Participants who are randomized to 
ALNX1840 in Period 1 will be 
attending visits every 12 weeks at the 
end of Period 1, so do not need to 
attend more regularly in Period 2. 
“ET” added to Week 24 in Period 2. 
Added for clarity, because similar to 
Period 1, the ET visit would occur 
during Period 2 in the event of early 
termination. 
Aligned assessment of lipid panel with 
chemistry assessments. 
To ensure that lipids are assessed at 
all time points that chemistry is 
assessed. 
Footnote k revised to state that transient 
elastography will be done when available. 
Footnote applied to the text “Transient 
elastography” and removed from the 
Screening and Day 1 timepoints. 
To reflect that it may not be possible 
to perform transient elastography at 
all study sites. 
Text on alternative blood sampling schedule 
for infants deleted from footnote l. 
To align with the change in guidance 
on blood sampling volumes (see 
below). 
Period 2 added to footnote l. 
To clarify that plasma/serum samples 
will be collected predose in both 
Periods 1 and 2. 
1.3 Schedule of 
Activities, Table 1 
Section 8, Study 
Assessments and 
Procedures 
Removal of text from the general footnote 
and footnote l stating that an alternative 
blood sampling schedule for infants will be 
given in the Study Operations Manual. 
Removal of the same text from Section 8, 
noting that it refers to “children and 
adolescents” 
Guidelines on blood sampling are 
provided in Section 10.7. No separate 
guidelines for infants are required, 
because the minimum age for 
enrollment into the study is 3 years. 
1.3 Schedule of 
Activities, Table 1 
8.8 Biomarkers 
10.2 Clinical Laboratory 
Tests, Table 10 
Footnote l simplified to state that serum 
ceruloplasmin will be assessed separately to 
plasma ceruloplasmin (which will be 
assessed as part of the PK/PD/biomarker 
parameters). 
To clarify that serum and plasma 
ceruloplasmin are analyzed 
separately. 
1.3 Schedule of 
Activities, Table 1 
10.2 Clinical Laboratory 
Tests 
Text requiring pregnancy testing for 
3 months after the EOS visit removed from 
footnote j and Section 10.2. 
To align with Clinical Trials 
Facilitation Group (CTFG) guidance 
on contraception and pregnancy 
testing recommendations. 
2.2 Background 
Text on Study ALXN1840-HV-109 updated 
to state that relative bioavailability of the 
1.25 mg enteric-coated mini-tablet 
Updated because Study ALXN1840-
HV-109 has been completed. 
Page 5 of 108 
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Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
Section # and Name 
Description of Change 
Brief rationale and/or 
clarifications 
formulation of ALXN1840 compared with 
the 15 mg EC tablet was confirmed. 
2.3 Benefit/Risk 
Assessment 
Text has been added stating that potential 
risk and mitigation strategies have been 
identified in line with the EU guidance 
“Ethical Considerations for Clinical Trials 
on Medicinal Products in Minors”. 
The change was made in response to 
a request from the BfArM (Germany) 
to assess and monitor the risk 
threshold by the Investigator, and to 
define it in the protocol. 
2.3.1 Risk Assessment, 
Table 2 
Potential risk, rationale for risk, and 
mitigation added regarding lipid elevations. 
To include guidance for monitoring 
of lipids, based on observations of 
lipid elevations that have been 
observed in patients with WD. 
4.2 Scientific Rationale 
for Study Design 
Addition of text stating that SoC PD will be 
assessed in children and adolescents.  
To clarify that SoC PD will be 
assessed in children and adolescents. 
4.2 Scientific Rationale 
for Study Design 
8.5 Pharmacokinetics 
9.4.3 Pharmacokinetic, 
Pharmacodynamic, and 
Biomarker Analyses 
Removal of “as surrogate measures of 
ALXN1840 PK” in text about analysis of 
samples.  
Removed for clarity. 
4.3 Justification for Dose 
Table 4 deleted. 
The table was deleted because the 
predicted dose range information in 
the table was modified due to the 
reduction in maximum dose. The 
information in the footnote was 
repurposed in the text to provide the 
necessary details.  
5.1 Inclusion Criteria 
Modification of the text in inclusion 
criterion #5, which now reads 
“Able to swallow intact ALXN1840 tablets 
or mini-tablets. Participants who require 
gastrostomy devices for feeding or 
medications may be enrolled if the inner 
diameter of the tube can accommodate an 
intact tablet or mini-tablet without 
obstruction.”  
This change was made in response to 
the request by the UK Medicines and 
Healthcare products Regulatory 
Agency (MHRA) to remove 
inclusion criteria that are not absolute 
and to predefine the attributes of the 
gastrostomy devices. 
5.2 Exclusion Criteria 
Removal of concomitant use of 
penicillamine, zinc, or trientine from 
exclusion criterion 10. 
Concomitant use of medications is 
not an exclusion criterion, but is 
covered in Section 6.5.2 Disallowed 
Medicine and Therapy. 
5.3.1 Meals and Dietary 
Restrictions 
Addition of text stating that ALXN1840 
mini-tablets may be administered with a 
small amount of apple sauce or yogurt. 
Results from a food vehicle study 
found that mini-tablets are stable in 
apple sauce and yogurt, so these 
foods have been included as an 
option for administration of 
ALXN1840. 
6.5.2 Disallowed 
Medicine and Therapy 
Addition of text stating that vitamin E and 
estrogen should not be initiated during the 
study, but can be continued if already being 
taken. 
To clarify that vitamin E and 
estrogen can continue to be taken 
during the study, if already being 
taken before the study start. 
6.6.1 Dose Modification 
for ALXN1840, Tables 5 
and 6 
Addition of dose modification rules for 
increased triglycerides and total cholesterol. 
To include guidance on dose 
modifications in the event of 
increased triglycerides or total 
cholesterol. 
Page 6 of 108 
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Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
Section # and Name 
Description of Change 
Brief rationale and/or 
clarifications 
8.2.3 Electrocardiograms 
Removal of cross-reference to Section 7 for 
QTc withdrawal criteria and any additional 
QTc readings that may be necessary. 
QTc withdrawal criteria are not 
required in this protocol. 
8.3.5 Adverse Events of 
Special Interest 
Text revised to state that all AESIs will be 
assessed by a panel of 3 independent 
neurologists. 
To reflect that all AESIs will be 
assessed by a panel of 3 independent 
neurologists, not just SAEs of special 
interest. 
8.6 Pharmacodynamics 
8.8 Biomarkers 
Addition of SoC to the text on analysis of 
PD. 
To clarify that PD will be measured 
for SoC. 
9.1.1 Primary Hypothesis 
9.4 Statistical Analyses 
Addition of PD to the types of evaluations 
in the study. 
For completeness. 
9.5 Interim Analyses 
Text added to state when the primary and 
final analyses will take place. Text modified 
to state that interim analyses of data may be 
performed to support regulatory submission. 
To clarify when the primary and final 
analyses will take place, and to note 
that interim analyses may be 
performed. 
9.7 Neurological Event 
Adjudication Panel 
Text revised to include AEs as well as 
SAEs. 
To reflect that the Neuro Event 
Adjudication Panel will review and 
monitor study for all AEs, not just 
SAEs. 
10.2 Clinical Laboratory 
Tests, Table 10 
Removal of text in footnote relating to Hy’s 
Law. 
Text removed as not needed. If 
participants experience INR 
prolongation and they are admitted to 
hospital, the event will meet the 
definition and be recorded as an 
SAE. 
Removal of reference to glycated 
hemoglobin (HbA1c). 
HbA1c is not assessed during the 
study. 
10.3.2 Definition of SAE 
Text added noting that SUSAR reporting 
will be in accordance with the Summary of 
Product Characteristics of the respective 
SoC products.  
To clarify SUSAR reporting 
requirements for SoC as an 
implication of designating SoC as 
IMP. 
10.4.2.1 Guidance for 
Female Participants 
Addition of “associated with inhibition of 
ovulation” to the following text: 
•
Combined (estrogen- and
progestogen-containing) hormonal
contraception - associated with
inhibition of ovulation (either oral,
intravaginal, or transdermal) for at
least 6 weeks prior to first dose of
study intervention.
For clarification and to align with 
CTFG guidance on contraception use 
in clinical studies. 
10.7 Blood Sampling 
Volumes 
Wording revised to state that the 
Investigator may, rather than should, apply 
an EMLA cream/plaster at the puncture site, 
and to add that use of an EMLA 
cream/plaster depends on clinical practice at 
the study site. 
To reflect that EMLA cream/plaster 
use depends on clinical practice at 
the study site. 
Reference changed from the European 
Commission guidance to the US guidelines. 
From: 
•
European Commission. European
Commission Ethical
Considerations for Clinical Trials
on Medicinal Products Conducted
The guidance on blood sampling 
volumes has been changed from the 
European Commission guidance to 
the US National Institutes of Health 
guidelines, because the US 
guidelines allow Investigators to 
conduct all tests planned without 
Page 7 of 108 
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Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
Section # and Name 
Description of Change 
Brief rationale and/or 
clarifications 
with the Paediatric Population: 
Recommendations of the ad hoc 
group for the development of 
implementing guidelines for 
Directive 2001/20/EC relating to 
the good clinical practice in the 
conduct of clinical trials on 
medicinal products for human use. 
2008 
To: 
•
POLICY- Guidelines for Limits of
Blood Drawn for Research
Purposes in the Clinical Center
https://irb.research.chop.edu/sites/d
efault/files/documents/g_nih_bloo
ddraws.pdf”
Text changed from: 
•
Volume of blood samples: Per
study participant, the study-related
blood loss (including any losses in
the collection procedure) should
not exceed 3% of the total blood
volume during a period of 4 weeks,
and should not exceed 1% at any
single time. The total volume of
blood is estimated at 80 to 90
mL/kg body weight. 3% is 2.4 mL
blood per kg body weight.
To: 
Volume of blood samples: Per study 
participant, the study-related blood loss 
(including any losses in the collection 
procedure) should not exceed more than 
5 mL/kg body weight (5% of total blood 
volume) in a single day and no more than 
9.5 mL/kg (11% of total blood volume) 
over any 8‐week period. 
increasing the number of blood draw 
points. 
10.11 Country-Specific 
Changes 
Addition of a section detailing country-
specific changes to the protocol. The 
changes included in this section apply to 
Germany only, and are as follows: 
•
Changes to the time specification
for reporting of SAEs
•
Addition of text on potential risk
and mitigation strategies
•
Addition of text noting that
measures have been taken to
minimize the burden of
participation and degree of distress
for the pediatric and adolescent
participants in the study.
To include changes requested by the 
BfArM in Germany that only apply 
to Germany. 
All 
Minor administrative changes. 
For consistency and clarity. 
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Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
Abbreviations: AESI = adverse event of special interest; BfArM = Bundesinstitut für Arzneimittel und 
Medizinprodukte (German Federal Institute for Drugs and Medical Devices); CL/F = apparent total body clearance; 
Ctrough = trough (predose) concentration observed at the start of the dosing interval; EMLA = eutectic mixture of 
local anesthetics; EOS = end of study; ET = early termination; IMP = Investigational Medicinal Product; 
PD = pharmacodynamics; PK = pharmacokinetics: PUF = plasma ultrafiltrate; SAE = serious adverse event; SoC = 
Standard of Care; SUSAR = suspected unexpected serious adverse reaction; Vd/F = apparent volume of 
distribution;WD = Wilson disease. 
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Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
INVESTIGATOR’S AGREEMENT ...............................................................................................2 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ..........................................................3 
TABLE OF CONTENTS ...............................................................................................................10 
LIST OF TABLES .........................................................................................................................15 
LIST OF FIGURES .......................................................................................................................15 
1.
PROTOCOL SUMMARY..........................................................................................16 
1.1. 
Synopsis ......................................................................................................................16 
1.2. 
Schema ........................................................................................................................22 
1.3. 
Schedule of Activities .................................................................................................23 
2.
INTRODUCTION ......................................................................................................26 
2.1. 
Study Rationale ...........................................................................................................26 
2.2. 
Background .................................................................................................................26 
2.3. 
Benefit/Risk Assessment ............................................................................................27 
2.3.1. 
Risk Assessment .........................................................................................................28 
2.3.1.1. 
Coronavirus Disease 2019 ..........................................................................................29 
2.3.2. 
Benefit Assessment .....................................................................................................29 
2.3.3. 
Overall Benefit: Risk Conclusion ...............................................................................30 
3.
OBJECTIVES AND ENDPOINTS ............................................................................31 
4.
STUDY DESIGN .......................................................................................................35 
4.1. 
Overall Design ............................................................................................................35 
4.2. 
Scientific Rationale for Study Design ........................................................................36 
4.2.1. 
Participant Input in Design .........................................................................................37 
4.3. 
Justification for Dose ..................................................................................................37 
4.4. 
End of Study Definition ..............................................................................................38 
5.
STUDY POPULATION .............................................................................................39 
5.1. 
Inclusion Criteria ........................................................................................................39 
5.2. 
Exclusion Criteria .......................................................................................................40 
5.3. 
Lifestyle Considerations .............................................................................................41 
5.3.1. 
Meals and Dietary Restrictions ...................................................................................41 
5.4. 
Screen Failures............................................................................................................41 
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Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
6.
STUDY INTERVENTION ........................................................................................42 
6.1. 
Study Interventions Administered ..............................................................................42 
6.1.1. 
Study Intervention(s) Packaging and Labeling ...........................................................42 
6.2. 
Preparation/Handling/Storage/Accountability ............................................................43 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ........................................43 
6.4. 
Study Intervention Compliance ..................................................................................43 
6.5. 
Prior and Concomitant Therapy ..................................................................................44 
6.5.1. 
Allowed Medicine and Therapy .................................................................................44 
6.5.2. 
Disallowed Medicine and Therapy .............................................................................44 
6.6. 
Dose Modification ......................................................................................................45 
6.6.1. 
Dose Modification for ALXN1840 ............................................................................45 
6.6.2. 
Dose Modification for Standard of Care ....................................................................53 
6.7. 
Intervention After the End of the Study .....................................................................54 
7.
DISCONTINUATION OF STUDY INTERVENTION AND
PARTICIPANT DISCONTINUATION/WITHDRAWAL .......................................55 
7.1. 
Discontinuation of Study Intervention........................................................................55 
7.2. 
Participant Discontinuation/Withdrawal from the Study ...........................................55 
7.3. 
Lost to Follow-up .......................................................................................................56 
8.
STUDY ASSESSMENTS AND PROCEDURES......................................................57 
8.1. 
Efficacy Assessments .................................................................................................57 
8.1.1. 
Assessment of Copper ................................................................................................57 
8.1.2. 
Model for End-stage Liver Disease and Pediatric End-stage Liver Disease 
scores ..........................................................................................................................57 
8.1.3. 
Unified Wilson Disease Rating Scale (Parts I, II, and III) .........................................58 
8.1.4. 
Clinical Global Impression-Severity Scale and the Clinical Global 
Impression Improvement Scale ..................................................................................58 
8.1.5. 
Fibrosis-4 Index and Transient Elastography .............................................................59 
8.1.6. 
Modified Nazer Score .................................................................................................59 
8.1.7. 
Brief Psychiatric Rating Scale-24 ...............................................................................59 
8.1.8. 
EuroQoL 5 Dimensions ..............................................................................................59 
8.1.8.1. 
EQ-5D Youth ..............................................................................................................59 
8.1.9. 
Treatment Satisfaction Questionnaire for Medication ................................................60 
8.1.10. 
Pediatric Quality of Life Inventory .............................................................................60 
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Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
8.1.11. 
Urinary and Fecal Copper Excretion ..........................................................................60 
8.2. 
Safety Assessments .....................................................................................................61 
8.2.1. 
Physical Examinations ................................................................................................61 
8.2.2. 
Vital Signs ..................................................................................................................61 
8.2.3. 
Electrocardiograms .....................................................................................................62 
8.2.4. 
Clinical Safety Laboratory Assessments ....................................................................62 
8.2.5. 
Suicidal Ideation and Behavior Risk Monitoring .......................................................62 
8.2.6. 
Pregnancy ...................................................................................................................63 
8.3. 
Adverse Events and Serious Adverse Events .............................................................63 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE Information .......................63 
8.3.2. 
Method of Detecting AEs and SAEs ..........................................................................64 
8.3.3. 
Follow-up of AEs and SAEs.......................................................................................64 
8.3.4. 
Regulatory Reporting Requirements for SAEs ...........................................................64 
8.3.5. 
Adverse Events of Special Interest .............................................................................65 
8.4. 
Treatment of Overdose ...............................................................................................65 
8.5. 
Pharmacokinetics ........................................................................................................65 
8.6. 
Pharmacodynamics .....................................................................................................66 
8.7. 
Genetics ......................................................................................................................66 
8.8. 
Biomarkers ..................................................................................................................66 
8.9. 
Immunogenicity Assessments ....................................................................................67 
8.10. 
Health Economics Data and/or Medical Resource Utilization ...................................67 
9.
STATISTICAL CONSIDERATIONS .......................................................................68 
9.1. 
Statistical Hypotheses .................................................................................................68 
9.1.1. 
Primary Hypothesis ....................................................................................................68 
9.2. 
Sample Size Determination ........................................................................................68 
9.3. 
Populations for Analyses ............................................................................................69 
9.4. 
Statistical Analyses .....................................................................................................69 
9.4.1. 
Efficacy Analyses .......................................................................................................70 
9.4.1.1. 
Analyses of Primary Efficacy Endpoint .....................................................................70 
9.4.1.2. 
Analyses of Secondary Efficacy Endpoints ................................................................70 
9.4.1.3. 
Multiplicity Adjustment..............................................................................................70 
9.4.1.4. 
Analyses of Exploratory Endpoints ............................................................................70 
9.4.2. 
Safety Analyses ..........................................................................................................70 
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Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
9.4.3. 
Pharmacokinetic, Pharmacodynamic, and Biomarker Analyses ................................71 
9.5. 
Interim Analyses .........................................................................................................73 
9.6. 
Data Monitoring Committee .......................................................................................73 
9.7. 
Neurological Event Adjudication Panel .....................................................................73 
9.8. 
Hepatic Adjudication Panel ........................................................................................73 
10.
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS ..................................................................................................74 
10.1. 
Regulatory, Ethical, and Study Oversight Considerations .........................................74 
10.1.1. 
Regulatory and Ethical Considerations ......................................................................74 
10.1.2. 
Financial Disclosure ...................................................................................................74 
10.1.3. 
Informed Consent Process ..........................................................................................75 
10.1.4. 
Data Protection ...........................................................................................................75 
10.1.5. 
Dissemination of Clinical Study Data ........................................................................76 
10.1.6. 
Data Quality Assurance ..............................................................................................76 
10.1.7. 
Source Documents ......................................................................................................77 
10.1.8. 
Study and Site Start and Closure ................................................................................77 
10.1.9. 
Publication Policy .......................................................................................................78 
10.1.10. 
Good Clinical Practice Compliance ............................................................................78 
10.2. 
Clinical Laboratory Tests ...........................................................................................79 
10.3. 
Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ...........................................................................................81 
10.3.1. 
Definition of AE .........................................................................................................81 
10.3.2. 
Definition of SAE .......................................................................................................82 
10.3.3. 
Recording and Follow-up of AE and/or SAE .............................................................82 
10.3.4. 
Reporting of SAEs ......................................................................................................84 
10.4. 
Contraceptive Guidance and Collection of Pregnancy Information ...........................85 
10.4.1. 
Definitions ..................................................................................................................85 
10.4.2. 
Contraception Guidance .............................................................................................85 
10.4.2.1. 
Guidance for Female Participants ...............................................................................85 
10.4.2.2. 
Guidance for Male Participants ..................................................................................87 
10.4.3. 
Collection of Pregnancy Information .........................................................................87 
10.4.3.1. 
Male Participants With Partners Who Become Pregnant ...........................................88 
10.4.3.2. 
Female Participants who become pregnant ................................................................88 
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Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
10.5. 
Genetics ......................................................................................................................89 
10.6. 
Biomarkers ..................................................................................................................90 
10.7. 
Blood Sampling Volumes ...........................................................................................91 
10.8. 
Population PK Simulations and Dose Selection in Pediatric Participants with 
Wilson Disease ...........................................................................................................92 
10.8.1. 
Participants aged 12 to < 18 years ..............................................................................92 
10.8.2. 
Participants aged 3 to < 12 years ................................................................................92 
10.9. 
COVID Safety Measures ............................................................................................95 
10.10. 
Abbreviations ............................................................................................................100 
10.11. 
Country-Specific Changes ........................................................................................103 
10.12. 
Protocol Amendment History ...................................................................................104 
11.
REFERENCES .........................................................................................................108 
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Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
LIST OF TABLES 
Table 1: 
Schedule of Activities .................................................................................................23 
Table 2: 
Potential Risks and Mitigation Strategy .....................................................................28 
Table 3: 
Study ALXN1840-WD-302 Objectives and Endpoints .............................................31 
Table 4: 
Study Intervention Dosage and Mode of Administration ...........................................42 
Table 5: 
ALXN1840 Dose Modifications for Individual Adolescent Participants ...................46 
Table 6: 
ALXN1840 Dose Modifications for Individual Pediatric Participants ......................50 
Table 7: 
Standard of Care Dose Modifications for Individual Participants ..............................54 
Table 8: 
Simulated Power for Pediatric Extrapolation Study ALXN1840-WD-303 
Primary Analysis ........................................................................................................69 
Table 9: 
Protocol-Required Safety Laboratory Assessments ...................................................80 
Table 10: COVID-19 Clinical Study Mitigation Measures (Optional and Temporary) 
for Study ALXN1840-WD-302 ..................................................................................96 
LIST OF FIGURES 
Figure 1: 
Study Schematic .........................................................................................................22 
Figure 2: 
Projected Pharmacokinetic Exposure Range for Participants Aged 12 to 
< 18 Years ...................................................................................................................92 
Figure 3: 
Projected Pharmacokinetic Exposure Range for Patients Aged 3 to 
< 12 Years ...................................................................................................................93 
Figure 4: Projected Pharmacokinetic Exposure Range for Participants Aged 3 to < 6 
Years ...........................................................................................................................94 
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Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
1.
PROTOCOL SUMMARY
1.1. 
Synopsis
Protocol Title: A multicenter, randomized, controlled, open-label, rater-blinded study to 
evaluate efficacy, safety, pharmacokinetics, and pharmacodynamics of ALXN1840 versus 
standard of care in pediatric participants with Wilson disease 
Short Title: Phase 3, open-label study of ALXN1840 versus standard of care in pediatric 
participants with Wilson disease 
Rationale: 
This study is being conducted to evaluate the efficacy, safety, pharmacokinetics (PK), and 
pharmacodynamics (PD) of ALXN1840 versus standard of care (SoC) in pediatric participants 
with Wilson disease (WD) who are 3 to < 18 years of age at the time of enrollment. Participants 
can be treatment-naïve or have previously received treatments approved for use in WD 
(penicillamine, trientine, zinc). 
Wilson Disease is most commonly diagnosed in teenagers and young adults and rarely presents 
symptomatically before 5 years of age (Socha, 2018). In a European cohort of 1357 patients, the 
average age at diagnosis of WD was 19.8 years (± 10 years), and half of all patients were 
diagnosed before the age of 18 (Ferenci, 2019). 
Treatments approved and used in adults with WD (penicillamine, trientine, zinc) are also 
approved for use in children and adolescents. However, significant unmet needs still exist with 
respect to efficacy, safety, tolerability, simplicity and frequency of dosing regimens, and 
especially with an appropriate compliance to therapy in young participants.  
At the time of preparation of this protocol, ALXN1840 is being evaluated versus SoC in 
adolescent (12 years and above) and adult participants (18 years and above) with WD in an 
ongoing Phase 3, multicenter, randomized study (Study WTX101-301). Since data from adults 
cannot be fully extrapolated to the whole pediatric population, this study will evaluate the 
efficacy, safety, PK, and PD of ALXN1840, compared with SoC, administered for 48 weeks in 
participants with WD aged 3 to < 18 years. Efficacy data from this study will subsequently be 
assessed together with those from Study WTX101-301, using Bayesian extrapolation methods to 
determine the efficacy of ALXN1840 compared with SoC in pediatric participants. 
Objectives and Endpoints 
Objectives 
Endpoints 
Period 1: Up to Week 48 
Primary 
•
To evaluate the efficacy of ALXN1840
administered for 48 weeks, compared to SoC, on
copper control in participants with WD aged 3 to
< 18 years of age at the time of enrollment
•
Percentage change from baseline (Day 1) to 48
weeks in NCC in plasma. For ALXN1840-treated
participants, the NCC in plasma will be corrected for
the amount of copper bound to the ALXN1840 TPC
(NCCcorrected)
Secondary 
•
Evaluate the safety and tolerability of
ALXN1840 administered for up to 48 weeks
•
Incidence of adverse AEs/SAEs, AESIs, tolerability,
clinical laboratory test data (including liver function
tests), neurological and physical examination
findings, 12-lead ECG data, and vital signs.
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Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
Objectives 
Endpoints 
•
Evaluate PD and biomarkers of ALXN1840 vs
SoC administered for 48 weeks
•
AUEC for NCC
•
AUEC for plasma total copper
•
Biomarkers: observed, absolute and percentage
changes of ceruloplasmin-bound copper and
ceruloplasmin
•
Evaluate the effects of ALXN1840 and SoC on
the NCC responder rate
•
NCC responder rate
•
Evaluate the effects of ALXN1840 and SoC on
participant reported disability status
•
Change from baseline to Week 48 in the UWDRS
Part II total score
•
Evaluate the effects of ALXN1840 and SoC on
rater-blinded neurological status
•
Change from baseline in UWDRS Part III total score
or individual items/subscales, as appropriate
•
Evaluate PK of ALXN1840 administered for
48 weeks
Estimation of PK parameters and accumulation ratios 
•
PK: Cmax, tmax, Ctrough, and AUCtau on Day 1, Day 43
(Week 6), and Day 337 (Week 48) for plasma total
molybdenum and plasma ultrafiltrate molybdenum
concentrations, accumulation ratio of Day 43 to
Day 1 and Day 337 to Day 1 based on Cmax, Ctrough,
and AUCtau
•
Derived secondary PK parameters such as CL/F and
Vd/F (as appropriate)
•
Evaluate the effects of ALXN1840 and SoC on
global clinical symptoms as assessed by the
Investigator
•
CGI-I
•
Change from Baseline to Week 48 in CGI-S
•
Evaluate the effects of ALXN1840 and SoC on
hepatic status
•
Change from Baseline to Week 48 in MELD score
(ages 12 years and older) or PELD score (ages 3 to
< 12 years)
•
Change from Baseline to Week 48 in Modified Nazer
score
Exploratory 
•
Evaluate the effects of ALXN1840 and SoC on
hepatic fibrosis
•
Change from Baseline to Week 48 in the FIB-4
Index and by transient elastography
•
Evaluate the effects of ALXN1840 and SoC on
psychiatric symptoms
•
Change from Baseline to Week 48 in BPRS-24 and
BPRS-C9
•
Evaluate the effects of ALXN1840 and SoC on
QoL/PROs
•
Change from Baseline to Week 48 in QoL/PRO
endpoint measures:
−
EQ-5D or EQ-5DY
−
PedsQL
NOTE: These tests will be administered by parent/proxy 
for participants unable to complete independently. 
•
Evaluate participant satisfaction of treatment
with ALXN1840 and SoC
•
Change from Baseline to Week 48 in TSQM-9
NOTE: This questionnaire will be administered by
parent/proxy for participants unable to complete
independently.
•
Evaluate the effects of ALXN1840 and SoC on
24-hour fecal copper and fecal molybdenum
•
Change from Baseline to Week 6 in 24-hour fecal
copper and fecal molybdenum
•
Evaluate the effects of ALXN1840 and SoC on
24-hour urinary copper and urinary molybdenum
•
Change from Baseline to Week 48 in 24-hour
urinary copper and urinary molybdenum
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Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
Objectives 
Endpoints 
•
Explore other directly measured
pharmacodynamics (PD) and biomarkers of
ALXN1840
•
Daily mean AUEC of NCC, and plasma total copper
from 0 to 24, and 24 to 48 weeks
•
Observed, absolute and percent changes of copper
levels (total copper, PUF copper, LBC)
•
Explore ALXN1840 effect on initial
decoppering phase compared to SoC based on
directly measured PK/PD and biomarkers
•
Time to first confirmed increase in plasma NCC and
total copper concentration
•
Time to minimum and maximum concentration of:
−Plasma total copper
−Plasma NCC
−Plasma LBC
−Ratio plasma NCC:total copper
−Ratio plasma LBC:total copper
−Plasma ceruloplasmin
−Plasma CpC
−Ratio plasma ceruloplasmin:total copper
−Plasma CpC:total copper
−24-hour urinary molybdenum
−Ratio urinary molybdenum:copper
−Ratio 24-hour urinary molybdenum:dosed
molybdenum
•
Explore ALXN1840 effect on subsequent
maintenance phase compared to SoC based on
directly measured PK/PD and biomarkers
•
Time for return to pre-dose baseline for the
following PK/PD parameters:
−Plasma total copper
−Plasma NCC
−Plasma LBC
−Ratio plasma NCC: total copper
−Ratio plasma LBC:total copper
−Plasma ceruloplasmin concentration
−Plasma CpC concentration
−Ratio plasma ceruloplasmin:total copper
−Ratio plasma CpC:total copper
−24-hour urinary molybdenum
−Ratio urinary molybdenum:copper
−Ratio urinary molybdenum:dosed
molybdenum
Period 2: Weeks 48 to 72 
Exploratory 
•
Safety and tolerability of ALXN1840 in the
Extension Period
•
AEs/SAEs, AESI, tolerability, clinical laboratory
test data, physical examination findings, vital signs,
and 12-lead ECG data
•
Evaluate PD and biomarkers of ALXN1840
•
AUEC for NCC
•
AUEC for plasma total copper
•
Observed, absolute and percent changes of copper
levels (total copper, PUF copper, LBC)
•
Biomarkers: observed, absolute and percent changes
of ceruloplasmin-bound copper and ceruloplasmin
•
Evaluate the effects of ALXN1840 on hepatic
status
•
Change from Baseline in MELD/PELD score and
modified Nazer score
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Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
Objectives 
Endpoints 
•
Evaluate the effects of ALXN1840 on disability
status
•
Change from Baseline in UWDRS Part II
•
Evaluate the effects of ALXN1840 on
neurological status
•
Change from Baseline in UWDRS Part III
•
Evaluate the effects of ALXN1840 on hepatic
fibrosis
•
Change from Baseline in transient elastography and
FIB-4 index
•
Evaluate the effects of ALXN1840 on
psychiatric symptoms
•
Change from Baseline in BPRS-24 and BPRS-C9
•
Evaluate the effects of ALXN1840 on global
clinical symptoms as assessed by the
Investigator
•
Change from Baseline in CGI-I and CGI-S
•
Evaluate the effects of ALXN1840 on QoL/PRO
•
Change from Baseline to Week 72 in QoL/PRO
endpoint measures:
−
EQ-5D or EQ-5DY
−
PedsQL
NOTE: These tests will be administered by parent/proxy 
for participants unable to complete independently. 
•
Evaluate participant satisfaction of treatment
with ALXN1840 and SoC
•
Change from Baseline to Week 72 in TSQM-9
NOTE: This questionnaire will be administered by
parent/proxy for participants unable to complete
independently.
Abbreviations: AE = adverse event; AESI = adverse event of special interest; AUCtau = area under the plasma 
concentration versus time curve from time 0 to the end of the dosing interval; AUEC = area under the effect versus 
time curve; BPRS-24 = Brief Psychiatric Rating Scale-24; BPRS-C9 = Brief Psychiatric Rating Scale for children; 
CGI-I = Clinical Global Impression-Improvement Scale; CGI-S = Clinical Global Impression-Severity Scale; 
CL/F = apparent total body clearance; Cmax = maximum observed concentration; CpC = ceruloplasmin-bound 
copper; Ctrough = trough (predose) concentration observed at the start of the dosing interval; 
ECG = electrocardiogram; EQ-5D(Y) = EuroQoL 5 Dimensions (Youth); FIB-4 = fibrosis-4; LBC = labile-bound 
copper; MELD = Model for End-stage Liver Disease; NCC = non-ceruloplasmin-bound copper; 
NCCcorrected = corrected NCC; PD = pharmacodynamics; PELD = Pediatric End-stage Liver Disease; PedsQL = 
Pediatric Quality of Life Inventory; PK = pharmacokinetics; PRO = patient-reported outcome; PUF = plasma 
ultrafiltrate; QoL = quality of life; SAE = serious adverse event; SoC = standard of care; tmax = time to maximum 
concentration; TPC = tripartite complex; TSQM-9 = Treatment Satisfaction Questionnaire for Medication-9; 
UWDRS = Unified Wilson Disease Rating Scale; Vd/F = apparent volume of distribution; WD = Wilson Disease. 
Overall Design 
This is a randomized, controlled, open-label, rater-blinded study designed to evaluate the 
efficacy, safety, PK, and PD of ALXN1840 versus SoC in pediatric participants aged 3 to 
<18 years with a confirmed diagnosis of WD, who meet pre-specified laboratory parameters and 
do not have decompensated cirrhosis. PK measured by plasma total molybdenum and plasma 
ultrafiltrate (PUF) molybdenum, and PD measured by plasma total copper and labile-bound 
copper (LBC), will be determined for all participants. 
The study includes 2 periods; the 48-week Primary Evaluation Period (Period 1) serves to 
evaluate the effect of ALXN1840 versus SoC on efficacy, safety, PK, and PD. Participants who 
complete the 48-week Period 1 will be offered the opportunity to participate in a 24-week 
Extension Period (Period 2), ie, up to 72 weeks in total, to further evaluate the safety and 
efficacy of ALXN1840. 
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Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
Disclosure Statement: This is a randomized, controlled, open-label treatment study with 
2 cohorts that is rater-blinded for the Unified Wilson Disease Rating Scale (UWDRS) 
assessment. 
Number of Participants: 
Approximately 48 participants will be randomized 1:1 to either ALXN1840 or SoC treatment 
with the goal of obtaining 40 evaluable participants at Week 48. Participants in Period 1 will be 
stratified by age group (3 to < 12 years, 12 to < 18 years) and into 1 of 2 cohorts: 
•
Cohort 1: Participants who have received SoC therapy (ie, chelation therapy with
penicillamine or trientine, treatment with zinc, or a combination of both chelation and
zinc therapy) for > 28 days prior to enrollment in the study
•
Cohort 2: Participants who are treatment naïve or who have received SoC therapy for
≤ 28 days prior to enrollment in the study
The primary enrollment and randomization objective is to have at least 12 participants in each 
age group and to achieve balanced treatment assignments both overall and within each age 
group. A secondary goal is to have at least 3 participants assigned to each treatment within each 
cohort of each age group. 
To achieve this goal, participants will be randomized to treatment within one of the following 
4 age groups/cohort strata: 
•
Stratum 1: 3 to < 12 years old at randomization and Cohort 1 (prior SoC treatment
> 28 days) (a minimum of 6 participants)
•
Stratum 2: 3 to < 12 years old at randomization and Cohort 2 (prior SoC treatment
≤ 28 days) (a minimum of 6 participants)
•
Stratum 3: 12 to < 18 years old at randomization and Cohort 1 (prior SoC treatment
> 28 days) (a minimum of 6 participants)
•
Stratum 4: 12 to < 18 years old at randomization and Cohort 2 (prior SoC treatment
≤ 28 days) (a minimum of 6 participants)
Note: “Enrolled” means a participant’s agreement to participate in a clinical study following 
completion of the informed consent/assent process and satisfying inclusion/exclusion criteria, 
and subsequent randomization to study treatment. Potential participants who are screened for the 
purpose of determining eligibility for the study, but do not participate in the study and are not 
randomized to treatment, are not considered enrolled.  
Intervention Groups and Duration: 
Throughout Period 1, participants randomized to receive ALXN1840 will be administered 
ALXN1840 orally daily at the following doses: 
•
For participants aged 12 to < 18 years, ALXN1840 will be administered at a starting
dose of 15 mg/day. Dose escalation is not permitted. Individualized doses ranging
from 15 mg every other day to 15 mg/day are allowed. Doses of < 15 mg every other
day may be considered, with approval of the Alexion Medical Monitor.
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Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
•
For participants aged 3 to < 12 years, a lower starting dose of 2.5 mg/day will be
administered for at least 4 weeks (based on scaling of the starting dose of 15 mg/day
in the ongoing Study WTX101-301). Dose escalation is permitted but not required.
The dose may be increased in increments of 2.5 mg daily with the permission of the
Alexion Medical Monitor, depending on the participant’s clinical status, NCCcorrected
concentrations, and safety laboratory results. Dose increases must occur at least
4 weeks apart and may only occur if no other dose modification (reduction or
interruption) criteria apply. Participants who require doses of 15 mg daily may use the
15-mg tablet.
Individualized ALXN1840 dosing will be utilized throughout the study (Periods 1 and 2) based 
on the following parameters: 
•
Clinical criteria: dose-titration based on hepatic and neurological status
•
NCCcorrected: dose-titration based on NCCcorrected concentrations. The reference range
for NCCcorrected is 0.8 to 2.3 µM.
•
Safety monitoring: dose modification criteria are based on regularly scheduled
assessments for recognized hematological effects of copper lowering, hepatic testing,
and neurological tests
The dose should be lowered or interrupted if any of the relevant dose modification criteria are 
met. Deviation from the dose modification guidelines must be agreed with the Alexion Medical 
Monitor. 
Participants randomized to receive SoC treatment will continue their current therapy or initiate 
SoC, ie, chelation therapy with penicillamine or trientine, zinc therapy, or a combination of both 
chelation and zinc therapy if they are not currently on SoC at the start of the study. The choice of 
SoC medication and dose will be individualized at the discretion of the Investigator. 
Data Monitoring Committee: Yes 
An independent Data and Safety Monitoring Board, a Neurological Event Adjudication Panel, 
and a Hepatic Adjudication Panel comprising experts in relevant fields with no direct 
relationship to the study will be implemented in this study. 
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Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
