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
Phase: PHASE3
Conditions: Wilson Disease
Sponsor: Alexion Pharmaceuticals, Inc.

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 
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 
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 
Alexion Confidential 

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 
Alexion Confidential 

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 
Alexion Confidential 

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. 
Page 8 of 108 
Alexion Confidential 

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. 
Page 9 of 108 
Alexion Confidential 

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 
Page 10 of 108 
Alexion Confidential 

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 
Page 11 of 108 
Alexion Confidential 

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 
Page 12 of 108 
Alexion Confidential 

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 
Page 13 of 108 
Alexion Confidential 

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 
Page 14 of 108 
Alexion Confidential 

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 
Page 15 of 108 
Alexion Confidential 

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.
Page 16 of 108 
Alexion Confidential 

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
Page 17 of 108 
Alexion Confidential 

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
Page 18 of 108 
Alexion Confidential 

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. 
Page 19 of 108 
Alexion Confidential 

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.
Page 20 of 108 
Alexion Confidential 

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. 
Page 21 of 108 
Alexion Confidential 

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
Page 22 of 108 
Alexion Confidential 

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 
Page 23 of 108 
Alexion Confidential 

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. 
Page 24 of 108 
Alexion Confidential 

Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
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. 
Page 25 of 108 
Alexion Confidential 

Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
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). 
Page 26 of 108 
Alexion Confidential 

Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
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. 
Page 27 of 108 
Alexion Confidential 

Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
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. 
Page 28 of 108 
Alexion Confidential 

Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
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.
Page 29 of 108 
Alexion Confidential 

Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
•
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. 
Page 30 of 108 
Alexion Confidential 

Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
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 
Page 31 of 108 
Alexion Confidential 

Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
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
Page 32 of 108 
Alexion Confidential 

Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
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; 
Page 33 of 108 
Alexion Confidential 

Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
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. 
Page 34 of 108 
Alexion Confidential 

Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
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.
Page 35 of 108 
Alexion Confidential 

Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
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 
Page 36 of 108 
Alexion Confidential 

Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
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 
Page 37 of 108 
Alexion Confidential 

Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
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. 
Page 38 of 108 
Alexion Confidential 

Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
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.
Page 39 of 108 
Alexion Confidential 

Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
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.
Page 40 of 108 
Alexion Confidential 

Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
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. 
Page 41 of 108 
Alexion Confidential 

Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
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
Page 42 of 108 
Alexion Confidential 

Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
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 
Page 43 of 108 
Alexion Confidential 

Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
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. 
Page 44 of 108 
Alexion Confidential 

Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
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. 
Page 45 of 108 
Alexion Confidential 

Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
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. 
Page 46 of 108 
Alexion Confidential 

Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
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. 
Page 47 of 108 
Alexion Confidential 

Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
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. 
Page 48 of 108 
Alexion Confidential 

Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
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. 
Page 49 of 108 
Alexion Confidential 

Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
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 
Page 50 of 108 
Alexion Confidential 

Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
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. 
Page 51 of 108 
Alexion Confidential 

Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
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. 
Page 52 of 108 
Alexion Confidential 

Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
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. 
Page 53 of 108 
Alexion Confidential 

Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
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). 
Page 54 of 108 
Alexion Confidential 

Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
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
Page 55 of 108 
Alexion Confidential 

Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
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. 
Page 56 of 108 
Alexion Confidential 

Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
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).
Page 57 of 108 
Alexion Confidential 

Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
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. 
Page 58 of 108 
Alexion Confidential 

Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
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 
Page 59 of 108 
Alexion Confidential 

Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
“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.
Page 60 of 108 
Alexion Confidential 

Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
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.
Page 61 of 108 
Alexion Confidential 

Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
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 
Page 62 of 108 
Alexion Confidential 

Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
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. 
Page 63 of 108 
Alexion Confidential 

Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
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.
Page 64 of 108 
Alexion Confidential 

Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
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).
Page 65 of 108 
Alexion Confidential 

Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
•
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. 
Page 66 of 108 
Alexion Confidential 

Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
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. 
Page 67 of 108 
Alexion Confidential 

Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
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. 
Page 68 of 108 
Alexion Confidential 

Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
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. 
Page 69 of 108 
Alexion Confidential 

Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
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. 
Page 70 of 108 
Alexion Confidential 

Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
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. 
Page 71 of 108 
Alexion Confidential 

Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
•
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. 
Page 72 of 108 
Alexion Confidential 

Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
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. 
Page 73 of 108 
Alexion Confidential 

Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
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 
Page 74 of 108 
Alexion Confidential 

Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
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
Page 75 of 108 
Alexion Confidential 

Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
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
Page 76 of 108 
Alexion Confidential 

Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
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: 
Page 77 of 108 
Alexion Confidential 

Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
•
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. 
Page 78 of 108 
Alexion Confidential 

Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
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.
Page 79 of 108 
Alexion Confidential 

Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
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. 
Page 80 of 108 
Alexion Confidential 

Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
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.
Page 81 of 108 
Alexion Confidential 

Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
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.
Page 82 of 108 
Alexion Confidential 

Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
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.
Page 83 of 108 
Alexion Confidential 

Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
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.
Page 84 of 108 
Alexion Confidential 

Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
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.
Page 85 of 108 
Alexion Confidential 

Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
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
Page 86 of 108 
Alexion Confidential 

Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
•
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 
Page 87 of 108 
Alexion Confidential 

Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
(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.
Page 88 of 108 
Alexion Confidential 

Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
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.
Page 89 of 108 
Alexion Confidential 

Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
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.
Page 90 of 108 
Alexion Confidential 

Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
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 
Page 91 of 108 
Alexion Confidential 

Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
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-
Page 92 of 108 
Alexion Confidential 

Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
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. 
Page 93 of 108 
Alexion Confidential 

Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
Figure 4: Projected Pharmacokinetic Exposure Range for Participants Aged 3 to < 6 Years 
Source: Population PK modelling simulations (data on file) 
Page 94 of 108 
Alexion Confidential 

Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
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. 
Page 95 of 108 
Alexion Confidential 

Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
Alexion Confidential 
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. 
Page 96 of 108 

Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
Alexion Confidential 
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. 
Page 97 of 108 

Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
Alexion Confidential 
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. 
Page 98 of 108 

Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
Alexion Confidential 
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
Page 99 of 108 

Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
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 
Page 100 of 108 
Alexion Confidential 

Protocol Amendment 3 (Global) 
ALXN1840-WD-302 
08 Mar 2022 
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 
Page 101 of 108 
Alexion Confidential 

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 
Page 102 of 108 
Alexion Confidential 

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.
Page 103 of 108 
Alexion Confidential 

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  
Page 104 of 108 
Alexion Confidential 

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. 
Page 105 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 
1.2 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 
Page 106 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 
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 
Alexion Confidential 

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 
Alexion Confidential