Conditions: Wilson Disease
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 77
Healthy volunteers: no

Brief summary:
This is a multicenter, randomized, open-label study with an active standard-of-care comparator (penicillamine)

Detailed description:
This is a multicenter, randomized, open label study with an active standard-of-care comparator.

Stable patients who are already considered to be stable on their standard-of-care penicillamine chelation therapy for at least 1 year will enroll in the study and enter a 12-week Penicillamine Baseline Period comprising of 1 month (4 weeks) run-in period followed by a 2 month (8 weeks) evaluation period. During this time all patients will continue to take their current penicillamine under study conditions. At the end of the Penicillamine Baseline Period, patients who fulfill the protocol definition of being adequately controlled and tolerating penicillamine will be randomized in a 1:1 ratio to receive either TETA 4HCl or to continue to receive penicillamine. There is then a 24-week Post-randomization Phase comprising of a 1 month (4 weeks) run-in period for both treatment arms and a 5 month (20 weeks) evaluation period.

Patients who successfully complete the 24-week Post-randomization Phase of the study will have the opportunity to enter an Extension Phase. In the first version of the clinical trial protocol, the intention was to have an 18 month (72 weeks) Extension Phase. During the first 24 weeks of the Extension Phase, subjects would continue receiving their allocated TETA 4HCl or penicillamine (i.e., up to Week 60 of the study). Thereafter all patients were receiving TETA 4HCl for a further 48 weeks (i.e., from Week 60 to Week 108). Study clinic visits occur were scheduled every 6 months in the Extension Phase.

With the final version of the protocol, the Extension Phase stopped at Week 60. Patients who already passed the Week 60 visit were allowed to end the study at the next planned visit.

As a consequece end of treatment varied Week 60 and Week 108

Arms:
arm 1: Patients randomized to penicillamine during the postrandomisation and 1st extension period arm 2: Patients randomized to TETA 4HCl during the postrandomisation and 1st extension period

Interventions: intervention 1: Penicillamine (D1-W12) intervention 2: TETA 4HCL (W12-60) intervention 3: Penicillamine (W12-W60) intervention 4: TETA 4HCL (60-<W108)
Intervention descriptions: intervention 1: Penicillamine during baseline period (D1-W12) intervention 2: TETA 4HCL during post randomisation and 1st extension period (W12-W60) intervention 3: Penicillamine during rondomisation and 1st extension period period (W12-W60) intervention 4: TETA 4HCL during 2nd extension period (W60-\<W108)

Protocol document:
Prot_000.pdf: 
Clinical Study Protocol 
GMPO-131-002 
Version 6.0 / 27 May 2020 
Page 1/72
CONFIDENTIAL 
Clinical Study Protocol 
Trientine tetrahydrochloride (TETA 4HCl) for the treatment of Wilson’s disease 
Study Number: 
GMPO-131-002 (CHELATE STUDY) 
Version / Date: 
Version 6.0 / 27 May 2020 
Investigational Drug: 
Trientine tetrahydrochloride (gmp-orphan) 
Comparator: 
Standard-of-care penicillamine  
Phase: 
3 
Sponsor: 
gmp-orphan SA 
Pépinière Paris Santé Cochin 
27-29 rue Faubourg Saint-Jacques
75014 Paris
France
EudraCT number:  
2016-003876-29 
IND number: 
128103 
GCP statement 
The experimental protocol for this study has been designed in accordance with the general ethical principles outlined in the Declaration of 
Helsinki. The review of this protocol by the Institutional Review Board and the performance of all aspects of the study, including the methods 
used for obtaining informed consent, must also be in accordance with principles enunciated in the declaration, the ICH E6 (R1) guidelines of 
Good Clinical Practice, 21 CFR 21.50 Protection of Human Subjects and 21 CFR 21.56 Institutional Review Boards, and all applicable 
regulatory authority requirements. 


Clinical Sfudy Protocol
GMPO-131-002
1. 
Signatures and agreement with protocol
Protocol Approval
Study title: CI{ELATE STUDY: Trientine tetrahydrochloride (TETA 4HCl) for the treatment
of Wilson's disease
Sponsor' s Representative
Laurence Skillern,
MD FRCOG FFPM,
Chief MedicalOfficer
u\cl \.ci\rr
Version 6.0 127 May 2020
CONFIDENTIAL
Page2172


Clinical Study Protocol 
GMPO-131-002 
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CONFIDENTIAL 
Investigator Signature page 
Study title: CHELATE STUDY: Trientine tetrahydrochloride (TETA 4HCl) for the treatment 
of Wilson’s disease 
I agree to conduct this study according to the Study Protocol. 
I agree that the study will be carried out in accordance with Good Clinical Practice (GCP), with 
the Declaration of Helsinki (with amendments) and with the laws and regulations of the 
countries in which the study takes place. 
Investigator 
Date 
Signature 
Address 


Clinical Study Protocol 
GMPO-131-002 
 
Version 6.0 / 27 May 2020 
 
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CONFIDENTIAL 
2. 
Study synopsis 
Title of the study: CHELATE STUDY: Trientine tetrahydrochloride (TETA 4HCl) for the 
treatment of Wilson’s disease 
Sponsor: 
gmp-orphan SA 
Protocol code: GMPO-131-002 (CHELATE) 
EudraCT number:  2016-003876-29 
IND number: 128103 
Investigator(s): 
Coordinating investigator: Professor Michael Schilsky, Yale University, USA 
Study center(s): 
Estimated 18-20 study sites  
Phase of development:  
Phase 3 
Planned study period: 
Each patient will participate in the initial part of the study for approximately 9 months, which 
may be followed by an extension phase  
Objectives:  
To evaluate the efficacy of TETA 4HCl compared to penicillamine. 
The safety of TETA 4HCl compared to penicillamine will also be evaluated. 
Clinical hypotheses: 
The efficacy of TETA 4HCl is not inferior to penicillamine, as assessed by the level of serum 
non-ceruloplasmin bound copper (NCC). 
TETA 4HCl is well tolerated. 
Study design:  
Multicenter, randomized, open label study with an active standard-of-care comparator. 
Stable patients who are already considered to be stable on their penicillamine chelation 
therapy for at least 1 year will enroll in the study and enter the 12-week Penicillamine 
Baseline Period comprising of a 1 month (4 weeks) run-in period followed by a 2 month (8 
weeks) evaluation period. During this time all patients will continue to take their current 
penicillamine under study conditions. At the end of the Penicillamine Baseline Period, 
patients who fulfill the protocol definition of being adequately controlled and tolerating 
penicillamine, as confirmed by the independent Adjudication Committee, will be randomized 
in a 1:1 ratio to receive either TETA 4HCl or to continue to receive penicillamine. 
There is then a 24-week Post-randomization Phase comprising of a 1 month (4 weeks) run-in 
period for both treatment arms followed by a 5 month (20 weeks) evaluation period.    
Scheduled study visits (clinic or telephone) will occur at screening/enrolment (clinic), Week 
4 (clinic), Week 8 (telephone), Week 12 (clinic), Week 16 (clinic), Week 20 (telephone), 
Week 24 (clinic), Week 28 (telephone), Week 32 (telephone) and Week 36 (clinic) – see 
figure below. For the telephone visits, the necessary lab samples will be collected directly 
from the patient. Note that the designated telephone visits are permitted to be performed at 
the clinic, but the reverse is not the case i.e. a designated clinic visit cannot be a telephone 
visit, unless circumstances arising from the Coronavirus disease 2019 (COVID-19) crisis are 
preventing the execution of planned visits at the clinic. 
Patients who successfully complete the 24-week Post-randomization Phase of the study will 
have the opportunity to enter an Extension Phase of maximally up to 18 months (72 weeks). 
Initially they will continue on their allocated treatment (penicillamine or TETA 4HCl) for a 


Clinical Study Protocol 
GMPO-131-002 
Version 6.0 / 27 May 2020 
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CONFIDENTIAL 
further 24 weeks. Thereafter patients may receive TETA 4HCl for a further 24 or 48 weeks. 
Study clinic visits will occur every 6 months (24 weeks), i.e. at Weeks 60, 84 and 108. An 
additional visit for patients who were previously allocated to the penicillamine treatment arm 
will occur at Week 64 (i.e. 4 weeks after starting to receive TETA 4HCl).  
From protocol version 6.0 onwards all patients reaching Week 60, 64, 84 and 108 will 
terminate the study at their first visit, i.e.:  
-
all patients that have previously completed the Week 36 visit will terminate at their
Week 60 visit; Patients initially randomized to the penicillamine arm and willing to
switch to TETA 4HCl will finish the study at the Week 64 visit.
-
all patients that have previously completed the Week 60 visit will stop the trial at the next
visit, either Week 84 visit, or an earlier unscheduled visit agreed between the patient and
investigator and
-
all patients that have previously completed the Week 84 visit will stop the trial at the next
visit either Week 108 visit or an earlier unscheduled visit agreed between the patient and
the investigator
Upon stopping all patients will have their end of treatment visit assessments to complete the 
study.  
In case local circumstances arising from the COVID-19 crisis are preventing the execution of 
the extension phase visits at the clinic, the scheduled assessments may be performed in part 
by telephone, in combination with collection of lab samples and vital signs obtained directly 
from the patient at home.   
The Adjudication Committee will review data up to and including Week 36 and Week 60 to 
confirm patients are well controlled and clinically stable post randomisation.   
Planned number of subjects: 
Evaluation
(20 weeks)
Run-in 2
(4 weeks)
Randomization of 
adequately controlled 
patients per protocol 
criteria
Evaluation
(8 weeks)
Penicillamine Baseline Period
Run-in 1 
(4 weeks)
Enrolment of stable patients 
receiving penicillamine for
≥ 52 weeks, stable dose for 
≥ 16 weeks
Post-randomization Phase: TETA 4HCl
*May be telephone visit 
with lab samples obtained
directly from patient
Screen/enrol 
(clinic)
Wk 4 
(clinic)
Wk 8 
(tel)*
Wk 12 
(clinic)
Wk 16 
(clinic)
Wk 20
(tel)*
Wk 24 
(clinic)
Wk 36 
(clinic)
Wk 28
(tel)*
Post-randomization Phase: Penicillamine
Extension Phase (72 weeks)
(continue allocated TETA 4HCl or 
penicillamine for further 
24 weeks, then all receive 
TETA 4HCl for 48 weeks)
Clinic visits at Wk 60, Wk 84, and 
Wk 108 for all patients (additional 
visit at Wk 64 for patients 
previously in penicillamine arm)
Evaluation
(20 weeks)
Run-in 2
(4 weeks)
Wk 16 
(clinic)
Wk 20
(tel)*
Wk 24 
(clinic)
Wk 36 
(clinic)
Wk 28
(tel)*
Wk 32
(tel)*
Wk 32
(tel)*