1.2. 
Schema 
Figure 1: 
Study Schematic 
*At randomization, participants will be stratified by age group (3 to < 12 years and 12 to < 18 years) and into one of
2 cohorts (prior SoC treatment > 28 days or ≤ 28 days):
•
Stratum 1: 3 to < 12 years old at randomization and Cohort 1 (prior SoC treatment > 28 days) (a
minimum of 6 participants)
•
Stratum 2: 3 to < 12 years old at randomization and Cohort 2 (prior SoC treatment ≤ 28 days) (a
minimum of 6 participants)
•
Stratum 3: 12 to < 18 years old at randomization and Cohort 1 (prior SoC treatment > 28 days) (a
minimum of 6 participants)
•
Stratum 4: 12 to < 18 years old at randomization and Cohort 2 (prior SoC treatment ≤ 28 days) (a
minimum of 6 participants)
Abbreviations: EOS = End of study; SoC = standard of care. 
Randomization
Day 1
Week 48
Screening
Period 1
48 weeks
EOS
ALXN1840
Standard of Care
ALXN1840
Primary Analysis
After 48 weeks
N = 24
N = 24
N = 48
Period 2
24 weeks
Days -28 to -1
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Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
1.3. 
Schedule of Activities 
Table 1: 
Schedule of Activities 
Screening 
Period 1 
Period 2 
UNSa Follow-
up/EO
Sb 
Day 
-28 to -1
1c
8 
15 29c 
43c 57c 85c 127c 169c 211 253c 295 
337c 
1 
8 
15 29 43 57 85 127 
169 
197 
Week 
1
d
2
d
4 
6 
8 
12 
18 
24 
30d 
36 
42d 48/ET 
1d 
2d 
4 
6 
8 
12 
18 
24/ET 
28 
Total Weeks 
1
d
2
d
4 
6 
8 
12 
18 
24 
30d 
36 
42d 48/ET 
49d 50d 52 54 56 60 
66 
72/ET 
76 
Window (days) 
±3 
±7 
±7 
±3 
±7 
±3 
±7 
±7 
±7 
Obtain informed 
consent/assent 
X 
Review eligibility 
criteria 
Xe 
Randomizationf 
X 
Medical history 
X 
WD medication 
history 
X 
X 
Physical 
examination 
X 
X 
Abbreviated 
physical 
examinationg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signsh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG
X 
X 
X 
X 
X 
X 
X 
HIV, hepatitis B & 
C screen 
X 
DNA sample 
Xi 
Pregnancy testj 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chemistry, 
coagulation, 
hematology, and 
lipid panel 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Iron profile 
X 
X 
X 
X 
Transient 
elastographyk 
X 
X 
X 
X 
X 
X 
Plasma/serum 
PK/PD/biomarkers 
samplesl 
Xl 
X 
Xl 
X 
X 
X 
X 
Xl 
X 
X 
X 
X 
X 
X 
X 
24-hour urinem 
X 
X 
X 
X 
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Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
Table 1: 
Schedule of Activities 
Screening 
Period 1 
Period 2 
UNSa Follow-
up/EO
Sb 
Day 
-28 to -1
1c
8 
15 29c 
43c 57c 85c 127c 169c 211 253c 295 
337c 
1 
8 
15 29 43 57 85 127 
169 
197 
Week 
1
d
2
d
4 
6 
8 
12 
18 
24 
30d 
36 
42d 48/ET 
1d 
2d 
4 
6 
8 
12 
18 
24/ET 
28 
Total Weeks 
1
d
2
d
4 
6 
8 
12 
18 
24 
30d 
36 
42d 48/ET 
49d 50d 52 54 56 60 
66 
72/ET 
76 
Window (days) 
±3 
±7 
±7 
±3 
±7 
±3 
±7 
±7 
±7 
24-hour fecesm 
X 
X 
UWDRS Parts I, II, 
and IIIn 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MELD/PELD and 
modified Nazero 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Fibrosis-4o 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
BPRS-24 and 
BPRS-C9p 
X 
X 
X 
X 
X 
X 
X 
CGI-Iq and CGI-S 
X
X 
X 
X 
X 
X 
X 
EQ-5D/EQ-5DY 
X 
X 
X 
X 
X 
X 
X 
TSQM-9 
X 
X 
X 
X 
PedsQL 
X 
X 
X 
X 
X 
X 
X 
AE and concomitant 
medication 
Administer/dispense 
ALXN1840 or SoCr 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Notes: Participants randomized to SoC who complete Period 1 will be given ALXN1840 in Period 2. Participants randomized to ALXN1840 in Period 1 do not 
need to attend Period 2 visits at Weeks 4, 6, 8, and 18. 
a. Unscheduled visits may occur at any time during the study and may include any study procedures (including dispensing of ALXN1840/SoC) as deemed
necessary by the Investigator. These visits may or may not be completed by a home healthcare nurse depending on the purpose of the Unscheduled Visit.
b. Follow-up Visit procedures will be performed at Week 52 for participants who do not enter Period 2, ie, 4 weeks after the Week 48 visit.
c. Assessments on Day 1 and other study visit days where laboratory sampling is planned should be performed pre-dose. Assessments at the Week 48 (Day 337)
visit in Period 1 should be used as the Period 2 Day 1 assessments. 
d. Week 1, Week 2, Week 30, and Week 42 (Day 8, Day 15, Day 211, and Day 295) of Period 1, and Weeks 1 and 2 of Period 2 will be performed via a safety
phone call. If a neurological AE is reported, the following assessments must be performed as soon as possible: UWDRS Parts II and III, CGI-I and CGI-S. 
Investigators can perform additional assessments or laboratory testing at their discretion. 
e. Individuals who do not meet the criteria for participation in this study (screen failure) may be rescreened up to 2 times after agreement on required repeated
assessments with the Medical Monitor. 
f. Participants will be randomized before Day 1 procedures begin, after meeting all inclusion and none of the exclusion criteria. All procedures required at
Screening must be completed prior to the Day 1 Visit. 
g. Abbreviated physical examination consists of a body system relevant examination based upon Investigator judgment and participant symptoms. At least 1 body
system must be checked for an abbreviated examination. 
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h. Vital signs include heart rate, blood pressure, respiratory rate, temperature, height (without shoes), and weight.
i. The DNA sample is optional and can be collected at any time on or after Day 1; the sample will only be taken if the participant’s parent/proxy has provided
separate informed consent/assent. 
j.
Serum and urine pregnancy tests will only be performed for females of childbearing potential. Female participants of childbearing potential must not be
pregnant and not breastfeeding and must have a negative serum pregnancy test at Screening. In addition to pregnancy tests detailed at the visits in the SoA,
females of childbearing potential will be required to perform urine pregnancy tests at least every 4 weeks at their home or the study site throughout their time
in the study. Positive urine pregnancy results will be confirmed by a serum pregnancy test.
k. Transient elastography will be done when available. If transient elastography results are available from within 28 days prior to Day 1, this procedure does not
have to be repeated at the Day 1 Visit. 
l. Plasma/serum samples will be obtained from the blood samples collected pre-dose on the day of all study visits in Period 1 and Period 2 for all participants.
Participants should be instructed not to take their dose of ALXN1840 in the morning of scheduled study visits so that PK/PD/biomarker samples are 
collected at pre-dose trough: total and PUF molybdenum (PK), total and PUF copper, NCC, LBC (PD), ceruloplasmin (note that serum ceruloplasmin will be 
assessed separately to plasma ceruloplasmin, which will be assessed as part of the PK/PD/biomarker parameters), and CpC (biomarker). At the Day 1, Week 
6 (Day 43), and Week 48 (Day 337) Visits, serial blood samples will be collected for plasma PK/PD/biomarker concentrations for all participants at the 
following time points: pre-dose at 0 hour, and at 2-, 4-, 8-, and 24-hours post-dose.  
m. Urine collected will be used for 24-hour creatinine, molybdenum and copper. 24-hour urine will be collected at home and brought to the study site on Day 1,
and Weeks 6, 24, and 48. 24-hour feces (optional) will be collected at home and brought to the study site on Day 1 and at Week 6. Containers for collection 
of urine and feces will be provided at the preceding study visit to collection. 
n. The UWDRS Part I and III must be performed by a blinded neurologist who is unaware of the randomized treatment assignment.
o. To be calculated by the central laboratory.
p. The BPRS-24 (adolescents aged 12 to < 18 years) and BPRS-C9 (children aged 3 to < 12 years) can be performed by a qualified person who has completed the
required training. 
q. CGI-I is not performed at Day 1.
r. Appropriately trained study staff will administer the ALXN1840 on Day 1 and will instruct participants and their parent/proxy on how to correctly dose
themselves on the days when they take drug at home. ALXN1840 will not be dispensed or administered at the Early Termination Visit. ALXN1840 will be 
monotherapy for WD. SoC medications may be taken through Day -1, then must be discontinued on Day 1 for participants randomized to ALXN1840. 
Abbreviations: AE = adverse event; BPRS-24 = Brief Psychiatric Rating Scale-24; BPRS-C9 = Brief Psychiatric Rating Scale for children; CGI-I = Clinical 
Global Impression-Improvement; CGI-S = Clinical Global Impression-Severity; CpC = ceruloplasmin-bound copper; DNA = deoxyribonucleic acid; ECG = 
electrocardiogram; EQ-5D(Y) = EuroQoL 5 Dimensions (Youth); ET = Early Termination; FIB-4 = Fibrosis-4 Index; LBC = labile-bound copper; MELD = 
Model for End-stage Liver Disease; PD = pharmacodynamic; PELD = Pediatric Model for End-stage Liver Disease; PedsQL = Pediatric Quality of Life 
Inventory; PK = pharmacokinetic; PUF = plasma ultrafiltrate; SoC = standard of care; TSQM-9 = Treatment Satisfaction Questionnaire for Medication-9; 
UNS = unscheduled; UWDRS = Unified Wilson Disease Rating Scale; WD = Wilson disease. 
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2.
INTRODUCTION
ALXN1840 (formerly known as ATN-224 or WTX101) or bis-choline tetrathiomolybdate 
(tiomolibdic acid, tiomolibdate choline) is a novel, copper-protein binding agent in development 
for the treatment of WD. 
2.1. 
Study Rationale 
This study is being conducted to evaluate the efficacy, safety, PK, and PD of ALXN1840, a 
novel copper-protein binding agent, versus SoC in pediatric participants with WD who are 3 to 
< 18 years of age. It is a part of the agreed Paediatric Investigational Plan for ALXN1840 (EMA 
Decision P/0234/2020). 
Wilson Disease is most commonly diagnosed in teenagers and young adults, and rarely presents 
symptomatically before 5 years of age (Socha, 2018). Males and females are equally likely to be 
affected by WD. In a large European cohort of 1357 patients, the average age at diagnosis of WD 
was 19.8 years (± 10 years), and half of all patients were diagnosed before the age of 18 
(Ferenci, 2019). The age of presentation of WD is generally over 5 years. Based on the literature 
and feedback from leading EU and US reference clinical institutions managing pediatric patients 
with WD, there are exceptionally few diagnosed cases of WD in children < 6 years of age. These 
exceptionally early newly diagnosed patients may include siblings or patients who may present 
symptoms as early as 3 years. 
The same treatments approved and used in adults with WD (penicillamine, trientine, and zinc) 
are also approved for use in children and adolescents. However, significant unmet needs still 
exist with respect to efficacy, safety, simplicity and frequency of dosing regimens, and especially 
with an appropriate compliance to therapy in young participants. Currently available drugs have 
high rates of treatment discontinuation due to tolerability issues. They also need to be dosed 2 to 
4 times per day. Their adverse event (AE) profiles and complicated dosing regimens lead to poor 
treatment compliance and, as a direct consequence, to high rates of treatment failure. This 
remains an area of major concern in the treatment of WD, which is a disease that requires life-
long treatment (Maselbas, 2010; Dziezyc, 2014). 
Unlike currently available treatments for WD, ALXN1840 is designed to provide an alternative 
copper-protein transport mechanism, rapidly form copper-protein complexes with very high 
specificity for copper to quickly remove excess copper in blood and promote biliary excretion of 
copper (the body’s natural route of elimination) to reduce copper overload. 
2.2. 
Background 
ALXN1840 has been selected for development in WD due to its improved stability properties 
over ammonium tetrathiomolybdate, which has previously been studied in patients with WD and 
other indications. Ammonium tetrathiomolybdate as well as bis-choline tetrathiomolybdate 
non-clinical and clinical data reported to date support the efficacy and safety of ALXN1840. 
Results from Studies WTX101-HV-106 and WTX101-201 support a proposed mechanism of 
action of ALXN1840 whereby copper is mobilized to the bloodstream and sequestered through 
the formation of stable tripartite complexes (TPCs). 
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In the Phase 2 proof of concept Study WTX101-201 in participants with WD, ALXN1840 
demonstrated a sustained control of exchangeable copper as measured by NCCcorrected. 
Importantly, ALXN1840 treatment resulted in improvements in disability and neurologic 
symptoms as measured by the UWDRS, Parts II and III, and stabilization of liver function 
(Weiss, 2017). Treatment with ALXN1840 resulted in an acceptable safety and tolerability 
profile when initiated at 15 mg/day with Investigator-driven, individual participant titration of 
dose based on safety, NCCcorrected, and symptoms.  
ALXN1840 is currently being evaluated in the Phase 3 multicenter, randomized 
Study WTX101-301 to assess the efficacy of ALXN1840 compared with SoC on plasma copper 
control as measured by NCCcorrected. Non-ceruloplasmin-bound copper in Study WTX101-301 
can be measured via LBC or assessed via NCC/NCCcorrected methods. 
An enteric-coated 1.25 mg mini-tablet has been developed for participants who may find 
minitablets more acceptable than the 15 mg tablet, or require doses lower than 15 mg, such as 
those aged 3 to < 6 years. A Phase 1 Study ALXN1840-HV-109 has been conducted to compare 
the relative bioavailability and dose-proportionality for the 1.25 mg EC minitablet and the 15 mg 
EC tablet under fasting conditions in healthy participants. 
The plasma total and PUF molybdenum concentration-time profiles as surrogate measures for 
ALXN1840 PK have shown that the ALXN1840 PK parameters were comparable between a 
single dose of ALXN1840 administered as 12 × 1.25 mg EC minitablets (15 mg total dose) and 
as 1 × 15 mg EC tablet without clinically relevant differences. Plasma total molybdenum PK 
parameters generally showed a dose-proportional increase from 2.5 mg to 30 mg for the 
ALXN1840 EC mini-tablet formulation. Plasma PUF molybdenum PK parameters showed a less 
than dose-proportional increase from 2.5 mg to 30 mg for the ALXN1840 EC mini-tablet 
formulation. ALXN1840 PK were apparently not affected by body weight or body mass index. 
There were no apparent differences in ALXN1840 PD parameters (plasma total and PUF copper 
concentrations) between 12 × 1.25 mg EC mini-tablets and the 15 mg reference EC tablet. There 
were modest, transient, and dose-dependent increases in plasma total copper concentration 
within 8 to 12 hours after dosing, but there were no apparent dose-dependent differences in PUF 
copper concentration. 
Detailed descriptions of the chemistry, pharmacology, efficacy, and safety of ALXN1840 are 
provided in the Investigator’s Brochure (IB). 
2.3. 
Benefit/Risk Assessment 
In line with the EU guidance “Ethical Considerations for Clinical Trials on Medicinal Products 
in Minors”, potential risks and mitigation strategies have been identified that allow the 
investigators to assess and monitor risks associated with the study drug and participation in the 
study for each participant. Specific strategies aimed at assessment, monitoring, and mitigation of 
risks to the participants are detailed in Section 2.3.1 (Table 2 Potential Risks and Mitigation 
Strategy), Section 6.6 (Dose Modification), and Section 7 (Discontinuation of Study Intervention 
and Participant Discontinuation/Withdrawal). 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of ALXN1840 can be found in the current edition of the IB. 
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2.3.1. 
Risk Assessment 
Details of the potential risks and mitigation strategy are provided in Table 2. 
Table 2: 
Potential Risks and Mitigation Strategy 
Potential Risk of Clinical 
Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
ALXN1840 
Anemia 
Anemia has been observed in patients 
with WD, attributed to overtreatment and 
resultant copper depletion, see the IB 
Monitoring complete blood count 
Dose modification (Section 6.6) or 
discontinuation (Section 7) 
Reduced volume blood collection 
for participants < 12 years of age. 
See Section 10.7 for details of 
blood sampling volumes. 
Elevation of lipids (Total 
Cholesterol and Triglyceride) 
Lipid elevations were observed in 
patients with WD. These lipid elevations 
were generally mild to moderate in 
severity and occurred within 4-12 weeks 
after starting treatment with ALXN1840. 
Regular monitoring of lipid 
concentrations. 
Dose modification (Section 6.6) 
Elevation of transaminases 
(ALT and AST) 
Generally mild to moderate in severity, 
asymptomatic and reversible with dose 
adjustments were reported, usually after 
3-6 weeks of treatment.
Results obtained from studies of
ALXN1840 and ammonium
tetrathiomolybdate in patients with WD;
see the IB
Maximum dose set as 15 mg/day. 
Regular monitoring of liver 
function tests 
Dose modification (Section 6.6) or 
discontinuation (Section 7) 
Low white blood cell count 
(leukopenia, neutropenia)  
Leukopenia and myelosuppression have 
been observed in patients with WD, 
potentially attributed to overtreatment 
and resultant copper depletion. 
Results obtained from studies of 
ALXN1840 and ammonium 
tetrathiomolybdate in patients with WD; 
see the IB 
Dose modification (Section 6.6) or 
discontinuation (Section 7) 
Study Procedures and Other 
Risks associated with the 
study design and procedures 
Participants will undergo repeated blood 
draws to measure the PK and metabolism 
of the study intervention. Blood draws 
may result in ecchymosis, redness, and 
minor pain to the site. On rare occasion, 
infection or thrombophlebitis can occur. 
Blood draws are optimized for PK. 
A cannula may be placed to 
minimize needle sticks during a 
single study visit, but shall not be 
left in place if the participant leaves 
the clinic. 
Details of the maximum number of 
attempts for sampling blood are 
provided in Section 10.7. 
Participants will be required to swallow 
tablets or mini-tablets that contain the 
study intervention. Participants should 
swallow the tablets or mini-tablets whole 
without crushing to maintain the enteric 
coating. 
Training will be provided to ensure 
that participants swallow tablets or 
mini-tablets intact, without 
crushing. Mini-tablets have been 
developed for participants who are 
unable to swallow the 15 mg 
tablets. The mini-tablet should be 
removed from the capsule and 
swallowed individually, as needed. 
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Potential Risk of Clinical 
Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
ALXN1840 
Anemia 
Anemia has been observed in patients 
with WD, attributed to overtreatment and 
resultant copper depletion, see the IB 
Monitoring complete blood count 
Dose modification (Section 6.6) or 
discontinuation (Section 7) 
Reduced volume blood collection 
for participants < 12 years of age. 
See Section 10.7 for details of 
blood sampling volumes. 
Elevation of lipids (Total 
Cholesterol and Triglyceride) 
Lipid elevations were observed in 
patients with WD. These lipid elevations 
were generally mild to moderate in 
severity and occurred within 4-12 weeks 
after starting treatment with ALXN1840. 
Regular monitoring of lipid 
concentrations. 
Dose modification (Section 6.6) 
Elevation of transaminases 
(ALT and AST) 
Generally mild to moderate in severity, 
asymptomatic and reversible with dose 
adjustments were reported, usually after 
3-6 weeks of treatment.
Results obtained from studies of
ALXN1840 and ammonium
tetrathiomolybdate in patients with WD;
see the IB
Maximum dose set as 15 mg/day. 
Regular monitoring of liver 
function tests 
Dose modification (Section 6.6) or 
discontinuation (Section 7) 
Neurological worsening 
Neurological worsening may occur due to 
disease progression  
Dose modification (Section 6.6) or 
discontinuation (Section 7) 
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; IB = Investigator’s Brochure; 
PK = pharmacokinetic; WD = Wilson disease. 
2.3.1.1. 
Coronavirus Disease 2019 
The COVID-19 pandemic is active in many countries at the time of this original protocol. Given 
this unique circumstance, specific consideration has been given to the risks and benefits of the 
study as they relate to COVID-19, and the global and local changes that exist as a result of the 
pandemic. This assessment is described in Section 10.9. 
2.3.2. 
Benefit Assessment 
The main objective of effective WD treatment is to provide: 
•
Rapid and sustained control of copper and clinical symptoms of WD through the
formation of irreversible copper-tetrathiomolybdate-protein complexes.
•
Improved compliance over current SoC through improved tolerability and the
convenience of a simplified dosing regimen (once daily) compared to current
therapeutic options (multiple daily dosing).
Potential benefits of study participation for participants include: 
•
Participation in a clinical study increases the participant’s understanding of the
pathophysiology and treatment of WD.
•
Removal of total body copper as a definitive treatment for WD.
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•
All participants will receive ALXN1840 in Period 2, ie, all participants will have
access to a potentially more convenient and effective treatment for removing excess
copper.
•
Participants in the study will contribute to expanded knowledge that will potentially
improve care for other people with WD in the future, particularly the pediatric
population.
2.3.3. 
Overall Benefit: Risk Conclusion
Accounting for the measures taken to minimize risk to participants in this study, the potential 
risks identified in association with the administration of ALXN1840 are justified by the 
anticipated benefits that may be afforded to pediatric participants with WD. 
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3.
OBJECTIVES AND ENDPOINTS
The study objectives and endpoints are presented in Table 3. 
Table 3: 
Study ALXN1840-WD-302 Objectives and Endpoints 
Objectives 
Endpoints 
Period 1: Up to Week 48 
Primary 
•
To evaluate the efficacy of ALXN1840
administered for 48 weeks, compared to SoC, on
copper control in participants with WD aged 3 to
< 18 years of age at the time of enrollment
•
Percentage change from baseline (Day 1) to 48
weeks in NCC in plasma. For ALXN1840-treated
participants, the NCC in plasma will be corrected for
the amount of copper bound to the ALXN1840 TPC
(NCCcorrected)
Secondary 
•
Evaluate the safety and tolerability of
ALXN1840 administered for up to 48 weeks
•
Incidence of AEs/SAEs, AESIs, tolerability, clinical
laboratory test data (including liver function tests),
neurological and physical examination findings, 12-
lead ECG data, and vital signs.
•
Evaluate PD and biomarkers of ALXN1840 vs
SoC administered for 48 weeks
•
AUEC for NCC
•
AUEC for plasma total copper
•
Biomarkers: observed, absolute and percentage
changes of ceruloplasmin-bound copper and
ceruloplasmin
•
Evaluate the effects of ALXN1840 and SoC on
the NCC responder rate
•
NCC responder rate
•
Evaluate the effects of ALXN1840 and SoC on
participant reported disability status
•
Change from baseline to Week 48 in the UWDRS
Part II total score
•
Evaluate the effects of ALXN1840 and SoC on
rater-blinded neurological status
•
Change from baseline in UWDRS Part III total score
or individual items/subscales, as appropriate
•
Evaluate PK of ALXN1840 administered for
48 weeks
Estimation of PK parameters and accumulation ratios 
•
PK: Cmax, tmax, Ctrough, and AUCtau on Day 1, Day 43
(Week 6), and Day 337 (Week 48) for plasma total
molybdenum and plasma ultrafiltrate molybdenum
concentrations, accumulation ratio of Day 43 to
Day 1 and Day 337 to Day 1 based on Cmax, Ctrough,
and AUCtau
•
Derived secondary PK parameters such as apparent
total body clearance (CL/F) and apparent volume of
distribution (Vd/F) (as appropriate)
•
Evaluate the effects of ALXN1840 and SoC on
global clinical symptoms as assessed by the
Investigator
•
CGI-I
•
Change from Baseline to Week 48 in CGI-S
•
Evaluate the effects of ALXN1840 and SoC on
hepatic status
•
Change from Baseline to Week 48 in MELD score
(ages 12 years and older) or PELD score (ages 3 to
< 12 years)
•
Change from Baseline to Week 48 in Modified Nazer
score
Exploratory 
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Table 3: 
Study ALXN1840-WD-302 Objectives and Endpoints 
Objectives 
Endpoints 
•
Evaluate the effects of ALXN1840 and SoC on
hepatic fibrosis
•
Change from Baseline to Week 48 in the FIB-4
Index and by transient elastography
•
Evaluate the effects of ALXN1840 and SoC on
psychiatric symptoms
•
Change from Baseline to Week 48 in BPRS-24 and
BPRS-C9
•
Evaluate the effects of ALXN1840 and SoC on
QoL/PROs
•
Change from Baseline to Week 48 in QoL/PRO
endpoint measures:
−
EQ-5D or EQ-5DY
−
PedsQL
NOTE: These tests will be administered by parent/proxy 
for participants unable to complete independently. 
•
Evaluate participant satisfaction of treatment
with ALXN1840 and SoC
•
Change from Baseline to Week 48 in TSQM-9
NOTE: This questionnaire will be administered by
parent/proxy for participants unable to complete
independently.
•
Evaluate the effects of ALXN1840 and SoC on
24-hour fecal copper and fecal Mo
•
Change from Baseline to Week 6 in 24-hour fecal
copper and fecal molybdenum
•
Evaluate the effects of ALXN1840 and SoC on
24-hour urinary copper and urinary Mo
•
Change from Baseline to Week 48 in 24-hour
urinary copper and urinary molybdenum
•
Explore other directly measured
pharmacodynamics (PD) and biomarkers of
ALXN1840
•
Daily mean AUEC of NCC, and plasma total copper
from 0 to 24, and 24 to 48 weeks
•
Observed, absolute and percent changes of copper
levels (total copper, PUF copper, LBC)
•
Explore ALXN1840 effect on initial decoppering
phase compared to SoC based on directly
measured PK/PD and biomarkers
•
Time to first confirmed increase in plasma NCC and
total copper concentration
•
Time to minimum and maximum concentration of:
−Plasma total copper
−Plasma NCC
−Plasma LBC
−Ratio plasma NCC:total copper
−Ratio plasma LBC:total copper
−Plasma ceruloplasmin
−Plasma CpC
−Ratio plasma ceruloplasmin:total copper
−Plasma CpC:total copper
−24-hour urinary molybdenum
−Ratio urinary molybdenum:copper
−Ratio 24-hour urinary molybdenum:dosed
molybdenum
•
Explore ALXN1840 effect on subsequent
maintenance phase compared to SoC based on
directly measured PK/PD and biomarkers
•
Time for return to pre-dose baseline for the
following PK/PD parameters:
−Plasma total copper
−Plasma NCC
−Plasma LBC
−Ratio plasma NCC: total copper
−Ratio plasma LBC:total copper
−Plasma ceruloplasmin concentration
−Plasma CpC concentration
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Table 3: 
Study ALXN1840-WD-302 Objectives and Endpoints 
Objectives 
Endpoints 
−Ratio plasma ceruloplasmin:total copper
−Ratio plasma CpC:total copper
−24-hour urinary molybdenum
−Ratio urinary molybdenum:copper
−Ratio urinary molybdenum:dosed
molybdenum
Period 2: Weeks 48 to 72 
Exploratory 
•
Safety and tolerability of ALXN1840 in the
Extension Period
•
AEs/SAEs, AESI, tolerability, clinical laboratory
test data, physical examination findings, vital signs,
and 12-lead ECG data
•
Evaluate PD and biomarkers of ALXN1840
•
AUEC for NCC
•
AUEC for plasma total copper
•
Observed, absolute and percent changes of copper
levels (total copper, PUF copper, LBC)
•
Biomarkers: observed, absolute and percent changes
of ceruloplasmin-bound copper and ceruloplasmin
•
Evaluate the effects of ALXN1840 on hepatic
status
•
Change from Baseline in MELD/PELD score and
modified Nazer score
•
Evaluate the effects of ALXN1840 on disability
status
•
Change from Baseline in UWDRS Part II
•
Evaluate the effects of ALXN1840 on
neurological status
•
Change from Baseline in UWDRS Part III
•
Evaluate the effects of ALXN1840 on hepatic
fibrosis
•
Change from Baseline in transient elastography and
FIB-4 index
•
Evaluate the effects of ALXN1840 on
psychiatric symptoms
•
Change from Baseline in BPRS-24 and BPRS-C9
•
Evaluate the effects of ALXN1840 on global
clinical symptoms as assessed by the
Investigator
•
Change from Baseline in CGI-I and CGI-S
•
Evaluate the effects of ALXN1840 on QoL/PRO
•
Change from Baseline to Week 72 in QoL/PRO
endpoint measures:
−
EQ-5D or EQ-5D-Y
−
PedsQL
NOTE: These tests will be administered by parent/proxy 
for participants unable to complete independently. 
•
Evaluate participant satisfaction of treatment
with ALXN1840 and SoC
•
Change from Baseline to Week 72 in TSQM-9
NOTE: This questionnaire will be administered by
parent/proxy for participants unable to complete
independently.
Abbreviations: AE = adverse event; AESI = adverse event of special interest; AUCtau = area under the plasma 
concentration versus time curve from time 0 to the end of the dosing interval; AUEC = area under the effect versus 
time curve; BPRS-24 = Brief Psychiatric Rating Scale-24; BPRS-C9 = Brief Psychiatric Rating Scale for children; 
CGI-I = Clinical Global Impression-Improvement Scale; CGI-S = Clinical Global Impression-Severity Scale; 
CL/F = apparent total body clearance; Cmax = maximum observed concentration; CpC = ceruloplasmin-bound 
copper; Ctrough = Trough (predose) concentration observed at the start of the dosing interval; 
ECG = electrocardiogram; EQ-5D(Y) = EuroQoL 5 Dimensions (Youth); FIB-4 = fibrosis-4; LBC = labile-bound 
copper; MELD = Model for End-stage Liver Disease; NCC = non-ceruloplasmin-bound copper; 
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NCCcorrected = corrected NCC; PD = pharmacodynamics; PELD = Pediatric End-stage Liver Disease; 
PedsQL = Pediatric Quality of Life Inventory; PK = pharmacokinetics; PRO = patient-reported outcome; 
PUF = plasma ultrafiltrate; QoL = quality of life; SAE = serious adverse event; SoC = standard of care; tmax = time 
to maximum concentration; TPC = tripartite complex; TSQM-9 = Treatment Satisfaction Questionnaire for 
Medication-9; UWDRS = Unified Wilson Disease Rating Scale; Vd/F = apparent volume of distribution. 
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4.
STUDY DESIGN
4.1. 
Overall Design
This is a multicenter, randomized, controlled, open-label, rater-blinded study designed to assess 
the efficacy, safety, PK, and PD of ALXN1840 versus SoC in pediatric participants aged 3 to 
<18 years with a confirmed diagnosis of WD, who meet pre-specified laboratory parameters and 
do not have decompensated cirrhosis. PK measured by plasma total molybdenum and plasma 
ultrafiltrate (PUF) molybdenum, and PD measured by plasma total copper and LBC will be 
determined for all participants. 
The study includes 2 periods; the 48-week Period 1 serves to evaluate the effect of ALXN1840 
versus SoC on efficacy, safety, and PD. Participants who complete the 48-week Period 1 will be 
offered the opportunity to participate in a 24-week, open-label Period 2, ie, up to 72 weeks in 
total, to evaluate the safety and efficacy of ALXN1840. 
Approximately 48 participants will be randomized 1:1 to either ALXN1840 or SoC treatment 
with the goal of obtaining 40 evaluable participants at Week 48. Participants in the Primary 
Evaluation Period will be stratified by age group (3 to < 12 years, 12 to < 18 years) and into 1 of 
2 cohorts: 
•
Cohort 1: Participants who have received SoC therapy (ie, chelation therapy with
penicillamine or trientine, treatment with zinc, or a combination of both chelation and
zinc therapy) for > 28 days prior to enrollment in the study.
•
Cohort 2: Participants who are treatment naïve or who have received SoC therapy for
≤ 28 days prior to enrollment in the study.
The primary enrollment and randomization objective is to have at least 12 participants in each 
age group and to achieve balanced treatment assignments both overall and within each age 
group. A secondary goal is to have at least 3 participants assigned to each treatment within each 
cohort of each age group. 
To achieve this goal, participants will be randomized to treatment within one of the following 4 
age groups/cohort strata: 
•
Stratum 1: 3 to < 12 years old at randomization and Cohort 1 (prior SoC treatment
> 28 days) (a minimum of 6 participants)
•
Stratum 2: 3 to < 12 years old at randomization and Cohort 2 (prior SoC treatment
≤ 28 days) (a minimum of 6 participants)
•
Stratum 3: 12 to < 18 years old at randomization and Cohort 1 (prior SoC treatment
> 28 days) (a minimum of 6 participants)
•
Stratum 4: 12 to < 18 years old at randomization and Cohort 2 (prior SoC treatment
≤ 28 days) (a minimum of 6 participants)
Throughout Period 1, participants randomized to receive ALXN1840 will be administered 
ALXN1840 orally daily at the following doses: 
•
Participants aged 12 to < 18 years will follow the same dosing paradigm as that in the
ongoing Phase 3 Study WTX101-301 conducted in adults and adolescents.
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ALXN1840 will be administered at a starting dose of 15 mg/day. Dose escalation is 
not permitted. Individualized doses ranging from 15 mg/day every other day to 
15 mg/day are allowed. Doses of < 15 mg every other day may be considered, with 
approval of the Alexion Medical Monitor. 
•
For participants aged 3 to < 12 years, a lower starting dose of 2.5 mg/day will be
administered for at least 4 weeks based on scaling of the starting dose of 15 mg/day in
the ongoing Study WTX101-301. Dose escalation is permitted but not required. The
dose may be increased in increments of 2.5 mg daily with the  permission of the
Alexion Medical Monitor, depending on the participant’s clinical status, NCCcorrected
concentrations, and safety lab results. Dose increases must occur at least 4 weeks
apart, and may only occur if no other dose modification (reduction or interruption)
criteria apply. Participants who require doses of 15 mg daily may use the 15-mg adult
tablet. The maximum dose for children under the age of 12 years is 15 mg/day.
Individualized ALXN1840 dosing will be utilized throughout the study based on the following 
parameters: 
•
Clinical criteria: dose-titration based on hepatic and neurological status
•
NCCcorrected: dose-titration based on NCCcorrected concentrations. The reference range
for NCCcorrected is 0.8 to 2.3 µM.
•
Safety monitoring: dose modification criteria are based on regularly scheduled
assessments for recognized hematological effects of copper lowering, hepatic testing,
and neurological tests
Participants randomized to receive SoC treatment will continue their current therapy or initiate 
SoC, ie, chelation therapy with penicillamine or trientine, zinc therapy, or a combination of both 
chelation and zinc therapy if they are not currently on SoC at the start of the study. 
4.2. 
Scientific Rationale for Study Design 
The study is designed as a randomized, open-label, exploratory study. The dosing strategy is 
similar to that employed in the current Phase 3 Study WTX101-301, with adjustments to the 
doses for pediatric patients based on the population PK simulations (Section 4.3 and 
Section 10.8). 
Following ALXN1840 administration, the active drug moiety, ie, the tetrathiomolybdate anion, 
rapidly binds copper to form TPCs, mostly in the liver and blood, and present as such in the 
systemic circulation. If TPCs are not rapidly formed, tetrathiomolybdate spontaneously 
undergoes serial hydrolysis to form molybdate, the most common form of nutrient molybdenum, 
and is excreted in the urine. The concentration of endogenous molybdenum in plasma is very 
low, therefore no background subtraction is required and plasma molybdenum can be attributed 
entirely to ALXN1840. Total molybdenum concentration cannot distinguish whether the 
molybdenum is protein-bound (mostly as TPC), free active drug as ALXN1840, intermediate 
hydrolysis products, or molybdate. To better characterize the amount of non-TPC bound drug 
and its unbound degradation products, plasma PUF molybdenum has also been measured, which 
represents the free parent drug (ALXN1840), short-lived intermediate hydrolysis products, and 
molybdate, which may have originated from the tetrathiomolybdate or from food intake as a 
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micronutrient. TTo better characterize the absorption, distribution, metabolism, and excretion of 
ALXN1840, the PK of both total molybdenum and PUF molybdenum will be characterized and 
described. 
ALXN1840 PK and PD in children and adolescents with WD will be assessed in this study. SoC 
PD will be assessed in children and adolescents. ALXN1840 PK and PD parameters are expected 
to scale with the body weight per allometric rules since higher blood flow rates in children may 
have an impact on drug clearance. In addition, copper content within a participant’s liver and, 
thus, liver volume may have an impact on the extent of drug binding in liver and clearance. 
Based on the ALXN1840 mechanism of action, it is anticipated that drug-copper binding and 
chemical degradation do not differ in the pediatric population compared with adults, after taking 
into account body weight and liver volume factors.  
4.2.1. 
Participant Input in Design 
WD patient/caregiver input into the study design was obtained and incorporated accordingly. 
4.3. 
Justification for Dose 
Results from Studies WTX101-101, WTX101-102, ALXN1840-HV-104, WTX101-HV-106, 
ALXN1840-HV-107, ALXN1840-HV-108, ALXN1840-HV-109, WTX101-201, and the 
ongoing Study WTX101-301 have shown that age, sex, or body weight are not significant 
covariates that may affect the PK of ALXN1840 in adults and adolescents.  
In the ongoing Phase 3 Study WTX101-301, participants were initially administered ALXN1840 
at a dose of 15 mg/day. Incremental dose increases are permitted, but not required, up to a 
maximum of 60 mg/day. In the completed 48-week Primary Evaluation Period of 
Study WTX101-301, the overall mean daily dose of ALXN1840 was 15.6 mg with a minimum 
daily dose of 12.6 mg and a maximum daily dose of 19.8 mg. Results from the Primary 
Evaluation Period showed approximately 3-fold greater copper mobilization from tissue to blood 
during treatment with ALXN1840 compared with SoC, as measured by daily mean dNCC 
AUEC0-48 weeks (µmol/L).  
Although 15 to 60 mg/day single or repeated daily doses have been shown to have acceptable 
safety profiles and to be generally well tolerated throughout the Phase 1 to Phase 3 clinical 
studies in both healthy adults and adult participants with WD, approximately 15% of the 
participants in Study WTX101-301 experienced ≥ Grade 2 ALT elevations during treatment with 
ALXN1840. In summary, the maximum daily dose permitted in Study ALXN1840-WD-302 has 
been set as 15 mg/day. 
Selection of the starting and maximum doses for ALXN1840-WD-302 in the pediatric 
population aged 3 to < 12 years is based on a combination of standard body weight-based 
allometric principles and on the approach to account for potential changes in liver copper content 
in pediatric participants driven by age-based changes in liver volume. 
Participants receiving the 1.25 mg mini-tablets who require a dose of 15 mg may be switched to 
the 15 mg tablet formulation. Participants may down-titrate to15 mg every other day, or a lower 
or less frequent dose, as appropriate. 
To support the dose selection, a population PK model for ALXN1840 was developed based on 
data from healthy volunteers and patients with WD. Single dose PK data from 18 healthy 
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volunteers (Study WTX101-102) and 27 patients (Study WTX101-201) were utilized for model 
building for the adult dosing. Simulations for pediatrics were based on typical parameter 
estimates without including variability components. For each simulation, the starting dose and 
concentration ranges were derived from the typical participants within the investigated age 
cohort at the extremes of the bodyweight range. 
Based on the modelling results, additional pediatric PK/PD studies were deemed unnecessary as 
endorsed in the agreed pediatric investigational plan (PIP) with the EMA Decision P/0234/2020. 
The general approach of dose selection for pediatric investigation used here is consistent with the 
EMA guidance (ICH E11(R1), 2017). 
Starting and maximal doses were selected using a conservative approach that involved 
consideration of lower end of the range, derived from the scaling methods, and further 
adjustment downward to a lower dose to ensure safety in the pediatric population aged 3 to 
<12 years. This cautious approach to starting and maximal dose selection (ie, adjustment 
downward to the lower end of the projected dose range) for participants aged 3 to < 12 years is 
supported by the fact that ALXN1840 has greater binding affinity to copper compared with other 
treatments. 
ALXN1840 PK and PD processes are expected to scale with the body weight per allometric rules 
since higher blood flow rates in children may have an impact on drug clearance. In addition, 
copper content within a participant’s liver and, thus, liver volume, may have an impact on extent 
of drug binding in liver and clearance. Based on the ALXN1840 mechanism of action, it is 
expected that drug-copper binding and chemical degradation do not differ in the pediatric 
population compared with adults, after taking into account body weight and liver volume factors.  
The results of the population PK simulation are provided in Section 10.8. 
4.4. 
End of Study Definition 
A participant is considered to have completed the study if he/she has completed both Period 1 
and Period 2 of the study including the last scheduled procedure shown in the Schedule of 
Activities (SoA) for Period 2. 
The end of the study is defined as the date the last participant completes the last visit shown in 
the SoA of Period 2. 
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5.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted.  
5.1. 
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
Age 
1. Participants must be aged 3 to <18 years at time of signing the informed consent/assent.
Type of Participants and Disease Characteristics 
2. Established diagnosis of WD by Leipzig-Score ≥ 4 documented by testing as outlined in
the 2012 European Association for the Study of Liver WD Clinical Practice Guidelines
(Ferenci, 2003; EASL, 2012). Note: Historical test results for WD, including some or all
of the following: presence of KF rings, neurologic symptoms, serum ceruloplasmin
below the reference range, Coombs-negative hemolytic anemia, elevated liver or urinary
copper, presence of mutations in the ATP7B gene, or other, as considered appropriate,
may be used instead to confirm the diagnosis of Wilson disease.
3. Participant's parent/proxy must be willing and able to give written informed consent and
the participant must be willing to give written informed assent (if applicable as
determined by the central or local Institutional Review Board [IRB]/Institutional [or
Independent] Ethics Committee [IEC]). If allowable per local regulations, a participant’s
Legally Acceptable Representative (LAR) may provide informed consent if a participant
is unable to do so.
4. Adequate venous access to allow collection of required blood samples.
5. Able to swallow intact ALXN1840 tablets or mini-tablets. Participants who require
gastrostomy devices for feeding or medications may be enrolled if the inner diameter of
the tube can accommodate an intact tablet or mini-tablet without obstruction.
6. Willing to avoid intake of foods and drinks with high contents of copper throughout the
study duration
Sex 
7. Female participants of childbearing potential and male participants must follow protocol-
specified- contraception guidance as described in Section 10.4.
Informed Consent 
8. Capable of giving signed informed consent or assent as described in Section 10.1.3,
which includes compliance with the requirements and restrictions listed in the informed
consent or assent form and in this protocol.
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5.2. 
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions 
1. Decompensated hepatic cirrhosis.
2. MELD score > 13 (ages 12 to <18) or PELD score > 13 (ages 3 to < 12).
3. Modified Nazer score > 7 (Dhawan, 2005).
4. Clinically significant gastrointestinal (GI) bleed within past 3 months
5. Alanine aminotransferase (ALT) > 2 × upper limit of normal (ULN) for participants
treated for > 28 days with WD therapy (Cohort 1).
6. ALT > 5 × ULN for treatment naïve participants or participants who have been treated
for ≤ 28 days (Cohort 2)
7. Marked neurological disease requiring either nasogastric feeding tube or intensive
inpatient medical care.
8. Hemoglobin less than lower limit of the reference range for age and sex.
9. History of seizure activity within 6 months prior to informed consent/assent.
Prior/Concomitant Therapy 
10. Previous use of ALXN1840 or ammonium tetrathiomolybdate.
Prior/Concurrent Clinical Study Experience 
11. The use of an investigational drug within 30 days before initiation of the first dose of
study intervention.
Diagnostic assessments 
12. Participants in renal failure, defined as in end-stage renal disease on dialysis (chronic
kidney disease stage 5 [CKD 5]) or estimated glomerular filtration rate
< 30 mL/min/1.73m2.
13. Active infection with hepatitis B virus (positive hepatitis B surface antigen) or C virus
(participants with positive hepatitis C antibody result would require confirmation of
active disease with a positive hepatitis C polymerase chain reaction test), or seropositivity
for HIV.
14. Any disability acquired from trauma or another illness that, in the opinion of the
Investigator, could interfere with evaluation of disability due to WD.
15. Systemic disease or other illness, or any deviation in laboratory values that are confirmed
on re-examination to be clinically significant by the Investigator that would, in the
opinion of the Investigator, compromise participant safety or interfere with the collection
or interpretation of study results.
Other Exclusions 
16. Pregnant (or females who are planning to become pregnant) or breastfeeding females.
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17. Known sensitivity to ALXN1840, ALXN1840 excipients (anhydrous di-calcium
phosphate, anhydrous sodium carbonate), or any of the ingredients contained in
ALXN1840 or related compounds.
18. Regular alcohol consumption within 6 months prior to the study defined as > 14 units for
males or > 7 units for females per week. One unit is equivalent to 14 g of alcohol: a half
pint (approx. 240 mL) of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits.
19. Abuse of illicit or prescribed drugs.
20. In the opinion of the Investigator, the participant and/or their parent/proxy is likely to be
non-compliant or uncooperative during the study.
5.3. 
Lifestyle Considerations 
5.3.1. 
Meals and Dietary Restrictions 
•
Participants should follow their study doctor's advice regarding adherence to a low
copper diet.
•
ALXN1840 will be administered in the fasted state (1 hour before or 2 hours after
meals) and will be taken with up to approximately 240 mL of water. ALXN1840
mini-tablets may also be administered with a small amount (approximately 5 mL or
5 g) of apple sauce or yogurt and swallowed immediately (no substitutions are
permitted). Further details are provided in the Pharmacy Manual.
5.4. 
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomly assigned to study intervention. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details (eg, failed eligibility criteria), and any AEs, including any serious adverse 
events (SAEs) and any related concomitant medication, occurring during the Screening Period. 