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CONFIDENTIAL 
The target is to have 55 patients randomized. 
Medical condition or disease under investigation: 
Patients with Wilson’s disease adequately controlled and tolerating penicillamine 
Inclusion criteria 
1. Patient is able to provide, and has provided, written informed consent  
2. Written documentation has been obtained in accordance with the relevant country and 
local privacy requirements, where applicable, including: 
a. For US sites: Authorization for Use and Release of Health Research Study 
Information 
b. For EU sites: Data Protection Consent 
3. Male or female, aged ≥ 18 and ≤ 75 years of age at time of consent 
4. Patient has a diagnosis of Wilson’s disease, as defined by a prior or current Leipzig 
score of ≥ 4  
5. Patient’s Wilson’s disease is clinically stable, in the opinion of the investigator, and 
being treated with penicillamine for at least 1 year (52 weeks) prior to the 
screening/enrolment visit 
6. Patient is on a stable dose and regimen of penicillamine for at least 4 months (16 weeks) 
prior to the screening/enrolment visit (other prescribed treatments for Wilson’s disease 
not permitted during this period) 
7. No anticipated need that patient will require additional pharmacological therapies other 
than study medication, including prescribed zinc therapy, for the management of copper 
levels during the study  
8. Patient must be willing to maintain stable diet throughout the study, and avoid foods 
with high copper content, including the Penicillamine Baseline Period  
9. Patient considered suitable to receive therapy with both TETA 4HCl and penicillamine 
administered twice a day 
10. Negative central laboratory tests for HIV and viral hepatitis (results will be available 
after start of run-in period) 
11. For female patients of childbearing potential, negative urine pregnancy test (at 
screening/enrolment visit and prior to randomization) 
12. For females of childbearing potential, use of a reliable form of contraceptive 
13. Patient is considered as able to complete study requirements and attend the study visits, 
in the opinion of the investigator 
Additional inclusion criteria following receipt of Screening laboratory results 
14. Patient is adequately controlled and tolerating penicillamine therapy as defined by 
fulfilment of all of the following: 
a. Serum non-ceruloplasmin bound copper (NCC) level between ≥ 25 and 
 
≤ 150 μg/L*  
b. 24-hour urinary copper excretion of between ≥ 100 and ≤ 900 μg/24 hours*  
c. Alanine transaminase (ALT) < 2 times upper limit of normal* 
d. No other laboratory or clinical findings that would prevent continuation of 
 
maintenance therapy, in the opinion of the investigator 


Clinical Study Protocol 
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Version 6.0 / 27 May 2020 
 
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CONFIDENTIAL 
* Based on results from screening/enrolment visit samples for which can be taken 
within ± 7 days of visit. Result should be within the assay limits of quantification 
for the sample. The ranges in μmol of copper are 0.40 to 2.38 μmol/L for NCC 
and 1.59 to 14.29 for 24-hour urinary copper excretion (using division by 63 of 
value in μg per Walshe, 2011). 
In the event that one or more of the above lab values fall outside the specified 
range, it can be repeated, including at the Week 4 and Week 8 visits.  
Additional inclusion criteria at Week 12 visit (end of Penicillamine Baseline Period) and 
prior to randomization 
15. Patient is adequately controlled and tolerating penicillamine therapy as defined by 
fulfilment of all of the following criteria: 
a. Serum non-ceruloplasmin bound copper (NCC) level between ≥ 25 and 
 
≤ 150 μg/L*  
b. 24-hour urinary copper excretion of between ≥ 100 and ≤ 900 μg/24 hours**  
c. Alanine transaminase (ALT) < 2 times upper limit of normal* 
d. No other laboratory or clinical findings that would prevent continuation of 
maintenance therapy, in the opinion of the investigator 
* Based on lab values from Week 8 visit; ** Based on lab value from Week 4 
visit as routinely not performed at Week 8 visit, however can also be based on 
value at Week 8 visit if a repeat (unscheduled) urinary copper excretion was 
performed at this visit. Result should be within the assay limits of quantification 
for the sample. The ranges in μmol of copper are 0.40 to 2.38 μmol/L for NCC 
and 1.59 to 14.29 for 24-hour urinary copper excretion (using division by 63 of 
value in μg per Walshe, 2011). 
In the event that one or more of the above lab values fall outside the specified 
range, it can be repeated. The repeat value(s) must be available prior to 
randomization at Week 12 and, if within specified range, the patient can continue 
to randomization. If a patient fails this additional criterion at the end of the 
Penicillamine Baseline Period, the patient can return to the start of the run-in 
period i.e. Day 1 (but only once). 
A negative urinary pregnancy test is also required prior to randomization for 
females of childbearing potential. 
Exclusion criteria 
1. Patient is in ‘de-coppering’ phase of treatment for Wilson’s disease, in the opinion of 
the investigator 
2. Patient evidence of uncontrolled liver disease, including but not limited to:  
a. Modified Nazer score of > 4 (result may not be available until after start of run-
in period since based on lab results*) 
b. decompensated cirrhosis 
c. acute hemolytic anemia 
d. acute hepatitis 
e. hepatic malignancy 
f. evidence of acute liver failure  
3. Cause of patient’s liver disease is due to another condition, in the investigator’s opinion 
4. Patient has severe anemia defined as hemoglobin of ≤ 9 g/dL (result will be available 


Clinical Study Protocol 
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Version 6.0 / 27 May 2020 
 
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CONFIDENTIAL 
after start of run-in period*) 
5. Patient has experienced a gastrointestinal bleed within 6 months (24 weeks) prior to 
screening/enrolment visit  
6. Patient has renal impairment defined as creatinine clearance of ≤ 30 mL/min (result 
may not be available until after start of run-in period*), or patient has nephritis or 
nephrotic syndrome, in the opinion of the investigator 
7. Patient has neurological disease that prevents swallowing of study medication (e.g. 
requires a nasogastric feeding tube) or requires intensive in-patient medical care 
8. Patient is currently taking medication containing trientine for management of Wilson’s 
disease or has taken it within 4 months (16 weeks) of screening/enrolment visit  
9. Patient is currently receiving prescribed zinc therapy for management of Wilson’s 
disease or has taken it within 4 months (16 weeks) of screening/enrolment visit  
10. Patient is taking any of the following concomitant therapies: gold therapy, antimalarial 
therapy, cytotoxic drugs, oxyphenbutazone, phenyl butazone  
11. Patient has a known intolerance, allergy or sensitivity to penicillamine (that is 
uncontrolled) or to TETA 4HCl, including any component of the study medication 
12. For female patients of childbearing potential, planning a pregnancy during study period 
or currently nursing 
13. For female patients of childbearing potential, unable or unwilling to use a reliable form 
of contraceptive throughout the study 
14. Patient is currently participating in another therapeutic study, or has previously 
participated in a therapeutic study within 30 days of screening/enrolment visit (or 
longer, if local requirements specify this) 
15. Patient has any condition or in any situation which, in the investigator’s opinion, puts 
the patient at significant risk, could confound study results, or may interfere 
significantly with the patient’s participation in the study 
* Samples for screening/enrolment labs can be taken within ± 7 days of visit. In the event 
that lab value is above the specified threshold, it can be repeated, including at the Week 4 
and Week 8 visits, with the result available prior to randomization at Week 12.   
Test product, dose and mode of administration: 
TETA 4HCl tablets  
Each tablet contains 150 mg of trientine base. 
Reference product, dose and mode of administration: 
Penicillamine (each patient’s current therapy) 
Duration of treatment: 
Each patient will receive chelation therapy (penicillamine/TETA 4HCl) for the duration of the 
study. 
Dosage, dose regimen: 
 
Day 1 to Week 12 (Penicillamine Baseline Period): 
• 
All patients continue to receive their current penicillamine therapy.  