Individuals who do not meet the criteria for participation in this study (screen failure) due to a 
reason that is expected to resolve, or has resolved, may be rescreened based on discussion and 
agreement between the Investigator and the Medical Monitor. 
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6.
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to the 
study protocol. 
6.1. 
Study Interventions Administered 
Participants randomized to receive SoC treatment will continue their current therapy or initiate 
chelation therapy with penicillamine or trientine, zinc, or a combination of both chelation and 
zinc therapy if they are not currently on SoC at the start of the study.  
Standard of care treatment should be stored according to the details in the package labeling. 
Details of ALXN1840 administered in the study are provided in Table 4. 
Table 4: 
Study Intervention Dosage and Mode of Administration 
Drug Name 
ALXN1840 (formerly WTX101) 
Type 
Drug 
Dose formulation 
•
15 mg white to off-white round enteric coated tablet
•
2.5mg capsule containing 2 × 1.25 mg round white to off-white enteric
coated mini-tablets
Unit dose strength(s) 
•
15 mg enteric coated tablet containing choline tetrathiomolybdate
•
1.25 mg enteric coated mini-tablet containing choline
tetrathiomolybdate
Dosage level(s) 
•
Participants aged 12 to < 18 years:  15 mg/day
•
Participants aged 3 to < 12 years: starting dose of 2.5 mg/day, with
increase in increments of 2.5 mg up to 15 mg/day. Dose escalation
requires the agreement of the Alexion Medical Monitor.
Route of administration 
Oral 
Use 
Experimental/study intervention 
IMP or NIMP 
IMP 
Sourcing 
Provided by Alexion 
Packaging and labeling 
ALXN1840 will be provided in treatment kits that will each have a unique 
identification number and be packaged and labelled in accordance with all 
applicable regulatory requirements. At a minimum, the treatment kit label 
will provide the following information: Alexion study identification, batch 
number, directions for use, required storage conditions, caution statements 
(including “New Drug-Limited by Federal Law to Investigational Use” 
language), study identification, and expiry date. 
Current/former name(s) or 
alias(es) 
bis-choline tetrathiomolybdate/tiomolibdic acid/WTX101 
Abbreviations: IMP = investigational medicinal product; NIMP = noninvestigational medicinal product. 
6.1.1. 
Study Intervention(s) Packaging and Labeling 
At a minimum, ALXN1840 will be labeled with: 
•
The protocol number
•
Lot number/expiry date
•
Alexion name and address
•
Instructions for use and storage
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ALXN1840 will be labeled according to the country’s regulatory requirements. 
6.2. 
Preparation/Handling/Storage/Accountability 
1. The Investigator, or designee, must confirm appropriate temperature conditions have
been maintained during transit for all study intervention received and any discrepancies
are reported and resolved before use of the study intervention.
a. The ALXN1840 treatment kits should be stored at refrigerated conditions, 2°C to 8°C
(36°F to 46°F).
2. Only participants enrolled in the study may receive the study intervention and only
authorized site staff may supply study intervention. All study intervention must be stored
in a secure, environmentally controlled, and monitored (manual or automated) area in
accordance with the labeled storage conditions with access limited to the Investigator and
authorized site staff.
3. The Investigator, institution, or the head of the medical institution (where applicable) is
responsible for study intervention accountability, reconciliation, and record maintenance
(ie, receipt, reconciliation, and final disposition records).
a. This responsibility includes the reporting of any product complaints to
productcomplaints@alexion.com within 1 business day. A product complaint is
defined as any written, electronic, or oral communication that alleges deficiencies
related to the identity, quality, durability, reliability, usability, safety, effectiveness, or
performance of a product or clinical study material and/or its packaging components
after it is has been released for distribution to an end customer that affects the
performance of such product.
4. Further guidance and information for the final disposition of unused study interventions
are provided in the Pharmacy Manual.
6.3. 
Measures to Minimize Bias: Randomization and Blinding 
Participants will be randomized after meeting all inclusion and none of the exclusion criteria. 
Participants will be randomized, stratified by cohort, via an interactive voice/web response 
system in a 1:1 ratio to treatment with ALXN1840 or continued treatment with SoC in Cohort 1, 
or as continued or initial therapy in Cohort 2. 
This study is rater-blinded for the UWDRS assessment only. The rater will be blinded and will 
have no knowledge of the participant’s treatment assignment and no access to systems that could 
result in potential unblinding of treatment assignment. Both raters and participants will be 
instructed to avoid lines of inquiry, questions, and responses that could potentially lead to their 
unblinding. The rater assessments will be strictly limited to administration of the protocol 
specified instruments and assessments. 
6.4. 
Study Intervention Compliance 
When participants are dosed at the site, they will receive study intervention directly from the 
Investigator or designee, under medical supervision. The date and time of each dose 
administered in the clinic will be recorded in the source documents and recorded in the case 
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report form (CRF). The dose of study intervention and study participant identification will be 
confirmed at the time of dosing by a member of the study site staff other than the person 
administering the study intervention. Study site personnel will examine each participant’s mouth 
to ensure that the study intervention was ingested. 
For additional information on study intervention compliance and management, refer to the 
Pharmacy Manual.  
When participants self-administer study intervention(s) at home (assisted or supervised by their 
parent or caregiver, as appropriate), compliance with the study intervention will be assessed at 
each visit by counting returned tablets during the site visits, and will be documented in the 
source documents and CRF. Deviation(s) from the prescribed dosage regimen should be 
recorded in the CRF. 
Records of the doses dispensed to and taken by each participant must be maintained and 
reconciled with study intervention and compliance records. Intervention start and stop dates, 
including dates for planned and unplanned intervention delays and/or dose reductions will also 
be recorded in the CRF. 
For additional information on study intervention compliance and management, refer to the 
Pharmacy Manual. 
6.5. 
Prior and Concomitant Therapy 
Any medication (including over-the-counter or prescription medicines, vitamins, and/or herbal 
supplements), or vaccine, or other specific categories of interest) that the participant is receiving 
within 30 days prior to enrollment or receives during the study must be recorded along with: 
•
Reason for use
•
Dates of administration including start and end dates
•
Dosage information including dose and frequency
Medications specific for copper control in WD taken at any time prior to the study (ie, all 
penicillamine, trientine or zinc ever taken for WD) will be recorded in a specific CRF for Prior 
WD Treatment. 
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
6.5.1. 
Allowed Medicine and Therapy 
Investigators should use caution in the coadministration of drugs known to be substrates of 
cytochromes 2C9 and 2B6 (CYP2C9 and CYP2B6).  
6.5.2. 
Disallowed Medicine and Therapy 
Concomitant use of penicillamine, trientine or zinc is prohibited for participants who are treated 
with ALXN1840 during the randomized Primary Evaluation Period (Period 1) or Open-label 
Extension Period (Period 2). Standard of care medications may only be taken by participants 
randomized to SoC during Period 1. 
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Use of nonprescription/ over-the-counter medications, including herbal remedies, nutritional 
supplements, or mineral supplements containing copper, zinc, iron, or molybdenum after dosing 
on Day 1 through the end of the study is also disallowed.  
Vitamin E and estrogen should not be initiated during the study but can be continued if already 
being taken. 
6.6. 
Dose Modification 
Alexion should be notified within 24 hours of any laboratory, vital sign, electrocardiogram 
(ECG) abnormality, or AE that is considered of clinical concern by the Investigator. 
Investigators must notify Alexion immediately of study intervention discontinuation. The 
decision to discontinue study intervention should not be delayed for causality assessment. 
6.6.1. 
Dose Modification for ALXN1840 
The ALXN1840 dose should be lowered or interrupted if any of the relevant dose modification 
criteria are met. Deviation from the dose modification guidelines must be agreed with the 
Alexion Medical Monitor. 
Adolescent Participants 
Adolescent participants (12 to <18 years) who are randomized to ALXN1840 in Period 1 will be 
initiated on ALXN1840 at 15 mg/day. Specific criteria for dose reduction or temporary 
interruption of dosing of ALXN1840 are detailed in Table 5. Repeat testing of laboratory 
parameters which prompt dose modification criteria should follow the instructions in Table 5. 
Laboratory testing should be performed through the Central Laboratory if possible. Results from 
non-scheduled safety laboratory assessments performed at a local laboratory must be recorded in 
the CRF. 
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Table 5: 
ALXN1840 Dose Modifications for Individual Adolescent Participants 
Test 
Result 
Conditions 
Action with ALXN1840 Dosing 
Changes in Safety 
Monitoringa 
Rechallengeb,c 
ALT 
> 5 × ↑ from
Baseline
ALT above 
reference 
range at 
Baseline 
Temporary interruption 
Contact participant within 48 
hours to arrange repeat testing 
(weekly repeat testing) 
At 15 mg QOD when ALT 
< 2 × ↑ from Baseline. 
> 5 × ULN
ALT within 
reference 
range at 
Baseline 
Temporary interruption 
Contact participant within 48 
hours to arrange repeat testing 
(weekly repeat testing) 
At 15 mg QOD when ALT < 2 
× ULN. 
> 2 × ↑ from
Baseline
ALT above 
reference 
range at 
Baseline 
Reduce dose - to 15 mg QOD if on 15 
mg QD. No further dose ↑ until 
resolution of abnormality. 
Weekly repeat testing 
Not applicable. 
> 2 × ULN
ALT within 
reference 
range at 
Baseline 
Reduce dose - to 15 mg QOD if on 15 
mg QD. No further dose ↑ until 
resolution of abnormality. 
Weekly repeat testing 
Not applicable. 
Increased 
triglycerides 
> 300 to 500
mg/dL or > 3.4
to 5.6 mmol/L
None 
Reduce dose to 15 mg QOD if on 15 
mg QD.  
Weekly repeat testing 
Not applicable 
> 500 mg/dL or
5.6 mmol/L
Temporary interruption 
At 15 mg QOD when 
triglyceride concentrations 
return to baseline  
Increased 
total 
cholesterol 
> 300 to 400
mg/dL or > 7.8
to 10.3 mmol/L
None 
Reduce dose to 15 mg QOD if on 15 
mg QD.  
Weekly repeat testing 
Not applicable 
> 400 mg/dL or
> 10.3 mmol/L
Temporary interruption 
At 15 mg QOD when 
cholesterol concentrations 
return to baseline 
Hemoglobin 
< 8 g/dL in the 
absence of 
bleeding 
None 
Temporary interruption 
Weekly repeat testing 
At 15 mg QOD when 
hemoglobin and other 
hematology parameters 
(neutrophils and platelets) are at 
baseline concentration. 
> 30% ↓ from
Baseline
None 
Reduce dose - to 15 mg QOD if on 
15 mg QD. No further dose ↑ until 
resolution of abnormality. 
Weekly repeat testing 
Not applicable. 
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Test 
Result 
Conditions 
Action with ALXN1840 Dosing 
Changes in Safety 
Monitoringa 
Rechallengeb,c 
Platelets 
< 30,000 µL 
None 
Temporary interruption 
Weekly repeat testing 
At 15 mg QOD when platelets 
and other hematology 
parameters (neutrophils and 
hemoglobin) are at baseline 
concentration. 
> 30% ↓ from
Baseline
Platelets 
below 
reference 
range at 
Baseline 
Reduce dose - to 15 mg QOD if on 
15 mg QD. No further dose ↑ until 
resolution of abnormality. 
Weekly repeat testing 
Not applicable. 
Neutrophils 
< 1.0 × 10
3/µL
None 
Temporary interruption 
Weekly repeat testing 
At 15 mg QOD when 
neutrophils and other 
hematology parameters 
(hemoglobin and platelets) are 
at Baseline concentration. 
> 30% ↓ from
Baseline
Neutrophils 
below 
reference 
range at 
Baseline 
Reduce dose - to 15 mg QOD if on 
15 mg QD. No further dose ↑ until 
resolution of abnormality. 
Weekly repeat testing 
Not applicable. 
Bilirubin 
> 2 × ULN
Accompanied 
by ALT > 3 × 
ULN, 
indicative of 
liver injury 
Temporary interruption 
Weekly repeat testing 
At 15 mg QOD or less frequent, 
when bilirubin is below ULN. 
Rechallenge under these 
conditions requires approval of 
the Alexion Medical Monitor. 
Neurological 
assessment 
Evidence of neurologic worsening 
by AEs or by neurologic physical 
exam assessment.  
Investigator and Alexion Medical 
Monitor will evaluate the need for 
dose modification (interruption, 
increase or decrease) based on copper 
control parameters and relevant 
clinical data. Rationale for dosing 
decision must be documented in study 
record and reevaluated at the next 
study visit. 
All neurologic worsening 
should be documented as AEs 
and followed up until study 
completion or resolution of 
symptoms. 
Discuss with the Alexion 
Medical Monitor. 
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Test 
Result 
Conditions 
Action with ALXN1840 Dosing 
Changes in Safety 
Monitoringa 
Rechallengeb,c 
Psychiatric 
assessment 
Evidence of clinically significant 
acute psychiatric worsening 
which may include, but is not 
limited to, suicidality, acute 
depression, or psychosis. 
Investigator and Alexion Medical 
Monitor will evaluate the need for 
dose modification (interruption, 
increase or decrease) based on copper 
control parameters and relevant 
clinical data. Rationale for dosing 
decision must be documented in study 
record and reevaluated at the next 
study visit. 
Worsening psychiatric 
symptoms will be documented 
as AEs in the eCRF and will 
be followed until completion 
of the study or resolution of 
symptoms. 
Discuss with the Alexion 
Medical Monitor. 
a For changes in safety monitoring, weekly repeat testing for laboratory parameters can be completed by a home healthcare nurse if a routine study visit is not 
scheduled during this time period. 
b For rechallenges, participants who were on ALXN1840 15 mg QOD should be rechallenged at the 15 mg QOD dose. 
c The Investigator, in consultation with the Medical Monitor, may change dose and dose frequency in participants who require rechallenge. 
Abbreviations: AEs = adverse event; ALT = alanine aminotransferase; eCRF = electronic case report form; QD = once daily; QOD = every other day; ULN = 
upper limit of normal. 
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Pediatric Participants 
Pediatric participants (age 3 to < 12 years) will be initiated on ALXN1840 at 2.5 mg/day. 
Following the first 4 weeks, the dose may be increased, in increments of 2.5 mg at least 4 weeks 
apart to a maximum of 15 mg/day with the agreement of the Alexion Medical Monitor. 
Incremental dose increase is permitted but not required. Specific criteria for dose reduction, 
temporary interruption of dosing, or restriction of dose increases of ALXN1840 are detailed in 
Table 6. Repeat testing of laboratory parameters that prompt dose modification criteria should 
follow the instructions in Table 6. Laboratory testing should be performed through the Central 
Laboratory if possible. Results from non-scheduled safety laboratory assessments performed by a 
local laboratory must be recorded in the CRF. 
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Table 6: 
ALXN1840 Dose Modifications for Individual Pediatric Participants 
Test 
Result 
Conditions 
Action with ALXN1840 Dosing 
Changes in Safety 
Monitoringa 
Rechallengeb,c 
ALT 
> 5 × ↑ from
Baseline
ALT above 
reference 
range at 
Baseline 
Temporary interruption 
Contact participant within 
48 hours to arrange repeat 
testing (weekly repeat 
testing) 
At 1.25 mg QD when ALT < 2 × ↑ 
from Baseline. 
> 5 × ULN
ALT within 
reference 
range at 
Baseline 
Temporary interruption 
Contact participant within 
48 hours to arrange repeat 
testing (weekly repeat 
testing) 
At 1.25 mg QD when ALT < 2 × 
ULN. 
> 2 × ↑ from
Baseline
ALT above 
reference 
range at 
Baseline 
Reduce dose to previous dose level if 
up-titration has occurred or reduce dose 
to 1.25 mg QD if on 2.5 mg QD. No 
further dose ↑ until resolution of 
abnormality. 
Weekly repeat testing 
Not applicable. 
> 2 × ULN
ALT within 
reference 
range at 
Baseline 
Reduce dose to previous dose level if 
up-titration has occurred or reduce dose 
to 1.25 mg QD if on 2.5 mg QD. No 
further dose ↑ until resolution of 
abnormality. 
Weekly repeat testing 
Not applicable. 
Increased 
triglycerides 
> 300 to 500
mg/dL or
> 3.4 to 5.6
mmol/L
None 
Reduce dose to previous dose level if 
up-titration has occurred or reduce dose 
to 1.25 mg QD if on 2.5 mg QD. No 
further dose increase until resolution of 
abnormality. 
Weekly repeat testing 
Not applicable 
> 500 mg/dL
or 5.6
mmol/L
Temporary interruption 
At 1.25 mg QD when triglyceride 
concentrations return to baseline  
Increased 
total 
cholesterol 
> 300 to 400
mg/dL or
> 7.8 to 10.3
mmol/L
None 
Reduce dose to 1.25 mg QD if on 
2.5 mg QD.  
Weekly repeat testing 
Not applicable 
> 400 mg/dL
or > 10.3 
mmol/L
Temporary interruption 
At 1.25 mg QOD when cholesterol 
concentrations return to baseline 
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Test 
Result 
Conditions 
Action with ALXN1840 Dosing 
Changes in Safety 
Monitoringa 
Rechallengeb,c 
Hemoglobin 
< 8 g/dL in 
the absence 
of bleeding 
None 
Temporary interruption 
Weekly repeat testing 
At 1.25 mg QD when hemoglobin 
and other hematology parameters 
(neutrophils and platelets) are at 
Baseline concentration. 
> 30% ↓
from baseline
None 
Reduce dose to previous dose level if 
up-titration has occurred or reduce dose 
to 1.25 mg QD if on 2.5 mg QD. No 
further dose ↑ until resolution of 
abnormality. 
Weekly repeat testing 
Not applicable. 
Platelets 
< 30,000 µL 
None 
Temporary interruption 
Weekly repeat testing 
At 1.25 mg QD when platelets and 
other hematology parameters 
(neutrophils and hemoglobin) are 
at Baseline concentration. 
> 30% ↓
from
Baseline
Platelets 
below 
reference 
range at 
Baseline 
Reduce dose to previous dose level if 
up-titration has occurred or reduce dose 
to 1.25 mg QD if on 2.5 mg QD. No 
further dose ↑ until resolution of 
abnormality. 
Weekly repeat testing 
Not applicable. 
Neutrophils 
< 1.0 × 
10
3/µL
None 
Temporary interruption 
Weekly repeat testing 
At 1.25 mg QD when neutrophils 
and other hematology parameters 
(hemoglobin and platelets) are at 
Baseline concentration. 
> 30% ↓
from
Baseline
Neutrophils 
below 
reference 
range at 
Baseline 
Reduce dose to previous dose level if 
up-titration has occurred or reduce dose 
to 1.25 mg QD if on 2.5 mg QD. No 
further dose ↑ until resolution of 
abnormality. 
Weekly repeat testing 
Not applicable. 
Bilirubin 
> 2 × ULN
Accompanied 
by ALT > 3 × 
ULN, 
indicative of 
liver injury 
Temporary interruption 
Weekly repeat testing 
At 1.25 mg QD or less frequent, 
when bilirubin is below ULN. 
Rechallenge under these 
conditions requires approval of the 
Alexion Medical Monitor. 
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Test 
Result 
Conditions 
Action with ALXN1840 Dosing 
Changes in Safety 
Monitoringa 
Rechallengeb,c 
Neurological 
assessment 
Evidence of neurologic 
worsening by AEs or by 
neurologic physical exam 
assessment.  
Investigator and Alexion Medical 
Monitor will evaluate the need for dose 
modification (interruption, increase or 
decrease) based on copper control 
parameters and relevant clinical data. 
Rationale for dosing decision must be 
documented in study record and re-
evaluated at the next study visit. 
All neurologic worsening 
should be documented as 
AEs and followed up until 
study completion or 
resolution of symptoms. 
Discuss with the Alexion Medical 
Monitor. 
Psychiatric 
assessment 
Evidence of clinically 
significant acute psychiatric 
worsening which may include, 
but is not limited to, 
suicidality, acute depression, 
or psychosis. 
Investigator and Alexion Medical 
Monitor will evaluate the need for dose 
modification (interruption, increase or 
decrease) based on copper control 
parameters and relevant clinical data. 
Rationale for dosing decision must be 
documented in study record and re-
evaluated at the next study visit. 
Worsening psychiatric 
symptoms will be 
documented as AEs in the 
eCRF and will be 
followed until completion 
of the study or resolution 
of symptoms. 
Discuss with the Alexion Medical 
Monitor. 
a For changes in safety monitoring, weekly repeat testing for laboratory parameters can be completed by a home healthcare nurse if a routine study visit is not 
scheduled during this time period. 
b For rechallenges, participants who were on ALXN1840 2.5 mg QD should be rechallenged at the 1.25 mg QD dose. 
c The Investigator, in consultation with the Medical Monitor, may change dose and dose frequency in participants who require rechallenge. 
Abbreviations: AEs = adverse event; ALT = alanine aminotransferase; eCRF = electronic case report form; QD = once daily; QOD = every other day; ULN = 
upper limit of normal. 
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6.6.2. 
Dose Modification for Standard of Care 
To the extent possible, without compromising the safety of individual participants, the type of 
SoC medication should not be changed throughout the 48-week Period 1, unless required as part 
of the treatment (eg, if a participant initiates SoC at the start of the study).  
Similarly, to the extent possible, without compromising the safety of individual participants, the 
dosing of the SoC medication should remain consistent throughout Period 1, unless required as 
part of the treatment (eg, titration of SoC initiated at the start of the study). 
If the SoC dose, frequency, or specific drug agent (ie, penicillamine, trientine or zinc) needs to 
be changed for efficacy or safety reasons, the specific change and rationale for it must be 
documented. The rationale for a change from one agent to another (eg, a change from 
penicillamine or trientine to zinc due to intolerance or AE) must also be documented. Deviation 
from the dose modification guidelines must be agreed with the Alexion Medical Monitor. 
Specific criteria for dose modification of SoC if neurologic or psychiatric worsening occurs are 
detailed in Table 7. 
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Table 7: 
Standard of Care Dose Modifications for Individual Participants 
Test 
Result and Conditions 
Action With SoC 
Dosing 
Changes in Safety 
Monitoringa 
Re-Challengea 
UWDRS 
Part III and 
clinical 
neurological 
assessment 
Increase in UWDRS 
Part III score from 
Baseline as follows 
AND is deemed 
clinically significant by 
the Investigator: 
Baseline UWDRS 
Part III score <20: 
≥ 4-point increase 
OR 
Baseline UWDRS 
Part III score >20: 
≥6-point increase 
Investigator and Medical 
Monitor will evaluate 
the need for dose 
modification 
(interruption, increase or 
decrease) based on 
copper control 
parameters and relevant 
clinical data. Rationale 
for dosing decision must 
be documented in study 
record and re-evaluated 
at the next study visit. 
Report neurologic 
adverse event of 
special interest and 
perform complete 
UWDRS examination. 
Re-evaluate 
neurologic status, 
including complete 
UWDRS examination, 
no later than next 
study visit, even if not 
planned per the SoA. 
Discuss with the 
Medical 
Monitor. 
Psychiatric 
assessment 
Clinically significant 
signs of psychiatric 
worsening 
Investigator and Medical 
Monitor will evaluate 
the need for dose 
modification 
(interruption, increase or 
decrease) based on 
copper control 
parameters and relevant 
clinical data. Rationale 
for dosing decision must 
be documented in study 
record and re-evaluated 
at the next study visit. 
Re-evaluate 
psychiatric status no 
later than next study 
visit, even if not 
planned per the SoA. 
Discuss with the 
Medical 
Monitor. 
a. The Investigator, in consultation with the Medical Monitor, may change dose and dose frequency in participants
who require re-challenge.  
Abbreviations:  SoA = Schedule of Activities; UWDRS = Unified Wilson Disease Rating Scale. 
6.7. 
Intervention After the End of the Study 
Following completion of Period 2 of the study, participants will either: 
•
Transition to therapy that was discontinued before enrollment, or
•
Participants who have successfully completed all study assessments and were not
withdrawn prematurely may be eligible for post-study access if deemed in the best
interest of the patient by the treating physician. Participants will receive study drug
for up to 2 years or until 1) the study drug is registered or approved and available by
prescription or 2) the study drug can be provided via Alexion post-study/early access
programs as allowed by local laws and regulations, whichever occurs first. Only the
investigational drug will be available for post-study/early access.
All participants should return to the site for the EOS Visit on Day 197 of Period 2 (+/- 7 days). 
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7.
DISCONTINUATION OF STUDY INTERVENTION AND
PARTICIPANT DISCONTINUATION/WITHDRAWAL
7.1. 
Discontinuation of Study Intervention
In rare instances, it may be necessary for a participant to permanently discontinue (definitive 
discontinuation) the study intervention. If the study intervention is definitively discontinued, the 
participant should have an Early Termination Visit and return within 4 weeks to be evaluated for 
safety follow-up. See the SoA (Section 1.3) for data to be collected at the time of discontinuation 
of study intervention and follow-up and for any further evaluations that need to be completed. 
Participants must be considered for discontinuation from study intervention if any of the 
following occur during the study: 
•
Occurrence of a decompensation cirrhosis event that is not responsive to standard
treatment
•
A decompensation cirrhosis event is defined as acute esophageal or gastric variceal
bleeding, development of new overt hepatic encephalopathy, or substantive de novo
ascites formation
•
Serious hypersensitivity reaction
•
Severe uncontrolled infection
•
Use of disallowed medication
•
Pregnancy or planned pregnancy (see Section 8.2.6); or
•
Alexion or the Investigator deems it is necessary for the participant.
See the SoA (Section 1.3) for samples and data to be collected at the time of study intervention 
discontinuation and follow-up and for any further evaluations that need to be completed. 
7.2. 
Participant Discontinuation/Withdrawal from the Study 
•
All efforts should be made to ensure participants are willing to comply with study
participation prior to conducting the Screening procedures.
•
The study staff should notify Alexion and their site monitor of all study withdrawals
as soon as possible. The reason for participant discontinuation must be recorded in the
source documents and CRF.
•
A participant must be withdrawn from this study if they receive an experimental or
unapproved/unlicensed therapy.
•
A participant may withdraw from the study at any time at his/her own request or may
be withdrawn at any time at the discretion of the Investigator for safety, behavioral,
compliance, or administrative reasons.
•
At the time of discontinuing from the study, if possible, an Early Termination Visit
should be conducted, as shown in the SoA. See the SoA (Section 1.3) for data to be
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collected at the time of study discontinuation and follow-up and for any further 
evaluations that need to be completed. 
−
The participant will be permanently discontinued both from the study intervention
and from the study at that time.
•
If the participant withdraws consent for disclosure of future information, Alexion may
retain and continue to use any data collected before such a withdrawal of consent.
•
If a participant withdraws from the study, he/she may request destruction of any
samples taken and not tested, and the Investigator must document this in the site
study records.
7.3. 
Lost to Follow-up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
•
The site must attempt to contact the participant and reschedule the missed visit as
soon as possible and counsel the participant on the importance of maintaining the
assigned visit schedule and ascertain whether or not the participant wishes to and/or
should continue in the study.
•
Before a participant is deemed lost to follow-up, the Investigator or designee must
make every effort to regain contact with the participant (where possible, 3 telephone
calls and, if necessary, a certified letter to the participant’s last known mailing
address or local equivalent methods). These contact attempts should be documented
in the participant’s medical record.
•
If participant is unreachable, then the participant is lost to follow-up (not withdrawn,
since withdrawn is a distinct event of removing informed consent/assent).
Discontinuation of specific sites or of the study as a whole are handled as part of Section 10.1.8. 
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8.
STUDY ASSESSMENTS AND PROCEDURES
•
Study procedures and their timing are summarized in the SoA (Section 1.3). Protocol
waivers or exemptions are not allowed.
•
Immediate safety concerns should be discussed with the Medical Monitor
immediately upon occurrence or awareness to determine if the participant should
continue or discontinue study intervention.
•
Adherence to the study design requirements, including those specified in the SoA, is
essential and required for study conduct.
•
All Screening evaluations must be completed and reviewed to confirm that potential
participants meet all eligibility criteria. The Investigator will maintain a screening log
to record details of all participants screened and to confirm eligibility or record
reasons for screening failure, as applicable.
8.1. 
Efficacy Assessments
Planned time points for all efficacy assessments are provided in the SoA (Section 1.3). 
8.1.1. 
Assessment of Copper 
Because measures of non-ceruloplasmin-bound copper control in the blood are the primary 
assessment for efficacy of treatment with ALXN1840, plasma samples will be collected to 
measure total copper, ceruloplasmin, ceruloplasmin-bound copper (CpC), NCC, and LBC in the 
blood. In ALXN1840-treated patients, an additional calculation will be performed that corrects 
the NCC level for the amount of copper bound to the ALXN1840 tripartite complex 
(NCCcorrected). 
The AUEC for plasma total copper concentration over time aims to quantify the dynamic tissue 
mobilization and decoppering effect of ALXN1840. This assessment is also applicable to SoC 
treatments. AUEC will be calculated for direct NCC and plasma total copper. 
Ongoing bioanalytical method development of new techniques to measure directly the TPC 
copper may allow additional analyses of copper control to be performed. As the method to 
indirectly estimate NCC concentration results in approximately 20% of samples from healthy 
participants yielding physiologically impossible negative values for NCC, the direct NCC and 
LBC assays have been developed. The LBC method measures exchangeable plasma copper that 
is not bound to either ceruloplasmin or the ALXN1840 TPC. 
8.1.2. 
Model for End-stage Liver Disease and Pediatric End-stage Liver Disease scores 
The Model for End-stage Liver Disease (MELD) is a scoring system for assessing the severity of 
chronic liver disease in adults and adolescents aged 12 years and above. The MELD score (range 
6-40, with higher values indicating more advanced disease) uses the participant’s values for
serum bilirubin, serum creatinine, and the international normalized ratio (INR) for prothrombin
time to predict survival. In participants with a MELD score > 11, the serum sodium is also taken
into account (UNOS, 2015).
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The Pediatric End-stage Liver Disease (PELD) score is used to estimate 90-day survival in the 
absence of liver transplantation (McDiarmid, 2002; Chang, 2018). The components of the PELD 
score are total bilirubin, INR, albumin, age, and growth failure. The PELD cutoff of > 13 was 
chosen to exclude participants with advanced liver failure, comparable to a MELD score > 13 or 
a modified Nazer score > 7 (Dhawan, 2005). 
The MELD and PELD scores will be calculated by a Central Laboratory. 
8.1.3. 
Unified Wilson Disease Rating Scale (Parts I, II, and III) 
The UWDRS is a clinical rating scale designed to evaluate the neurological manifestations of 
WD that generally can be divided into 3 movement disorder syndromes: dystonic, ataxic, and 
Parkinsonian syndrome. The UWDRS comprises 3 parts: UWDRS Part I (level of consciousness, 
item 1), UWDRS Part II (a participant-reported review of daily activity items [disability], items 2 
to 11), and UWDRS Part III (a detailed neurological examination, items 12 to 34). 
The UWDRS Part I and Part III will be assessed by a neurologist who is blinded to the treatment 
randomization, while UWDRS Part II may be reported to a non-blinded member of the study 
team by the participant, family member, or caregiver (Czlonkowska, 2007; Leinweber, 2008). 
The UWDRS has not been formally evaluated in children. However, the components of Part I 
(level of consciousness), Part II (participant or caregiver-reported disability) and Part III 
(neurologic examination findings) are not fundamentally different between adults and children. 
Participants aged 12 years and older are expected to be able to comply with UWDRS 
assessments without modification. The UWDRS assessments should be conducted to the greatest 
extent feasible in children < 12 years. 
8.1.4. 
Clinical Global Impression-Severity Scale and the Clinical Global Impression 
Improvement Scale 
The Clinical Global Impression (CGI) rating scales are commonly used measures of symptom 
severity, treatment response, and the efficacy of treatments in treatment studies of adult and 
pediatric participants with mental disorders. 
Clinical Global Impression-Severity Scale 
The Clinical Global Impression-Severity scale (CGI-S) is a 7-point scale that requires the 
clinician to rate the severity of the participant's illness at the time of assessment, relative to the 
clinician's past experience with participants who have the same diagnosis. Considering total 
clinical experience, a participant is assessed on severity of illness at the time of rating as: 1, 
normal, not at all ill; 2, borderline ill; 3, mildly ill; 4, moderately ill; 5, markedly ill; 6, severely 
ill; or 7, extremely ill.  
Clinical Global Impression-Improvement Scale 
The Clinical Global Impression-Improvement scale (CGI-I) is a 7-point scale that requires the 
clinician to assess how much the participant's illness has improved or worsened relative to a 
baseline state at the beginning of the intervention and rated as: 1, very much improved; 2, much 
improved; 3, minimally improved; 4, no change; 5, minimally worse; 6, much worse; or 7, very 
much worse. 
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8.1.5. 
Fibrosis-4 Index and Transient Elastography 
The FIB-4 Index is a formula used to predict liver fibrosis based on standard biochemical values 
(ALT, AST, and platelet count) and age. The FIB-4 Index will be calculated by a Central 
Laboratory. 
Transient elastography is a non-invasive imaging method that evaluates the degree of liver 
fibrosis or fatty deposits in the liver, by determining the speed of sound waves through the liver 
utilizing a sonogram. 
8.1.6. 
Modified Nazer Score 
The modified Nazer score is an assessment of liver status and consists of a composite of 
5 laboratory parameters: AST, INR, bilirubin, albumin, and white blood cell count. The score has 
a total range of 0 to 20, and lower values indicate a healthier liver status (Dhawan, 2005).  
The modified Nazer score will be calculated by a Central Laboratory. 
8.1.7. 
Brief Psychiatric Rating Scale-24 
The Brief Psychiatric Rating Scale-24 (BPRS-24) is a 24-item instrument for adolescents aged 
12 to < 18 years and the that allows the rater to measure psychopathology severity. The presence 
and severity of psychiatric symptoms are rated on a Likert scale ranging from 1 (not present) to 7 
(extremely severe). The BPRS-24 can be performed by a qualified person (eg, neurologist, 
psychiatrist, psychologist, licensed mental health practitioner, social worker, etc) who has 
completed the training required to administer the instrument. 
The BPRS-C9 is a 9-item instrument for children aged 3 to < 12 years. The presence and severity 
of symptoms are rated on a scale ranging from 1 (not present) to 6 (extremely severe). As with 
the BPRS-24, the BPRS-C9 can be performed by a qualified person who has been appropriately 
trained. 
8.1.8. 
EuroQoL 5 Dimensions 
The EuroQoL 5 Dimensions (EQ-5D) consists of 2 different assessments – the EQ-5D-5L 
Descriptive System and the EQ Visual Analogue Scale (VAS). The descriptive system comprises 
measures of health-related quality of life state and consists of 5 dimensions: mobility, self-care, 
usual activities, pain/discomfort, and anxiety/depression. Each dimension has 5 levels of 
severity: no problems, slight problems, moderate problems, severe problems, or extreme 
problems. The EQ VAS records the participant’s self-rated health on a vertical VAS. Together, 
this can be used as a quantitative measure of health outcome that reflects the participant’s own 
judgement. 
Note that although the EQ-5D is designed for use in participants aged 16 years and older, the 
EQ-5D can also be used in participants aged 12 to 15 years and is appropriate given these 
participants will be followed for several years in the study (Van Reenen, 2014). 
8.1.8.1. 
EQ-5D Youth 
The child-friendly EQ-5D version (EQ-5D-Y) was introduced as a more comprehensible 
instrument suitable for children and adolescents. The wording was changed to be more suitable 
for children and adolescents, the most severe label for the mobility dimension was changed from 
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“confined to bed” to “a lot of problems walking about” to increase the applicability and 
sensitivity of the mobility dimension, and the instructions for the EQ VAS task were simplified, 
making the task easier to complete and to score (https://euroqol.org/eq-5d-instruments/eq-5d-y-
about/). 
8.1.9. 
Treatment Satisfaction Questionnaire for Medication 
The Treatment Satisfaction Questionnaire for Medication-9 (TSQM-9) is used to assess the 
overall level of satisfaction or dissatisfaction with medication participants are taking. This 
composite scale is comprised of 3 items on the TSQM-9 survey: 
•
Overall, how confident are you that taking this medication is a good thing for you?
•
How satisfied are you that good things about this medication outweigh the bad
things?
•
Taking all things into account, how satisfied or dissatisfied are you with this
medication?
The TSQM-9 is expected to be completed by adolescent participants and by the parent or 
caregiver for younger participants. 
8.1.10. 
Pediatric Quality of Life Inventory 
The Pediatric Quality of Life Inventory (PedsQL ) Measurement Model is a modular approach 
to measuring health-related quality of life in healthy children and adolescents and those with 
acute and chronic health conditions.  
The 23-item PedsQL  Generic Core Scales were designed to measure the core dimensions of 
health as delineated by the World Health Organization (WHO), as well as role (school) 
functioning. The 4 Multidimensional Scales and 3 Summary Scores are: 
Scales 
•
Physical Functioning (8 items)
•
Emotional Functioning (5 items)
•
Social Functioning (5 items)
•
School Functioning (5 items)
Summary Scores 
•
Total Scale Score (23 items)
•
Physical Health Summary Score (8 items)
•
Psychosocial Health Summary Score (15 items)
8.1.11. 
Urinary and Fecal Copper Excretion 
24-hour urinary copper excretion will be assessed at Baseline, Week 6, Week 24, and Week 48
in all participants.
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24-hour fecal copper excretion will be assessed at Baseline and Week 6 in all participants. This
assessment is optional.
Containers for collection of urine and feces will be provided at the preceding study visit. The 
purpose of these assessments is to assess the change from Baseline in urinary and fecal copper 
excretion in participants with WD who are treated with ALXN1840 or SoC. 
8.2. 
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA (Section 1.3). 
When multiple procedures are scheduled to occur at the same time, the following order of events 
should be strictly adhered to whenever possible: ECG, vital signs, blood sampling, study 
intervention administration, and meal. 
Pharmacokinetic collection should occur as close as possible to the scheduled time. 
8.2.1. 
Physical Examinations 
•
A complete physical examination will include, at a minimum, assessments of the
cardiovascular, respiratory, GI, and neurological systems.
•
An abbreviated physical examination consists of a body system relevant examination
based upon Investigator judgment and participant symptoms. At least 1 body system
must be checked for an abbreviated examination.
•
A symptom-driven physical examination may be performed at other times, at the
Principal Investigator’s discretion.
8.2.2. 
Vital Signs
•
Body temperature, heart rate, respiratory rate, and systolic and diastolic blood
pressure (mm Hg) will be assessed. Height and weight will also be measured and
recorded.
•
Blood pressure and pulse measurements will be assessed with a completely
automated device. Manual techniques will be used only if an automated device is not
available.
•
Blood pressure and pulse measurements should be preceded by at least 5 minutes of
rest for the participant in a quiet setting without distractions (eg, television, cell
phones). Ideally, the same arm for each participant should be used for measurements.
•
Vital signs will be measured in a supine position after 5 minutes rest and will include
temperature, systolic and diastolic blood pressure, and heart rate. Vital signs will
consist of a single pulse and blood pressure measurement. If vital signs are abnormal
as defined by inclusion/exclusion criteria, 2 additional vital signs measurements will
be made. The average of the 3 vital signs measurements will be recorded in the CRF
and used to determine participant eligibility. The average of the blood pressure
readings will be recorded in the CRF.
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8.2.3. 
Electrocardiograms 
•
Triplicate 12-lead ECGs will be conducted as outlined in the SoA (see Section 1.3) to
obtain heart rate, PR, QRS, QT, and QTc intervals. As with vital signs, if ECG interval
measurements are abnormal, an additional triplicate will be performed and recorded in
the CRF.
8.2.4. 
Clinical Safety Laboratory Assessments 
•
See Section 10.2 for the list of clinical laboratory tests to be performed and to the
SoA (Section 1.3) for the timing and frequency.
•
The Investigator must review the laboratory report, document this review, and record
any clinically relevant changes occurring during the study in the AE section of the
CRF. The laboratory reports must be filed with the source documents. Clinically
significant abnormal laboratory findings are those which are not associated with the
underlying disease, unless judged by the Investigator to be more severe than expected
for the participant’s condition.
•
All laboratory tests with values considered clinically significantly abnormal during
participation in the study or after the last dose of study intervention should be
repeated until the values return to normal or Baseline or are no longer considered
clinically significant by the Investigator or Medical Monitor.
−
If such values do not return to normal/Baseline within a period of time judged
reasonable by the Investigator, the etiology should be identified, and Alexion
notified.
−
All protocol-required laboratory assessments, as defined in Section 10.2, must be
conducted in accordance with the laboratory manual and the SoA.
−
If laboratory values from non-protocol specified laboratory assessments
performed at the institution’s local laboratory require a change in participant
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.
8.2.5. 
Suicidal Ideation and Behavior Risk Monitoring 
Suicidal ideation and behavioral changes will be recorded as AEs and may, at the discretion of 
the Investigator, result in withdrawal of the participant from the study and urgent referral for 
psychiatric treatment. 
Participants being treated with study intervention should be monitored appropriately and 
observed closely for suicidal ideation and behavior or any other unusual changes in behavior, 
especially at the beginning and end of the course of intervention, or at the time of dose changes, 
either increases or decreases. Consideration should be given to discontinuing the study 
intervention in participants who experience signs of suicidal ideation or behavior, following a 
risk assessment.  
Families and caregivers of participants being treated with study intervention should be alerted 
about the need to monitor participants for the emergence of unusual changes in behavior, as well 
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as the emergence of suicidal ideation and behavior and to report such symptoms immediately to 
the study Investigator. 
Baseline assessment of suicidal ideation and behavior/intervention emergent suicidal ideation 
and behavior will be monitored during the study using the BPRS-24 and BPRS-C9 
(Section 8.1.7).  
8.2.6. 
Pregnancy 
•
Pregnancy data from female participants and female spouses/partners of male participants
will be collected from first dose of study intervention up to 3 months after the last dose of
study intervention. Any female participant who becomes pregnant while participating in
the study will be discontinued from the study intervention and withdrawn from the study.
If a pregnancy is reported, the Investigator must immediately inform Alexion within
24 hours of awareness of the pregnancy and follow the procedures outlined in
Section 10.4.
•
For all Alexion products, both in development or post-approval, exposure during
pregnancy must be recorded and the pregnancy followed until the outcome of the
pregnancy is known (ie, spontaneous miscarriage, elective termination, normal birth or
congenital abnormality), even if the participant discontinues the study intervention or
withdraws from the study. The corresponding infant must be followed for 3 months
postpartum.
•
Pregnancy is not considered as an AE (Section 10.4.3) unless there is a suspicion that the
study intervention may have interfered with the effectiveness of a contraceptive
medication. However, complications of pregnancy and abnormal outcomes of pregnancy
are AEs and may meet the criteria for an SAE (eg, ectopic pregnancy, spontaneous
abortion, intrauterine fetal demise, neonatal death, or congenital anomaly) (Section 8.3).
Elective abortions without complications should not be reported as AEs.
8.3. 
Adverse Events and Serious Adverse Events 
The definitions of AEs and SAEs can be found in Section 10.3. 
All AEs will be reported to the Investigator or qualified designee by the participant (or, when 
appropriate, by a caregiver, surrogate, or the participant’s legally authorized representative). 