Clinical Study Protocol 
GMPO-131-002 
Version 6.0 / 27 May 2020 
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CONFIDENTIAL 
•
The total daily dose in milligrams (mg) is to be the same as the patient’s current
maintenance dose of penicillamine. This will be administered as 2 divided doses for all
patients (BID).
•
In the event that the total daily dose needs to be changed, this is permitted during the 4-
week run-in period and subsequently, if deemed clinically necessary (see dose
modification criteria)
Week 12 to Week 36 (24-week Post-randomization Phase) 
•
Patients are randomized to receive TETA 4HCl or to continue to receive their current
penicillamine therapy
•
For patients randomized to TETA 4HCl the total daily dose in mg of trientine base will be
the same as the patient’s total daily dose of penicillamine in mg at the end of the
Penicillamine Baseline Period at Week 12, rounded to the nearest 150 mg, administered
as 2 divided doses for all patients (BID)
•
For patients randomized to penicillamine the total daily dose in mg will be the same as at
the end of the Penicillamine Baseline Period at Week 12. This will be administered as 2
divided doses for all patients (BID)
•
In the event that the total daily dose needs to be changed, this is permitted during the 4-
week run-in period and subsequently, if deemed clinically necessary (see dose
modification criteria)
Week 36 to Week 60 (first 24 weeks of Extension Phase) 
•
All patients continue to receive their allocated TETA 4HCl or penicillamine therapy
according to their randomized allocation
•
The total daily dose will be the continuation of the patient’s total daily dose in mg
(trientine base or penicillamine) at the end of the 24-week Post-randomization Phase at
Week 36. This will continue to be administered as 2 divided doses for all patients (BID)
•
In the event that the total daily dose needs to be changed, this is permitted, if deemed
clinically necessary, during the Extension Phase (see dose modification criteria)
Week 60 to Week 108 (last 48 weeks of Extension Phase) 
•
All patients receive TETA 4HCL
•
The total daily dose in mg of trientine base will be the same as the total daily dose the
patient is receiving at the end of Week 60, rounded to the nearest 150 mg if the patient
had been in the penicillamine arm. This will be administered as 2 divided doses for all
patients (BID)
•
In the event that the total daily dose needs to be changed, this is permitted at any time
during the extension phase (see dose modification criteria)
Dose modification: 
The investigator may modify (increase or decrease) the total daily dose of penicillamine or 
TETA 4HCl by protocol-defined increments if the patient is no longer fulfilling the protocol 
criteria of being adequately controlled and tolerating the chelation therapy. The investigator’s 
decision therefore includes the evaluations of serum NCC, 24-hour urinary copper excretion, 
alanine transaminase (ALT) level, and any safety parameters that could warrant a change in 
dose; the investigator will also take into account other factors e.g. compliance with study 
medication. See protocol for full details. 


Clinical Study Protocol 
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CONFIDENTIAL 
Criteria for evaluation: 
Efficacy measures: 
Primary: 
•
Serum NCC concentration
Secondary:
•
24-hour urinary copper excretion
•
Clinical stability assessment by independent Adjudication Committee
•
Clinical Global Impression of Change (CGIC) rating scale
Other:
•
Unified Wilson’s Disease Rating Scale (UWDRS), neurological scale
•
Serum total copper and serum ceruloplasmin concentrations
Safety measures:
•
Adverse events and serious adverse events
o
Clinically significant laboratory abnormalities and significant changes in
neurological signs/symptoms will be reported as AEs
•
Hematology, biochemistry and coagulation analysis
•
Urinalysis
•
Neurological signs and symptoms (using the relevant UWDRS items)
•
Cognitive assessment using the semantic verbal fluency test
•
Modified Nazer score
•
Vital signs (heart rate, blood pressure, respiration rate, body temperature)
•
Urine pregnancy test (for females of childbearing potential)
Pharmacokinetic measures:
•
Plasma samples will be obtained at designated sites/visits for patients who receive TETA
4HCl for subsequent pharmacokinetic evaluation of plasma concentrations of trientine
and the metabolites N1-acetyltriethylenetetramine (MAT) and N1, N10-
diacetyltriethylenetetramine (DAT)
Statistical methods: 
The intention-to-treat population will consist of all randomized patients. 
All safety analyses will be performed using the safety population, consisting of all patients 
who received at least one dose penicillamine in the Penicillamine Baseline Period.  
The pharmacokinetic population will be defined in a separate pharmacokinetic analysis plan. 
Efficacy: The primary efficacy measure of the study is serum NCC concentration. The 
absolute values at screening/enrolment, Weeks 4, 8, 12, 16, 20, 24, 28, 32 and 36, will be 
analysed using a restricted maximum likelihood (REML) based general linear model for 
correlated data. The model will be used to test if there is a difference between the absolute 
values of serum NCC in the two treatment groups at Week 36. Non-inferiority of TETA 
4HCl compared to penicillamine will be declared if the limit of the one-sided 97.5% 
confidence interval of the difference in mean serum NCC level under these two treatments 
excludes the non-inferiority margin. 
The same model will be used for the repeatedly measured 24-hour urinary copper excretion 
absolute values. In addition, the proportion of patients with serum NCC levels below certain 
thresholds at Week 36 will be summarised as will be the proportion of patients with 24-hour 
urinary copper excretion above certain thresholds, as will the proportion of patients 
remaining within the entry criteria ranges of serum NCC and urinary copper excretion. 


Clinical Study Protocol 
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Version 6.0 / 27 May 2020 
 
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CONFIDENTIAL 
The outcome of the adjudication will state whether patients are well controlled and clinically 
stable. The proportion of clinically stable patients at Week 36 and at Week 60 will be 
computed and reported with their 95% confidence intervals.  
The results of the UWDRS neurological scale will also be presented, including graphical 
representation e.g. within-patient shifts. 
Efficacy data for the Extension Phase will be summarized separately. 
Safety: AEs will be summarized by system organ class (SOC), preferred term (PT), and 
treatment group as the number and percentage of patients with an event. The following 
subsets of AEs will also be summarized by treatment group: AEs related to study treatment, 
severe AEs, AEs leading to treatment withdrawal and SAEs.  
Categorical endpoints will be summarized by frequencies and percentages, continuous 
endpoints by summary statistics.  
Safety data for penicillamine will be tabulated separately for the following 4 periods: 
screening/enrolment visit to Week 12 visit (i.e. Penicillamine Baseline Period), Week 12 visit 
+1 day to Week 36 visit (i.e. 24-week Post-randomization Phase), Extension Phase from 
Week 36 visit +1 day up to Week 60 visit, Extension Phase from Week 60 visit +1 day to 
Week 108 visit, or end of treatment visit, whichever is earlier.  

SAP_001.pdf: 
 
 
 
Confidential 
 
 
 
Page 1 of 24 
 
TPL N°: eTPL SA-02-01 
TPL Version: 02 
Of SOP SA-02.08 
TPL Effective Date: 31 Mar 2016 
 
 
Statistical Analysis Plan 
 
 
 
 
Sponsor:  
gmp-orphan 
Protocol Title:  
CHELATE STUDY: Trientine tetrahydrochloride (TETA 
4HCl) for the treatment of Wilson’s disease 
Study Code: 
GMPO-131-002 (CHELATE STUDY) 
Status 
Final, version 03 August 2020 
 
 
 
For IDDI: 
Author : Nicolas Dubois– Biostatistician 
Reviewer: Koenraad D’Hollander – Biostatistician 
 
For Sponsor: 
Approval: Naseem Amin – CEO 
DocuSign Envelope ID: 865E391F-2BB2-408A-91B2-22F5663395FE
18 August 2020


 
 
 
Confidential 
 
 
 
Page 2 of 24 
 
TPL N°: eTPL SA-02-01 
TPL Version: 02 
Of SOP SA-02.08 
TPL Effective Date: 31 Mar 2016 
 
Table of Contents 
 
KJRZELF 
1. 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ............................... 4 
2. 
INTRODUCTION ........................................................................................... 5 
3. 
STUDY DESIGN AND OBJECTIVES ................................................................ 5 
3.1 
Study Objectives...................................................................................... 5 
3.1.1 
Efficacy endpoints ............................................................................. 5 
3.1.2 
Safety endpoints ............................................................................... 5 
3.2 
Study Design ........................................................................................... 5 
3.3 
Planned analyses ................................................................................... 10 
3.3.1 
Interim Analysis .............................................................................. 10 
3.3.2 
Primary Analysis ............................................................................. 10 
3.3.3 
Additional Extension Phase Analysis ................................................... 10 
3.4 
Non-inferiority (NI) Margin and Sample Size Justification ............................ 10 
3.4.1 
NI Margin ....................................................................................... 10 
3.4.1.1 
Provisional NI Margin ................................................................... 10 
3.4.1.2 
Revised NI Margin ........................................................................ 11 
3.4.2 
Sample size .................................................................................... 11 
3.4.2.1 
Provisional Sample size ................................................................ 11 
3.4.2.2 
Sample Size Re-assessment .......................................................... 11 
4. 
GENERAL ANALYSIS DEFINITIONS ............................................................ 12 
4.1 
Definition of Populations ......................................................................... 12 
4.1.1 
Intention-To-Treat (ITT) Population ................................................... 12 
4.1.2 
Per Protocol (PP) Population ............................................................. 12 
4.1.3 
Safety Population ............................................................................ 12 
4.1.4 
Extension Phase population .............................................................. 13 
4.2 
Treatment Assignment and Treatment Arms .............................................. 13 
4.3 
Calculated Variables ............................................................................... 13 
4.4 
Partial Dates ......................................................................................... 13 
4.5 
Methods To Be Used For Handling Missing Data ......................................... 13 
4.5.1 
Missing data in the efficacy evaluation primary analyses. ..................... 13 
4.5.1.1 
Tipping point analysis ................................................................... 14 
4.5.2 
Missing data in the non-primary analyses ........................................... 14 
5. 
STUDY PATIENTS ....................................................................................... 15 
5.1 
Disposition of Patients ............................................................................ 15 
5.2 
In- and Exclusion Criteria ........................................................................ 15 
6. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ........................ 15 
7. 
PRIOR AND CONCOMITANT TREATMENT, PRIOR AND CONCOMITANT 
PROCEDURES AND SURGERIES ......................................................................... 16 
8. 
EFFICACY EVALUATION ............................................................................. 16 
8.1 
Serum NCC Values ................................................................................. 16 
8.1.1 
Difference at Week 36 ..................................................................... 16 
8.1.2 
Difference at Week 60 ..................................................................... 17 
8.1.3 
Summary Statistics ......................................................................... 17 
8.1.4 
Serum NCC Thresholds .................................................................... 17 
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8.1.5 
Serum NCC within subject variability ................................................. 18 
8.1.6 
Visualization of the evolution of Serum NCC ....................................... 18 
8.2 
24-hour Urinary Copper Excretion ............................................................ 18 
8.2.1 
Difference at Week 36 ..................................................................... 18 
8.2.2 
Difference at Week 60 ..................................................................... 19 
8.2.3 
Summary Statistics ......................................................................... 19 
8.2.4 
Urinary Copper Excretion Thresholds ................................................. 19 
8.2.5 
24-hour urinary copper excretion within subject variability ................... 20 
8.2.6 
Visualisation of the evolution of 24-hour urinary copper excretion ......... 20 
8.3 
Adjudication results ................................................................................ 20 
8.4 
Combined Serum NCC and Urinary Copper Excretion Thresholds .................. 20 
8.5 
CGIC Score ........................................................................................... 21 
8.6 
UWDRS Neurological Scale ...................................................................... 21 
8.7 
Serum Total Copper and Serum Ceruloplasmin .......................................... 21 
9. 
SAFETY EVALUATION ................................................................................. 21 
9.1 
General Definitions ................................................................................. 21 
9.2 
Extent of Exposure ................................................................................. 22 
9.3 
Adverse Events ...................................................................................... 22 
9.4 
Cognitive Assessment ............................................................................. 23 
9.5 
Clinical Laboratory Determination ............................................................ 23 
9.6 
Vital Signs ............................................................................................ 24 
10. 
REFERENCES .......................................................................................... 24 
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1. 
List of Abbreviations and Definition of Terms 
 