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the study intervention or study procedures, or that 
caused the participant to discontinue the study intervention (see Section 7). 
Procedures for recording, evaluating, follow-up, and reporting AEs and SAEs are outlined in 
Section 10.3. 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE Information 
All AEs and SAEs will be collected from the signing of the ICF until the EOS Visit. 
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All SAEs will be recorded and reported to Alexion or the designee immediately and under no 
circumstance should this exceed 24 hours, as indicated in Section 10.3. The Investigator will 
submit any updated SAE data to Alexion within 24 hours of it being available. 
Investigators are not obligated to actively seek AE or SAE data after conclusion of the study 
participation. However, if the Investigator learns of any SAE, including a death, at any time after 
a participant has been discharged from the study, and the Investigator considers the event to be 
reasonably related to the study intervention or study participation, he/she must promptly notify 
Alexion. 
See Section 10.11 for instructions specific to Germany. 
8.3.2. 
Method of Detecting AEs and SAEs 
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Section 10.3.  
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about AE 
occurrences. 
8.3.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the Investigator is required to proactively follow-up on each 
participant at subsequent visits/contacts. All SAEs will be followed up until resolution, 
stabilization, the event is otherwise explained, or the participant is lost to follow-up (as defined 
in Section 7.3). Further information on follow-up procedures is provided in Section 10.3. 
8.3.4. 
Regulatory Reporting Requirements for SAEs 
•
Prompt notification of an SAE by the Investigator to Alexion is essential so that legal
obligations and ethical responsibilities towards the safety of participants and the
safety of a study intervention under clinical investigation are met.
•
Alexion has a legal responsibility to notify both the local regulatory authority and
other regulatory agencies about the safety of a study intervention under clinical
investigation. Alexion will comply with country-specific regulatory requirements
relating to safety reporting to the regulatory authority, IRBs/ IECs, and Investigators.
•
Alexion is required to submit individual suspected unexpected serious adverse
reaction (SUSAR) reports (defined in Section 10.3.2) in the format of
MedWatch 3500 or Council for International Organizations of Medical Sciences
(CIOMS) I Form to health authorities and Investigators as required. Forms submitted
to Investigators will be blinded to treatment assignment. In limited circumstances, the
blind may be broken in the case of urgent safety issues that could compromise
participant safety.
•
An Investigator who receives an Investigator safety report describing an SAE or other
specific safety information (eg, summary or listing of SAEs) from Alexion will
review and then file it along with the IB and will notify the IRB/IEC, if appropriate
according to local requirements.
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8.3.5. 
Adverse Events of Special Interest 
Any new neurological symptom or clinically significant worsening of an ongoing neurological 
symptom after initiation of study intervention (ALXN1840 or SoC) will be designated an 
adverse event of special interest (AESI), whether serious or non-serious. All AESIs should be 
recorded in the eCRF and AESIs meeting the criteria for an SAE should be reported per 
Section 8.3.4. 
If a participant has an AESI, in addition to assessments deemed clinically relevant by the 
Investigator, the following assessments should be performed to the extent possible to help assess 
the AE and participant status: UWDRS Part III, and the CGI-I and CGI-S. The Investigator or 
Sub Investigator can perform additional assessments or laboratory testing at their discretion.  
All adverse events of special interest (serious or nonserious) will be assessed by a panel of 3 
independent neurologists not participating in the study. The panel will assess the probability that 
clinically significant worsening or a new clinically significant neurological symptom is related to 
disease progression or caused by the study intervention (ALXN1840 or SoC). They will be 
blinded to the treatment given to the participant. All available relevant participant information 
will be provided to this panel to aid in their assessment. The assessment of AESIs by the panel 
will be independent of and in addition to the usual assessments of the AE, including assessments 
of severity (intensity) and causality, by both the Investigator and Alexion. 
8.4. 
Treatment of Overdose 
For participants receiving ALXN1840, an overdose is defined as any daily dose exceeding 15 mg 
for adolescents aged 12 to < 18 years and in children < 12 years of age.  
For participants receiving SoC, an overdose is defined as any daily dose exceeding the maximum 
daily dose listed on the local label in that country.  
Alexion does not recommend specific treatment for an overdose. 
Overdoses are medication errors that are not considered AEs unless there is an untoward medical 
occurrence resulting from the overdose. 
In the event of an overdose or suspected overdose, the Investigator/treating physician should: 
1. Contact the Medical Monitor immediately.
2. Closely monitor the participant for any AE/SAE.
3. Obtain a plasma sample for PK analysis if requested by the Medical Monitor (determined
on a case-by-case basis).
4. Document the quantity of the excess dose as well as the duration of the overdose in the
CRF.
Decisions regarding dose interruptions or modifications will be made by the Investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the participant. 
8.5. 
Pharmacokinetics 
•
Whole blood samples will be collected for analyzing plasma concentrations of total
molybdenum and PUF molybdenum as  specified in the SoA (Section 1.3).
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•
Instructions for the collection and handling of biological samples will be provided by
Alexion. The actual date and time (24-hour clock time) of each sample will be
recorded.
•
Excess/additional samples may be stored for up to 5 years and used for PD and/or
diagnostic biomarker development and research to understand the pathways
associated with the mechanism of action of ALXN1840. These samples will not be
used for genetic analyses (ie, RNA or DNA analyses).
•
Genetic analyses will not be performed on the whole blood samples collected for
PK/PD analysis.
8.6. 
Pharmacodynamics
•
Whole blood will be collected for measurement of plasma total and PUF copper,
NCC, and LBC as specified in the SoA (Section 1.3).
•
Instructions for the collection and handling of biological samples will be provided by
Alexion. The actual date and time (24-hour clock time) of each sample will be
recorded.
•
Plasma samples will be used to evaluate ALXN1840 or SoC PD via the measurement
of total copper and copper measured as NCC and PUF copper, and/or LBC, or
assessed via NCC/NCCcorrected methods. Samples collected for PD measurements of
ALXN1840 and SoC may also be used to evaluate safety or efficacy aspects related to
concerns arising during or after the study.
•
Excess/additional samples may be stored for up to 5 years and used for PD and/or
diagnostic biomarker development and research to understand the pathways
associated with the mechanism of action of ALXN1840 (see also Section 10.6). These
samples will not be used for genetic analyses (ie, RNA or DNA analyses).
8.7. 
Genetics
A blood sample for DNA isolation will be collected from participants who have consented to 
participate in the genetic analysis component of the study. Participation is optional. Participants 
who do not wish to participate in the genetic research may still participate in the study.  
Details on processes for collection and shipment and destruction of these samples can be found 
in the laboratory manual. Details of the use, analysis, and storage of the DNA samples collected 
are provided in Section 10.5. 
8.8. 
Biomarkers 
ALXN1840 biomarkers such as ceruloplasmin and CpC will be measured in plasma/serum 
samples. Note that serum ceruloplasmin will be analyzed separately to plasma ceruloplasmin. 
Please see Section 8.6 for details of ALXN1840 or SoC PD measurements such as plasma total 
copper and PUF copper and/or LBC, or assessed via NCC/NCCcorrected methods.  
Further details of biomarker analyses are provided in Section 10.6. 
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8.9. 
Immunogenicity Assessments 
Not applicable. 
8.10. 
Health Economics Data and/or Medical Resource Utilization 
Health economic and medical resource utilization parameters are not evaluated in this study. 
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9.
STATISTICAL CONSIDERATIONS
9.1. 
Statistical Hypotheses 
9.1.1. 
Primary Hypothesis 
This study is not statistically powered to be a stand-alone hypothesis testing study with respect to 
efficacy. Efficacy data from this study will subsequently be combined with those of the ongoing 
Phase 3 Study WTX101-301, which includes participants ≥12 years of age, using Bayesian 
extrapolation methods to assess the efficacy of ALXN1840 and SoC in pediatric participants 
with WD. 
Accordingly, the evaluations of PK, PD, safety, and efficacy of ALXN1840 and SoC will be 
summarized descriptively using frequentist statistical methods. A separate analysis and report 
will present the results of the Bayesian extrapolations, which use adult/adolescent participants in 
Study WTX101-301 and pediatric participants in Study ALXN1840-WD-302 to perform 
statistical testing of the efficacy of ALXN1840 compared with SoC in pediatric participants. 
9.2. 
Sample Size Determination 
This study will enroll 48 pediatric participants (1:1 ratio to ALXN1840 or SoC) with the goal of 
obtaining 40 evaluable participants at Week 48.  
The proposed sample size for this study was assessed for its adequacy for the extrapolation Study 
ALXN1840-WD-303 via simulation using the proposed Bayesian hierarchical model. To explore 
the performance of the design, 3 distinct states of efficacy were considered in each of the 
populations with respect to the mean 48 week change in NCC/NCCcorrected: 
1. ALXN1840 is superior to SoC by 15%
2. ALXN1840 is equivalent to SoC; and
3. ALXN1840 is inferior to SoC by 15%.
Given the 2 populations (adult population: adults in Study WTX101-301, and pediatric 
population: pediatrics in Study ALXN1840-WD-302 plus adolescents from Study WTX101-
301), there are 9 possible combinations representing potential underlying scenarios. For each of 
these scenarios, 5,000 studies were simulated and the proportion of studies that claim 
non-inferiority in the pediatric participant population was estimated. Statistical power is captured 
in scenarios in which ALXN1840 is either superior or equivalent to SoC in the pediatric 
participant population. Type I error is captured in scenarios in which ALXN1840 is inferior to 
SoC in the pediatric participant population. Table 8 shows the simulation results assuming a 
standard deviation of 30% (absolute) on the 48-week change in NCC/NCCcorrected. 
The proposed primary analysis for the pediatric extrapolation Study ALXN1840-WD-303 has 
70% to 99% power for scenarios in which ALXN1840 is either equivalent or superior to SoC in 
both populations and has Type I error <13% when ALXN1840 is inferior to SoC in the pediatric 
population. These calculations assume 165 adult participants and 15 adolescents from Study 
WTX101-301(2:1 ratio to ALXN1840 or SoC) have evaluable 48-week data, and 40 evaluable 
pediatric participants (1:1 ratio to ALXN1840 or SoC) have evaluable 48-week data from Study 
ALXN1840-WD-302. The data simulations were done using FACTS v6.3. 
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To accommodate a 15% dropout rate, a total of 48 pediatric participants will be enrolled. 
Table 8: 
Simulated Power for Pediatric Extrapolation Study ALXN1840-WD-303 
Primary Analysis 
Adult Population 
Pediatric Population 
Superior 
Equivalent 
Inferior 
Superior 
99.2% 
69.9% 
9.8% 
Equivalent 
99.0% 
73.6% 
12.7% 
Inferior 
83.1% 
23.8% 
1.0% 
9.3. 
Populations for Analyses 
The population sets used as analysis sets are defined in the following: 
Population 
Description 
Screened 
All participants who sign the ICF. 
Enrolled 
All participants who agree to participate in the study following completion 
of the informed consent process and who satisfy the inclusion/exclusion 
criteria and are randomized. 
Safety Analysis Set 
All participants who receive at least 1 dose of ALXN1840 or SoC 
treatment.  
Full Analysis Set 
All participants who receive at least 1 dose of ALXN1840 or SoC 
treatment.  
Per Protocol Set 
All participants who receive at least 1 dose of ALXN1840 or SoC 
treatment and have both baseline and Week 48 NCC/NCCcorrected 
concentrations. Participants with major protocol deviations that are likely 
to impact the primary endpoint analysis will be excluded from the Per 
Protocol Set. Major protocol deviations and the Per Protocol Set will be 
defined, documented, and agreed within Alexion prior to database lock. 
Extension Analysis Set 
This dataset includes all participants who enter Period 2 and receive at 
least 1 dose of ALXN1840 in the Period 2 
Pharmacokinetic/Pharmacodynamic 
Analysis Set 
All participants who have sufficient plasma samples to enable the 
calculation of PK parameters and provide PK/PD profiles. 
Abbreviations: ICF = informed consent form; PD = pharmacodynamic; PK = pharmacokinetic; SoC = standard of 
care. 
9.4. 
Statistical Analyses 
The evaluations of PK, PD, safety, and efficacy of ALXN1840 and SoC in this study will be 
summarized descriptively using summary statistics. 
A separate analysis and report will present the results of the Bayesian extrapolations and 
statistical testing of the efficacy of ALXN1840 compared with SoC in pediatrics (Study 
ALXN1840-WD-303). The analyses at Weeks 48 and 72 will be performed and reported 
sequentially and separately. 
The evaluation of safety and efficacy of ALXN1840 from 48 to 72 weeks will be summarized by 
the treatment groups assigned in Period 1 using descriptive statistics. For participants who are 
randomized to ALXN1840 in Period 1, change/percent change from Period 1 baseline and 
change/percent change from Period 2 baseline will both be summarized. For participants who 
were randomized to SoC in Period 1, only change/percent change from Period 2 baseline will be 
summarized. 
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Missing data will not be imputed. 
Statistical methods described in this section will be further elaborated in a separate Statistical 
Analysis Plan (SAP). Summary statistics will be computed and displayed by treatment group and 
by visit, where applicable. Descriptive statistics for continuous variables will minimally include 
the number of participants, mean, standard deviation (SD), minimum, median, and maximum. 
For categorical variables, frequencies and percentages will be presented. Graphical displays will 
be provided as appropriate. 
Analyses will be performed using the SAS® software Version 9.4 or higher. 
9.4.1. 
Efficacy Analyses 
9.4.1.1. 
Analyses of Primary Efficacy Endpoint 
The primary endpoint, the percentage change from Baseline to 48 weeks in NCC/NCCcorrected 
concentrations, will be analyzed by treatment group within each cohort and by treatment group 
overall using descriptive summary statistics. Analyses will be based on the Per Protocol Set and 
Full Analysis Set. 
Subgroup analysis may be performed (eg, age group) if sample sizes permit. 
9.4.1.2. 
Analyses of Secondary Efficacy Endpoints 
Analyses of secondary efficacy endpoints will be based on the Full Analysis Set. All secondary 
efficacy endpoints will be summarized by treatment groups within each cohort and by treatment 
group overall using descriptive statistics. 
Subgroup analysis may be performed (eg, age group) if sample sizes permit. 
9.4.1.3. 
Multiplicity Adjustment 
No statistical testing, not applicable. 
9.4.1.4. 
Analyses of Exploratory Endpoints 
All exploratory endpoints will be summarized by treatment groups within each cohort and by 
treatment group overall using descriptive statistics using the Full Analysis Set. 
9.4.2. 
Safety Analyses 
All safety analyses will be performed on the Safety Set. 
Safety analyses will include all AEs, ECGs, clinical laboratory data, physical examinations, and 
vital sign measurements using descriptive statistics. 
Treatment-emergent adverse events (TEAEs) are defined as those AEs with onset after the first 
dose of randomized treatment or existing events that worsened in severity after the first dose of 
randomized treatment. Events reported with a partial onset date (eg, month and year are reported, 
but the day is missing) will be considered to be treatment-emergent if it cannot be confirmed that 
the event onset was prior to the first dose of study drug based on the available date entries. 
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Additionally, for patients randomized to SoC in Period 1 who switch to ALXN1840 in Period 2, 
any AEs that initiate after the switch or existing events that worsen in severity will be attributed 
to ALXN1840. 
No inferential statistical analyses are planned for the safety parameters of this study. 
An overall summary of TEAEs will be presented by treatment, including frequency of 
participants experiencing the event (n) and relative frequency (n/N*100, where N is the number 
of patients in the Safety Set for each treatment group). The summary will include categories 
indicating how many events are TEAEs, treatment-emergent SAEs, and treatment-emergent non-
SAEs. Within TEAEs, the following subcategories will also be summarized: 
•
Severity of TEAEs (Grade 1 through Grade 5)
•
Related TEAEs (not related, related)
•
TEAEs leading to withdrawal of study drug
•
TEAEs leading to death
The incidence of AEs and SAEs will be summarized by System Organ Class and Preferred Term 
for each treatment and overall, and by relationship to study intervention. 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. Participants having multiple AEs within a category (eg, 
overall, System Organ Class, Preferred Term) will be counted once in that category. For severity 
tables, a participant’s most severe event within a category will be counted.  
Changes from Baseline in vital sign measurements and laboratory assessments (eg, chemistry, 
hematology, coagulation, 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 participants with each baseline grade 
relative to the reference ranges and changes to the worst highest grade assessed post-dose during 
the study. 
Electrocardiogram parameters will be measured at the specified time points as per the SoA 
(Section 1.3), including heart rate, PR, RR, QRS, QT, and QT intervals corrected for heart rate 
using Fridericia’s formula (QTcF intervals). The average of the triplicate ECG readings at the 
time points collected will be calculated, and changes from Baseline values will be assessed by 
each treatment. 
All concomitant medications will be coded and summarized using the WHO Drug Dictionary. 
9.4.3. 
Pharmacokinetic, Pharmacodynamic, and Biomarker Analyses 
For PK, PD, and biomarker endpoints, analyses will be performed using the PK/PD Analysis Set.  
The following plasma PK parameters will be calculated for total molybdenum and PUF 
molybdenum, if measured, using noncompartmental methods with Phoenix® WinNonlin® 
(Certara USA Inc., Princeton, New Jersey) Version 8.0 or higher or SAS Version 9.3 or higher 
(SAS Institute Inc., Cary, North Carolina), as applicable. Calculations will be based on the actual 
sampling times recorded during the study. 
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•
Maximum observed concentration (Cmax)
•
Time to maximum concentration (Tmax)
•
Trough (predose) concentration observed at the start of the dosing interval (Ctrough)
•
Area under the plasma concentration versus time curve (AUC) over the dosing
interval (AUCtau)
Additional plasma PK parameters may be calculated if deemed appropriate. Population PK 
analysis may be formed with pooled data from other clinical studies if deemed appropriate. 
Population PK parameters such as, but may not be limited to, apparent total body clearance 
(CL/F) and apparent volume of distribution (Vd/F) will be estimated for addition modeling and 
simulation purposes. 
Plasma concentrations of total molybdenum and PUF molybdenum (if measured) versus time 
data will be presented in a data listing by participant. Plasma concentration data will be 
summarized separately by analyte and time point for each treatment by day using the following 
descriptive statistics: number of participants, arithmetic mean, geometric mean (GM), SD, 
coefficient of variation (CV), GMCV, median, minimum, and maximum. Mean plasma 
concentration versus scheduled time profiles will be presented in figures on both linear and 
semilogarithmic scales. Individual plasma concentration versus actual time profiles will be 
presented similarly. 
Pharmacokinetic parameters derived from plasma concentrations of total molybdenum and PUF 
molybdenum (if measured) will be presented in data listings and summarized separately using 
the following descriptive statistics: number of participants, arithmetic mean, GM, SD, arithmetic 
CV, GMCV, median, minimum, and maximum.  
For PD (total and PUF (if measured) copper, NCC, LBC and NCC/NCCcorrected) and biomarker 
endpoints (ceruloplasmin, CpC), concentration versus time data will be listed and summarized 
with descriptive statistics and plotted. The same analyses will be conducted on the absolute and 
percent changes from Baseline of these concentration versus time data. 
The following plasma PD parameters, as data permits, will be calculated for total copper, NCC, 
and LBC using noncompartmental methods with Phoenix® WinNonlin® Version 8.0 or higher or 
SAS Version 9.4 or higher, as applicable.  
•
Maximum observed effect after dosing (CEmax)
•
Time after dosing at which the maximum effect was observed (TEmax)
•
Area under the effect versus time curve (AUEC) from the start of dose administration
to the last observed quantifiable concentration (AUECt)
Pharmacodynamic parameters derived from plasma concentrations of total copper, NCC, and 
LBC will be presented and summarized by analyte and day similar to PK parameters.  
Additional PK/PD correlation plots and analysis may be performed. 
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9.5. 
Interim Analyses 
The primary analysis will be performed after 48 weeks and the final analysis after completion of 
Period 2. Interim analyses of data may be performed to support regulatory submissions. These 
analyses will be descriptive only; they will not include formal hypothesis testing and will not be 
used to adapt the study. Full details will be provided in the SAP. 
Interim efficacy data will also be used in an efficacy extrapolation to develop evidence for 
ALXN1840 efficacy on copper control for pediatric participants (ages 3 to < 18 years) using 
adult/adolescent participant data from Studies WTX101-301 and ALXN1840-WD-302. Full 
details of the extrapolation exercise will be provided in a separate analysis and report. 
9.6. 
Data Monitoring Committee 
An independent Data Monitoring Committee (DMC), comprising experts in relevant fields with 
no direct relationship to the study, will be appointed by Alexion. The specific responsibilities of 
the DMC will be described in the DMC Charter. 
9.7. 
Neurological Event Adjudication Panel 
A separate independent Neuro Event Adjudication Panel, comprising independent experts in 
relevant fields will be appointed by Alexion. As detailed in the Neuro Event Adjudication Panel 
Charter (maintained separately from the study protocol), the Neuro Event Adjudication Panel 
will review and monitor study data for neurological AEs/SAEs that may impact safety, 
effectiveness, and study conduct, and make recommendations regarding study continuation, 
changes to the study population, and/or modification to study procedures. The specific 
responsibilities are described in the Neuro Event Adjudication Panel Charter. 
9.8. 
Hepatic Adjudication Panel 
A separate independent Hepatic Adjudication Panel, comprising experts in hepatology and drug-
induced liver injury, will be appointed by Alexion. As detailed separately in the Hepatic 
Adjudication Panel Charter (maintained separately from the study protocol), the Hepatic 
Adjudication Panel will review and monitor study data for abnormalities of liver tests and liver 
function that may impact safety, effectiveness, and study conduct, and make recommendations 
regarding study continuation, changes to the study population, and/or modification to study 
procedures. The specific responsibilities are described in the Hepatic Adjudication Panel Charter. 
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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 (CIOMS) International Ethical Guidelines
−
Applicable ICH Good Clinical Practice (GCP) Guidelines
−
Applicable laws and regulations
•
The protocol, protocol substantial amendments, ICF, IB, and other relevant
documents (eg, advertisements) must be submitted to an IRB/IEC by the Investigator
and reviewed and approved by the IRB/IEC before the study is initiated.
−
If any of these documents require regulatory/health authority approval per local
regulations, Alexion will also obtain such approval before the study is initiated.
•
Any substantial amendments to the protocol will require IRB/IEC approval before
implementation of changes made to the study design, except for changes necessary to
eliminate an immediate hazard to study participants.
•
For studies to be approved by the Medicines and Healthcare products Regulatory
Agency: The Investigator will notify the IRB/IEC of deviations from the study
protocol or GCP as defined by UK legislation as a serious breach or as required by
IRB/IEC procedures.
•
The Investigator will be responsible for the following:
−
Providing written summaries of the status of the study to the IRB/IEC annually or
more frequently in accordance with the requirements, policies, and procedures
established by the IRB/IEC
−
Notifying the IRB/IEC of SAEs or other significant safety findings as required by
IRB/IEC procedures
−
Providing oversight of the conduct of the study at the site and adherence to
requirements of 21 Code of Federal Regulations (CFR), ICH guidelines, the
IRB/IEC, Directive 2001/20/EC, European regulation 536/2014 for clinical
studies (if applicable), and all other applicable local regulations
10.1.2. 
Financial Disclosure 
Investigators and Sub-investigators will provide Alexion with sufficient, accurate financial 
information as requested to allow Alexion to submit complete and accurate financial certification 
or disclosure statements to the appropriate regulatory authorities. Investigators are responsible 
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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 
•
It is the responsibility of the Investigator to obtain signed (written or electronic
signature) informed consent and assent, where applicable from all study participants
and/or his/her legally authorized representative, defined according to local and
country regulations where the study is taking place, prior to any study-related
procedures including Screening assessments.
•
The Investigator or his/her representative will explain the nature of the study
(including but not limited to the objectives, potential benefits and risks,
inconveniences, and the participant’s rights and responsibilities) to the participant or
his/her legally authorized representative, defined according to local and country
regulations where the study is taking place, and answer all questions regarding the
study.
•
Participants must be informed that their participation is voluntary. Participants or
their legally authorized representative will be required to sign a statement of informed
consent or assent or a certified translation if applicable, that meets the requirements of
21 CFR 50, local regulations, EU General Data Protection Regulation (GDPR), ICH
guidelines, Health Insurance Portability and Accountability Act (HIPAA)
requirements, where applicable, and the IRB/IEC or study site.
•
The participant’s medical record must include a statement that signed (written or
electronic) informed consent or assent was obtained before the participant was
screened in the study and the date the written consent was obtained. The authorized
person obtaining the informed consent or assent must also sign the informed consent
or assent form(s).
•
Participants must be reconsented or reassented to the most current version of the
informed consent or assent form(s) during their participation in the study.
•
A copy of the signed (written or electronic) informed consent or assent
documentation (ie, a complete set of participant information sheets and fully executed
signature pages) must be provided to the participant or the participant’s legally
authorized representative, as applicable. This document may require translation into
the local language. Signed (written or electronic) consent [or assent] forms must
remain in each participant’s study file and must be available for verification at any
time.
•
A participant who is rescreened is not required to sign another ICF unless an updated
ICF is available.
10.1.4. 
Data Protection 
•
Participants will be assigned a unique identifier by Alexion. Any participant records
or datasets that are transferred to Alexion will contain the identifier only; participant
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names or any information which would make the participant identifiable will not be 
transferred.  
•
Participants must be informed that their personal study related data will be used in
accordance with applicable data protection law, and participants must also be
informed of any individuals rights they may have with regard to their personal data.
Participants will be informed about how their personal study related data will be
disclosed, and will be required to agree to the information contained in the informed
consent and provide consent to the processing of their personal data, if required by
applicable data protection law.
•
Participants must be informed that their medical records may be examined by Clinical
Quality Assurance auditors or other authorized personnel appointed by Alexion, by
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
•
Alexion as a data controller has implemented privacy and security controls designed
to help protect participant personal data; including information security controls,
firewalls, incident detection, and secure transfer measures.
•
In the event of any accidental or unlawful destruction, loss, alteration, unauthorized
disclosure of, or access to, personal data (“breach”), the controller has implemented
procedures and measures to promptly address and mitigate any risk to the data
participant. In the event of a breach, the controller will notify the appropriate
regulatory authorities and/or the data participant in accordance with applicable data
protection law.
10.1.5. 
Dissemination of Clinical Study Data 
Study-related information and study results may be posted on publicly accessible clinical study 
databases (eg, the US website www.clinicaltrials.gov or the EU website 
www.clinicaltrialsregister.eu), as appropriate, and in accordance with national, regional, and 
local regulations. 
10.1.6. 
Data Quality Assurance 
•
All participant data relating to the study will be recorded on printed or electronic case
report forms (CRFs) unless transmitted to Alexion or designee electronically (eg,
laboratory data). The Investigator is responsible for verifying that data entries are
accurate and correct by physically or electronically signing the CRF.
•
The Investigator must maintain accurate documentation (source data) that supports
the information entered in the CRF.
•
The Investigator must permit study-related monitoring, audits, IRB/IEC review, and
regulatory agency inspections and provide direct access to source data documents.
•
Alexion or designee is responsible for the data management of this study including
quality checking of the data.
•
Study monitors will perform ongoing source data verification to confirm that data
entered into the CRF by authorized site personnel are accurate, complete, and
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verifiable from source documents; that the safety and rights of participants are being 
protected; and that the study is being conducted in accordance with the currently 
approved protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements.  
−
Remote source data verification may be employed where permitted by local
regulations.
−
The scope of the source data verification will be described in detail in the Clinical
Monitoring Plan.
•
Records and documents, including signed ICFs, pertaining to the conduct of this
study must be retained by the Investigator for 2 years after the last marketing
application approval, or if not approved, 2 years following the discontinuance of the
study intervention, unless local regulations or institutional policies require a longer
retention period. No records may be destroyed during the retention period without the
written approval of Alexion. No records may be transferred to another location or
party without written notification to Alexion.
10.1.7. 
Source Documents 
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. The Investigator or designee will prepare and maintain adequate 
and accurate source documents (eg, medical records, ECGs, AE and concomitant medication 
reporting, raw data collection forms) designed to record all observations and other pertinent data 
for each participant. 
Data reported on the CRF that are transcribed from source documents must be consistent with 
the source documents or the discrepancies must be explained. The Investigator may need to 
request previous medical records or transfer records, depending on the study. Also, current 
medical records must be available. Source documents are filed at the Investigator’s site. 
Per ICH E6 (R2) guidelines and good documentation practice requirements, source documents 
and study records in all media (eg, paper, electronic) must be Attributable, Legible, 
Contemporaneous, Original, Accurate, and Complete. 
10.1.8. 
Study and Site Start and Closure 
The study start date is the date on which the first participant is consented or assented. 
Alexion reserves the right to close the study site or terminate the study at any time for any reason 
at the sole discretion of Alexion. Study sites will be closed after the study is completed or 
following the decision to close or terminate the study. A study site is considered closed when all 
participants have completed the End of Study or Early Termination Visit, all data have been 
collected and entered into an electronic data capture (EDC) system, all required documents and 
study supplies have been collected, and a study-site closure visit has been performed. 
The Investigator may initiate study-site closure at any time, provided there is reasonable cause, 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by Alexion or Investigator may include but are not 
limited to: 
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•
Failure of the Investigator to comply with the protocol, the requirements of the
IRB/IEC or local health authorities, Alexion’s procedures, or GCP guidelines
•
Inadequate recruitment of participants by the Investigator
•
Discontinuation of further study intervention development
If the study is prematurely terminated or suspended, Alexion shall promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified by the 
applicable regulatory requirements. The Investigator shall promptly inform the participant and 
should assure appropriate participant therapy and/or follow-up. 
10.1.9. 
Publication Policy 
The full terms regarding publication of the results of this study are outlined in the applicable 
Clinical Study Agreement. 
10.1.10. 
Good Clinical Practice Compliance 
Alexion and any third party to whom aspects of the study management or monitoring have been 
delegated will undertake their assigned roles for this study in compliance with all applicable 
industry regulations, ICH GCP Guideline E6 R2, EU Directive 2001/20/EC, as well as all 
applicable national and local laws and regulations. 
Visits to sites are conducted by representatives of Alexion and/or the company 
organizing/managing the research on behalf of Alexion to inspect study data, participants’ 
medical records, and CRFs in accordance with current GCP and respective local and 
(inter)national government regulations and guidelines. Records and data may additionally be 
reviewed by auditors or by regulatory authorities. 
Alexion ensures that local regulatory authority requirements are met before the start of the study. 
Alexion (or designee) is responsible for the preparation, submission, and confirmation of receipt 
of any regulatory authority approvals required prior to release of study intervention for shipment 
to the site. 
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10.2. 
Clinical Laboratory Tests 
•
The tests detailed in Table 9 will be performed by the Central Laboratory.
•
Protocol-specific requirements for inclusion or exclusion of participants are detailed
in Section 5 of the protocol.
•
Additional tests may be performed at any time during the study as determined
necessary by the Investigator or required by local regulations.
•
Pregnancy testing: Women of childbearing potential can only be enrolled after a
negative serum pregnancy test result at Screening. Additional urine pregnancy testing
will be standard for the protocol unless serum testing is required by site policies, local
regulation, or IRB/IEC and should be performed per the time points specified in the
SoA (Section 1.3). In addition to pregnancy tests detailed at the visits in the SoA,
females of childbearing potential will be required to perform urine pregnancy tests at
least every 4 weeks at their home or the study site throughout their time in the study.
Screening pregnancy criteria are detailed in Section 5.1.
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Table 9: 
Protocol-Required Safety Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Hematology 
• Platelet count
• RBC count
• Hemoglobin
• Hematocrit
• RBC indices (MCV, MCH, % reticulocytes)
• White blood cell count with differential (neutrophils, lymphocytes, monocytes,
eosinophils, basophils)
Clinical 
chemistrya 
• ALT
• Alkaline phosphatase
• AST
• Blood urea nitrogen
• Calcium
• Ceruloplasmin (note that serum and plasma ceruloplasmin are assessed separately)
• Cholesterol
• Creatinine
• Gamma glutamyltransferase
• Glucose
• Potassium
• Sodium
• Total and direct bilirubin
• Total protein
• Lipid profile
Iron profile 
• Iron profile (plasma iron, ferritin, transferrin saturation)
Routine 
urinalysis 
• Specific gravity
• pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocyte esterase
by dipstick
• Microscopic examination (if blood or protein is abnormal)
Coagulation 
• Prothrombin time
• Partial thromboplastin time
• International normalized ratio
Other 
Screening tests 
• Highly sensitive serum or urine human chorionic gonadotropin pregnancy test at
Screening and urine at subsequent study visits, with confirmation by serum test if the
urine test is positive (as needed for women of childbearing potential)
• HIV antibody screen
• Hepatitis B surface antigen
• Hepatitis C virus antibody (positive antibody screen should be confirmed by RNA test)
a Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping or 
monitoring event are given in Section 6.6.  
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; HIV= human 
immunodeficiency virus; INR = international normalized ratio; MCH = mean corpuscular hemoglobin; 
MCV = mean corpuscular volume; RBC = red blood cell; SAE = serious adverse event; ULN = upper limit of 
normal. 
Investigators must document their review of each laboratory safety report. 
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10.3. 
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting 
10.3.1. 
Definition of AE 
AE Definition 
•
An AE is any untoward medical occurrence in a patient or clinical investigation participant administered a
pharmaceutical product and which does not necessarily have to have a causal relationship with this
treatment (ICH E2A).
•
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 
•
Medical or surgical procedure (eg, endoscopy, appendectomy): The condition that leads to the procedure
is the AE. Situations in which an untoward medical occurrence did not occur (eg, hospitalization for
elective surgery if planned before the signing the ICF, admissions for social reasons or for convenience).
•
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected at the
start of the study that do not worsen.
•
A medication error (including intentional misuse, abuse, and overdose of the product) or use other than
what is defined in the protocol is not considered an AE unless there is an untoward medical occurrence
as a result of a medication error.
•
Cases of pregnancy that occur during maternal or paternal exposure to study intervention are to be
reported within 24 hours of Investigator/site awareness. Data on fetal outcome and breastfeeding will be
collected for regulatory reporting and safety evaluation.
•
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 participant’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 participant’s condition.
•
Situations in which an untoward medical occurrence did not occur (social and/or convenience admission
to a hospital).
•
“Lack of efficacy” or “failure of expected pharmacological action” per se will not be reported as an AE
or SAE. Such instances will be captured in the efficacy assessments. However, the signs, symptoms,
and/or clinical sequelae resulting from lack of efficacy will be reported as AE or SAE if they fulfil the
definition of an AE or SAE.
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10.3.2. 
Definition of SAE 
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). 
An SAE is defined as any untoward medical occurrence that, at any dose: 
1.
Results in death
2.
Is life-threatening
The term “life-threatening” in the definition of “serious” refers to an event in which the participant was at risk of
death at the time of the event. It does not refer to an event, which hypothetically might have caused death, if it
was more severe.
3.
Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been detained (usually involving at least an overnight
stay) at the hospital or emergency ward for observation and/or treatment that would not have been appropriate in
the physician’s office or outpatient setting. Complications that occur during hospitalization are AEs. If a
complication prolongs hospitalization or fulfills any other serious criteria, the event is serious. When in doubt as
to whether “hospitalization” occurred or was necessary, the AE should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen from Baseline is not
considered an AE.
4.
Results in persistent disability/incapacity
•
The term disability means a substantial disruption of a person’s ability to conduct normal life functions.
•
This definition is not intended to include experiences of relatively minor medical significance such as
uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma (eg, sprained ankle)
which may interfere with or prevent everyday life functions but do not constitute a substantial disruption.
5.
Is a congenital anomaly/birth defect
6.
Other situations:
•
Medical or scientific judgment should be exercised in deciding whether SAE reporting is appropriate in
other situations such as important medical events that may not be immediately life-threatening or result in
death or hospitalization but may jeopardize the participant or may require medical or surgical intervention to
prevent one of the other outcomes listed in the above definition. These events should usually be considered
serious.
•
Examples of such events include invasive or malignant cancers, intensive treatment in an emergency room
or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization,
or development of drug dependency or drug abuse.
A suspected unexpected serious adverse reaction (SUSAR) is defined as: 
An event that is assessed as serious by the Investigator and/or Alexion that is not listed in the appropriate 
Reference Safety Information (IB) and has been assessed that there is at least a reasonable possibility that the 
event is related to the investigational medicinal product by the Investigator and/or Alexion. 
Alexion has procedures that will be followed for the recording, medical assessment, and expedited reporting of 
SUSARs that are consistent with global regulations, legislation, and guidance documents. 
For the purposes of this study, SoC SUSAR reporting will be in accordance with Section 4.8 of the Summary of 
Product Characteristics (SmPC) of the respective SoC products. 
Suspected unexpected serious adverse reactions will undergo expedited reporting to the national regulatory 
authorities, IRBs/IECs, and Investigators following local regulatory reporting requirements where applicable. 
10.3.3. 
Recording and Follow-up of AE and/or SAE 
Recording of AE and/or SAE 
•
When an AE/SAE occurs, it is the responsibility of the Investigator to review all documentation (eg, hospital
progress notes, laboratory reports, and diagnostics reports) related to the event.
•
The Investigator will then record all relevant AE/SAE information in the CRF.
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Recording of AE and/or SAE 
•
It is not acceptable for the Investigator to send photocopies of the participant’s medical records to Alexion
in lieu of completion of the AE/SAE CRF page.
•
There may be instances when copies of medical records for certain cases are requested by Alexion GDS. In
this case, all participant identifiers, with the exception of the participant number, will be redacted on the
copies of the medical records before submission to Alexion.
•
The Investigator will attempt to establish a diagnosis of the event based on signs, symptoms, and/or other
clinical information. Whenever possible, the diagnosis (not the individual signs/symptoms) will be
documented as the AE/SAE.
Assessment of Intensity 
The Investigator will make an assessment of intensity for each AE and SAE reported during the study and assign 
it to one of the following categories from National Cancer Institute CTCAE v5.0, published 27 Nov 2017:  
•
Grade 1: Mild (awareness of sign or symptom, but easily tolerated)
•
Grade 2: Moderate (discomfort sufficient to cause interference with normal activities)
•
Grade 3: Severe (incapacitating, with inability to perform normal activities)
•
Grade 4: Life-threatening
•
Grade 5: Fatal
An event is defined as “serious” when it meets at least one of the predefined outcomes as described in the 
definition of an SAE, not when it is rated as severe. 
Assessment of Causality 
•
The Investigator is obligated to assess the relationship between the study intervention and each occurrence
of each AE or SAE. An Investigator causality assessment must be provided for all AEs (both nonserious and
serious). This assessment must be recorded in the CRF and on any additional forms, as appropriate. The
definitions for the causality assessments are as follows:
−
Not related: There is no reasonable possibility the study intervention caused the AE.