Abbreviation 
Term 
 
AE 
Adverse Event 
 
ALT 
Alanine transaminase 
 
aPTT 
Activated partial thromboplastin time 
 
AST 
Aspartate transaminase 
 
BID 
Twice a day 
 
BUN 
Blood urea nitrogen 
 
CRF 
Case report form 
 
GGT 
Gamma glutamyl transpeptidase 
 
INR 
International normalised ratio 
 
ITT 
Intention-To-Treat 
 
LDH 
Lactate dehydrogenase 
 
MedDRA 
Medical Dictionary for Regulatory Activities 
 
NCC 
Non-ceruloplasmin bound copper 
 
PP 
Per protocol 
 
PT (AE) 
Preferred Term 
 
PT 
Prothrombin time 
 
RBC 
Red blood cells 
 
SAE 
Serious adverse event 
 
SOC 
System Organ Class 
 
TETA 4HCl 
Trientine tetrahydrochloride 
 
WBC 
White blood cells 
 
WHO 
World Health Organization 
 
 
 
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2. 
Introduction 
This Statistical Analysis Plan was written for the Phase 3 clinical trial GMPO-131-002 
(CHELATE STUDY) conducted in 15 sites. The ICH guideline E3 “Structure and Content of 
Clinical Study Reports” was used as a guide to the writing of the plan.  
3. 
Study Design and Objectives 
3.1 Study Objectives 
The primary objective of this study is to evaluate the efficacy of trientine tetrahydrochloride 
(TETA 4HCl) as compared to standard-of-care penicillamine, in adult patients with Wilson’s 
disease who are adequately controlled and tolerating their penicillamine chelation therapy. 
The safety of TETA 4HCl compared to standard-of-care penicillamine will also be evaluated. 
3.1.1 Efficacy endpoints 
The primary endpoint of this study is the absolute value of non-ceruloplasmin bound copper 
(NCC) concentration (µg/L), measured at Screening/enrolment, Weeks 4, 8, 12, 16, 20, 
24, 28, 32 and 36 (additional unscheduled measurements may also be taken). The primary 
hypothesis is that the efficacy of TETA 4HCl, as assessed by NCC levels, is not inferior to 
the efficacy of penicillamine, at Week 36. 
The secondary efficacy measures are:  
 
24-hour urinary copper excretion (µg/24 hours) 
 
Clinical global Impression of Change (CGIC) rating scale  
Other efficacy measures are:  
 
Unified Wilson’s Disease Rating Scale (UWDRS), neurological scale  
 
Serum total copper and serum ceruloplasmin 
3.1.2 Safety endpoints 
 
Adverse events and serious adverse events  
 
Hematology, biochemistry and coagulation analysis  
 
Urinalysis  
 
Neurological signs and symptoms (using the relevant UWDRS items)  
 
Cognitive assessment using the semantic verbal fluency test 
 
Modified Nazer score  
 
Vital signs (heart rate, blood pressure, respiration rate, body temperature)  
 
Urine pregnancy test (for females of childbearing potential) 
3.2 Study Design 
This is a multicenter, randomized, open label study, comparing TETA 4HCl (tablets 
containing 150 mg of active product, individually dosed) with an active standard-of-care 
comparator, penicillamine (oral therapy, individually dosed). Patients will take their total 
daily dose as 2 divided doses (BID).  
Patients who are considered to be stable on their penicillamine chelation therapy for at 
least 1 year will enroll in the study and enter a 12-week Penicillamine Baseline Period. 
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During this time all patients will continue to take their current penicillamine under study 
conditions.  
At the end of the Penicillamine Baseline Period i.e. Week 12, patients who fulfill the protocol 
definition of being adequately controlled and tolerating penicillamine will be randomized in 
a 1:1 ratio to receive either TETA 4HCl (same total daily dose in mg as penicillamine dose 
at the end of the Penicillamine Baseline Period, rounded to the nearest 150 mg) or to 
continue to receive penicillamine (same total daily dose in mg as at the end of the 
Penicillamine Baseline Period). Post randomization there is a 24-week Post-randomization 
Phase. Scheduled study visits (clinic or telephone) will occur at Screening/enrolment 
(clinic), Week 4 (clinic), Week 8 (telephone), Week 12 (clinic), Week 16 (clinic), Week 20 
(telephone), Week 24 (clinic), Week 28 (telephone), Week 32 (telephone) and Week 36 
(clinic) – see Figure 1. For the telephone visits, the necessary lab samples will be collected 
directly from the patient.  
On completion of 24-week Post-randomization phase at Week 36, patients will then have 
the opportunity to enter a 72-week extension phase where initially they will continue on 
their allocated treatment (penicillamine or TETA 4HCl) for a further 24 weeks i.e. until 
Week 60. The total daily dose will be the continuation of the patient’s total daily dose in 
mg at the end of the 24-week Post-randomization phase at Week 36. Thereafter all patients 
will receive TETA 4HCl for a further 48 weeks and the total daily dose in mg of TETA 4HCl 
will be the same as the total daily dose the patient is receiving at the end of Week 60, 
rounded to the nearest 150 mg for those patients who were receiving penicillamine. Study 
clinic visits will occur every 24 weeks for all patients i.e. at Weeks 60, 84 and 108. An 
additional visit for patients who were previously allocated to the penicillamine treatment 
arm will occur at Week 64 (i.e. 4 weeks after starting to receive TETA 4HCl). Figure 1 
depicts the overall study design. Table 1 shows the schedule of events.  
Dose modification is permitted during the study. 
 
Figure 1 
Evaluation
(20 weeks)
Run-in 2
(4 weeks)
Randomization of 
adequately controlled 
patients per protocol 
criteria
Evaluation
(8 weeks)
Penicillamine Baseline Period
Run-in 1 
(4 weeks)
Enrolment of stable patients 
receiving penicillamine for
≥ 52 weeks, stable dose for 
≥ 16 weeks
Post-randomization Phase: TETA 4HCl
*May be telephone visit 
with lab samples obtained 
directly from patient
Screen/enrol 
(clinic)
Wk 4 
(clinic)
Wk 8 
(tel)*
Wk 12 
(clinic)
Wk 16 
(clinic)
Wk 20
(tel)*
Wk 24 
(clinic)
Wk 36 
(clinic)
Wk 28
(tel)*
Post-randomization Phase: Penicillamine
Extension Phase (72 weeks)
(continue allocated TETA 4HCl or 
penicillamine for further 
24 weeks, then all receive 
TETA 4HCl for 48 weeks)
Clinic visits at Wk 60, Wk 84, and 
Wk 108 for all patients (additional 
visit at Wk 64 for patients 
previously in penicillamine arm)
Evaluation
(20 weeks)
Run-in 2
(4 weeks)
Wk 16 
(clinic)
Wk 20
(tel)*
Wk 24 
(clinic)
Wk 36 
(clinic)
Wk 28
(tel)*
Wk 32
(tel)*
Wk 32
(tel)*
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Table 1 
Assessment 
Day 1 
Screening/
enrolment 
(clinic) 
Week 4 
± 4 days 
(clinic) 
Week 8b 
± 4 days 
(tel) 
Week 12 
± 4 days  
(clinic) 
Week 16 
± 7 days 
(clinic) 
Week 20b 
± 7 days 
(tel) 
Week 24 
± 7 days 
(clinic) 
Week 28b 
± 7 days 
(tel) 
Week 32b 
± 7 days 
(tel) 
Week 36i 
± 7 days 
(clinic) 
Weeks 60, 
(64)j, 84  
± 10 days 
(clinic) 
Week 108k 
± 10 days 
(clinic) 
Signed informed consent and data 
protectiona 
Xr 
 
 
 
 
 
 
 
 
 
 
 
Wilson’s disease medical history 
and prior medication 
X 
 
 
 
 
 
 
 
 
 
 
 
Other medical history and prior 
medication 
X 
 
 
 
 
 
 
 
 
 
 
 
Demography, height/weight, HIV 
and viral hepatitis analysis 
Xr 
 
 
 
 
 
 
 
 
 
 
 
Vital signs  
X 
X 
 
X 
X 
 
X 
 
 
X 
X 
X 
Non-ceruloplasmin bound copperl 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum total copperm 
X 
 
 
X 
 
 
X 
 
 
X 
Xq 
X 
Serum ceruloplasminm 
X 
 
 
X 
 
 
X 
 
 
X 
Xq 
X 
24-hour urinary copper excretion 
X 
X 
(X – if 
repeat 
required) 
X 
X 
 
X 
 
 
X 
X 
X 
Clinical Global Impression of 
Change 
 
X 
 
X 
X 
 
X 
 
 
X 
X 
X 
Hematology, biochemistry and 
coagulation analysisc  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
X 
 