The AE has a more likely alternative etiology; it may be due to underlying or
concurrent illness, complications, concurrent treatments, or effects of another
concurrent drug.

The event does not follow a reasonable temporal relationship to administration of the
study intervention.
−
Related: There is a reasonable possibility the study intervention caused the AE.

The AE has a temporal relationship to the administration of the study intervention.

The event does not have a likely alternative etiology.

The event corresponds with the known pharmaceutical profile of the study
intervention.

There is improvement on discontinuation and/or reappearance on rechallenge.
•
The Investigator will use clinical judgment to determine the relationship.
•
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, as well as the
temporal relationship of the event to study intervention administration will be considered and investigated.
•
The Investigator will also consult the IB and/or Product Information, for marketed products, in his/her
assessment.
•
For each AE/SAE, the Investigator must document in the medical notes that he/she has reviewed the
AE/SAE and has provided an assessment of causality.
•
There may be situations in which an SAE has occurred, and the Investigator has minimal information to
include in the initial report to Alexion. However, it is very important that the Investigator always make an
assessment of causality for every event before the initial transmission of the SAE data to Alexion.
•
The Investigator may change his/her opinion of causality in light of follow-up information and send an SAE
follow-up report with the updated causality assessment.
•
The causality assessment is one of the criteria used when determining regulatory reporting requirements.
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Follow-up of AEs and SAEs 
•
The Investigator is obligated to perform or arrange for the conduct of supplemental measurements and/or
evaluations as medically indicated or as requested by Alexion to elucidate the nature and/or causality of the
AE or SAE as fully as possible. This may include additional laboratory tests or investigations,
histopathological examinations, or consultation with other health care professionals.
•
If a participant dies during participation in the study or during a recognized follow-up period, the
Investigator will provide Alexion with a copy of any 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 Alexion within 24 hours of receipt of the
information. See Section 10.11 for instructions specific to Germany.
10.3.4. 
Reporting of SAEs 
SAE Reporting to Alexion 
•
All SAEs will be recorded and reported to Alexion or designee immediately and within 24 hours of
awareness. See Section 10.11 for instructions specific to Germany.
•
The primary mechanism for reporting an SAE to Alexion will be the electronic data collection tool.
•
If the electronic system is unavailable at the time that the Investigator or site becomes aware of an SAE, the
site will use the paper Contingency Form for SAE Reporting via fax or email. Facsimile transmission or
email may be used in the event of electronic submission failure.
−
Email: clinicalsae@alexion.com or Fax: + 1.203.439.9347
•
The site will enter the SAE data into the EDC system as soon as it becomes available.
•
When further information becomes available, the EDC should be updated within 24 hours with the new
information and an updated SAE report should be submitted to Alexion.
•
After the study is completed at a given site, the electronic data collection tool will be taken offline to
prevent the entry of new data or changes to existing data.
•
If a site receives a report of a new SAE from a study participant or receives updated data on a previously
reported SAE after the electronic data collection tool has been taken off-line, then the site can report this
information on a paper Contingency Form for SAE Reporting.
•
If applicable, additional information such as relevant medical records should be submitted to Alexion via
the email address or fax number noted above.
•
All paper forms and follow-up information submitted to Alexion outside of the RAVE Safety Gateway (eg,
discharge summary) MUST be accompanied by a cover page signed by the Investigator.
•
Paper source documents and/or reports should be kept in the appropriate section of the study file.
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10.4. 
Contraceptive Guidance and Collection of Pregnancy Information 
10.4.1. 
Definitions 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below). 
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first dose of study intervention, additional evaluation should be considered. 
Women in the following categories are not considered WOCBP 
1. Premenarchal
2. Premenopausal female with one of the following:
•
Documented hysterectomy
•
Documented bilateral tubal ligation or bilateral salpingectomy
•
Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the above, 
(eg, Mullerian agenesis, androgen insensitivity), Investigator discretion should be applied to 
determining study entry. 
Note: Documentation can come from the site personnel’s: review of the participant’s medical 
records, medical examination, or medical history interview. 
3. Permanent sterilization at least 6 weeks prior to the Day 1 Visit.
10.4.2. 
Contraception Guidance 
Contraceptive use by male or female participants should be consistent with local regulations 
regarding the methods of contraception utilized for those participating in clinical studies. If 
teratogenic effects are suspected to be transferred to a fetus/embryo from a female spouse/partner 
of a male participant, pregnancy follow-up information will be obtained for the partner who 
becomes pregnant (refer to Section 10.4.3.1). In these cases, follow-up will be conducted on the 
pregnant partner in the same manner as a female participant who becomes pregnant during the 
study. 
10.4.2.1. Guidance for Female Participants 
Female participants of childbearing potential must have a negative pregnancy test (urine or 
serum) as required by local regulations within 24 hours before the first dose of study 
intervention. In addition to pregnancy tests detailed at the visits in the SoA (Section 1.3), females 
of childbearing potential will be required to perform urine pregnancy tests at least every 4 weeks 
at their home or the study site throughout their time in the study. 
•
If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum
pregnancy test is required. In such cases, the patient must be excluded from
participation if the serum pregnancy result is positive.
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The Investigator is responsible for the review of medical history, menstrual history, and recent 
sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy. 
A highly effective method of contraception, including at least 1 of the following must be used 
until at least 3 months after the final dose of study intervention. 
1. Intrauterine device (without copper) in place for at least 6 weeks prior to first dose of
study intervention.
2. Progestogen-only hormonal contraception associated with inhibition of ovulation (either
oral, injectable, or implantable) for at least 6 weeks prior to first dose of study
intervention.
3. Intrauterine progestogen releasing system for at least 6 weeks prior to first dose of study
intervention.
4. Bilateral tubal occlusion for at least 6 weeks prior to first dose of study intervention.
5. Combined (estrogen- and progestogen-containing) hormonal contraception - associated
with inhibition of ovulation (either oral, intravaginal, or transdermal) for at least 6 weeks
prior to first dose of study intervention. Estrogen-containing hormonal contraception is
acceptable only if it has been used for at least 6 weeks immediately prior to the first dose.
Estrogen-containing hormonal contraception may not be initiated during the study period.
6. Surgical sterilization of the male partner (medical assessment of azoospermia is required
if vasectomy was performed within 6 months prior to first dose of study intervention).
Male partner is still required to use condom during sexual intercourse.
7. Sexual abstinence for female participants:
a. Sexual abstinence is considered a highly effective method only if defined as
refraining from heterosexual intercourse. In this study, abstinence is only acceptable
if consistent with the participant’s preferred and usual lifestyle. Abstinent female
participants must refrain from heterosexual intercourse for at least 3 months after the
final dose of study intervention.
Female participants must not donate ova from the first dose of study intervention until at least 3 
months after their final dose of study intervention. 
The following methods of contraception are considered unacceptable in this study: 
•
Periodic abstinence (calendar, symptothermal or post ovulation methods
•
Withdrawal (coitus interruptus)
•
Spermicides only
•
Lactational amenorrhea method
•
Female condom and male condom should not be used together
•
Progestogen-only oral hormonal contraception, where inhibition of ovulation is not
the primary mode of action
•
Male or female condom with or without spermicide
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•
Cap, diaphragm, or sponge with spermicide
•
A combination of male condom with cap, diaphragm, or sponge with spermicide
(double barrier methods)
10.4.2.2. Guidance for Male Participants 
Male participants must use a condom during heterosexual intercourse from the first dose of study 
intervention until at least 3 months after their final dose of study intervention. 
Female partners of male participants who are of childbearing potential must use highly effective 
contraception as defined above, starting at least 6 weeks before (the male participant’s) first 
study intervention administration and continuing until at least 3 months after the end of their 
male partner’s systemic exposure to the study intervention. 
Male participants must not donate sperm from the first dose of study intervention until at least 
3 months after their final dose of study intervention. 
10.4.2.2.1. Sexual Abstinence for Male Participants 
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse. In this study, abstinence is only acceptable if consistent with the 
participant’s preferred and usual lifestyle. Abstinent male participants who become 
heterosexually active must use a condom during intercourse.  
Periodic abstinence (eg, calendar, symptothermal, or post-ovulation methods for a female 
partner) is not considered a highly effective method of contraception for male participants. 
10.4.3. 
Collection of Pregnancy Information 
Pregnancy data will be collected during this study for female participants and female 
spouses/partners of male participants from the first dose of study intervention until 3 months 
after the final dose of study intervention is administered. Any female participant who becomes 
pregnant during the study must be discontinued from the study intervention and withdrawn from 
the study. 
Exposure during pregnancy (also referred to as exposure in utero) can be the result of either 
maternal exposure or transmission of study intervention via semen following paternal exposure. 
If a female participant or a male participant’s female spouse/partner becomes pregnant during the 
conduct of this study, the Investigator must submit the “Pregnancy/Breastfeeding Reporting and 
Outcome Form” to Alexion GDS via facsimile or email within 24 hours of awareness of the 
pregnancy. When the outcome of the pregnancy becomes known, the form should be updated 
and submitted to Alexion GDS. If additional follow-up is required, the Investigator will be 
requested to provide the information.  
Exposure of an infant to study intervention during breastfeeding must also be reported (via the 
“Pregnancy/Breastfeeding Reporting and Outcome Form”) and any AEs experienced by the 
infant must be reported to Alexion GDS via email or facsimile. 
Pregnancy is not regarded as an AE unless there is a suspicion that the study intervention may 
have interfered with the effectiveness of a contraceptive medication. However, complications of 
pregnancy and abnormal outcomes of pregnancy are AEs and may meet the criteria for an SAE 
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(eg, ectopic pregnancy, spontaneous abortion, intrauterine fetal demise, neonatal death, or 
congenital anomaly). Elective abortions without complications should not be reported as AEs. 
10.4.3.1. Male Participants With Partners Who Become Pregnant 
•
The Investigator will attempt to collect pregnancy information on any male participant’s
female partner who becomes pregnant while the male participant is in this study. This
applies only to male participants who receive study intervention.
•
After obtaining the necessary signed informed consent from the pregnant female partner
directly, the Investigator will record pregnancy information on the appropriate
“Pregnancy/Breastfeeding Reporting and Outcome Form” and submit it to Alexion GDS
within 24 hours of learning of the partner’s pregnancy. The female partner will also be
followed to determine the outcome of the pregnancy. Information on the status of the
mother and child will be forwarded to Alexion GDS. Generally, the follow-up will be for
up to 3 months following the estimated delivery date. Any termination of the pregnancy
will be reported regardless of fetal status (presence or absence of anomalies) or indication
for the procedure.
10.4.3.2. Female Participants who become pregnant 
•
The Investigator will collect pregnancy information on any female participant who
becomes pregnant while participating in this study. The initial information will be
recorded on the appropriate form and submitted to Alexion GDS within 24 hours of
learning of a participant’s pregnancy.
•
For all Alexion products, both in development or postapproval, exposure during
pregnancy must be recorded and the pregnancy followed, until the outcome of the
pregnancy is known (ie, spontaneous miscarriage, elective termination, normal birth, or
congenital abnormality), even if the participant discontinues the study intervention or
withdraws from the study. The Investigator will collect follow-up information on the
participant and the neonate and the information will be forwarded to Alexion. Generally,
follow-up will not be required for longer than 3 months beyond the estimated delivery
date. Any termination of pregnancy will be reported, regardless of fetal status (presence
or absence of anomalies) or indication for the procedure.
•
While pregnancy itself is not considered to be an AE or SAE, any pregnancy
complication or elective termination of a pregnancy for medical reasons will be reported
as an AE or SAE. A spontaneous abortion (occurring at < 22 weeks gestational age) or
still birth (occurring at > 22 weeks gestational age) is always considered to be an SAE
and will be reported as such. Any poststudy pregnancy-related SAE considered
reasonably related to the study intervention by the Investigator will be reported to
Alexion. While the Investigator is not obligated to actively seek this information in
former study participants, he or she may learn of an SAE through spontaneous reporting.
•
Any female participant who becomes pregnant while participating in the study will
discontinue study intervention and be withdrawn from the study.
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10.5. 
Genetics 
Use/Analysis of Deoxyribonucleic Acid 
•
Genetic variation in the ATP7B gene may impact a patient’s response to study
intervention, susceptibility to, and severity and progression of disease. Therefore,
where local regulations and IRB/IEC allow, a blood sample will be collected for
DNA analysis from consenting patients.
•
DNA samples will be used for research related to WD. They may also be used to
develop tests/assays including diagnostic tests related to ALXN1840 and WD.
•
DNA samples will be analyzed for variants in the coding and regulatory sequences of
the ATP7B gene and other genes, if considered related to WD. Additional analyses
may be conducted if it is hypothesized that this may help further understand the
clinical data, such as identifying gene mutations that may affect the metabolism of
ALXN1840.
•
The samples may be analyzed as part of a multi-study assessment of genetic factors
involved in the response to ALXN1840 or study interventions of this class to
understand study disease or related conditions.
•
The results of genetic analyses may be reported in the clinical study report (CSR) or
in a separate study summary.
•
Alexion or designee will store the DNA samples in a secure storage space with
adequate measures to protect confidentiality.
•
The samples will be retained while research on ALXN1840 continues but no longer
than 10 years or other period as per local requirements.
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10.6. 
Biomarkers 
•
Blood samples will be collected for biomarker analyses and the data will be used for
research (eg, exploratory) related to ALXN1840 or WD and related diseases. The
samples may also be used to develop tests/assays including diagnostic tests related to
ALXN1840 and WD.
•
The samples may be analyzed as part of a multistudy assessment of biomarkers in the
response to ALXN1840 to understand study disease or related conditions.
•
Biomarker samples will not be used for genetic testing.
•
The results of biomarker analyses may be reported in the CSR or in a separate study
summary.
•
Alexion or designee will store the samples obtained for biomarker analyses in a
secure storage space with adequate measures to protect confidentiality.
•
The samples will be retained while research on ALXN1840 continues but no longer
than 5 years after all data has been collected for the study or other period as per local
requirements.
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10.7. 
Blood Sampling Volumes 
The following procedures for blood collection should be adhered to: 
1. Number of attempts: The number of attempts for sampling blood is limited to 3 times per
day. This means that after 3 punctures for collection of blood have been performed and
no or insufficient blood could be collected, no other puncture will be done on the same
day.
2. Volume of blood samples: Per study participant, the study-related blood loss (including
any losses in the collection procedure) should not exceed more than 5 mL/kg body weight
(5% of total blood volume) in a day and no more than 9.5 mL/kg (11%) of total blood
volume) over any 8-week period.  If an Investigator decides to deviate from these limits,
the deviation must be fully documented, and the investigator should provide justification
for the deviation. If the required blood volume cannot be obtained, due to the above-
mentioned safety limits, priority will be given to safety-relevant investigations.
3. Eutectic mixture of local anesthetics (EMLA) cream/plaster: To minimize the possible
pain and discomfort due to collection of blood, the Investigator may apply an EMLA
cream/plaster at the puncture site, depending on clinical practice at the study site.
Reference: POLICY – Guidelines for Limits of Blood Drawn for Research Purposes in the 
Clinical Center. Available at: 
https://irb.research.chop.edu/sites/default/files/documents/g_nih_blooddraws.pdf 
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10.8. 
Population PK Simulations and Dose Selection in Pediatric 
Participants with Wilson Disease 
10.8.1. 
Participants aged 12 to < 18 years 
The simulation showed that projected PK exposure range for participants aged 12 to < 18 years 
(Figure 2) are expected to be overlapping with the exposure range for adults at the proposed dose 
of 15 mg in Studies WTX101-301 and ALXN1840-WD-302.  
Figure 2: 
Projected Pharmacokinetic Exposure Range for Participants Aged 12 to 
< 18 Years 
Simulations are based on a 2-compartmental population-PK model for pediatric participants based on allometric 
scaling of adult population-PK model currently under development using Day 1 PK data from Study WTX101-201 
in participants with WD and relevant PK data from Study WTX101-102 in healthy volunteers. Simulations results 
will be updated once final data are available from the Study WTX101-201. 
Abbreviations: hr = hour; Mo = molybdenum; PK = pharmacokinetic; WD = Wilson Disease; yrs = years. 
Source: Population PK modelling simulations (data on file) 
The 15 mg EC tablet formulation is the current formulation being used for administration of the 
dose and subsequent individualized dose modifications in the ongoing Phase 3 Study WTX101-
301, which includes participants aged 12 years and older, as per Protocol Amendment 1. The 
15/day single or repeated daily doses has been shown to have favorable safety profiles and to be 
well tolerated throughout the Phase 1 to Phase 3 clinical studies in both healthy adults and adult 
participants with WD. 
Of note, the current ongoing Phase 3 Study WTX101-301 has enrolled 17 pediatric participants, 
including a participant weighing 39.5 kg who was dosed at the starting dose of 15 mg 
ALXN1840 once daily, and has shown an acceptable safety profile. To date, the TEAEs 
observed in the adolescent participants are similar to those reported in the overall study. 
10.8.2. 
Participants aged 3 to < 12 years 
The projected PK exposures at the starting dose of 5 mg every other day are lower than those in 
adults administering a starting dose of 15 mg, a more conservative dosing approach in the 
youngest age group of 3 to < 12 years. The projected exposures at the original maximum dose 
(ie, 30 mg once daily) allowed for participants aged 3 to < 12 years in Study ALXN1840-WD-
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302 are similar to those administering the highest dose (ie, 60 mg once daily) allowed in the 
ongoing Phase 3 Study WTX101-301 in adults and adolescents (Figure 3).  
Figure 3: 
Projected Pharmacokinetic Exposure Range for Patients Aged 3 to 
< 12 Years 
Simulations are based on a 2-compartmental population-PK model for pediatric participants based on allometric 
scaling of adult population-PK model currently under development using Day 1 PK data from Study WTX101-201 
in patients with WD and relevant PK data from Study WTX101-102 in healthy volunteers. Simulations results will 
be updated once final data are available from Study WTX101-201. 
Abbreviations: hr = hour; Mo = molybdenum; PK = pharmacokinetic; WD = Wilson Disease; yrs = years; 
QD = once daily; QOD = every other day. 
Source: Population PK modelling simulations (data on file) 
Looking specifically at participants aged 3 to < 6 years, the modeling results showed that a 5 mg 
dose has comparable exposure as 15 mg administered to adult participants, and that a 15 mg dose 
has a higher exposure than 30 mg but a lower exposure than 60 mg administered to adult 
participants (Figure 4). Hence, the predicted dose range for participants aged 3 to < 6 years is 
5 mg to 15 mg, which is anticipated to provide comparable safety and efficacy outcomes to those 
in adolescent and adult participants over 12 years of age with a dose range of 15 mg to 60 mg 
allowed in the ongoing Phase 3 Study WTX101-301.  
A more conservative starting dose at 2.5 mg will be used for the pediatric study ALXN1840-
WD-302 for participants aged 3 to < 12 years. 
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Figure 4: Projected Pharmacokinetic Exposure Range for Participants Aged 3 to < 6 Years 
Source: Population PK modelling simulations (data on file) 
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10.9. 
COVID Safety Measures 
The COVID-19 pandemic has the potential to restrict access to ALXN1840 and SoC treatment 
and safety monitoring visits for study participants. During this pandemic period, Alexion has set 
up mitigation measures providing additional options whereby study procedures, laboratory 
assessments, safety monitoring and study drug dispensation may be conducted (Table 10). These 
include visits at the participant’s home, by an investigator or home healthcare provider, in-
person, by telephone or by video conference, at another study site located near the participant’s 
home, or an alternative center located near the participant’s home. These visits are conducted 
under the orders of the study site Investigator by trained qualified staff and in accordance with all 
national, state, and local laws or regulations.  
Participants with WD may be at risk of complications if treatment is missed or delayed. Alexion 
has not identified a safety signal with ALXN1840 that would prevent its use during a viral 
infection and does not recommend suspending treatment in participants receiving ALXN1840 or 
SoC. The risk to benefit assessment favors continuity of treatment for WD, when possible.  
Informed consents forms will permit release of medical records for participants transferring to 
another study site and to enable remote data verification where permitted. 
The future of this pandemic is uncertain. These specific measures in the conduct of the study are 
intended to be temporary. Alexion intends to revert back to the original measures described in 
the protocol after the end of the pandemic period. Alexion will be making every effort to 
maintain participant safety in the setting of COVID-19 transmission while continuing treatment 
for WD. Any questions concerning the mitigation measures in place should be discussed with the 
Alexion Medical Monitor. 
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Table 10: 
COVID-19 Clinical Study Mitigation Measures (Optional and Temporary) for Study ALXN1840-WD-302 
Study Impact 
Clinical Study Temporary Measures 
Justification for COVID-19 Mitigation 
Site Staff via 
Home 
Visit/Phone/Video 
Alternative staff 
at home 
Alternative 
study/local 
site 
Courier 
Abbreviated 
physical 
examination 
PI/Sub-I 
Due to COVID-19 pandemic restrictions, participant study visits may 
need to be completed remotely at the participant’s home, by site staff. 
This alternative temporary measure will limit impact of the pandemic 
on the parameter assessment. 
Vital signs 
(Weight, temp, 
BP and HR) 
PI/Sub-I/SC/Other 
certified staff 
Home Healthcare 
Provider 
Primary Care 
Physician/ 
Other 
Due to COVID-19 pandemic restrictions, participant study visits may 
need to be completed remotely at the participant’s home, by site staff or 
home healthcare provider, at another study site located near the 
participant’s home, or an alternative center located near the 
participant’s home. This alternative temporary measure will limit 
impact of the pandemic on the parameter assessment. 
12-lead ECG 
PI/Sub-I/SC/Other 
certified staff 
Home Healthcare 
Provider 
Primary Care 
Physician/ 
Other 
Due to COVID-19 pandemic restrictions, participant study visits may 
need to be completed remotely at another study site located near the 
participant’s home, or an alternative center located near the 
participant’s home. This alternative measure will limit impact of the 
pandemic on the parameter assessment. 
DNA sample 
In-clinic after 
restriction is lifted 
NA 
Pregnancy testa 
PI/Sub-I/SC/Other 
certified staff 
Home Healthcare 
Provider 
Primary Care 
Physician/ 
Other 
Courier may be 
used for shipment 
of lab kits from 
site to participant 
Due to COVID-19 pandemic restrictions, participant study visits may 
need to be completed remotely at the participant’s home, by site staff or 
home healthcare provider, at another study site located near the 
participant’s home, or an alternative center located near the patient’s 
home. Site staff and home healthcare providers will be trained on the 
study laboratory manual to ensure proper collection, processing, 
shipping of samples. If local labs are used for collection of safety 
samples, results and reference ranges will be collected. This alternative 
temporary measure will limit impact of the pandemic on the parameter 
assessment. 
Urinalysis 
PI/Sub-I/SC/Other 
certified staff 
Home Healthcare 
Provider 
Primary Care 
Physician/ 
Other 
Courier may be 
used for shipment 
of lab kits from 
site to participant 
Due to COVID-19 pandemic restrictions, participant study visits may 
need to be completed remotely at the participant’s home, by site staff or 
home healthcare provider, at another study site located near the 
patient’s home, or an alternative center located near the participant’s 
home. Site staff and home healthcare providers will be trained on the 
study laboratory manual to ensure proper collection, processing, 
shipping of samples. If local labs are used for collection of safety 
samples, results and reference ranges will be collected. This alternative 
temporary measure will limit impact of the pandemic on the parameter 
assessment. 
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Table 10: 
COVID-19 Clinical Study Mitigation Measures (Optional and Temporary) for Study ALXN1840-WD-302 
Study Impact 
Clinical Study Temporary Measures 
Justification for COVID-19 Mitigation 
Site Staff via 
Home 
Visit/Phone/Video 
Alternative staff 
at home 
Alternative 
study/local 
site 
Courier 
Chemistry, 
coagulation, 
hematology 
panela 
 PI/Sub-I/SC/Other 
certified staff 
Home Healthcare 
Provider 
Primary Care 
Physician/ 
Other 
Courier may be 
used for shipment 
of lab kits from 
site to participant 
Due to COVID-19 pandemic restrictions, participant study visits may 
need to be completed remotely at the participant’s home, by site staff or 
home healthcare provider, at another study site located near the 
participant’s home, or an alternative center located near the patient’s 
home. Site staff and home healthcare providers will be trained on the 
study laboratory manual to ensure proper collection, processing, 
shipping of samples. If local labs are used for collection of safety 
samples, results and reference ranges will be collected.  This alternative 
temporary measure will limit impact of the pandemic on the parameter 
assessment. 
AEsa 
PI/Sub-I 
Home healthcare 
provider to query 
patient about 
changes from last 
visit. Contact 
Investigator if any 
changes.  
Due to COVID-19 pandemic restrictions, participant study visits may 
need to be completed remotely at the participant’s home, by site staff or 
home healthcare provider. This alternative temporary measure will limit 
impact of the pandemic on the parameter assessment. 
Concomitant 
Medicationsa 
PI/Sub-I 
Home healthcare 
provider to query 
patient about 
changes from last 
visit. Contact 
Investigator if any 
changes.  
Due to COVID-19 pandemic restrictions, participant study visits may 
need to be completed remotely at the participant’s home, by site staff or 
home healthcare provider. This alternative temporary measure will limit 
impact of the pandemic on the parameter assessment. 
MELD, PELD, 
and modified 
Nazer 
NA 
NA 
Fibrosis-4 
NA 
NA 
Transient 
elastography 
In-Clinic after 
restriction is lifted 
NA 
Plasma/serum 
PK/PD/Biomar
kers and 
Biobank 
samples 
PI/Sub-I/SC/Other 
certified staff 
Home Healthcare 
Provider 
Primary Care 
Physician/ 
Other 
Courier may be 
used for shipment 
of lab kits from 
site to participant 
Due to COVID-19 pandemic restrictions, participant study visits may 
need to be completed remotely at the participant’s home, by site staff or 
home healthcare provider, at another study site located near the 
participant’s home, or an alternative center located near the patient’s 
home. This alternative temporary measure will limit impact of the 
pandemic on the parameter assessment. 
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Table 10: 
COVID-19 Clinical Study Mitigation Measures (Optional and Temporary) for Study ALXN1840-WD-302 
Study Impact 
Clinical Study Temporary Measures 
Justification for COVID-19 Mitigation 
Site Staff via 
Home 
Visit/Phone/Video 
Alternative staff 
at home 
Alternative 
study/local 
site 
Courier 
24-hour urine 
and feces Cu 
and Mo 
PI/Sub-I/SC/Other 
certified staff 
Home Healthcare 
Provider 
Courier may be 
used for shipment 
of lab kits from 
site to participant 
Due to COVID-19 pandemic restrictions, participant study visits may 
need to be completed remotely at the participant’s home by site staff or 
home healthcare provider. This alternative temporary measure will limit 
impact of the pandemic on the parameter assessment. 
Investigational 
Product (IP) 
PI/Sub-I/SC/Other 
certified staff 
Home healthcare 
provider may 
transport IP from 
site to patient 
Courier may be 
used for shipment 
of IP from site to 
participant 
Due to COVID-19 pandemic restrictions, participant study visits may 
need to be completed remotely at the participant’s home, by site staff or 
home healthcare provider, at another study site located near the 
participant’s home, or an alternative center located near the 
participant’s home. IP may be transported by site staff, home healthcare 
provider, or shipped to patient via courier in a refrigerated (ALXN1840, 
trientine) or ambient (zinc, penicillamine) container. This alternative 
temporary measure will limit impact of the pandemic on the IP supply 
to the patient. 
UWDRS II 
Site staff 
Phone/Video 
Due to COVID-19 pandemic restrictions, participant study visits may 
need to be completed remotely at the participant’s home by site staff. 
This alternative temporary measure will limit impact of the pandemic 
on the parameter assessment. . 
UWDRS I & 
III 
Video by 
Neurologist if 
feasible 
Due to COVID-19 pandemic restrictions, participant study visits may 
need to be completed remotely at the participant’s home by site staff. 
This alternative temporary measure will limit impact of the pandemic 
on the parameter assessment. 
BPRS-24 and 
BPRS-C9 
Site staff 
Phone/Video 
Due to COVID-19 pandemic restrictions, participant study visits may 
need to be completed remotely at the patient’s home by site staff. This 
alternative temporary measure will limit impact of the pandemic on the 
parameter assessment. 
CGI-S, CGI-I 
Site staff 
Phone/Video 
Due to COVID-19 pandemic restrictions, participant study visits may 
need to be completed remotely at the participant’s home by site staff. 
This alternative temporary measure will limit impact of the pandemic 
on the parameter assessment. 
EQ-5D/ EQ-
5DY 
Participant to 
complete 
Home healthcare 
provider may 
provide completed 
questionnaire to 
site 
Courier may be 
used for shipment 
of questionnaires 
from site to 
participant 
Due to COVID-19 pandemic restrictions, participant study visits may 
need to be completed remotely at the participant’s home, by site staff or 
home healthcare provider. This alternative temporary measure will limit 
impact of the pandemic on the parameter assessment. 
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Table 10: 
COVID-19 Clinical Study Mitigation Measures (Optional and Temporary) for Study ALXN1840-WD-302 
Study Impact 
Clinical Study Temporary Measures 