X 
X 
 
X 
 
 
X 
X 
X 
Unified Wilson’s Disease Rating 
Scale (Neurological scale)n 
Xr 
Xr 
 
X 
X 
 
X 
 
 
X 
X 
X 
Cognitive assessment (semantic 
fluency test)n 
 
 
 
X 
X 
 
X 
 
 
X 
Xq 
X 
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Assessment 
Day 1 
Screening/
enrolment 
(clinic) 
Week 4 
± 4 days 
(clinic) 
Week 8b 
± 4 days 
(tel) 
Week 12 
± 4 days  
(clinic) 
Week 16 
± 7 days 
(clinic) 
Week 20b 
± 7 days 
(tel) 
Week 24 
± 7 days 
(clinic) 
Week 28b 
± 7 days 
(tel) 
Week 32b 
± 7 days 
(tel) 
Week 36i 
± 7 days 
(clinic) 
Weeks 60, 
(64)j, 84  
± 10 days 
(clinic) 
Week 108k 
± 10 days 
(clinic) 
Modified Nazer score 
X 
X 
 
X 
X 
 
X 
 
 
X 
X 
X 
Recording of significant change in 
dietary copper intake 
 
X 
 
X 
X 
 
X 
 
 
X 
X 
X 
Samples for PK analysiso 
 
 
 
 
 
 
X 
 
 
X 
 
 
Urine pregnancy testp 
X 
 
 
X 
X 
 
X 
 
 
X 
X 
X 
Eligibility criteria 
X 
Xd 
 
Xd 
 
 
 
 
 
 
 
 
Randomization 
 
 
 
X 
 
 
 
 
 
 
 
 
Study medication dispensed  
Xe 
Xe 
 
Xf 
Xf 
 
Xf 
 
 
Xg 
Xg 
 
Concomitant medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse eventsh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
a Informed consent and data protection documentation must be signed prior to any study specific procedure being performed. 
b For telephone visits, lab samples obtained directly from patient.   
c Analysed by central laboratories.  
d All criteria must still be fulfilled at Week 4 and at Week 12 (prior to randomization), including additional entry criterion regarding patient defined as adequately controlled and 
tolerating penicillamine.  
e Study medication (standard-of-care penicillamine) taken from Day 1 (starting with the evening dose on the day of the screening/enrolment visit) to the Week 12 visit.  
f Study medication (TETA 4HCl or continuation of standard-of-care penicillamine per randomized allocation) taken from Week 12 visit (starting with the evening dose on the 
day of the visit) to the Week 36 visit.  
g For the Extension Phase, the allocated study medication (TETA 4HCl or standard-of-care penicillamine) will continue to be taken to Week 60 visit. Then all patients receive 
TETA 4HCl to Week 108 visit. 
h Adverse events recorded from time of informed consent signature. 
i End of 36-week phase of study/Exit if not continuing into extension phase (if a patient discontinues early during this phase, all effort should be made to perform all assessments). 
j Week 64 visit only performed in patients previously allocated to penicillamine arm.  
k End of the 18 month extension phase/Exit (if a patient discontinues early during this phase, all effort should be made to perform all assessments). 
l Performed using validated assay (direct serum NCC assay) at a central laboratory . 
m Performed using validated assays at a central laboratory, with results available at periodic intervals.  
n Should be performed by an independent neurologist. 
o Only for patients receiving TETA 4HCl at designated sites.  
p For all women of childbearing potential. In addition, for any reported case of delayed menstrual period (over 1 month between menstruations) and for those women with 
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infrequent or irregular menstrual cycles, confirmation of absence of pregnancy should occur. 
q Performed only at Week 60 visit. 
r A patient may return to Day 1 if they do not fulfill the laboratory criteria defined by the inclusion/exclusion criteria. In this case these specified examinations do not need to be 
repeated. 
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3.3 Planned analyses 
3.3.1 Interim Analysis  
A pre-planned interim analysis will be performed when approximately 10 evaluable patients, 
who fulfil the protocol definition of being adequately controlled and tolerating penicillamine, have 
reached the Week 12 visit i.e. at the end of the Penicillamine Baseline Period, prior to 
randomization. Additional interim analyses may be conducted, if appropriate. 
Only data collected at screening/enrolment and during the Penicillamine Baseline Period will be 
utilized for the interim analysis. 
The purpose of the interim analysis is to perform an evaluation of the within-patient data for 
serum NCC in order to re-calculate the NI margin and sample size, if required (see Section 3.4). 
This will also be performed for the 24-hour urinary copper excretion. 
3.3.2 Primary Analysis 
The primary analysis of this study will occur following completion of the Week 36 visit, after all 
data are available. At this time, the database will be locked. Available data from the Extension 
Phase will also be evaluated at this time. However, they will be presented separately from the 
data analyzed in the primary analysis, which will only contain data up to Week 36.  
The values of NCC used for the primary analysis will be those obtained using the selected, 
primary validated NCC assay. Analysis of NCC values using the initial assay for entry of the 
subject in the study will be supportive secondary analysis. 
3.3.3 Additional Extension Phase Analysis 
An analysis will be performed when all patients have completed the Extension Phase of the 
study. 
Additional analyses after the primary analysis may occur as required e.g. to fulfill regulatory 
submission requirements.  
3.4 Non-inferiority (NI) Margin and Sample Size Justification 
There are no reliable historical data for within-patient serum NCC or 24-hour urinary copper 
excretion in stable patients with Wilson’s disease on maintenance therapy, including comparison 
versus a control. The provisional NI margin and sample size calculation is based on data from 8 
patients with stable Wilson’s disease (Ala et al, 2015).  
3.4.1 NI Margin 
3.4.1.1  Provisional NI Margin 
In a series of 8 patients with stable Wilson’s disease (Ala et al, 2015), the standard 
deviation of the within-patient measurements of serum NCC varied between 10 and 70 
µg/L; so 50 µg/L was chosen as a plausible, provisional value for the non-inferiority margin 
of serum NCC. 
Although not the primary endpoint, a NI margin is also provided for the 24-hour urinary 
copper excretion. The standard deviation of the within-patient measurements of urinary 
copper excretion in the aforementioned 8 patients varied between 1.4 and 276 μg/24 
hours, which shows the large variability of urinary copper excretion; a 100 μg /24 hours 
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was chosen as a plausible, provisional value for the non-inferiority margin of serum urinary 
excretion. 
3.4.1.2  Revised NI Margin  
At the time of the interim analysis (see Section 3.3.1) all available NCC data during the 
Penicillamine Baseline Period (using NCC values obtained from the initial NCC assay utilized 
for inclusion of the subjects in the study) will be utilized to assess the mean observed 
within-patient standard deviation (𝜎𝑜𝑏𝑠).  
In addition, the observed within-patient standard deviation for 24-hour urinary copper 
excretion during the Penicillamine Baseline Period will be evaluated. 
In order to put these serum NCC data in context, per patient demography, baseline disease 
characteristics and prior/current treatment may also be provided. 
If deemed appropriate, this may also be performed when more patients have completed 
the Penicillamine Baseline period. 
In addition, for the primary analysis the final 𝜎𝑜𝑏𝑠 for serum NCC during the Penicillamine 
Baseline Period will also inform the interpretation of the Non Inferiority (NI). This will be 
utilizing the values of NCC obtained using the selected, validated NCC assay for the primary 
analysis. The primary endpoints (i.e. the difference of NCC between the two arms at week 
36) will be compared to the final within-patient standard deviation measured during the 
Penicillamine Baseline Period in order to provide hindsight on the Non Inferiority (NI) 
Margin. Similarly the difference of 24-hour urinary copper excretion between the two arms 
at week 36 will be compared to the final within-patient standard deviation measured during 
the Penicillamine Baseline Period in order to provide hindsight on the Non Inferiority (NI) 
Margin. 
3.4.2 Sample size 
3.4.2.1  Provisional Sample size 
The provisional sample is calculated under the following assumptions  
 
One-tailed significance level= 0.025  
 
Power = 0.8  
 
Observed standard deviation (SD) of within-patient difference in serum NCC= 60 
µg/L  
 
NI margin for serum NCC (See Section 3.4.1.1) = 50 µg/L 
With these assumptions, a sample size of approximately 46 patients is required. Therefore, 
approximately 55 patients will initially be planned to be randomized to account for drop-
outs. This sample size is calculated under the conservative assumption that serum NCC 
will be compared at a single time point, whereas in fact the model will use repeated 
measures of serum NCC, thus providing more power for the comparison. 
3.4.2.2  Sample Size Re-assessment 
The sample size will be recalculated at the time of the interim analysis (see Section 3.3.1), 
if needed, based exclusively on data from the Penicillamine Baseline Period, i.e. regardless 
of any difference between the randomized groups at the time of the pre-planned evaluation 
of the within-patient serum NCC and 24-hour urinary copper excretion data.  
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The interim analysis will be carried out by a statistician independent of the study team. A 
firewall will be put in place in such a way that the study team, i.e. the study statistician(s), 
statistical programmers and the people directly managing the sites, remains completely 
blinded to the details of the results of the interim analysis. In order to minimize any bias 
arising from the sample size re-assessment, participating investigators will also not be 
provided with details of the results of the interim analysis. 
4. 
General Analysis Definitions 
Data will be analyzed using SAS (Version 9.3 or higher). No tests of significance will be 
carried out to compare treatment arms on baseline data because any observed differences 
between them must be attributed to chance. 
The significance level will be set at 𝛼 = 0.05 for two-tailed tests, and at 𝛼 = 0.025 for one-
tailed tests. 
Descriptive statistics will be tabulated as follows:  
 
Categorical data will be summarized in contingency tables presenting frequencies and 
percentages. Percentages will be calculated using the total number of patients in the 
population of interest in the denominator (See Section 4.1), or the number of patients 
with non-missing information. This will be specified in the tables.  
 