Justification for COVID-19 Mitigation 
Site Staff via 
Home 
Visit/Phone/Video 
Alternative staff 
at home 
Alternative 
study/local 
site 
Courier 
TSQM-9 
Participant to 
complete 
Home healthcare 
provider may 
provide completed 
questionnaire to 
site 
Courier may be 
used for shipment 
of questionnaires 
from site to 
participant 
Due to COVID-19 pandemic restrictions, participant study visits may 
need to be completed remotely at the participant’s home, by site staff or 
home healthcare provider. This alternative temporary measure will limit 
impact of the pandemic on the parameter assessment. 
Re-consent 
Site staff 
Phone/Video 
Home healthcare 
provider may 
provide signed 
consent to site 
Due to COVID-19 pandemic restrictions, participant study visits may 
need to be completed remotely at the participant’s home, by site staff or 
home healthcare provider. This alternative temporary measure will limit 
impact of the pandemic on the re-consent of participants if needed. 
a.
Critical for safety monitoring
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10.10. 
Abbreviations 
Abbreviation 
Definition 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration versus time curve 
AUCtau 
area under the plasma concentration versus time curve from time 0 to the end of the 
dosing interval 
AUEC 
area under the effect versus time curve 
AUECt 
area under the effect versus time curve from the start of dose administration to the last 
observed quantifiable concentration 
BfArM 
Bundesinstitut für Arzneimittel und Medizinprodukte (German Federal Institute for 
Drugs and Medical Devices) 
BPRS-24 
Brief Psychiatric Rating Scale-24 
BPRS-C9 
Brief Psychiatric Rating Scale for children; 
CEmax 
maximum observed effect after dosing 
CFR 
Code of Federal Regulations 
CGI 
Clinical Global Impression 
CGI-I 
Clinical Global Impression-Improvement 
CGI-S 
Clinical Global Impression-Severity 
CIOMS 
Council for International Organizations of Medical Sciences 
CKD 
chronic kidney disease 
CL/F 
apparent total body clearance 
Cmax 
maximum observed concentration 
CONSORT 
Consolidated Standards of Reporting Trials 
COVID-19 
coronavirus disease 2019 
CpC 
ceruloplasmin-bound copper 
CRF 
case report form 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events  
CTFG 
Clinical Trials Facilitation Group 
CV 
coefficient of variation 
CYP 
cytochrome P450 
CYP2C9/2B6 
cytochromes 2C9 and 2B6 
DMC 
Data Monitoring Committee 
DNA 
deoxyribonucleic acid 
ECG 
electrocardiogram 
EDC 
electronic data capture 
EMLA 
eutectic mixture of local anesthetics 
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EOS 
End of Study 
EQ-5D 
EuroQoL 5 Dimensions 
EQ-5DY 
EuroQoL 5 Dimensions Youth 
ET 
Early Termination 
FIB-4 
fibrosis 4 
FSH 
follicle stimulating hormone 
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulation 
GDS 
Global Drug Safety 
GI 
gastrointestinal 
GM 
geometric mean 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
HRT 
hormonal replacement therapy 
IB 
Investigator’s Brochure 
ICH 
International Council for Harmonisation 
ICF 
informed consent form 
IEC 
Independent Ethics Committee 
IMP 
investigational medicinal product 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
IUD 
intrauterine device 
LBC 
labile-bound copper 
MELD 
Model for End-stage Liver Disease 
MHRA 
Medicines and Healthcare products regulatory Agency 
Mo 
molybdenum 
NCC 
non-ceruloplasmin-bound copper 
NCCcorrected 
non-ceruloplasmin-bound copper concentration corrected for the amount of copper 
bound to the TPC 
NIMP 
noninvestigational medicinal product 
PD 
pharmacodynamic 
PedsQL 
Pediatric Quality of Life Inventory 
PELD 
Pediatric End-stage Liver Disease 
PK 
pharmacokinetic(s) 
PRO 
patient-reported outcome 
PUF 
plasma ultrafiltrate  
QD 
once daily 
QOD 
every other day 
QoL 
quality of life 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula  
RNA 
ribonucleic acid 
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Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
standard deviation 
SoA 
Schedule of Activities 
SoC 
standard of care 
SUSAR 
suspected unexpected serious adverse reaction 
TEmax 
time after dosing at which the maximum effect was observed 
tmax 
time to maximum concentration 
TPC 
(tetrathiomolybdate-copper-albumin) tripartite complex 
TSQM-9 
Treatment Satisfaction Questionnaire for Medication-9 
ULN 
upper limit of normal 
UWDRS 
Unified Wilson Disease Rating Scale 
VAS 
Visual Analogue Scale 
Vd/F 
apparent volume of distribution  
WD 
Wilson disease 
WHO 
World Health Organization 
WOCBP 
woman of childbearing potential 
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Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
10.11. 
Country-Specific Changes 
The following changes only apply to Germany, and have been incorporated from Protocol 
Amendment 2 (08 Nov 2021), which was prepared in response to a request from the 
Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM; German Federal Institute for 
Drugs and Medical Devices) to revise the time specification for reporting an SAE by the 
Investigator to Alexion to “immediately” from “within 24 hours” and “should not exceed 
24 hours”, and to include text on the potential risk and mitigation strategies for pediatric 
participants. 
•
Section 8.3.1 Time Period and Frequency for Collecting AE and SAE Information
−
For Germany, all SAEs will be recorded and reported to Alexion or the designee
immediately, and the Investigator will submit any updated SAE data to Alexion
immediately after they become available.
•
Section 10.3.3 Recording and Follow-up of AE and/or SAE
In Germany, the Investigator will submit any updated SAE data to Alexion immediately after 
receipt of the information. 
•
Section 10.3.4 Reporting of SAEs
−
For Germany, all SAEs will be recorded and reported to Alexion or designee
immediately after awareness.
In addition, Section 2.3.4 Burden of Participation and Degree of Distress was added to Protocol 
Amendment 2 in response to a request by the BfArM to assess and monitor the burden of 
participation in this clinical study by the investigator, and to define it in the protocol. 
•
Section 2.3.4 Burden of Participation and Degree of Distress
−
The burden of participation in this study has been minimized to significantly
reduce the degree of distress typically associated with participating in a clinical
study for children and adolescents. No additional assessments, tests, visits, or
procedures other than those described in the SoA (Table 1) should be performed,
unless warranted for the evaluation and management of safety events, or for
follow up of the participants. The Investigator will monitor the degree of distress
and may contact the Medical Monitor to mitigate potential increase in the degree
of distress.
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Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
10.12. 
Protocol Amendment History 
The protocol amendment summary of changes table for the current amendment is located 
directly before the Table of Contents. 
DOCUMENT HISTORY 
Document 
Type of Amendment (Global 
or Country-specific) 
Date 
Summary of Key Changes in 
the Amendment 
Amendment 3 
Global 
08 Mar 2022 
See Summary of Changes table 
Amendment 2 
Germany 
08 Nov 2021 
See below 
Amendment 1.1 
UK 
30 Sep 2021 
See below 
Amendment 1 
UK 
07 Jul 2021 
See below 
Original protocol 
Global 
15 Mar 2021 
Not applicable 
Amendment 2 (Germany) (08 Nov 2021) 
This amendment was considered to be substantial and applied only to Germany. 
Rationale for the Amendment: 
The reason for this amendment was in response to a request from the Bundesinstitut für 
Arzneimittel und Medizinprodukte (BfArM; German Federal Institute for Drugs and Medical 
Devices) to revise the time specification for reporting an SAE by the Investigator to Alexion to 
“immediately” from “within 24 hours” and “should not exceed 24 hours”, and to include text on 
the potential risk and mitigation strategies for pediatric participants. 
The changes are described below. Note that these changes are included in Section 10.11 
(Country-Specific Changes) of this current protocol amendment 3.  
Section # and Name 
Description of Change 
Brief rationale and/or 
clarifications 
Section 8.3.1 Time Period 
and Frequency for 
Collecting AE and SAE 
Information 
Section 10.3.3 Recording 
and Follow-up of AE 
and/or SAE 
Section 10.3.4 Reporting 
of SAEs 
The time specification for reporting an SAE 
by the Investigator to Alexion was revised to 
state immediately, instead of within 24 hours. 
The same change was applied to reporting of 
follow-up information. 
The change was made in response 
to a request from the BfArM, 
because in Germany, the 
Investigator has to inform the 
Sponsor of an SAE immediately.  
2.3 Benefit/Risk 
Assessment 
Text has been added stating that potential risk 
and mitigation strategies have been identified 
in line with the EU guidance “Ethical 
Considerations for Clinical Trials on 
Medicinal Products in Minors”  
The change was made in response 
to a request from the BfArM to 
assess and monitor the risk 
threshold by the Investigator, and 
to define it in the protocol. 
2.3.4 Burden of 
Participation and Degree 
of Distress 
Section added to note that measures have been 
taken to minimize the burden of participation 
and degree of distress for the pediatric and 
adolescent participants in this study, and that 
the Investigator will monitor the degree of 
distress. 
The change was made in response 
to a request from the BfArM to 
assess and monitor the burden of 
participation in this clinical study 
by the investigator, and to define it 
in the protocol. 
Abbreviations: BfArM = Bundesinstitut für Arzneimittel und Medizinprodukte (German Federal Institute for Drugs 
and Medical Devices); SAE = serious adverse event  
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Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
Amendment 1.1, UK (30 Sep 2021) 
This amendment was considered to be substantial and applied only to the UK. 
Overall Rationale for the Amendment: 
The main reason for this amendment was to specify gastrostomy devices in inclusion criterion 
#5, as requested by the UK Medicines and Healthcare products Regulatory Agency (MHRA). 
Additional changes were also made for consistency and clarity. 
Changes from protocol amendment 1 are detailed in the table below. 
Section # and Name 
Description of Change 
Brief rationale and/or 
clarifications 
1.1 Synopsis 
Removal of term “standard” from “standard 
treatment” from the protocol  
This change was made for 
consistency and to avoid confusion 
between ‘standard treatment’ and 
‘standard of care’ 
Addition of IMP wording 
for standards of care 
including SUSAR 
reporting 5.1 Inclusion 
Criteria 
Modification of the text in inclusion criterion 
#5, which now reads 
•
Able to swallow intact ALXN1840 tablets
or mini-tablets. Participants who require
gastrostomy devices for feeding or
medications may be enrolled if the inner
diameter of the tube can accommodate an
intact tablet or mini-tablet without
obstruction.
This change was made in response 
to the request by MHRA to remove 
inclusion criteria that are not 
absolute and to predefine the 
attributes of the gastrostomy 
devices. 
10.3.2 Definition of SAE 
Text added noting that SUSAR will be in 
accordance with the Summary of Product 
Characteristics of the respective SoC products 
To clarify SUSAR reporting 
requirements for SoC. 
Abbreviations: SoC = Standard of Care; SUSAR = suspected unexpected serious adverse reaction 
Amendment 1, UK (07 Jul 2021) 
This amendment was considered to be substantial and applied only to the UK. 
Overall Rationale for the Amendment: 
The main reason for this amendment was to include language relating to the coronavirus disease 
2019 (COVID-19) vaccine risk assessment, as requested by the UK Medicines and Healthcare 
products Regulatory Agency (MHRA) in its updated guidance on managing clinical trials during 
the COVID-19 pandemic.  
Additional changes were also made to incorporate changes made in Administrative Change 
Letter 1, dated 09 Jun 2021, which were to change the guidance on blood volume and to make 
some minor clarifications and corrections. Minor administrative changes were also made for 
clarity. 
Note that COVID-19 specific text was not included in this protocol amendment 3 (Global) 
because it was specific to the UK, but other updates incorporated with Amendment 1 have been 
included in this amendment. 
Changes from the original protocol are detailed in the table below. 
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Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
Section # and Name 
Description of Change 
Brief rationale and/or 
clarifications 
1.2 Study Schema, Figure 
1 
1.3 Schedule of 
Activities, Table 1 
Screening period changed from Day -28 to Day 
-2 to Day -28 to Day -1, with randomization to
occur before Day 1 procedures begin.
To enable sites to perform 
randomization up to the start of 
Day 1 procedures, rather than just 
on Day -1. 
1.3 Schedule of 
Activities, Table 1 
“ET” added to Week 24 in Period 2 
Added for clarity, because similar 
to Period 1, the ET visit would 
occur during Period 2 in the event 
of early termination. 
Footnote k revised to state that transient 
elastography will be done when available. 
To reflect that it may not be 
possible to perform transient 
elastography at all study sites. 
Text on alternative blood sampling schedule 
for infants deleted from footnote l. 
To align with the change in 
guidance on blood sampling 
volumes (see below). 
Period 2 added to footnote l. 
To clarify that plasma/serum 
samples will be collected predose 
in both Periods 1 and 2. 
1.3 Schedule of 
Activities, Table 1 
Section 8, Study 
Assessments and 
Procedures 
Text in the footnote stating that an alternative 
blood sampling schedule for infants will be 
given in the Study Operations Manual. 
Guidelines on blood sampling are 
provided in Section 10.7. No 
separate guidelines for infants are 
required, because the minimum 
age for enrollment into the study is 
3 years. 
1.3 Schedule of 
Activities, Table 1 
8.8 Biomarkers 
10.2 Clinical Laboratory 
Tests, Table 10 
Footnote l simplified to state that serum 
ceruloplasmin will be assessed separately to 
plasma ceruloplasmin (which will be assessed 
as part of the PK/PD/biomarker parameters). 
To clarify that serum and plasma 
ceruloplasmin are analyzed 
separately. 
1.3 Schedule of 
Activities, Table 1 
10.2 Clinical Laboratory 
Tests 
Text requiring pregnancy testing for 3 months 
after the EOS visit removed from footnote j 
and Section 10.2. 
To align with CTFG guidance on 
contraception and pregnancy 
testing recommendations, and to 
be consistent with the Phase 3 
study WTX101-301. 
6.5.2 Disallowed 
Medicine and Therapy 
Addition of text stating that vitamin E and 
estrogen should not be initiated during the 
study, but can be continued if already being 
taken. 
To clarify that vitamin E and 
estrogen can be taken during the 
study, if already being taken before 
the study start. 
8.2.3 Electrocardiograms 
Removal of cross-reference to Section 7 for 
QTc withdrawal criteria and any additional 
QTc readings that may be necessary. 
QTc withdrawal criteria are not 
required in this protocol. 
10.2 Clinical Laboratory 
Tests, Table 10 
Removal of text in footnote relating to Hy’s 
Law. 
Text removed as not needed. If 
participants experience INR 
prolongation and they are admitted 
to hospital, the event will meet the 
definition and be recorded as an 
SAE. 
10.7 Blood Sampling 
Volumes 
Wording revised to state that the Investigator 
may, rather than should, apply an EMLA 
cream/plaster at the puncture site, and to add 
that use of an EMLA cream/plaster depends 
on clinical practice at the study site. 
To reflect that EMLA 
cream/plaster use depends on 
clinical practice at the study site. 
Reference changed from the European 
Commission guidance to the US guidelines. 
The guidance on blood sampling 
volumes has been changed from 
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Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
Section # and Name 
Description of Change 
Brief rationale and/or 
clarifications 
From: 
•
European Commission. European
Commission Ethical Considerations for
Clinical Trials on Medicinal Products
Conducted with the Paediatric Population:
Recommendations of the ad hoc group for
the development of implementing
guidelines for Directive 2001/20/EC
relating to the good clinical practice in the
conduct of clinical trials on medicinal
products for human use. 2008
To: 
•
POLICY- Guidelines for Limits of Blood
Drawn for Research Purposes in the
Clinical Center
https://irb.research.chop.edu/sites/default/fi
les/documents/g_nih_blooddraws.pdf”
Text changed from: 
•
Volume of blood samples: Per study
participant, the study-related blood loss
(including any losses in the collection
procedure) should not exceed 3% of the
total blood volume during a period of 4
weeks, and should not exceed 1% at any
single time. The total volume of blood is
estimated at 80 to 90 mL/kg body weight.
To: 
•
Volume of blood samples: Per study
participant, the study-related blood loss
(including any losses in the collection
procedure) should not exceed more than
5 mL/kg body weight (5% of total blood
volume) in a single day and no more than
9.5 mL/kg (11% of total blood volume)
over any 8‐week period.
the European Commission 
guidance to the US National 
Institutes of Health guidelines, 
because the US guidelines allow 
Investigators to conduct all tests 
planned without increasing the 
number of blood draw points. 
10.10 COVID-19 Vaccine 
Risk Assessment 
Text on the COVID-19 vaccine risk 
assessment performed with respect to 
ALXN1840 added. 
A vaccine risk assessment has been 
requested by the UK MHRA for 
studies performed in the UK. 
All 
Minor administrative changes. 
For clarity. 
Page 107 of 108 
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Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
11.
REFERENCES
Chang C-CH, Bryce CL, Shneider BL, et al. Accuracy of the pediatric end-stage liver disease 
score in estimating pretransplant mortality among pediatric liver transplant candidates. JAMA 
Pediatr. 2018;172(11):1070-1077. 
Czlonkowska A, Tarnacka B, Moller JC, et al. Unified Wilson's Disease Rating Scale - a 
proposal for the neurological scoring of Wilson's disease patients. Neurol Neurochir Pol. 
2007;41(1):1-12. 
Dhawan A, Taylor RM, Cheeseman P, De Silva P, Katsiyiannakis L, Mieli-Vergani G. Wilson's 
disease in children: 37-year experience and revised King's score for liver transplantation. Liver 
Transpl. 2005;11(4):441-448. 
Dziezyc K, Karlinski M, Litwin T, Czlonkowska A. Compliant treatment with anti-copper agents 
prevents clinically overt Wilson's disease in pre-symptomatic patients. Eur J Neurol. 
2014;21(2):332-337. 
EASL. European Association for the Study of Liver (EASL) Clinical Practice Guidelines: 
Wilson's disease. J Hepatol. 2012;56(3):671-685. 
Ferenci P, Caca K, Loudianos G, et al. Diagnosis and phenotypic classification of Wilson 
disease. Liver Int. 2003;23(3):139-142. 
Ferenci P, Stremmel W, Czlonkowska A, et al. Age, sex, but not ATP7B genotype effectively 
influences the clinical phenotype of Wilson disease. Hepatology. 2019;69(4):1464-1476. 
Leinweber B, Moller JC, Scherag A, et al. Evaluation of the Unified Wilson's Disease Rating 
Scale (UWDRS) in German patients with treated Wilson's disease. Mov Disord. 2008;23(1):54-
62. 
Maselbas W, Chabik G, Czlonkowska A. Persistence with treatment in patients with Wilson 
disease. Neurol Neurochir Pol. 2010;44(3):260-263. 
McDiarmid SV, Anand R, Lindblad AS, Principal Investigators and Institutions of the Studies of 
Pediatric Liver Transplantation (SPLIT) Research Group. Development of a pediatric end-stage 
liver disease score to predict poor outcome in children awaiting liver transplantation. 
Transplantation. 2002;74(2):173-181. 
Socha P, Janczyk W, Dhawan A, et al. Wilson's Disease in Children: A Position Paper by the 
Hepatology Committee of the European Society for Paediatric Gastroenterology, Hepatology and 
Nutrition. J Pediatr Gastroenterol Nutr. 2018;66(2):334-344. 
UNOS UNfOS. Policy Notice. Policy Clarification to KPD Histocompatibility Requirements – 
Test Date. 2015. 
Van Reenen MJ, Oppe M, Kreimeier S, Greiner W, EuroQol Group. EQ-5D-Y User Guide. 
Basic information on how to use the EQ-5D-Y instrument. Version 1.0. 2014. 
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;2(12):869-876. 
Page 108 of 108 
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SAP_001.pdf: 
Statistical Analysis Plan 
Version 1.0 
ALXN1840-WD-302 
21 Jun 2022 
Page 1 of 48 
Alexion Confidential 
TITLE PAGE 
STATISTICAL ANALYSIS PLAN 
Primary Evaluation Period 
Version Number: 1.0 
Protocol Title: A multicenter, randomized, controlled, open-label, rater-blinded study to 
evaluate efficacy, safety, pharmacokinetics, and pharmacodynamics of ALXN1840 versus 
standard of care in pediatric participants with Wilson disease 
Protocol Number: ALXN1840-WD-302  
Protocol Amendment Number: 3 (Global) 
Compound: ALXN1840 (formerly known as ATN-224 and WTX101) or bis-choline 
tetrathiomolybdate (tiomolibdic acid, tiomolibdate choline) 
Short Title: Phase 3, open-label study of ALXN1840 versus standard of care in pediatric 
participants with Wilson disease 
Sponsor Name: Alexion Pharmaceuticals, Inc. 
Legal Registered Address:  
121 Seaport Blvd 
Boston, MA 02210 
USA 
Authors:
Version Date: 21 June 2022 
NCT05047523


Statistical Analysis Plan 
 
Version 1.0  
ALXN1840-WD-302 
 
21 Jun 2022 
Page 2 of 48 
Alexion Confidential 
TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
VERSION HISTORY ......................................................................................................................4 
APPROVAL SIGNATURES...........................................................................................................5 
1. 
INTRODUCTION ........................................................................................................6 
1.1. 
Objectives and Estimand(s) and/or Endpoint(s) ...........................................................6 
1.2. 
Study Design .................................................................................................................8 
1.2.1. 
Study Schematic .........................................................................................................11 
2. 
STATISTICAL HYPOTHESES ................................................................................12 
3. 
SAMPLE SIZE DETERMINATION .........................................................................13 
4. 
ANALYSIS SETS ......................................................................................................14 
5. 
STATISTICAL ANALYSES .....................................................................................15 
5.1. 
General Considerations ...............................................................................................15 
5.2. 
Study Participants .......................................................................................................15 
5.3. 
Primary Analysis ........................................................................................................16 
5.3.1. 
Estimands and/or Endpoint(s) .....................................................................................16 
5.3.2. 
Main Analytical Approach .........................................................................................16 
5.3.3. 
Sensitivity Analysis ....................................................................................................17 
5.3.4. 
Supplementary Analyses ............................................................................................17 
5.4. 
Secondary Analysis ....................................................................................................17 
5.4.1. 
Key Secondary Estimand(s) and/or Endpoint(s) ........................................................17 
5.4.2. 
Other Secondary Analysis ..........................................................................................17 
5.5. 
Tertiary/Exploratory Analysis ....................................................................................20 
5.6. 
Other Safety Analyses ................................................................................................22 
5.6.1. 
Study Duration, Treatment Compliance, and Exposure .............................................22 
5.6.2. 
Adverse Events ...........................................................................................................25 
5.6.2.1. 
AEs by System Organ Class and Preferred Term .......................................................25 
5.6.2.2. 
AEs by System Organ Class .......................................................................................26 
5.6.2.3. 
AEs by Preferred Term ...............................................................................................26 
5.6.2.4. 
AEs by System Organ Class, Preferred Term, and Relationship ...............................26 
5.6.2.5. 
AEs by System Organ Class, Preferred Term, and Severity ......................................26 
5.6.2.6. 
Deaths, Other SAEs, and AESIs .................................................................................26 


Statistical Analysis Plan 
 
Version 1.0  
ALXN1840-WD-302 
 
21 Jun 2022 
Page 3 of 48 
Alexion Confidential 
5.6.2.7. 
Other Significant Adverse Events ..............................................................................27 
5.6.3. 
Additional Safety Assessments...................................................................................27 
5.6.3.1. 
Evaluation of Drug-Induced Serious Hepatotoxicity .................................................28 
5.7. 
Other Analyses ............................................................................................................29 
5.7.1. 
PK and PD Analyses ...................................................................................................29 
5.7.1.1. 
PK/PD Sampling Schedule .........................................................................................29 
5.7.1.2. 
Plasma PK Parameters ................................................................................................29 
5.7.1.3. 
Handling of Missing Data ...........................................................................................30 
5.7.1.4. 
Plasma PK Concentration and PK Parameter Data ....................................................30 
5.7.1.5. 
PD Parameters ............................................................................................................31 
5.7.1.6. 
Urinary and Fecal Cu Excretion .................................................................................31 
5.7.2. 
Subgroup Analyses .....................................................................................................31 
5.8. 
Interim Analyses .........................................................................................................32 
5.8.1. 
DMC or Other Review Board .....................................................................................32 
6. 
SUPPORTING DOCUMENTATION ........................................................................34 
6.1. 
Appendix 1: Technical Specifications for Derived Variables ....................................34 
6.2. 
Appendix 2: Study and Participant Characteristics ....................................................37 
6.3. 
Appendix 3: Instrument Scoring Details ....................................................................41 
6.4. 
Appendix 4: Additional Details on Statistical Methods .............................................42 
6.5. 
Appendix 5: Changes to Protocol-planned Analyses .................................................42 
6.6. 
Appendix 6: List of Abbreviations .............................................................................44 
7. 
REFERENCES ...........................................................................................................46 
 
LIST OF TABLES 
Table 1: 
Simulated Power for Pediatric Extrapolation Study ALXN1840-WD-303 
Primary Analysis ........................................................................................................13 
Table 2: 
Modified Nazer Score .................................................................................................19 
 
 


Statistical Analysis Plan 
 
Version 1.0  
ALXN1840-WD-302 
 
21 Jun 2022 
Page 4 of 48 
Alexion Confidential 
VERSION HISTORY 
 
This Statistical Analysis Plan (SAP) for Study ALXN1840-WD-302 is based on Protocol 
Amendment 3 (Global), dated 08 Mar 2022.  
SAP Version 
Version Date 
Change 
Rationale 
1.0 
21 Jun  2022 
Not applicable 
Original version 
More details are provided in Section 6.5. 
 


Statistical Analysis Plan 
 
Version 1.0  
ALXN1840-WD-302 
 
21 Jun 2022 
Page 5 of 48 
Alexion Confidential 
APPROVAL SIGNATURES 
 
 
 
 
Date dd Mmm yyyy 
 
 
 
Date dd Mmm yyyy 
 
 
 
 
 
 
 
Date dd Mmm yyyy 
 
07-Jul-2022 | 09:58:30 EDT
07-Jul-2022 | 10:05:03 EDT
07-Jul-2022 | 09:53:08 EDT


Statistical Analysis Plan 
 
Version 1.0  
ALXN1840-WD-302 
 
21 Jun 2022 
Page 6 of 48 
Alexion Confidential 
1. 
INTRODUCTION  
This Statistical Analysis Plan (SAP) describes the statistical methods for analyzing data for 
Protocol ALXN1840-WD-302 (“A multicenter, randomized, controlled, open-label, rater-blinded 
study to evaluate efficacy, safety, pharmacokinetics, and pharmacodynamics of ALXN1840 
versus standard of care in pediatric participants with Wilson disease”). Standard data 
presentation instructions, and table, figure, and listing specifications are contained in the Data 
Presentation Plan in a separate document. 
This SAP describes the analytical plan for the randomized Primary Evaluation Period (Period 1). 
A separate SAP will be generated for the nonrandomized, exploratory, open-label Extension 
Period (Period 2). 
1.1. 
Objectives and Estimand(s) and/or Endpoint(s) 
Objectives 
Period 1: Up to Week 48 
Estimand(s) and/or Endpoint(s) 
Primary 
• 
To evaluate the efficacy of ALXN1840 
administered for 48 weeks, compared to standard 
of care (SoC), on Cu control in participants with 
Wilson disease (WD) aged 3 to < 18 years of age 
at the time of enrollment 
• 
Treatment: ALXN1840 and SoC 
• 
Population: pediatric participants with WD who 
meet all inclusion and no exclusion criteria 
• 
Variable: Percent change from baseline (Day 1) to 
48 weeks in non-ceruloplasmin-bound Cu (NCC) in 
plasma. For ALXN1840-treated participants, the 
NCC in plasma will be corrected for the amount of 
Cu bound to the ALXN1840 tripartite 
(tetrathiomolybdate-Cu-albumin) complex 
(NCCcorrected). 
• 
Intercurrent event: For participants who die or 
discontinue early for any reason, a 
while-on-treatment strategy will be applied 
reflecting that missing data will not be imputed. For 
participants who use another medication that affects 
plasma-calculated NCC (cNCC)/cNCC corrected for 
Cu bound in tripartite (tetrathiomolybdate-Cu-
albumin) complexes (cNCCcorrected), the treatment 
policy strategy will be applied. 
• 
Summary measure: Comparison of the percent 
change from baseline (Day 1) to 48 weeks in 
cNCC/cNCCcorrected in plasma between treatment 
groups 
Secondary 
• 
Evaluate the safety and tolerability of 
ALXN1840 administered for up to 48 weeks 
• 
Incidence of adverse events (AEs)/serious adverse 
events (SAEs), adverse events of special interest 
(AESIs), tolerability, clinical laboratory test data 
(including liver function tests), neurological and 
physical examination findings, 12-lead 
electrocardiogram (ECG) data, and vital signs. 
• 
Evaluate pharmacodynamics (PD) and 
biomarkers of ALXN1840 vs SoC administered 
for 48 weeks 
• 
Area under the effect-versus-time curve (AUEC) for 
directly measured NCC (dNCC) 
• 
AUEC for plasma total Cu 


Statistical Analysis Plan 
 
Version 1.0  
ALXN1840-WD-302 
 
21 Jun 2022 
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Alexion Confidential 
Objectives 
Period 1: Up to Week 48 
Estimand(s) and/or Endpoint(s) 
• 
Biomarkers: observed, absolute, and percent 
changes of ceruloplasmin-bound Cu (CpC) and 
ceruloplasmin 
• 
Evaluate the effects of ALXN1840 and SoC on 
the NCC responder rate 
• 
cNCC/cNCCcorrected responder rate 
• 
Evaluate the effects of ALXN1840 and SoC on 
participant-reported disability status 
• 
Change from baseline to Week 48 in the Unified 
Wilson Disease Rating Scale (UWDRS) Part II total 
score 
• 
Evaluate the effects of ALXN1840 and SoC on 
rater-blinded neurological status 
• 
Change from baseline in UWDRS Part III total 
score or individual items/subscales, as appropriate 
• 
Evaluate pharmacokinetics (PK) of ALXN1840 
administered for 48 weeks 
Estimation of PK parameters and accumulation ratios: 
• 
PK: maximum observed concentration (Cmax), 
time to Cmax (tmax), trough (predose) 
concentration observed at the start of the dosing 
interval (Ctrough), and area under the plasma 
concentration-versus-time curve from time 0 to 
the end of the dosing interval (AUCtau) on 
Day 1, Day 43 (Week 6), and Day 337 
(Week 48) for plasma total Mo and plasma 
ultrafiltrate (PUF) Mo concentrations, 
accumulation ratio of Day 43 to Day 1 and 
Day 337 to Day 1 based on Cmax, Ctrough, and 
AUCtau 
• 
Derived secondary PK parameters such as 
apparent total body clearance (CL/F) and 
apparent volume of distribution (Vd/F; as 
appropriate)  
• 
Evaluate the effects of ALXN1840 and SoC on 
global clinical symptoms as assessed by the 
Investigator 
• 
Clinical Global Impression-Improvement Scale 
(CGI-I) 
• 
Change from Baseline to Week 48 in Clinical Global 
Impression-Severity scale (CGI-S) 
• 
Evaluate the effects of ALXN1840 and SoC on 
hepatic status 
• 
Change from Baseline to Week 48 in Model for 
End-Stage Liver Disease (MELD) score (ages 
12 years and older) or Pediatric End-Stage Liver 
Disease (PELD) score (ages 3 to < 12 years) 
• 
Change from Baseline to Week 48 in modified Nazer 
score 
Exploratory 
• 
Evaluate the effects of ALXN1840 and SoC on 
hepatic fibrosis 
• 
Change from Baseline to Week 48 in the Fibrosis-4 
(FIB-4) Index and by transient elastography 
• 
Evaluate the effects of ALXN1840 and SoC on 
psychiatric symptoms 
• 
Change from Baseline to Week 48 in Brief 
Psychiatric Rating Scale-24 (BPRS-24) and Brief 
Psychiatric Rating Scale for Children (BPRS-C9) 
• 
Evaluate the effects of ALXN1840 and SoC on 
quality of life (QoL)/patient-reported outcomes 
• 
Change from Baseline to Week 48 in 
QoL/patient-reported outcome endpoint measures: 
− EuroQoL 5 Dimensions (EQ-5D) or EuroQoL 
5 Dimensions-Youth (EQ-5D-Y) 
− Pediatric Quality of Life Inventory (PedsQL™) 
NOTE: These tests will be administered by parent/proxy 
for participants unable to complete them independently. 


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Objectives 
Period 1: Up to Week 48 
Estimand(s) and/or Endpoint(s) 
• 
Evaluate participant satisfaction of treatment 
with ALXN1840 and SoC 
• 
Change from Baseline to Week 48 in Treatment 
Satisfaction Questionnaire for Medication-9 
(TSQM-9) 
NOTE: This questionnaire will be administered by 
parent/proxy for participants unable to complete them 
independently. 
• 
Evaluate the effects of ALXN1840 and SoC on 
24-hour fecal Cu and fecal Mo 
• 
Change from Baseline to Week 6 in 24-hour fecal Cu 
and fecal Mo 
• 
Evaluate the effects of ALXN1840 and SoC on 
24-hour urinary Cu and urinary Mo 
• 
Change from Baseline to Week 48 in 24-hour urinary 
Cu and urinary Mo   
• 
Explore other directly measured PD and 
biomarkers of ALXN1840 
• 
Daily mean AUEC of dNCC and plasma total Cu 
from 0 to 24 weeks and from 24 to 48 weeks 
• 
Observed, absolute and percent changes of Cu levels 
(total Cu, PUF Cu, labile-bound Cu [LBC]) 
• 
Explore ALXN1840 effect on initial 
decoppering phase compared to SoC based on 
directly measured PK/PD and biomarkers 
• 
Time to first confirmed increase in plasma dNCC 
and total Cu concentration 
• 
Time to minimum and maximum concentration of: 
− Plasma total Cu 
− Plasma dNCC 
− Plasma LBC 
− Ratio plasma dNCC:total Cu 
− Ratio plasma LBC:total Cu 
− Plasma ceruloplasmin 
− Plasma CpC 
− Ratio plasma ceruloplasmin:total Cu 
− Plasma CpC:total Cu 
− 24-hour urinary Mo 
− Ratio urinary Mo:Cu 
− Ratio 24-hour urinary Mo:dosed Mo  
• 
Explore ALXN1840 effect on subsequent 
maintenance phase compared to SoC based on 
directly measured PK/PD and biomarkers 
• 
Time for return to predose baseline for the following 
PK/PD parameters: 
− Plasma total Cu 
− Plasma dNCC 
− Plasma LBC 
− Ratio plasma dNCC:total Cu 
− Ratio plasma LBC:total Cu 
− Plasma ceruloplasmin concentration 
− Plasma CpC concentration 
− Ratio plasma ceruloplasmin:total Cu 
− Ratio plasma CpC:total Cu 
− 24-hour urinary Mo 
− Ratio urinary Mo:Cu 
− Ratio urinary Mo:dosed Mo 
1.2. 
Study Design  
This is a multicenter, randomized, controlled, open-label, rater-blinded study designed to assess 
the efficacy, safety, PK, and PD of ALXN1840 versus SoC in pediatric participants aged 3 to 
< 18 years with a confirmed diagnosis of WD, who meet prespecified laboratory parameters and 


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do not have decompensated cirrhosis. PK measured by plasma total Mo and PUF Mo, and PD 
measured by plasma total Cu and LBC will be determined for all participants. 
The study includes 2 periods: the 48-week Period 1 serves to evaluate the effect of ALXN1840 
versus SoC on efficacy, safety, PK, and PD. Participants who complete the 48-week Period 1 
will be offered the opportunity to participate in a 24-week, open-label Period 2, ie, up to 
72 weeks in total, to evaluate the safety and efficacy of ALXN1840. 
Approximately 48 participants will be randomized 1:1 to either ALXN1840 or SoC treatment 
with the goal of obtaining 40 evaluable participants at Week 48. Participants in the Primary 
Evaluation Period will be stratified by age group (3 to < 12 years, 12 to < 18 years) and into 1 of 
the following 2 cohorts: 
• Cohort 1: Participants who have received SoC therapy (ie, chelation therapy with 
penicillamine or trientine, treatment with zinc, or a combination of both chelation and 
zinc therapy) for > 28 days prior to enrollment in the study 
• Cohort 2: Participants who are treatment naïve or who have received SoC therapy for 
≤ 28 days prior to enrollment in the study 
The primary enrollment and randomization objective is to have at least 12 participants in each 
age group and to achieve balanced treatment assignments both overall and within each age 
group. A secondary goal is to have at least 3 participants assigned to each treatment within each 
cohort of each age group. 
To achieve this goal, participants will be randomized to treatment within one of the following 
4 age groups/cohort strata: 
• Stratum 1: 3 to < 12 years old at randomization and Cohort 1 (prior SoC treatment 
> 28 days) (a minimum of 6 participants) 
• Stratum 2: 3 to < 12 years old at randomization and Cohort 2 (prior SoC treatment 
≤ 28 days) (a minimum of 6 participants) 
• Stratum 3: 12 to < 18 years old at randomization and Cohort 1 (prior SoC treatment 
> 28 days) (a minimum of 6 participants) 
• Stratum 4: 12 to < 18 years old at randomization and Cohort 2 (prior SoC treatment 
≤ 28 days) (a minimum of 6 participants) 
Throughout Period 1, participants randomized to receive ALXN1840 will be administered 
ALXN1840 orally daily at the following doses: 
• For participants aged 12 to < 18 years: ALXN1840 will be administered at a starting 
dose of 15 mg/day. Dose escalation is not permitted. Individualized doses ranging 
from 15 mg/day every other day to 15 mg/day are allowed. Doses < 15 mg every 
other day may be considered, with approval of the Alexion Medical Monitor. 
• For participants aged 3 to < 12 years, a lower starting dose of 2.5 mg/day will be 
administered for at least 4 weeks based on scaling of the starting dose of 15 mg/day in 
the ongoing Study WTX101-301. Dose escalation is permitted but not required. The 
dose may be increased in increments of 2.5 mg daily with the permission of the 
Alexion Medical Monitor, depending on the participant’s clinical status, 


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cNCC/cNCCcorrected concentrations, and safety laboratory results. Dose increases must 
occur at least 4 weeks apart and may only occur if no dose modification (reduction or 
interruption) criteria apply. Participants who require doses of 15 mg daily may use the 
15-mg adult tablet. The maximum dose for children aged < 12 years is 15 mg/day.  
Individualized ALXN1840 dosing will be utilized throughout the study based on the following 
parameters: 
• Clinical criteria: dose-titration based on hepatic and neurological status 
• cNCC/cNCCcorrected: dose-titration based on cNCC/cNCCcorrected concentrations. The 
reference range for cNCC is 0.8 to 2.3 µM. 
• Safety monitoring: Dose modification criteria are based on regularly scheduled 
assessments for recognized hematological effects of copper lowering, hepatic testing, 
and neurological tests 
Participants randomized to receive SoC treatment will continue their current therapy or initiate 
SoC (ie, chelation therapy with penicillamine or trientine, zinc therapy, or a combination of both 
chelation and zinc therapy if they are not currently on SoC at the start of the study). 
The primary analysis will be performed after 48 weeks, and the final analysis after completion of 
Period 2. Interim analyses of data may be performed to support regulatory submissions. The 
interim analyses will be descriptive only and will be performed to assess safety data only; they 
will not include formal hypothesis testing and will not be used to adapt the study. The efficacy 
data available at the time of primary analysis will also be used in an efficacy extrapolation to 
develop evidence for ALXN1840 efficacy on Cu control for pediatric participants (ages 3 to 
< 18 years) with WD using adult/adolescent participant data from Studies WTX101-301 and 
ALXN1840-WD-302. Full details of the extrapolation exercise will be provided in the Study 
ALXN1840-WD-303 SAP. 
An independent Data Monitoring Committee (DMC), comprising experts in relevant fields with 
no direct relationship to the study, will be appointed by Alexion. The specific responsibilities of 
the DMC will be described in the DMC Charter. 
 
 
 
 
 
 
 
 
 
 
 


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1.2.1. 
Study Schematic 
 
 
Randomization
Day 1
Week 48
Screening
Period 1
48 weeks
EOS
ALXN1840
Standard of Care
ALXN1840
Primary Analysis
After 48 weeks
N = 24
N = 24
N = 48
Period 2
24 weeks
Days -28 to -1


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2. 
STATISTICAL HYPOTHESES  
This study is not statistically powered to be a standalone hypothesis testing study with respect to 
efficacy. Efficacy data from this study will subsequently be combined with those of the ongoing 
Phase 3 Study WTX101-301, which includes participants ≥ 12 years of age, using Bayesian 
extrapolation methods to assess the efficacy of ALXN1840 and SoC in pediatric participants 
with WD. 
Accordingly, the evaluations of PK, PD, safety, and efficacy of ALXN1840 and SoC in the 
Primary Evaluation Period will be summarized descriptively using frequentist statistical 
methods. A separate analysis and report will present the results of the Bayesian extrapolations, 
which will use adult/adolescent participants in Study WTX101-301 and pediatric participants in 
Study ALXN1840-WD-302 to perform statistical testing of the efficacy of ALXN1840 compared 
with SoC in pediatric participants. 


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3. 
SAMPLE SIZE DETERMINATION  
This study will enroll 48 pediatric participants (1:1 ratio to ALXN1840 or SoC) with the goal of 
obtaining 40 evaluable participants at Week 48.  
The proposed sample size for this study was assessed for its adequacy for the extrapolation Study 
ALXN1840WD-303 via simulation using the proposed Bayesian hierarchical model. To explore 
the performance of the design, 3 distinct states of efficacy were considered in each of the 
populations with respect to the mean 48-week percent change from baseline in 
cNCC/cNCCcorrected: 
1. ALXN1840 is superior to SoC by 15%. 
2. ALXN1840 is equivalent to SoC. 
3. ALXN1840 is inferior to SoC by 15%.  
Given the 2 populations (adult population: adults in Study WTX101-301, and pediatric 
population: pediatrics in Study ALXN1840-WD-302 plus adolescents from Study 
WTX101-301), there are 9 possible combinations representing potential underlying scenarios. 
For each of these scenarios, 5000 studies were simulated and the proportion of studies that claim 
noninferiority in the pediatric participant population was estimated. Statistical power is captured 
in scenarios in which ALXN1840 is either superior or equivalent to SoC in the pediatric 
participant population. Type I error is captured in scenarios in which ALXN1840 is inferior to 
SoC in the pediatric participant population. Table 1 shows the simulation results assuming an SD 
of 30% (absolute) on the 48-week change in cNCC/cNCCcorrected. 
The proposed primary analysis for the pediatric extrapolation Study ALXN1840-WD-303 has 
70% to 99% power for scenarios in which ALXN1840 is either equivalent or superior to SoC in 
both populations and has Type I error < 13% when ALXN1840 is inferior to SoC in the pediatric 
population. These calculations assume 165 adult participants and 15 adolescents from Study 
WTX101-301 (2:1 ratio to ALXN1840 or SoC) have evaluable 48-week data, and 40 evaluable 
pediatric participants (1:1 ratio to ALXN1840 or SoC) have evaluable 48-week data from Study 
ALXN1840-WD-302. The data simulations were done using FACTS v6.3. 
To accommodate a 15% dropout rate, a total of 48 pediatric participants will be enrolled. 
Table 1: 
Simulated Power for Pediatric Extrapolation Study ALXN1840-WD-303 
Primary Analysis 
Adult Population 
Pediatric Population 
Superior 
Equivalent  
Inferior 
Superior 
99.2% 
69.9% 
9.8% 
Equivalent 
99.0% 
73.6% 
12.7% 
Inferior 
83.1% 
23.8% 
1.0% 
 


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4. 
ANALYSIS SETS 
The population sets used as analysis sets are defined in the following: 
Population 
Description 
Screened 
All participants who sign the informed consent form 
Enrolled 
All participants who agree to participate in the study following completion 
of the informed consent process and who satisfy the inclusion/exclusion 
criteria and are randomized. 
Safety Analysis Set 
All participants who receive at least 1 dose of ALXN1840 or SoC 
treatment. Participants will be analyzed according to the study intervention 
they actually received. 
Full Analysis Set (FAS) 
All participants who receive at least 1 dose of ALXN1840 or SoC 
treatment. Participants will be analyzed as randomized. 
Per Protocol Analysis Set (PPS) 
All participants who receive at least 1 dose of ALXN1840 or SoC 
treatment and have both baseline and Week 48 cNCC/cNCCcorrected 
concentrations. Participants with major protocol deviations that are likely 
to impact the primary endpoint analysis will be excluded from the PP 
Analysis Set. Major protocol deviations and the PP Analysis Set will be 
defined, documented, and agreed within Alexion prior to database lock. 
Extension Analysis Set 
This dataset includes all participants who enter Period 2 and receive at 
least 1 dose of ALXN1840 in Period 2. 
PK/PD Analysis Set 
All participants who have sufficient plasma samples to enable the 
calculation of PK parameters and provide PK/PD profiles 
 


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5. 
STATISTICAL ANALYSES 
5.1. 
General Considerations  
The evaluations of PK, PD, safety, and efficacy of ALXN1840 and SoC in the Primary 
Evaluation Period of this study will be summarized descriptively using summary statistics. A 
separate SAP will be generated for the nonrandomized, exploratory, open-label Extension 
Period. 
A separate analysis and report will present the results of the Bayesian extrapolations and 
statistical testing of the efficacy of ALXN1840 compared with SoC in pediatrics (Study 
ALXN1840-WD-303).  
Missing data will not be imputed.  
Summary statistics will be computed and displayed by treatment group, cohort, age group, and 
visit, where applicable and if sample size allows. Descriptive statistics for continuous variables 
will minimally include the number of participants, mean, SD, minimum, median, and maximum. 
For categorical variables, frequencies and percentages will be presented. Graphical displays will 
be provided as appropriate. 
Analyses will be performed using the SAS® software Version 9.4 or higher. 
All prior and concomitant medications will be coded using the World Health Organization 
(WHO) Drug Dictionary version from September 2021 or later. AE severity will be evaluated 
using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) 
version 5.0 (published 27 Nov 2017) (NCI, 2017). System Organ Class and Preferred Term for 
medical history will be coded using the most up-to-date version of the Medical Dictionary for 
Regulatory Activities (MedDRA), version 24.1 or higher. 
Summaries of study and participant characteristics (eg, demographics and baseline 
characteristics, medical history, and protocol deviations) are described in Section 6.2. 
5.2. 
Study Participants  
The number and percentage of all participants enrolled, randomized, and included in the FAS 
and PP, Safety, PK, and PD analysis sets will be summarized. The reasons for exclusion from the 
analysis sets will also be provided. Frequency counts and percentages of participants excluded 
prior to randomization will be provided for participants who failed to meet study entry 
requirements during Screening at the start of the study.  
The number and percentage of participants who completed or prematurely discontinued from the 
study will be described by randomized treatment group within each cohort, for rollover 
participants, and overall. For participants who discontinued the study, the number and percentage 
will be summarized by their reason for premature discontinuation and withdrawal of consent. A 
summary of participants will be provided by region, country, and site. Additionally, a summary 
of participants who did not meet inclusion or who met exclusion criteria will be provided.  
Descriptive statistics of the number of days in the study will be summarized. The date of the first 
and last use of study medications in each period and the study termination date will be listed. 
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be presented in a listing. All enrolled participants will be listed, indicating their analysis set 
along with the reason for exclusion. A listing of screen failure participants will also be provided. 
Additionally, a listing of the inclusion/exclusion criteria and a listing of participants and the 
inclusion criteria they failed to meet and the exclusion criteria they met will be provided. 
5.3. 
Primary Analysis 
The primary analysis will be based on the FAS. The primary endpoint will also be assessed on 
the PP Analysis Set.  
5.3.1. 
Estimands and/or Endpoint(s)  
The primary estimand is the percent change from baseline (Day 1) to 48 weeks in 
cNCC/cNCCcorrected in plasma between ALXN1840 and SoC in pediatric participants with WD, 
regardless of less-than-complete adherence or use of another medication that affects plasma 
cNCC with no imputation for missing data after discontinuation or death. 
cNCC will be calculated as follows (EASL, 2012; Roberts, 2008): 
cNCC[μmol/L]= Plasma total Cu [μg/L] −3.15 ∗ceruloplasmin[mg/L]
63.5 [μg/μmol]
 
For ALXN1840-treated participants, the cNCC in plasma will be corrected for the amount of Cu 
bound to the ALXN1840 tripartite (tetrathiomolybdate-Cu-albumin) complex (ie, cNCCcorrected) 
using the square root-based cNCC correction method as determined based on data from Study 
WTX101-201 as follows (Plitz, 2017):  
cNCCcorrected=(√cNCC −0.993√Mo)2 
In the calculation of cNCC and cNCCcorrected, the following rules apply: 
• For plasma total Cu concentration values < lower limit of quantification (LLOQ), 
cNCC will be considered missing. 
• Serum ceruloplasmin concentration values < LLOQ are set to 0. 
• Plasma total Mo concentration values < LLOQ are set to 0. 
• In cases where cNCC calculation produces a negative result, cNCC will be 
considered missing and cNCCcorrected will not be derived. 
• cNCCcorrected will be set to 0 when 0.993√Mo > √cNCC. 
5.3.2. 
Main Analytical Approach 
The primary endpoint, the percent change from Baseline (Day 1) to 48 weeks in 
cNCC/cNCCcorrected concentrations, will be analyzed by treatment group within each cohort and 
overall using descriptive summary statistics.  
Missing data will not be imputed. 
Subgroup analysis may be performed (eg, age group, sex, cohort, and randomization 
stratification) if sample sizes permit. 


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5.3.3. 
Sensitivity Analysis 
No sensitivity analyses are planned. 
5.3.4. 
Supplementary Analyses 
No supplementary analyses are planned. 
5.4. 
Secondary Analysis 
Analyses of secondary efficacy endpoints will be based on the FAS. 
5.4.1. 
Key Secondary Estimand(s) and/or Endpoint(s) 
Not applicable. 
 
5.4.2. 
Other Secondary Analysis 
All secondary efficacy endpoints will be summarized by treatment group within each cohort and 
overall using descriptive statistics. 
Subgroup analysis may be performed (eg, age group) if sample sizes permit. 
cNCC responder 
A cNCC/cNCCcorrected responder is defined as a participant who achieved or maintained 
normalized cNCC/cNCCcorrected concentration (0.8 to 2.3 µM) (Brewer, 2009) within (at or 
before) 48 weeks or reached a reduction of at least 25% in cNCC/cNCCcorrected within 48 weeks. 
Thus, a participant will be considered a cNCC/cNCCcorrected responder if they meet at least one of 
the following criteria: 
• Achieved normalized cNCC/cNCCcorrected concentration for 2 consecutive 
measurements within 48 weeks for participants who had elevated concentration at 
baseline 
• Maintained normalized cNCC/cNCCcorrected concentration within 48 weeks for 
participants who had normal concentration at baseline 
• Reached a reduction of at least 25% in cNCC/cNCCcorrected for 2 consecutive 
measurements within 48 weeks 
A nonresponder will be defined as a participant who did not meet the responder criteria. 
UWDRS (Part I, II, and III) 
The UWDRS is a clinical rating scale designed to evaluate the neurological manifestations of 
WD that generally can be divided into 3 movement disorder syndromes: dystonic, ataxic, and 
Parkinsonian syndrome. The UWDRS comprises 3 parts: UWDRS Part I (level of consciousness, 
item 1), UWDRS Part II (a participant-reported review of daily activity items [disability], items 2 
to 11), and UWDRS Part III (a detailed neurological examination, items 12 to 34). 


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The UWDRS Part I and Part III will be assessed by a neurologist who is blinded, while UWDRS 
Part II may be reported to a nonblinded member of the study team by the participant, family 
member, or caregiver (Czlonkowska, 2007; Leinweber, 2008). The UWDRS has not been 
formally evaluated in children. However, the components of Part I (level of consciousness), 
Part II (participant or caregiver-reported disability), and Part III (neurologic examination 
findings) are not fundamentally different between adults and children. Participants aged 12 years 
and older are expected to be able to comply with UWDRS assessments without modification 
(Rohay, 2020). The UWDRS assessments should be conducted to the greatest extent feasible in 
children < 12 years. 
CGI-S and CGI-I 
The Clinical Global Impression (CGI) rating scales are commonly used measures of symptom 
severity, treatment response, and the efficacy of treatments in treatment studies of adult and 
pediatric participants with mental disorders. Although originally developed for participants with 
mental disorders (Guy, 1976), the CGI rating scales have been adapted to use generalized 
language (Busner, 2007), which supports their application to any clinically assessed disease 
setting. 
Clinical Global Impression-Severity Scale 
The CGI-S is a 7-point scale that requires the clinician to rate the severity of the participant’s 
illness at the time of assessment, relative to the clinician’s past experience with participants who 
have the same diagnosis. Considering total clinical experience, a participant is assessed on the 
severity of illness at the time of rating as follows: 1, normal, not at all ill; 2, borderline ill; 
3, mildly ill; 4, moderately ill; 5, markedly ill; 6, severely ill; or 7, extremely ill.  
Clinical Global Impression-Improvement Scale 
The CGI-I is a 7-point scale that requires the clinician to assess how much the participant’s 
illness has improved or worsened relative to a baseline state at the beginning of the intervention 
and rated as follows: 1, very much improved; 2, much improved; 3, minimally improved; 4, no 
change; 5, minimally worse; 6, much worse; or 7, very much worse. Transformed CGI-I is 
derived as CGI-4, and it ranges between -3 (very much improved) and 3 (very much worse) with 
0 indicating no change. 
MELD and PELD Scores 
The MELD is a scoring system for assessing the severity of chronic liver disease in adults and 
adolescents aged 12 years and above. The MELD score (range 6 to 40, with higher values 
indicating more advanced disease) uses the participant’s values for serum bilirubin, serum 
creatinine, and the international normalized ratio (INR) for prothrombin time to predict survival. 
The initial MELD score, MELD(i), is calculated according to the following formula: 
MELD(i) = 3.78 × ln (serum bilirubin [mg/dL]) + 11.2 × ln(INR) + 9.57 × ln [serum creatinine 
(mg/dL)] + 6.43 
Creatinine, bilirubin, and INR values less than 1.0 are set to 1.0 and creatinine values greater 
than 4.0 are set to 4.0 when calculating MELD(i). Additionally, creatinine, bilirubin, and INR are 


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rounded to the 10th decimal place prior to performing the calculation. The initial MELD score is 
then rounded to the nearest integer. The maximum MELD score is 40. 
In participants with a MELD(i) score > 11, the serum sodium is also taken into account (UNOS, 
2015), and MELD is recalculated as follows: 
MELD = MELD(i) + 1.32×(137-sodium[mmol/L]) - 0.033 × MELD(i) × (137-sodium[mmol/L]) 
Sodium values less than 125 mmol/L will be set to 125 and values greater than 137 mmol/L will 
be set to 137. 
The PELD score is used to estimate 90-day survival in the absence of liver transplantation 
(McDiarmid, 2002; Chang, 2018). The components of the PELD score are total bilirubin, INR, 
albumin, age, and growth failure. The PELD cutoff of > 13 was chosen to exclude participants 
with advanced liver failure, comparable to a MELD score > 13 or a modified Nazer score > 7 
(Dhawan, 2005). 
The PELD score is based on the following formula and will be calculated by a central laboratory:  
PELD = 4.80 × ln (bilirubin[mg/dL]) + 18.57 × ln (INR) - 6.87 × ln (albumin[g/dL]) + 4.36 (if 
participant under 12 months) + 6.67 (if history of growth failure positive) 
The bilirubin, albumin and INR values less than 1.0 are set to 1.0. 
The MELD and PELD scores will be calculated by a Central Laboratory. 
Modified Nazer Score 
The modified Nazer score is an assessment of liver status and consists of a composite of 
5 laboratory parameters: aspartate aminotransferase (AST), INR, bilirubin, albumin, and white 
blood cell count. The score has a total range of 0 to 20, and lower values indicate a healthier liver 
status (Dhawan, 2005). If any of the 5 parameters required to compute the modified Nazer score 
are unavailable at any given visit, the modified Nazer score will not be derived for that visit. The 
score for an individual analyte (bilirubin, AST, INR, leukocytes, and albumin) should be derived 
from Table 2, and all 5 scores will be added to obtain the final score. 
The modified Nazer score will be calculated by a Central Laboratory. 
Table 2: 
Modified Nazer Score 
Score 
Billirubin 
(μmol/L) 
AST (IU/L) 
INR 
Leukocytes 
(109/L) 
Albumin 
(g/L) 
0 
0-100 
0-100 
0-1.29 
0-6.7 
> 44 
1 
101-150 
101-150 
1.3-1.6 
6.8-8.3 
34-44 
2 
151-200 
151-300 
1.7-1.9 
8.4-10.3 
25-33 
3 
201-300 
301-400 
2.0-2.4 
10.4-15.3 
21-24 
4 
> 300 
> 400 
> 2.4 
> 15.3 
< 21 
Abbreviations: AST = aspartate aminotransferase; INR = international normalized ratio 
 


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5.5. 
Tertiary/Exploratory Analysis  
All exploratory endpoints will be summarized by treatment group within each cohort and overall 
using descriptive statistics using the FAS. 
FIB-4 Index and Transient Elastography 
The FIB-4 Index (Vallet-Pichard, 2007) is a formula used to predict liver fibrosis based on 
standard biochemical values (alanine aminotransferase [ALT], AST, and platelet count) and age. 
The FIB-4 Index will be calculated by a central laboratory. The formula is as follows: 
Age (years) × AST (U/L)/[Platelets (109/L × sqrt (ALT (U/L))] 
Transient elastography is a noninvasive imaging method that evaluates the degree of liver 
fibrosis or fatty deposits in the liver by determining the speed of sound waves through the liver 
using a sonogram. If any of the parameters required to compute the FIB-4 Index are unavailable 
at any given visit, the FIB-4 Index will be set to missing for that visit. 
Brief Psychiatric Rating Scale-24 
The BPRS-24 (Ventura, 1993) is a 24-item instrument for adolescents aged 12 to < 18 years that 
allows the rater to measure psychopathology severity. The presence and severity of psychiatric 
symptoms are rated on a Likert scale ranging from 1 (not present) to 7 (extremely severe). The 
BPRS-24 can be performed by a qualified person (eg, neurologist, psychiatrist, psychologist, 
licensed mental health practitioner, and social worker) who has completed the training required 
to administer the instrument.  
The BPRS-24 will be obtained at Day 1, Week 12, Week 24, Week 36, and Week 48/Early 
Termination. The total score across the 24 items will be used as the endpoint for analysis. A 
minimum of 20/24 items are required to be completed at any given visit; the total score will then 
be taken for the nonmissing items and scaled up to the 24-item score for the purpose of data 
summary and analysis. If fewer than 20/24 items are completed at any given visit, the BPRS-24 
total score will be set to missing for that visit. 
Brief Psychiatric Rating Scale for Children 
The BPRS-C9 is a 9-item instrument for children aged 3 to < 12 years.  
The BPRS-C9 will be obtained at Day 1, Week 12, Week 24, Week 36, and Week 48/Early 
Termination. The presence and severity of symptoms are rated on a scale ranging from 1 (not 
present) to 6 (extremely severe). As with the BPRS-24, the BPRS-C9 can be performed by a 
qualified person who has been appropriately trained. A minimum of 7/9 items are required to be 
completed at any given visit.  
EuroQoL-5 Dimensions 
The EQ-5D (EuroQol Group, 2015) consists of 2 different assessments: the EQ-5D-5-Level 
Descriptive System and the EuroQoL visual analog scale (EQ VAS). The descriptive system 
comprises measures of health-related QoL state and consists of 5 dimensions: mobility, self-care, 
usual activities, pain/discomfort, and anxiety/depression. Each dimension has 5 levels of 
severity: no problems, slight problems, moderate problems, severe problems, or extreme 
problems. The EQ VAS records the participant’s self-rated health on a vertical EQ VAS. 


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Together, this can be used as a quantitative measure of health outcome that reflects the 
participant’s own judgement. 
Note that, although the EQ-5D is designed for use in participants aged 16 years and older, the 
EQ-5D can also be used in participants aged 12 to 15 years and is appropriate given these 
participants will be followed for several years in the study (Van Reenen, 2014). 
EuroQoL 5 Dimensions-Youth 
The EQ-5D-Y (Wille N, 2010). was introduced as a more comprehensible instrument suitable for 
children and adolescents. The wording was changed to be more suitable for children and 
adolescents, the most severe label for the mobility dimension was changed from “confined to 
bed” to “a lot of problems walking about” to increase the applicability and sensitivity of the 
mobility dimension. and the instructions for the EQ VAS task were simplified, making the task 
easier to complete and to score. 
Pediatric Quality of Life Inventory 
The PedsQL™ Measurement Model is a modular approach to measuring health-related QoL in 
healthy children and adolescents and those with acute and chronic health conditions.  
The 23-item PedsQL™ Generic Core Scales were designed to measure the core dimensions of 
health as delineated by the WHO, as well as role (school) functioning. The 4 Multidimensional 
Scales and 3 Summary Scores are as follows: 
Scales: 
• Physical Functioning (8 items) 
• Emotional Functioning (5 items) 
• Social Functioning (5 items) 
• School Functioning (5 items) 
Summary Scores: 
• Total Scale Score (23 items) 
• Physical Health Summary Score (8 items) 
• Psychosocial Health Summary Score (15 items) 
Treatment Satisfaction Questionnaire for Medication 
The TSQM-9 is used to assess the overall level of satisfaction or dissatisfaction with medication 
participants are taking (Atkinson, 2004; Atkinson, 2005; Bharmal, 2009). This composite scale 
comprises 3 items on the TSQM-9 survey: 
• Overall, how confident are you that taking this medication is a good thing for you? 
• How satisfied are you that good things about this medication outweigh the bad 
things? 


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• Taking all things into account, how satisfied or dissatisfied are you with this 
medication? 
The TSQM-9 is expected to be completed by adolescent participants and by the parent or 
caregiver for younger participants. 
Urinary and Fecal Cu Excretion 
24-hour urinary Cu excretion will be assessed at Baseline, Week 6, Week 24, and Week 48 in all 
participants.  
24-hour fecal Cu excretion will be assessed at Baseline and Week 6 in all participants. This 
assessment is optional. 
The purpose of these assessments is to assess the change from Baseline in urinary and fecal Cu 
excretion in participants with WD who are treated with ALXN1840 or SoC. 
Urinary and Fecal Mo  
24-hour urinary Mo will be assessed at Baseline, Week 6, Week 24, and Week 48 in all 
participants.  
24-hour fecal Mo will be assessed at Baseline and Week 6 in all participants. This assessment is 
optional. 
The purpose of these assessments is to assess the change from Baseline in urinary and fecal Mo 
in participants with WD who are treated with ALXN1840 or SoC. 
5.6. 
Other Safety Analyses 
All safety analyses will be performed on the Safety Analysis Set. 
Safety analyses will include all AEs, ECGs, clinical laboratory data, physical examinations, and 
vital sign measurements using descriptive statistics. No inferential statistical analyses are 
planned for the safety parameters of this study. 
5.6.1. 
Study Duration, Treatment Compliance, and Exposure 
Study duration will be summarized for all enrolled participants by treatment within each cohort. 
Treatment compliance and exposure will be summarized for the Safety Analysis Set by treatment 
within each cohort. Supportive listings will also be provided. 
Study Duration 
Study duration is defined as the time from informed consent to the end of the Primary Evaluation 
Period (ie, Week 48) or study discontinuation date, whichever occurs first. 
Treatment Compliance 
The treatment compliance is defined as: 
Compliance (%) = (number of dose received)/(total number of dose scheduled) × 100. 
Furthermore, the compliance will be summarized in the following ways: 
• Compliance (%) 


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• Compliance (< 80%, ≥ 80%) 
Treatment compliance will be summarized using descriptive statistics by visit, by randomized 
treatment within cohort and overall. Compliance up to Week 48 (Primary Evaluation Period) will 
be summarized for all participants. If a participant prematurely discontinues during the Primary 
Evaluation Period, his or her compliance will be based on the period up to the point of 
discontinuation from the study. Additionally, drug interruptions or missed doses as the result of a 
physician decision or AE will be factored into the number of doses scheduled, whereas drug 
interruptions or missed doses for any reason will be factored into calculating the number of doses 
received. A supporting listing will also be produced. 
Exposure 
The number of participants exposed to the study intervention will be summarized in terms of 
counts for the overall duration of the study, and by periods specified in the International Council 
for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use E3 guideline. 
The number of participants will also be summarized by the following mean daily dose groups: 
1. ≤ 2.5 mg  
2. > 2.5 mg to ≤ 5 mg 
3. > 5 mg to ≤ 7.5 mg 
4. > 7.5 mg to ≤ 10 mg  
5. > 10 mg to ≤ 12.5 mg  
6. > 12.5 mg to ≤ 15 mg  
This summary will be for the overall duration and in each specified time period, as follows: 
• 1 day or less 
• 2 days to 1 week 
• 1 week to 1 month 
• 1 month to 6 months 
• 6 months to 1 year 
• > 1 year 
The duration (days) of exposure to treatment will be calculated as follows: 
date of the last exposure to treatment – date of the first dose + 1.  
Patient-years of exposure will be derived individually for each participant. Patient-years will be 
defined for each participant as the total time (in years) from first dose to the last available dose of 
study drug. Dose adjustments and/or interruptions will not be factored into this derivation.  
Results will be analyzed using descriptive statistics and the frequency and percentage of 
participants in the following dose categories: 
1. ≤ 2.5 mg  
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3. > 5 mg to ≤ 7.5 mg  
4. > 7.5 mg to ≤ 10 mg  
5. > 10 mg to ≤ 12.5 mg  
6. > 12.5 mg to ≤ 15 mg  
The gap in drug exposure will not be included in the calculation of duration of exposure. Dosing 
will be described by mean daily dose, final daily dose, minimum daily dose, maximum daily 
dose, and total accumulative dose. 
• Mean daily dose = sum (each dose × each dose frequency × each period)/total 
treatment period  
• Final daily dose is defined as the last dispensed dose in titration studies  
• Minimum daily dose is defined as the minimum daily dose over the Treatment Period  
• Maximum daily dose is defined as the maximum daily dose over the Treatment 
Period  
• Total cumulative dose is the sum of doses over the total Treatment Period  
The dosing regimen was individualized. The mean daily dose (mg), minimum daily dose (mg), 
and maximum daily dose (mg) will be summarized using descriptive statistics. All available 
dosing data will be presented in a listing. Where available, reasons for dose adjustment will also 
be presented in a listing.  
Listings of exposure, drug interruptions, and missed doses will also be presented. 
Relationships to duration of study therapy and dose of study therapy may be explored along with 
examination within relevant subgroups, eg, WD severity at study entry prior, prior therapies 
received, age, and sex. WD severity at study entry may be assessed by the following: 
• Cirrhosis status (yes, no) 
• MELD/PELD score at baseline above (>) or below (≤) median 
• Modified Nazer score at baseline above (>) or below (≤) median 
• Total bilirubin (µmol/L) > upper limit of normal (ULN) 
• Platelets (109/L) < lower limit of normal (LLN) 
• UWDRS Part II total score at baseline > 0 or = 0 
• UWDRS Part III total score at baseline > 0 or = 0 
• CGI-S at baseline above (>) or below (≤) median 
• LBC (µmol/L) at baseline above (>) or below (≤) median 
• Leukocytes (109/L) < LLN 
• Neutrophils (109/L) < LLN 


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Prior therapies received may be assessed as follows: 
• Cohort 1 will be categorized by prior SoC, where prior SoC is defined as the most 
recent treatment prior to or at time of Screening (whichever is later) and is 
categorized as penicillamine, trientine hydrochloride, zinc, or combination. This 
cohort will have participants who have received SoC therapy for > 28 days prior to 
enrollment in the study. 
• Cohort 2 will be categorized into participants who are treatment naïve and those who 
have received SoC therapy for ≤ 28 days prior to enrollment in the study. 
5.6.2. 
Adverse Events 
Treatment-emergent adverse events (TEAEs) are defined as those AEs with onset after the first 
dose of randomized treatment or existing events that worsened in severity after the first dose of 
randomized treatment. Events reported with a partial onset date (eg, month and year are reported, 
but the day is missing) will be considered to be treatment emergent if it cannot be confirmed that 
the event onset was prior to the first dose of study drug based on the available date entries. 
An overall summary of TEAEs will be presented by treatment, including frequency of 
participants experiencing the event (n) and relative frequency (n/N*100, where N is the number 
of participants in the Safety Analysis Set for each treatment group). The summary will include 
categories indicating how many events are TEAEs, treatment-emergent SAEs, and 
treatment-emergent non-SAEs. Within TEAEs, the following subcategories will also be 
summarized: 
• Severity of TEAEs (Grade 1 through Grade 5) 
• Related TEAEs (not related, related) 
• TEAEs leading to withdrawal of study drug 
• TEAEs leading to dose interruption 
• TEAEs leading to dose reduction 
• TEAEs leading to death 
• AESIs 
The incidence of AEs and SAEs will be summarized by System Organ Class and Preferred Term 
for each treatment and overall and by relationship to study intervention. AEs will also be 
summarized by treatment and, overall, by severity. SAEs and AEs resulting in withdrawal from 
the study will be listed.  
5.6.2.1. 
AEs by System Organ Class and Preferred Term 
The number of TEAEs and the number and percentage of participants with events will be 
presented by System Organ Class and Preferred Term. Percentages will be based on the Safety 
Analysis Set. System Organ Class will be listed in descending frequency as will PTs within each 
System Organ Class. If needed, terms will also be ordered alphabetically. 
Treatment-emergent SAEs, treatment-emergent non-SAEs, TEAEs leading to withdrawal of 
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(PTAEs), and TEAEs occurring in ≥ 5% or ≥ 10% of participants will be summarized using the 
same approach. 
5.6.2.2. 
AEs by System Organ Class 
The number of TEAEs and the number and percentage of participants with events will be 
presented by System Organ Class. Patients are counted once in each System Organ Class. 
Percentages will be based on the total number of treated participants in the treatment cohort. 
5.6.2.3. 
AEs by Preferred Term 
The number of TEAEs and the number and percentage of participants with events will be 
presented by Preferred Term. Patients are counted once in each Preferred Term. Percentages will 
be based on the total number of treated participants in the treatment cohort. 
5.6.2.4. 
AEs by System Organ Class, Preferred Term, and Relationship 
The number of TEAEs and the number and percentage of participants with events will be 
presented by System Organ Class and Preferred Term as described in Section 5.6.2.1 and by 
relationship (related, not related). If a participant has more than 1 occurrence of an AE, the 
strongest relationship to study treatment will be used in the summary table. If the relationship to 
study drug is missing, the AE will be assumed to be related. A similar analysis will be conducted 
for treatment-emergent SAEs. 
The number of related TEAEs and the number and percentage of participants with related 
TEAEs will be summarized by System Organ Class and Preferred Term and separately by 
Preferred Term only. The same analyses will be produced for related treatment-emergent SAEs. 
Lastly, the number of TEAEs by System Organ Class, Preferred Term, and relationship, without 
considering the highest relationship, will be analyzed. A similar analysis will be conducted for 
treatment-emergent SAEs. 
5.6.2.5. 
AEs by System Organ Class, Preferred Term, and Severity 
The number of TEAEs and the number and percentage of participants with events will be 
presented by System Organ Class, Preferred Term, and severity. If a participant has more than 1 
occurrence of an AE, the highest severity reported will be used. If severity is missing, the AE 
will be assumed to be severe. The number of TEAEs by System Organ Class, Preferred Term, 
and severity, without taking into account the highest severity, will also be analyzed. 
Additionally, a summary of related TEAEs by System Organ Class, Preferred Term, and severity 
using the highest severity will be presented. 
5.6.2.6. 
Deaths, Other SAEs, and AESIs 
SAEs and AESIs will be reportable from the time the participant signs the informed consent 
through the EOS Visit or until the Investigator and Alexion Pharmaceuticals determine that 
follow-up is no longer necessary.  
Any new neurological symptom or clinically significant worsening of an ongoing neurological 
symptom after initiation of study intervention (ALXN1840 or SoC) will be designated an AESI, 
whether serious or nonserious. This includes all AEs in the MedDRA System Organ Class 