Continuous data will be summarized using number of non-missing values (n), mean, 
standard deviation, median, first and third quartiles, minimum and maximum values. 
The tables will be created by treatment arm and overall, unless specified otherwise. 
Listings with individual values will be provided for all data presented in the tables.  
4.1 Definition of Populations 
4.1.1 Intention-To-Treat (ITT) Population  
The Intention-To-Treat population (ITT) will consist of all randomized subjects, whether or 
not they receive one administration of study treatment post randomization. All subjects 
will be analyzed according to their randomized treatment allocation i.e. penicillamine or 
TETA 4HCl. This is the primary population for the primary efficacy analysis. All other 
efficacy analyses, except for those only including data of the Extension Phase, will also 
analyze the ITT population.  
Data will be presented according to randomized treatment allocation i.e. penicillamine or 
TETA 4HCl and, in addition, for the Penicillamine Baseline period only, overall. 
4.1.2 Per Protocol (PP) Population 
The Per Protocol population (PP) consists of all patients without significant protocol 
deviations who complete up to Week 36 of the study. Subjects will be analyzed by actual 
treatment first received after randomization. The significant protocol deviations will be 
defined before database lock. 
4.1.3 Safety Population  
The Safety population will include all randomized subjects who received at least one dose 
of study medication post-randomization. Data will be presented according to the actual 
first treatment received after randomization i.e. penicillamine or TETA 4HCl and, in 
addition, for the Penicillamine Baseline period only, overall.  
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4.1.4 Extension Phase population 
For the Extension Phase, efficacy and safety analyses will be based on patients who receive 
at least one dose of study medication in the Extension Phase. Subjects will be analyzed 
according to their actual treatment sequence received after randomization.  
4.2 Treatment Assignment and Treatment Arms 
Randomization will be performed through an interactive web based system. Patients will 
be centrally allocated in a 1:1 ratio to TETA 4HCl or penicillamine. A dynamic minimization 
procedure will be used, stratified by site and serum NCC concentration at Week 8 (≤ 75 
µg/L or > 75 µg/L), using a stochastic treatment allocation algorithm based on the variance 
method (Freedman and White, 1976). This implementation of minimization guarantees 
that all treatment allocations are stochastic (Pocock and Simon, 1975). 
4.3 Calculated Variables 
 
Baseline is defined as the last non-missing value of the Penicillamine Baseline 
Period, including unscheduled values.  
 
In case of repeated measure of lab values, the last value, i.e. the repeat result, will 
be used for analysis.  
4.4 Partial Dates 
Partial or missing dates in general will not be imputed, except for AEs’ and laboratory 
information. 
Partial adverse event (AE) start date and laboratory sample date will be imputed in order 
to include events and laboratory results in table summaries in case of doubt. The following 
rules will be applied: 
 
Partial date (only day missing): 
o 
If partial date falls in the same month as the first dose of randomized study 
treatment, then assign to first dose of study treatment + 1 day. 
o 
Else assign to the first day of the month. 
 
Partial date (day and month missing): 
o 
If partial date falls in the same year as the first dose of randomized study 
treatment, then assign to first dose of study treatment + 1 day. 
o 
Else if the partial date falls in the same year as a previous visit (before the 
first dose of randomized study treatment), then assign to this date of 
previous visit + 1 day. 
o 
Else assign to the first day of the year. 
The imputed date will not be reported in the corresponding derived data listing. If a 
medication date is missing or partially missing, in a way that it cannot be determined if it 
was taken prior or concomitantly to the screening/enrolment visit (using the date and the 
eCRF variable that indicates if the medication was taken prior to the date of first 
screening/enrolment visit), it will be considered both as a prior and concomitant 
medication. 
4.5 Methods To Be Used For Handling Missing Data 
4.5.1 Missing data in the efficacy evaluation primary analyses. 
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If there are any missing data, the results obtained using a general linear model for 
correlated data, are valid under the missingness at random (MAR) assumption (See also 
Section 8.1.1). This means that results are valid, as long as the probability of missingness 
depends on the covariates in the model, and on observed outcomes, but not on the 
unobserved values of the endpoint. In this sense, imputation of missing data is not 
necessary, however a tipping point analysis will also be performed (see below). 
4.5.1.1 Tipping point analysis 
A tipping point analysis to evaluate sensitivity to potential violations of the missing data 
assumption (MAR) will be applied for the efficacy evaluation of serum NCC and 24-hour 
Urinary Copper Excretion at Week 36.  
The general linear model described in section 8.1.1 will be used to estimate the: 
 
Differences between the means of the TETA and penicillamine arms at each 
timepoint: Δ = 𝜇𝑝,𝑥 𝑤𝑒𝑒𝑘𝑠− 𝜇𝑡,𝑥 𝑤𝑒𝑒𝑘𝑠 , …, with 𝑡=TETA and 𝑝=penicillamine 
 
The variance-covariance matrix of the repeated measures 
All missing data will be imputed using SAS PROC MI procedure by using a Fully Conditional 
Specification (FCS) approach and the MNAR statement with the SHIFT option. Twenty 
different scenarios will be generated, in which the mean of the TETA arm will be gradually 
increased by steps of 10% of the estimated difference between the two arms. The marginal 
mean for imputing missing values according to scenario k will be  
𝜇𝑚𝑖𝑠𝑠𝑖𝑛𝑔,   𝑡,   𝑡𝑖𝑚𝑒𝑝𝑜𝑖𝑛𝑡 𝑖,   𝑠𝑐𝑒𝑛𝑎𝑟𝑖𝑜 𝑘= 𝜇𝑡,   𝑡𝑖𝑚𝑒𝑝𝑜𝑖𝑛𝑡 𝑖+  𝛿𝑡,𝑘. The space of plausible values for 𝛿𝑡,𝑘 
is defined as 
𝛿𝑡∈ [Δ𝑡𝑖𝑚𝑒𝑝𝑜𝑖𝑛𝑡 𝑖× 𝐶𝑜𝑒𝑓𝑓𝑖𝑐𝑖𝑒𝑛𝑡𝑘],  
With 
 
[Δ𝑡𝑖𝑚𝑒𝑝𝑜𝑖𝑛𝑡 𝑖 the difference between estimated TETA and pencillamine mean at timepoint 
i 
 
𝑪𝒐𝒆𝒇𝒇𝒊𝒄𝒊𝒆𝒏𝒕𝒌 going from 0.1 to 2 by steps of 0.1 
For each of the 20 scenarios, 25 imputations of missing data will be performed. The missing 
values will be replaced by a value from a random number generator for the multivariate 
normal distribution using the assumption:  
𝑚𝑖𝑠𝑠𝑖𝑛𝑔 𝑣𝑎𝑙𝑢𝑒𝑠 ~𝑁(𝝁𝒎𝒊𝒔𝒔𝒊𝒏𝒈,   𝒕,   𝒔𝒄𝒆𝒏𝒂𝒓𝒊𝒐 𝒌, 𝚺)  
With 
 
𝝁𝒎𝒊𝒔𝒔𝒊𝒏𝒈,   𝒕,   𝒔𝒄𝒆𝒏𝒂𝒓𝒊𝒐 𝒌= the vector of shifted marginal means at each timepoint 
 
𝚺 the variance-covariance matrix estimated by the linear mixed model without 
imputation 
The linear mixed models described in section 8.1.1 will then be applied on the 500 datasets 
(20 scenarios x the 25 imputations). The SAS procedure proc mianalyze will be used to 
combine the results of the 25 imputations linear mixed models of each scenario. A table, 
including the shift 𝐶𝑜𝑒𝑓𝑓𝑖𝑐𝑖𝑒𝑛𝑡𝑘 , p-values and 95% confidence interval, will indicate if there 
is a tipping point that reverses the study conclusion. 
4.5.2 Missing data in the non-primary analyses 
Other missing, unused and spurious data will be treated as such and none of these data 
will be imputed, other than the aforementioned dates for AEs and laboratory information. 
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5. 
Study Patients 
5.1 Disposition of Patients 
The number of patients in each population, as defined in section 4.1, will be tabulated by 
randomized treatment arm and overall.  
The number of patients treated and percentage of patients who prematurely discontinued 
post-randomization will be given by treatment arm and overall for the ITT population. The 
primary reason for premature discontinuation will be summarized. The details of the ‘other 
reason’ will be included in the listing.  
Screen failures, including reason for failure will be tabulated separately. 
5.2 In- and Exclusion Criteria 
Listing of all in- and exclusion criteria not met will be provided by treatment arm. This will 
include all patients who entered the Penicillamine Baseline Period who did not get 
randomized (no treatment arm allocated). 
6. 
Demographic and Other Baseline Characteristics 
Descriptive statistics with respect to patient characteristics at baseline will be displayed for 
the ITT population by treatment arm and, where applicable for data collected in the 
Penicillamine Baseline Period (Period (up to and including Week 12), overall.  
 Age, Gender and Race 
 Height and weight 
 Stratification factor: serum NCC concentration  (≤ 75 µg/L or > 75 µg/L - value for the 
Week 8 visit) 
 Wilson’s disease medical history 
o 
Time since diagnosis (months) 
o 
Mutation analysis result (On both chromosomes detected/On 1 chromosome 
detected/No mutations detected) 
o 
Hepatic symptoms 
 
At diagnosis 
 
Clinical hepatic symptoms? (Yes/No) 
 
Laboratory abnormality? (yes/No) 
 
Approximately 1 year ago 
o 
Neurologic symptoms 
 
At diagnosis (Yes/No) 
 
Approximately 1 year ago (Yes/No) 
o 
Psychiatric symptoms 
 
At diagnosis (Yes/No) 
 
Approximately 1 year ago (Yes/No) 
o 
Other symptoms 
 
At diagnosis (Yes/No) 
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 
Approximately 1 year ago (Yes/No) 
 HIV results 
 Viral hepatitis results (Hepatitis C antibodies, hepatitis B surface antigen) 
 Significant medical history (within the past 12 months prior to the screening/enrolment 
visit) other than Wilson’s Disease will be tabulated by system organ class and preferred 
term for the ITT population, using the Medical Dictionary for Regulatory Activities (MedDRA 
Version 20.0). 
7. 
Prior 
and 
Concomitant 
Treatment, 
prior 
and 
concomitant 
procedures and surgeries 
Prior and concomitant medications will be classified according to WHO Drug Dictionary, 
starting with 2017 version 1 which will be upgraded each year. The most recent version in 
place at the time of database lock will be used (WHO Drug Dictionary 1 June 2020).   
The number and percentage of participants receiving a prior or concomitant medication 
will be displayed by generic term and first Anatomical Therapeutic Chemical class (ATC 1) 
for each treatment arm and overall for the safety population.  
ATC classes will be sorted by descending frequency. Prior and Concomitant medication 
summaries will be sorted alphabetically by generic term within ATC class. A listing of all 
medications recorded on the prior and concomitant medications CRF page will provide 
details including indication, dose, route, frequency, and start and stop dates.  
 Will be considered as prior medications: 
o 
For Wilson disease: All medications taken prior to the screening/enrolment visit 
but stopped on or prior to the date of the screening/enrolment visit 
o 
For other disease: 
Medications taken in the 30 days prior to the 
screening/enrolment visit but stopped on or prior to the date of the 
screening/enrolment visit 
 Will be considered as concomitant medications: medication continued to be taken after the 
screening/enrolment visit date, or initiated at or after the screening/enrolment visit. 
Prior and concomitant procedures and surgeries will also be tabulated by system organ 
class and dictionary-derived term.  
 Will be considered as prior procedures and surgeries: prior to the screening/enrolment visit 
but stopped on or prior to the date of the screening/enrolment visit 
 Will be considered as concomitant procedures and surgeries: continued after the 
screening/enrolment visit date, or initiated at or after the screening/enrolment visit. 
In addition, a per patient listing will be produced containing both the prior Wilson's disease 
medication as well as the study medication information, including details of dose and any 
dose modification during the study. 
8. 
Efficacy Evaluation  
8.1 Serum NCC Values 
8.1.1 Difference at Week 36 
The primary variable of absolute serum NCC values at Screening/enrolment, Weeks 4, 8, 
12, 16, 20, 24, 28, 32 and 36, will be analyzed using a restricted maximum likelihood 
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(REML) based general linear model (GLM) for correlated data. The analyzed populations 
will be the ITT and PP populations (See Section 4.1). 
The correlation due to repeated measures will be modelled by specifying the variance 
covariance matrix. In particular, the model will assume a general (unstructured) variance-
covariance matrix for the measurements. If convergence problems are noted with the 
general variance-covariance matrix, a simpler structure of variance-covariance matrix will 
be considered: in hierarchical order, the Heterogenous Toeplitz (TOEPH), the 
Heterogeneous First-Order Autoregressive (ARH(1)) and the heterogeneous compound 
symmetry structure (CSH). If there are any missing data, the results obtained using GLM 
are valid under the missingness at random (MAR) assumption, i.e., as long as the 
probability of missingness depends on the covariates and observed outcomes, but not on 
the unobserved values of the endpoint. The Kenward-Roger approximation will be used to 
estimate the denominator degrees of freedom. The test for the treatment effect at the 
endpoint visit (Week 36) will be obtained by using an appropriate contrast of the model 
parameters. Non-inferiority of TETA 4HCl compared to penicillamine will be declared if the 
limit of the one-sided 97.5% confidence interval of the difference in mean serum NCC level 
under these two treatments excludes the non-inferiority margin. 
An example of SAS code corresponding to the GLM described above is provided below: 
proc mixed data=data method=reml;  
class subject treatment visit site;  
model serum_NCC=treatment visit site treatment*visit /ddfm=kr;  
repeated visit/ subject=subject type=un;  
estimate 'Penicillamine vs. TETA 4HCl  at Week 36' treatment 1 -1 treatment*visit 0 0 0 0 0 0 
0 0 0 1 0 0 0 0 0 0 0 0 0 -1 /CL;                                                     
run; 
 
with:  
subject = subject id 
treatment = treatment group (penicillamine or TETA 4HCl) 
visit = scheduled visit time  
 
8.1.2 Difference at Week 60 
Absolute serum NCC values at Screening/enrolment, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 
36 and 60 will be analyzed in the same way as in Section 8.1.1. The analyzed population 
will be the ITT population.  
8.1.3 Summary Statistics 
Summary statistics will be presented at all visits, both for absolute values and change from 
baseline, including observed (arithmetic) mean, least-squares mean plus 95%CI (provided 
by the models described in Section 8.1.1 and 8.1.2 above), median, standard deviation, 
interquartile range, minimum and maximum. For the Penicillamine Baseline Period (up to 
and including Week 12) data will be presented by treatment arm and overall. 
8.1.4 Serum NCC Thresholds 
By visit, the number and percent of subjects will be summarized for all visits and for the 
following serum NCC thresholds, including 95% confidence interval. The proportions of the 
two arms will be compared with a Fisher Exact test.  
 
Serum NCC ≤50 µg/L 
 
Serum NCC ≤100 µg/L 
 
Serum NCC ≤150 µg/L 
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 
Serum NCC between ≥ 25 and ≤150 µg/L 
 
Serum NCC between >150 µg/L 
 
The proportion of patients above and below each of these categories will be computed. 
Data will be presented according to randomized treatment arm, and for visits in the 
Penicillamine Baseline Period only, overall. If deemed appropriate new thresholds will be 
used. 
These thresholds will also be used to summarize the serum NCC level by periods: 
 
The number and percent of subjects for whom the serum NCC measured during 
Penicillamine baseline visits are within the threshold values. 
 
The number and percent of subjects for whom the serum NCC measured from 
week 12 visit (excluded) until week 36 (included) are within the threshold values. 
 
The number and percent of subjects for whom the serum NCC measured from 
week 36 visit (excluded) until week 60 (included) are within the threshold values. 
 
The number and percent of subjects for whom the serum NCC measured from 
week 60 visit (excluded) until week 108 are within the threshold values. 
8.1.5 Serum NCC within subject variability 
The within subject variability of serum NCC will be estimated for each patient: 
 
during the Penicillamine Baseline Period and  
 
during the post randomisation phase (week 12 [excluded] to week 36 [included], 
week 36 [excluded] to week 60 [included]). 
Descriptive statistics will present the within subject standard deviation by treatment arms 
(TETA/Penicillamine) and overall for the Penicillamine Baseline Period and for the post 
randomisation phase only by treatment arms. 
A general linear mixed effects model will be applied to test the equality of the within patient 
post-randomization variability between the two treatments arms. An example of SAS code 
corresponding to the model mentioned above is provided below: 
proc glimmix data=test; 
class timepoint arm usubjid; 
model Y=  arm timepoint/solution; 
random intercept / subject=usubjid; 
random timepoint / subject=usubjid type=un(1) residual group=’arm’; 
covtest homogeneity; 
run; 
8.1.6 Visualization of the evolution of Serum NCC 
The Serum NCC will be plotted in order to show its evolution by subjects and by treatment 
arms. 
8.2 24-hour Urinary Copper Excretion 
8.2.1 Difference at Week 36 
Values at Screening/enrolment, Weeks 4, 12, 16, 24, and 36 will be analyzed as in Section 
8.1.1. The analyzed population will be the ITT population.  
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8.2.2 Difference at Week 60 
Values at Screening/enrolment, Weeks 4, 12, 16, 24, 36 and 60 will be analysed in the 
same way as in Section 8.1.1. The analysed population will be the ITT population.   
 
8.2.3 Summary Statistics 
As described in Section 8.1.3 
8.2.4 Urinary Copper Excretion Thresholds 
By visit, the number and percent of subjects will be summarized for the following urinary 
copper excretion thresholds, including 95% confidence interval. The proportions of the two 
arms will be compared with a Fisher Exact test.  
 
24-hour urinary copper excretion ≥ 100 µg/24 hours 
 
24-hour urinary copper excretion ≥ 200 µg/24 hours 
 
24-hour urinary copper excretion ≥ 300 µg/24 hours 
 
24-hour urinary copper excretion ≥ 400 µg/24 hours 
 
24-hour urinary copper excretion ≥ 500 µg/24 hours 
 
24-hour urinary copper excretion ≥ 600 µg/24 hours 
 
24-hour urinary copper excretion ≥ 700 µg/24 hours 
 
24-hour urinary copper excretion ≥ 800 µg/24 hours 
 
24-hour urinary copper excretion ≥ 900 µg/24 hours 
 
24-hour urinary copper excretion between ≥ 100 and ≤ 900 µg/24 hours 
 
24-hour urinary copper excretion between ≥ 100 and ≤ 400 µg/24 hours 
 
< 200 µg/24 hours 
The proportion of patients above and below each of these categories will be computed. 
Data will be presented according to randomized treatment arm, and for visits in the 
Penicillamine Baseline Period only, overall. If deemed appropriate new thresholds will be 
used. 
These thresholds will also be used to summarize the urinary copper excretion level by 
periods: 
 
The number and percent of subjects for whom the urinary copper excretion 
measured during Penicillamine baseline visits are within the threshold values. 
 
The number and percent of subjects for whom the urinary copper excretion 
measured from week 12 visit (excluded) until week 36 (included) are within the 
threshold values. 
 
The number and percent of subjects for whom the urinary copper excretion 
measured from week 36 visit (excluded) until week 60 (included) are within the 
threshold values. 
 