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“Nervous system disorders” or any AE where the “Is this an AESI?” check box is checked in the 
case report form (CRF). 
AESIs will be assessed by a panel of 3 independent neurologists not participating in the study. 
The panel will assess the probability that clinically significant worsening or a new clinically 
significant neurological symptom is related to disease progression or caused by the study drug 
(ALXN1840 or SoC). They will be blinded to the treatment given to the participant. All available 
relevant participant information will be provided to this panel to aid in their assessment. The 
assessment of AESIs by the panel will be independent of and in addition to the usual assessments 
of the AE, including assessments of severity (intensity) and causality, by both the Principal 
Investigator and Alexion. A summary and listing of assessments given by the Neurological 
Adverse Event Panel will be presented. 
A separate independent Hepatic Adjudication Panel, comprising experts in hepatology and 
drug-induced liver injury, will be appointed by the Sponsor. The Hepatic Adjudication Panel will 
review and monitor study data for abnormalities of liver tests and liver function that may impact 
safety, effectiveness, and study conduct. A summary and listing of assessments given by the 
Hepatic Adjudication Panel will be presented. 
5.6.2.7. 
Other Significant Adverse Events  
Other significant TEAEs encompass those for abnormal liver function tests (also known as 
hepatic events), hematopoietic cytopenias, and dyslipidemia. These include any new AE, or 
worsening of an ongoing AE, after initiation of study drug therapy that meet the criteria 
described below: 
• Hepatic events: All AEs in the “Drug related hepatic disorder” Standardized 
MedDRA Queries (SMQ) (comprehensive search) or any AE where the “Is this a 
Hepatic AE?” check box is ticked. 
• Hematopoietic cytopenias: All AEs in the “Haematopoietic cytopenias” SMQ 
• Dyslipidemia: All AEs in the “Dyslipidaemia” SMQ 
5.6.3. 
Additional Safety Assessments  
Changes from Baseline in vital sign measurements and laboratory assessments (eg, chemistry, 
hematology, coagulation, and urinalysis) will be summarized by treatment. Laboratory parameter 
values will be graded according to the National Cancer Institute CTCAE. Shift tables by 
treatment will be produced for these laboratory parameters. These tables will summarize the 
number of participants with each baseline grade relative to the reference ranges and changes to 
the worst highest grade assessed postdose during the study. 
Clinically Significant Laboratory Test Abnormalities 
The following laboratory tests will be graded according to the National Cancer Institute CTCAE 
V5.0 at ADaM level. 
• Hematology: Absolute neutrophil count (neutrophil) (NEUT), total leukocytes 
(Leukocytes) (WBC), hemoglobin (HGB), platelet count (PLAT), and lymphocytes 
(LYM). Grading for all of these hematology laboratory parameters is based on 
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•
Coagulation: International normalized ratio (INR)
•
Chemistry: Alanine aminotransferase (ALT), albumin (ALB), alkaline phosphatase 
(ALP), aspartate aminotransferase (AST), total bilirubin (BILI), creatinine
(CREAT), gamma-glutamyl transferase (GGT), glucose (GLUC) (only grading for 
hypoglycemia, no grading for hyperglycemia), creatine kinase (CK), cholesterol
(CHOL), non-high density lipoprotein (non-HDL-C), low-density lipoprotein
(LDL-C), high-density lipoprotein (HDL-C), very low density lipoprotein (VLDL), 
and triglycerides (TRIG)
Laboratory toxicity grade 0 will be derived for the shift table as any nonmissing results outside 
the range of the National Cancer Institute CTCAE criteria. Laboratory tests with missing either 
LLN or ULN or both will not be graded. Abnormal laboratory tests values will be summarized 
by National Cancer Institute CTCAE Laboratory Toxicity Grade. Shift from baseline tables of 
the number and percentage of participants in each of the National Cancer Institute CTCAE 
categories will also be presented for each treatment group for each parameter and visit time 
window (scheduled visits only). An overall shift summary will also be provided comparing 
baseline to worst postdose toxicity observed across all scheduled visits. 
Lipid profile plots will be produced for individual participants, showing total cholesterol, HDL-
C, non-HDL-C, LDL-C, VLDL, and triglycerides, and ALT as a multiple of the respective 
baseline (BLN) values and a multiple of ULN values.  
ECG parameters will be measured at the specified time points as per the Schedule of Activities 
(Protocol Section 1.3), including heart rate, PR, RR, QRS, QT, and QT intervals corrected for 
heart rate using Fridericia’s formula. The average of the triplicate ECG readings at the time 
points collected will be calculated, and changes from Baseline values will be assessed by each 
treatment. 
5.6.3.1. 
Evaluation of Drug-Induced Serious Hepatotoxicity 
A Hy’s law case refers to an increase in aminotransferase > 3× the reference ULN, with bilirubin 
> 2× ULN. Possible Hy’s law cases can be visualized with use of evaluation of drug-induced
serious hepatotoxicity (eDISH) plots, a log-log scatter plot where the x-axis is the peak
postbaseline ALT as a multiple of ULN, and the y-axis is the peak postbaseline total bilirubin as
a multiple of ULN (Guo, 2009).
The following series of figures, adapted from Tesfaldet et al (2016), will be produced for each 
treatment group (ALXN1840 and SoC) separately for the Safety Analysis Set. 
1. Distribution of ULN of liver serum enzymes, showing the ULN reference values used in
each test (bilirubin, ALT, AST, and ALP) and their respective frequencies in percentiles
2. Distribution of baseline liver serum enzymes for each test by cohort
3. Distribution of baseline liver serum enzymes (×ULN) for each test by cohort
4. Status of baseline liver serum enzymes as function of ULN. Baseline status categorized
as normal, > 1 ×, > 1.5 ×, > 2 ×, > 3 ×, > 5 ×, and > 10 ×
5. eDISH plot by treatment group
6. eDISH plot by quadrant


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7. Panel of eDISH quadrant shift plots at baseline. Patients will be color coded to 
correspond to the quadrant to which they belong in the eDISH plot. The data presented in 
the panel will correspond to each participant’s baseline value as a multiple of the ULN. 
8. Panel of shift plots by eDISH quadrants. Patients will be color coded to correspond to the 
quadrant to which they belong in the eDISH plot. The data will be presented as multiples 
of the baseline value (BLN) rather than the ULN. The shift in peak postbaseline 
laboratory value will be compared to each participant’s baseline value. 
9. Panel of eDISH shift plots by eDISH quadrants. The panels will represent the 
on-treatment eDISH quadrants, whereas the colored symbols will represent the eDISH 
quadrants of the baseline values (not postbaseline) as multiples of ULN. 
10. Time course of liver tests as × BLN and × ULN. 
5.7. 
Other Analyses  
5.7.1. 
PK and PD Analyses 
For PK, PD, and biomarker endpoints, analyses will be performed using the PK/PD Analysis Set. 
5.7.1.1. 
PK/PD Sampling Schedule 
At the Day 1, Week 6 (Day 43), and Week 48 (Day 337) Visits, serial blood samples will be 
collected for plasma PK/PD/biomarker concentrations at the following time points: predose at 
0 hours and at 2, 4, 8, and 24 hours postdose. Samples collected within ± 10% in minutes or 
30 minutes of the scheduled time, whichever is less, will not be considered a protocol deviation. 
5.7.1.2. 
Plasma PK Parameters 
The following plasma PK parameters will be calculated for total Mo and PUF Mo, if measured,  
using noncompartmental methods with Phoenix® WinNonlin® (Version 8.0 or higher; Certara 
USA Inc., Princeton, New Jersey) or SAS Version 9.3 or higher (SAS Institute Inc., Cary, North 
Carolina), as applicable. Calculations of individual PK parameters will be based on the measured 
plasma total and PUF Mo concentrations and the actual sampling times elapsed from the actual 
reference dosing time data recorded during the study. 
PK: 
• Cmax 
• tmax 
• Ctrough 
• AUCtau 
Additional plasma PK parameters may be calculated if deemed appropriate. Population PK 
analysis may be formed with pooled data from other clinical studies if deemed appropriate. 
Secondary PK parameters such as, but may not be limited to, CL/F, and Vd/F will be estimated 
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5.7.1.3. 
Handling of Missing Data 
Missing concentration data for all participants who are administered scheduled study treatments 
will be considered as noninformative missing and will not be imputed. No concentration 
estimates will be provided for missing sample values. 
For the derivation of area under the plasma concentration-versus-time curve and for the 
individual plasma concentration-versus-time curves, the following rules will apply: 
• Concentration values below the assay’s lower limit of quantification (BLQ) in 
predose Day 1 samples will be treated as 0. 
• The sampling time of predose samples relative to dosing will also be treated as 0. 
• BLQs between 2 quantifiable samples will be set to missing. 
• The first BLQ after the last measurable sample will be set to missing; any subsequent 
BLQs will be set to 0. 
For the plasma concentrations summary, the following rules will apply: 
• All BLQ values will be set to 0. 
• No further imputation will be applied to any missing values. 
5.7.1.4. 
Plasma PK Concentration and PK Parameter Data 
Plasma concentrations of total Mo and PUF Mo (if measured) versus time data will be presented 
in a data listing by participant. Plasma concentration data will be summarized separately by 
analyte and time point for each treatment by day using the following descriptive statistics: 
number of participants, arithmetic mean, geometric mean, SD, coefficient of variation, geometric 
mean coefficient of variation, median, minimum, and maximum. Mean plasma concentration-
versus-scheduled time profiles will be presented in figures on both linear and semilogarithmic 
scales. Individual plasma concentration-versus-actual time profiles will be presented similarly. 
PK parameters derived from plasma concentrations of total Mo and PUF Mo (if measured) will 
be presented in data listings and summarized separately using the following descriptive statistics: 
number of participants, arithmetic mean, geometric mean, SD, arithmetic coefficient of variation, 
geometric mean coefficient of variation, median, minimum, and maximum.  
Individual and mean Ctrough for total Mo versus day will be plotted on both linear and semi-
logarithmic scales. Time to reach steady state will be graphically assessed by plotting mean 
Ctrough versus study day in both linear and semilogarithmic scales. In addition, attainment of 
steady state will be assessed via a stepwise, linear trend test. This approach involved an 
examination of Ctrough over time by conducting a linear regression of Ctrough versus time and 
calculating a 95% confidence interval around the slope estimate, and a first instance where 0 was 
included in the 95% confidence interval would indicate that the steady state was achieved. 
 
 
 


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Urinary and Fecal Mo  
24-hour urinary Mo will be assessed at Baseline, Week 6, Week 24, and Week 48 in all 
participants. 24-hour fecal Mo will be assessed at Baseline and Week 6 in all participants. This 
assessment is optional. The purpose of these assessments is to assess the change from Baseline in 
urinary and fecal Mo in participants with WD who are treated with ALXN1840 or SoC. 
5.7.1.5. 
PD Parameters 
For PD (total and PUF [if measured] Cu, dNCC, LBC, and cNCC/cNCCcorrected) and biomarker 
endpoints (CpC), concentration-versus-time data will be listed and summarized with descriptive 
statistics and plotted. The same analyses will be conducted on the absolute, change from 
Baseline, and percent changes from Baseline of these concentration-versus-time data. 
Observed, absolute, and percent changes of molar ratio of CpC to ceruloplasmin have been added 
as an exploratory endpoint and will be summarized.  
The following plasma PD parameters, as data permits, will be calculated for total Cu, dNCC, and 
LBC using noncompartmental methods with Phoenix® WinNonlin® Version 8.0 or higher or 
SAS Version 9.4 or higher, as applicable.  
• Maximum observed effect after dosing (CEmax)  
• Time after dosing at which the maximum effect was observed (TEmax)  
• AUEC from the start of dose administration to the last observed quantifiable 
concentration 
PD parameters derived from plasma concentrations of total Cu, dNCC, and LBC will be 
presented and summarized by analyte and day similar to PK parameters. 
5.7.1.6. 
Urinary and Fecal Cu Excretion 
24-hour urinary and 24-hour fecal Cu excretion-versus-time data will be listed and summarized 
with descriptive statistics and plots. The same analyses will be conducted on the absolute, change 
from Baseline, and percent changes from Baseline of these concentration-versus-time data. 
5.7.2. 
Subgroup Analyses 
For exploratory purposes, the primary and secondary efficacy endpoints will also be summarized 
in clinically relevant subgroups. As a general rule, a subgroup is analyzed only if the number of 
participants is ≥ 3 in each treatment group.  
• Age in years group (≥ 3 to < 12, ≥ 12 to < 18) 
• Sex (Male, Female) 
• Ethnicity (Hispanic or Latino, not Hispanic or Latino, Unknown) 
• Race (White, Black or African American, Asian, American Indian or Alaska native, 
Native Hawaiian or other Pacific Islander, Other) 
• Country/Region (US, EU, UK, Germany, Japan, Rest of the World) 
• Body mass index (BMI) group (< 25 kg/m2, 25 to 30 kg/m2, > 30 kg/m2) 


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• UWDRS Part II total score at Baseline (> 0, = 0) 
• UWDRS Part III total score at Baseline (> 0, = 0) 
• Cirrhosis at Baseline (Yes, No) 
• Psychiatric symptoms at Baseline (Yes, No; at least 1 symptom present on BPRS-24 and 
BPRS-C9) 
• Renal function status at Baseline  
− G1 
− G2 
− G3a/G3b/G4/G5 combined 
• ALT at Baseline (> ULN, ≤ ULN) 
5.8. 
Interim Analyses 
The primary analysis will be performed after 48 weeks, and the final analysis will be performed 
after completion of Period 2. Interim analyses of data may be performed to support regulatory 
submissions. These will primarily focus on analyzing safety endpoints only, and the safety 
summaries described in Section 5.6 may be performed. These analyses will be descriptive only; 
they will not include formal hypothesis testing and will not be used to adapt the study.  
The efficacy data available at the time of primary analysis will also be used in an efficacy 
extrapolation to develop evidence for ALXN1840 efficacy on Cu control for pediatric 
participants (ages 3 to < 18 years) with WD using adult/adolescent participant data from 
Studies WTX101-301 and ALXN1840-WD-302. Full details of the extrapolation exercise will be 
provided in the Study ALXN1840-WD-303 SAP.  
5.8.1. 
DMC or Other Review Board 
An independent DMC, comprising experts in relevant fields with no direct relationship to the 
study, will be appointed by Alexion. The specific responsibilities of the DMC will be described 
in the DMC Charter. 
A separate independent Neuro Event Adjudication Panel, comprising independent experts in 
relevant fields, will be appointed by Alexion. As detailed in the Neuro Event Adjudication Panel 
Charter (maintained separately from the study protocol), the Neuro Event Adjudication Panel 
will review and monitor study data for neurological SAEs that may impact safety, effectiveness, 
and study conduct and make recommendations regarding study continuation, changes to the 
study population, and/or modification to study procedures. The specific responsibilities are 
described in the Neuro Event Adjudication Panel Charter. 
A separate independent Hepatic Adjudication Panel, comprising experts in hepatology and 
drug-induced liver injury, will be appointed by Alexion. As detailed separately in the Hepatic 
Adjudication Panel Charter (maintained separately from the study protocol), the Hepatic 
Adjudication Panel will review and monitor study data for abnormalities of liver tests and liver 
function that may impact safety, effectiveness, and study conduct and make recommendations 


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regarding study continuation, changes to the study population, and/or modification to study 
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6. 
SUPPORTING DOCUMENTATION  
6.1. 
Appendix 1: Technical Specifications for Derived Variables 
The following derived data will be calculated prior to analysis. 
Adverse Events 
The analysis of AEs is described in detail in Section 5.6.2 . 
TEAEs are adverse events with start dates and start times onset or after the date and time of the 
first study intervention dose or existing events that worsened in severity after the first dose of 
randomized treatment. If the start date of an AE is partially or completely missing and the end 
(stop) date and time of the AE does not indicate that it occurred prior to the first dose, then the 
determination of treatment-emergent status will be based on the following: 
• If the start year is after the year of the first study intervention dose, then the AE is 
treatment emergent; else 
• If the start year is the same as the year of the first study intervention dose and  
− The start month is missing, then the AE is treatment emergent; else if 
− The start month is present and is the same or after the month of the first study 
intervention dose, then the AE is treatment-emergent; else 
• If the start date is completely missing, then the AE is treatment emergent. 
All other AEs are considered PTAEs.  
Percentages are based on the total number of treated participants in the particular treatment 
group. 
Age 
Age will be presented as the number of years between the date of birth and the reference date. 
For age at enrollment, the reference date will be the date of signing the informed consent form. 
The following formula should be followed for the calculation of age, if needed: 
Age (year) = FLOOR([reference date – date of birth]/365.25), where the FLOOR(  ) function 
returns the integer part of the result. 
In cases where only the month and year are provided for a date, the day for the date will be 
imputed as 15. The missing month will be imputed as June. In cases where the day is observed 
but the month is missing, the date will be imputed as June 15. In instances when the imputed 
reference date is earlier than the birth date, the birth date will be used as the reference date. 
Analysis Relative Day 
Analysis relative day is the day relative to the first dosing day. It will be calculated as analysis 
date – first dose date + 1 if the analysis date is after the first dose date; otherwise, it will be 
calculated as first dose date – analysis date. 


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Baseline Value 
Baseline is defined as the last nonmissing value collected on or prior to the first dose. 
Body Mass Index 
BMI is derived as follows: weight (kg)/[height (cm)/100]2 
Change from Baseline 
Change from baseline will be calculated as postbaseline assessment value – baseline assessment 
value when both values are not missing.  
Percent change from baseline is calculated as change from baseline/baseline × 100. 
If either the baseline or the postbaseline value is missing, the change from baseline and/or 
percent change from baseline is set to missing. Additionally, if the baseline is 0, the percent 
change from baseline will be missing. 
Medications and Therapies 
Concomitant medications/therapies are any events with administration dates and times on or after 
the date and time of the first study drug dose. If the start date of a medication or therapy is 
partially or completely missing and the end (stop) date and time of the medication/therapy does 
not indicate that it occurred prior to the first dose, then the determination of concomitant status 
will be based on the following:  
If the start year is after the year of the first study drug dose, then the medication/therapy is 
concomitant; else, if the start year is the same as the year of the first study drug dose and the start 
month is missing, then the medication/therapy is concomitant. If the start month is present and is 
the same or after the month of the first study drug dose, then the medication/therapy is 
concomitant. If the start date is completely missing, then the medication/therapy is concomitant.  
All other medications/therapies are considered prior medications/therapies and could occur from 
30 days prior to informed consent up through the Screening Period and prior to the first dose. 
UWDRS 
As described in Section 5.4.2, UWDRS has 3 subscores. The algorithms for calculating the 
subscores are given below. The UWDRS total score will be the sum of the 3 subscores. 
UWDRS Part I: Consciousness; maximum score of 3 
Set to Question 1, range 0 to 3. 
UWDRS Part II total score: Disability; maximum score of 40 
• Calculate the sum of Questions 2 to 11; each question has range 0 to 4.  
• If all 10 items are populated, the subscore will be the sum calculated above. If 8 or 
9 items are populated, prorate the score by dividing by the number of answered items 
and multiplying by 10. This is done in order to estimate the value the participant 
could have achieved if they had answered all the questions. If less than 8 items are 
populated, the score will not be derived.  


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UWDRS Part III total score: Neurological status; maximum score of 175 
• Calculate the following new scores for Questions 12 to 34: 
− Question 12: range 0 to 4; set to Q12A 
− Question 13: range 0 to 6;  
If Q13 = 0 then set to 0;  
else if Q13 = 1 then do;  
if Q13A > 2 then set to Q13A  
else set to Q13A + Q13B  
end; 
− Question 14: range 0 to 1; set to Q14 
− Question 15: range 0 to 16; set to Q15A + Q15B + Q15C + Q15D 
− Question 16: range 0 to 4; set to Q16 
− Question 17: range 0 to 20; set to Q17A + Q17B + Q17C + Q17D + Q17E 
− Question 18: range 0 to 8; set to Q18A + Q18B 
− Question 19: range 0 to 8; set to Q19A + Q19B 
− Question 20: range 0 to 4; set to Q20 
− Question 21: range 0 to 16; set to Q21A1 + Q21A2 + Q21B1 + Q21B2 
− Question 22: range 0 to 8; set to Q22A + Q22B 
− Question 23: range 0 to 8; set to Q23A + Q23B 
− Question 24: range 0 to 8; set to Q24A + Q24B 
− Question 25: range 0 to 4; set to Q25 
− Question 26: range 0 to 8; set to Q26A + Q26B 
− Question 27: range 0 to 4; set to Q27 
− Question 28: range 0 to 10 
Visit Windowing  
In analysis of data summarized by study visit, all data collection will be reassigned a study visit 
where data are scheduled for collection based on the actual days relative to baseline. All visits 
will be assigned a target study day; for the determination of target days, weeks will be assumed 
to have 7 days. Baseline will have a target study day of 1. Thus, Week 4 would have a target day 
of 4 × 7 + 1 = 29. For each assessment, the postbaseline period will be divided using the 
scheduled visit’s target days. The lower bound of each visit interval will be evaluated as the 
midpoint between the target day and the previous visit’s target day in the following manner: 
study day interval lower bound = target study day – ([target study day – last target study day]/2). 
If more than 1 value is mapped to the same scheduled visit, the closer of those values will be 
considered for summarization. Visit windows are intended to be contiguous such that all data 
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The visit displayed on participant data listings will be reflective of the scheduled visit label as 
reported on the CRF. Study days relative to baseline will be displayed for each visit so it is 
apparent which visit the data may have been reassigned to in the summaries. 
6.2. 
Appendix 2: Study and Participant Characteristics 
Disposition of Participants  
The number and percentage of all participants enrolled, randomized, included in the FAS and PP, 
Safety, PK, and PD analysis sets will be summarized. The reasons for exclusion from the 
analysis sets will also be provided. Frequency counts and percentages of participants excluded 
prior to randomization will be provided for participants who failed to meet study entry 
requirements during Screening at the start of the study.  
The number and percentage of participants who completed or prematurely discontinued from the 
study will be described by randomized treatment group within each cohort, for rollover 
participants and overall. For participants who discontinued the study, the number and percentage 
will be summarized by their reason for premature discontinuation and withdrawal of consent. A 
summary of participants will be provided by region, country, and site. Additionally, a summary 
of participants who did not meet inclusion or who met exclusion criteria will be provided.  
Descriptive statistics of the number of days in the study will be summarized. The date of the first 
and last use of study medications in each period and the study termination date will be listed. 
Individual reasons for premature discontinuation and withdrawal of consent from the study will 
be presented in a listing. All enrolled participants will be listed, indicating their analysis set 
along with the reason for exclusion. A listing of screen failure participants will also be provided. 
Additionally, a listing of the inclusion/exclusion criteria and a listing of participants and the 
inclusion criteria they failed to meet and the exclusion criteria they met will be provided. 
All demographic and baseline characteristics information will be summarized on the FAS. 
Summary statistics will be presented by randomized treatment within cohort, for rollover 
participants and overall. Continuous variables will be presented using descriptive statistics, and 
categorical variables will be presented using frequencies and percentages. Age will be calculated 
relative to the date of informed consent and will be summarized as both a continuous and 
categorical variable. Time since WD treatment start date (months) will be calculated as months 
occurring between the date of informed consent and the start date from WD treatment history 
CRF and will be summarized using descriptive statistics. Listings will also be provided. 
Demographics 
The following demographic variables will be summarized: 
• Age (years) 
• Age in years group (3 to < 12, 12 to < 18) 
• Sex (Male, Female) 
• Ethnicity (Hispanic or Latino, Not Hispanic or Latino, Unknown)  
• Race (White, Black or African American, Asian, American Indian or Alaska native, 
Native Hawaiian or other Pacific Islander, Other) 


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• Country/Region (US, UK, Germany, Japan, Rest of the World)  
• Height (cm) 
• Weight (kg) 
• BMI (kg/m2) 
Disease Characteristics 
The following disease characteristics will be summarized: 
• Time since WD treatment start date (months) 
• Cumulative duration of prior WD treatment (months) 
• Prior WD therapy: (i) zinc monotherapy versus penicillamine or trientine (± zinc); 
(ii) zinc monotherapy versus penicillamine (± zinc) versus trientine (± zinc) 
• Cirrhosis (Yes, No) 
• CGI severity 
• Psychiatric symptom (Yes, No; at least 1 symptom present on BPRS-24 and 
BPRS-C9) 
• cNCC and dNCC 
• Plasma total Cu 
• Plasma total Mo 
• PUF-Cu 
• PUF-Mo 
• Cp 
• CpC 
• 24-hour urinary Cu concentration 
• 24-hour urinary Mo concentration 
• LBC 
• MELD score 
• Modified Nazer score 
• UWDRS Part II total score (original score and FDA-suggested score) 
• UWDRS Part III total score 
• UWDRS Part III Functional Subscale (original score and FDA-suggested score) 
• UWDRS Part III individual symptoms (original score and FDA-suggested score of 
arising from a chair, gait, speech, and handwriting) 
• UWDRS activities of daily living subgroup at baseline 


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• EQ VAS 
• EQ-5D-5 levels 
In addition, the following baseline laboratory measures will be summarized: 
• ALT 
• ALT groups (> 2× ULN, ≤ 2× ULN) 
• Albumin 
• AST 
• Total and direct bilirubin 
• Total bilirubin groups (> ULN, ≤ ULN) 
• Gamma-glutamyl transferase (GGT) 
• INR 
• Platelets 
• Leukocytes 
• Creatinine 
• Total cholesterol, high-density lipoprotein, low-density lipoprotein 
• Triglycerides 
• Renal function status at baseline 
o Normalized glomerular filtration rate (GFR) (mL/min/1.73 m2) 
− 
G1: GFR > 90 mL/min/1.73 m2 
− 
G2: GFR 60 to 89 mL/min/1.73 m2 
− 
G3a: GFR 45 to 59 mL/min/1.73 m2 
− 
G3b: GFR 30 to 44 mL/min/1.73 m2 
o Absolute GFR (mL/min) 
− 
G1: GFR ≥ 90 mL/min 
− 
G2: GFR 60 to < 90 mL/min 
− 
G3: GFR 30 to < 60 mL/min 
 
 


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Renal function status at baseline: 
Participants will be classified into 4 different stages of kidney disease based on normalized GFR 
estimated from the serum concentration of creatinine at baseline. Participants will also be 
classified based on the absolute GFR (EMA/CHMP/83874/2014). 
For children and adolescent participants (age < 18 years), the equation provided by Schwartz 
(2009) (“bedside” formula) provides a better estimate of the normalized GFR (Frequently Asked 
Questions, National Kidney Foundation, 2014): 
Normalized GFR (mL/min/1.73 m2) = 0.41 × [Height (cm)/Scr (mg/dL)] 
The relationship between normalized GFR and absolute GFR can be obtained using body surface 
area (BSA), as presented in Frequently Asked Questions, National Kidney Foundation, 2014: 
Absolute GFR (mL/min) = Normalized GFR (mL/min/1.73 m2) × BSA/1.73 
For young and adolescent participants, BSA can be determined using the formula by Haycock 
et al, 1978, and also presented in Schwartz (2009): 
Age < 18 years: BSA (m2) = 0.024265 × (Weight [kg])0.5378 × (Height [cm])0.3964 
Participants with end-stage renal disease on dialysis (chronic kidney disease Stage 5) or 
estimated glomerular filtration rate < 30 mL/min/1.73 m2 are excluded from the study. 
Protocol Deviations 
All protocol violations will be determined and appropriately categorized prior to database lock. 
The number and percentage of participants with any important/not important protocol violations, 
as well as the number and percentage of participants with violations within each category, will be 
presented. A listing will also be provided. 
Medical History 
Medical history will be summarized by counts and percentages and displayed by System Organ 
Class and Preferred Term within each System Organ Class. System Organ Class and Preferred 
Term will be coded using the most up-to-date version of the MedDRA, version 24.1 or higher, 
available at the start of the study. This dictionary will be used throughout the life of the study 
and will not be updated during study conduct. The number and percentage of participants will be 
presented for ongoing conditions and previous conditions separately by System Organ Class and 
Preferred Term. A by-participant listing will also be created.  
All details of WD diagnosis will be listed in full. WD treatment history will be summarized by 
counts and percentages for Cohort 1 and Cohort 2 by prior SoC, where prior SoC is defined as 
the later of the treatment at the time of Screening or the most recent treatment prior to Screening 
and is categorized as penicillamine, trientine hydrochloride, zinc, or combination. 
Prior and Concomitant Medications 
The WHO Drug Dictionary version from September 2021 or later will be used to code the 
medications. Medications will be summarized by Anatomical Therapeutic Chemical (ATC) 
level 3 class and generic drug name.  


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Prior and concomitant medications will be summarized for the FAS by randomized treatment 
within treatment cohort, for rollover participants and overall. The number and percentage of 
participants receiving any concomitant medication will be summarized, as well as the number 
and percentage receiving any concomitant medication by ATC drug class and generic drug name. 
Participants reporting use of more than 1 medication at each level of summarization (any 
medication received, ATC class, and generic drug name) will be counted only once. ATC class 
terms will be displayed by descending order of incidence, as well as generic drug names within 
each ATC class. Prior medications used to treat WD and an additional analysis of all prior 
medications will be summarized similarly.  
Prior medications will be defined as medications that were discontinued prior to the start of study 
drug. Concomitant medications will be defined as medications that either started prior to the first 
dose of study drug and were continuing at the time of the first dose of study drug or started on or 
after the date of the first dose of study drug. If it cannot be determined whether a medication was 
stopped prior to the start of study drug dosing due to partial or missing medication start or end 
date, it will be considered a concomitant medication.  
Prior and concomitant medications will be presented in a by-participant data listing by 
participant and medication name. 
6.3. 
Appendix 3: Instrument Scoring Details 
Not applicable 


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6.4. 
Appendix 4: Additional Details on Statistical Methods 
To maintain study integrity and minimize bias in this open-label study, draft tables, listings, and 
figures will be produced with blinded treatment assignments for review prior to database lock for 
the Primary Evaluation Period. 
Analysis Considerations Related to COVID-19 
On 11 Mar 2020, Coronavirus Disease 2019 (COVID-19) was declared a pandemic by the WHO. 
This section summarizes additional analysis considerations to assess the potential impact of 
COVID-19 (Meyer, 2020). The following additional sensitivity and supplementary analyses will 
be included to assess the impact of the pandemic disruption on the study and to address 
pandemic-related data missingness.  
1. The summary of participant disposition will include COVID-19 related discontinuations 
and withdrawals.  
2. A summary of known COVID-19 exposure or diagnosis during the Primary Evaluation 
Period will be provided by treatment group using the Safety Analysis Set.  
3. A summary of COVID-19 related important protocol deviations during the Primary 
Evaluation Period will be provided. A by-participant listing of all protocol deviations will 
be provided.  
4. A summary of the number and percentage of participants who missed a study visit or had 
a modified study visit during the Primary Evaluation Period, along with the reasons 
(COVID-19 related/not), will be provided by treatment group and by visit using the FAS 
and Safety Analysis Set. For participants who had a modified study visit, the method for 
the different assessments will be summarized.  
5. Alternative data collection methods required during the pandemic may introduce 
additional variability. Two sensitivity analyses will be performed to assess this 
possibility. Descriptive statistics for the primary and key secondary endpoints by visit 
(and by randomized treatment and cohort) can be calculated, with the visits split into the 
categories described below. In the sensitivity analysis, each visit for each participant will 
be categorized as either “collected as planned” or “modified.”  
6. Missing data on the primary endpoint due to any COVID-19 related reasons will be 
handled as described in Section 5.3.2, where no imputation will be performed.  
6.5. 
Appendix 5: Changes to Protocol-planned Analyses 
• NCC or NCC/NCCcorrected has been clearly specified as dNCC or cNCC/NCCcorrected in 
the SAP. 
• Observed, absolute, and percent changes of molar ratio of CpC to ceruloplasmin have 
been added as an exploratory endpoint. 
• Assessing change from Baseline in urinary and fecal Mo Urinary and Fecal Mo  
− 24-hour urinary Mo will be assessed at Baseline, Week 6, Week 24, and Week 48 
in all participants.  


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− 24-hour fecal Mo will be assessed at Baseline and Week 6 in all participants. This 
assessment is optional. 
 
 


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6.6. 
Appendix 6: List of Abbreviations 
Abbreviation 
Definition 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
AUCtau 
area under the plasma concentration-versus-time curve from time 0 to the end of the 
dosing interval 
AUEC 
area under the effect-versus-time curve 
BLQ 
below the assay’s lower limit of quantification 
BMI 
body mass index 
BPRS-24 
Brief Psychiatric Rating Scale-24 
BPRS-C9 
Brief Psychiatric Rating Scale for children 
BSA 
body surface area 
CEmax 
maximum observed effect after dosing 
CGI 
Clinical Global Impression 
CGI-I 
Clinical Global Impression-Improvement scale 
CGI-S 
Clinical Global Impression-Severity scale 
CL/F 
apparent total body clearance 
Cmax 
maximum observed concentration 
cNCC 
calculated non-ceruloplasmin-bound Cu 
cNCCcorrected 
calculated non-ceruloplasmin-bound Cu corrected for Cu bound in tripartite 
(tetrathiomolybdate-Cu-albumin) complexes 
COVID-19 
Coronavirus Disease 2019 
CpC 
ceruloplasmin-bound Cu 
CRF 
case report form 
CTCAE 
Common Terminology Criteria for Adverse Events 
Ctrough 
trough (predose) concentration observed at the start of the dosing interval 
DMC 
Data Monitoring Committee 
dNCC 
directly measured non-ceruloplasmin-bound Cu 
ECG 
electrocardiogram 
eDISH 
evaluation of drug-induced serious hepatotoxicity 
EQ-5D 
EuroQoL 5 Dimensions 
EQ-5D-Y 
EuroQoL 5 Dimensions-Youth 
EQ VAS 
EuroQoL visual analogue scale 
FAS 
Full Analysis Set 
FIB-4 
fibrosis-4 
GFR 
glomerular filtration rate 
GGT 
gamma-glutamyl transferase 
INR 
international normalized ratio 
LBC 
labile-bound Cu 
LLN 
lower limit of normal 
LLOQ 
lower limit of quantification 
MedDRA 
Medical Dictionary for Regulatory Activities 
MELD 
Model for End-Stage Liver Disease 
NCC 
non-ceruloplasmin-bound Cu 
NCCcorrected 
non-ceruloplasmin-bound Cu in plasma corrected for the amount of Cu bound to the 
ALXN1840 tripartite (tetrathiomolybdate-Cu-albumin) complex 
PD 
pharmacodynamic(s) 
PedsQL 
Pediatric Quality of Life Inventory 
PELD 
Pediatric End-stage Liver Disease 


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Abbreviation 
Definition 
PK 
pharmacokinetic(s) 
PPS 
Per Protocol 
PTAE 
pretreatment adverse events 
PUF 
plasma ultrafiltrate 
QoL 
quality of life 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SMQ 
Standardized MedDRA Queries 
SoC 
standard of care 
t½ 
terminal elimination half-life 
TEAE 
treatment-emergent adverse event 
TEmax 
time after dosing at which the maximum effect was observed 
tmax 
time to maximum observed concentration 
TSQM-9 
Treatment Satisfaction Questionnaire for Medication-9 
ULN 
upper limit of normal 
UWDRS 
Unified Wilson Disease Rating Scale 
Vd/F 
apparent volume of distribution 
WD 
Wilson Disease 
WHO 
World Health Organization 


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7. 
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Statistical Analysis Plan 
 
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