The number and percent of subjects for whom the urinary copper excretion 
measured from week 60 visit (excluded) until week 108 are within the threshold 
values. 
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8.2.5 24-hour urinary copper excretion within subject variability 
The within subject variability of 24-hour urinary copper excretion will be estimated as 
described in section 8.1.5. 
8.2.6 Visualisation of the evolution of 24-hour urinary copper excretion 
The 24-hour urinary copper excretion will be plotted in order to show its evolution by 
subjects and by treatment arms. 
8.3 Adjudication results 
Each subject clinical stability is assessed by an independent clinical adjudication committee 
prior to Week 12 (randomisation) to confirm the subject is considered well-controlled and 
clinically stable prior to randomisation. The assessment of whether each subject is 
considered well-controlled and clinically stable is also performed post-randomization at 
Week 36 and at Week 60 by the independent clinical adjudication committee, who are 
blinded to the randomized treatment allocation. 
The proportion of clinically stable subjects at Week 36 and Week 60 will be computed and 
reported with their exact 95% confidence interval. A Fisher Exact test will compare the two 
treatment arms. 
8.4 Combined Outcomes 
By visit, the number and percent of subjects will be summarized for the outcomes, 
including 95% confidence interval. The proportions of the two arms will be compared with 
a Fisher Exact test. 
Combined outcome number 1 
 
serum NCC between ≥ 25 and ≤150 µg/L 
AND 
 
24-hour urinary copper between ≥ 100 and ≤ 900 µg/24 hours 
 
Combined outcome number 2 (at Week 36 and Week 60 only) 
 
Combined outcome number 1 
AND 
 
Adjudication results 
 
Combined outcome number 3 (at Week 36 and Week 60 only) 
 
Combined outcome number 2 
AND 
 
Adjudication results 
If deemed appropriate, different or additional thresholds may also be selected. 
 
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8.5 CGIC Score 
The secondary variable of CGIC score (7 points ordinal score), including all available 
values, will be summarized by visit.  
At Week 36 and Week 60, the difference between the randomized groups will be tested 
using a stratified Cochran-Mantel-Haenszel test with modified ridit scores using the ITT 
population, based on the strata as defined in Section 4.2 (site and serum NCC 
concentration).  
8.6 UWDRS Neurological Scale 
The UWDRS scores (including all available values) will be summarized descriptively.  
Summary statistics including change versus baseline will be presented by visit, for the 
overall neurological score, and for the two sub-components: patient assessment 
component and physician’s assessment component. Data will be presented according to 
randomized treatment arm, and for visits in the Penicillamine Baseline Period only, overall 
Also, all values will be graphically represented, depicting both individual and mean values, 
using spaghetti or comparable plots. This graphical representation may be done for the 
overall neurological score, the two sub-components, and all individual items.  
The patient assessment component consists of the items 2 to 11: “mobility”, “falling”, 
“transfer”, “salivation”, “swallowing”, “feeding”, “dressing”, “Taking a bath or a shower”, 
“Grooming” and “Toilet use”.  
The physician’s assessment component consists of items 1, and 12 to 34: “Consciousness”, 
“Speech”, “Facial expression”, “Oculumotor function”, “Tremor at rest”, “Head tremor”, 
“Rigidity”, “Finger taps”, “Rapid alternating movements of hands”, “Handwriting”, “Tremor 
in arms”, “Finger-to-nose-test”, “Leg ability”, “Postural tremor in legs”, “Cervical dystonia”, 
“Arm and hand dystonia”, “Arising from chair”, “Posture”, “Gait”, “Chorea”, “Jaw tremor”, 
“Pyramidal signs”, “Stereotyped actions” and “Involuntary crying” 
 
8.7 Serum Total Copper and Serum Ceruloplasmin 
Summary statistics will be presented by study visit, both for absolute values and change 
from baseline, including observed mean, standard error of the mean, 95% confidence 
interval for the observed mean, median, standard deviation, interquartile range, minimum 
and maximum. 
Data will be presented according to randomized treatment arm, and for visits in the 
Penicillamine Baseline Period only, overall. 
9. 
Safety Evaluation 
9.1 General Definitions 
Safety data will be tabulated separately for each of the 4 following study periods: 
1. Screening/enrolment visit to Week 12 visit (included) i.e. Penicillamine Baseline 
Period. These tables will be created both overall and for the subset of randomized 
patients. 
2. Week 12 visit (excluded) to Week 36 visit (included) i.e. the 24-week Post-
randomization Phase 
3. Extension Phase from Week 36 visit (excluded) up to Week 60 visit (included) 
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4. Extension Phase from Week 60 visit (excluded) to Week 108 visit (included) 
Safety data will be tabulated by treatment sequence, based on actual received treatment, 
and overall:  
 
‘penicillamine/penicillamine’ 
 
‘penicillamine/TETA 4HCl’ 
 
‘Overall’ 
For the fourth period described above, i.e. the Extension Phase from Week 60 onwards, 
these columns will be named: 
 
‘penicillamine/penicillamine/TETA 4HCl’ 
 
‘penicillamine/TETA 4HCl/ TETA 4HCl’ 
 
‘Overall’ 
An AE is allocated to one of the 4 defined periods stated above according to the period in 
which the start date of the AE occurred. If an AE started in one period but was still ongoing 
in another period, it will only be allocated to the period in which the AE started.  
AE listings will show the study period in which the AE occurred i.e. which of the 4 defined 
the AE occurred and number of days from the start of this period to the onset of the AE.  
9.2 Extent of Exposure 
A summary of the total daily dose (in mg) by treatment arm and overall will be done for 
the reported total daily dose at each visit, for the Penicillamine Baseline Period and post 
randomization, specifying if it is penicillamine or TETA 4HCl. 
Also, for each visit, by period as defined in Section 9.1 and overall, the number of patients 
with dose modification will be summarized, along with the criteria for dose modification. 
Unscheduled visits with dose modification will be attributed to the first visit after the date 
of the unscheduled visit.  
In addition, a per patient listing will be produced containing both the prior Wilson's disease 
medication as well as the study medication information, including details of dose and any 
dose modification during the study (see also Section 7). 
Overall cumulative exposure to penicillamine and TETA 4HCl will also be summarized by 
providing 
the 
number 
of 
patients 
in 
the 
safety 
population 
(starting 
from 
screening/enrolment) who have received penicillamine or TETA 4HCl for ≥ 12 weeks, ≥ 24 
weeks, ≥ 36 weeks and ≥ 52 weeks. 
In addition to these summary statistics: 
 
The dose of each subject will be presented on graphs by treatments and arms. 
 
A listing of the dose adjustment and compliance will be presented by subjects.  
 
The visit window compliance will be presented in a listing 
9.3 Adverse Events 
All AEs occurring after enrolment into the study for the Penicillamine Baseline Period will 
be considered treatment-emergent. 
Treatment emergent Adverse events (TEAEs) will be coded using the Medical Dictionary 
for Regulatory Activities (MedDRA Version 20.0). TEAEs will be analyzed in terms of their 
type, incidence, severity and relationship to the study treatment.  
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Related TEAEs are defined as events with a relationship to study treatment equal to 
‘Possible’, ’Probable’, ‘Definite’ or with missing relationship. 
Missing or partial AE start date will be estimated in order to include events in summary 
tables in case of doubt (see section 4.4 for more details). 
A summary table will present by treatment arm the number and percentage of patients 
with at least one: 
 
TEAE 
 
Serious TEAE 
 
Moderate or severe TEAE 
 
TEAE leading to dose modification 
 
TEAE leading to dose increase 
 
TEAE leading to dose reduction 
 
TEAE leading to drug interruption 
 
TEAE leading to drug withdrawal 
 
Fatal TEAE 
In addition, tabulations of the number of patients who experienced AEs as well as severity 
of the events will be presented by system organ class and preferred term. Patients will 
only be counted once for each preferred term. In case a patient experienced the same 
event more than once, the worst severity will be presented. In case of missing severity, it 
will be reported as missing. The following tabulations will be presented: 
 
All TEAEs 
 
TEAEs related to study treatment 
 
Severe TEAEs 
 
TEAEs leading to drug withdrawal 
 
Serious TEAEs 
 
Fatal TEAEs 
Listings of all adverse events by treatment arm will be provided, including the patient 
identifier, age, race, sex, verbatim, preferred term, duration of the event, seriousness, 
fatality, other resulting medical event (life-threatening, hospitalization, cancer, congenital 
anomaly, other), severity, outcome, relationship to study drug, date of onset.  
Separate listings will be produced for serious AEs, fatal AEs and severe AEs, similarly to 
the listing of all AEs.  
9.4 Cognitive Assessment 
The absolute values and change from baseline values will be summarized for each visit 
Data will be presented according to treatment arm, and for visits in the Penicillamine 
Baseline Period only, overall. Change from baseline will only be reported for post-
randomization periods.  
9.5 Clinical Laboratory Determination 
The following categories of lab results will be presented: hematology (hemoglobin, 
hematocrit, RBC, platelet count, WBC, reticulocyte count), biochemistry (sodium, 
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potassium, bicarbonate, chloride, phosphorous, calcium, glucose, creatinine, uric acid, 
BUN or urea, total bilirubin, albumin, total protein, LDH, AST, ALT, GGT), coagulation 
analysis (PT, aPTT, INR), urinalysis (pH, protein, glucose, ketones, bilirubin, blood, nitrite, 
urobilinogen, specific gravity), pre-calculated Modified Nazer score as recorded in the 
eCRF, and urine pregnancy test.  
Missing or partial lab dates will be estimated in order to include events in summary tables 
in case of doubt (see section 4.4 for more details). 
Unscheduled visits will be imputed to the corresponding visit based on the lab date, 
applying rules of section 4.7 for missing/partial lab date. The unscheduled visit will be 
attributed to the closest scheduled visit in the same period, which could be before or after.  
Lab data will be presented in two ways:  
- Continuously:  
Absolute values and change from baseline values will be summarized for each visit. Data 
will be presented according to treatment arm, and for visits in the Penicillamine Baseline 
Period only, overall. Change from baseline will only be reported for post-randomization 
periods.  
- Categorically 
The values will be compared to the limits of the normal range and classified as low, normal 
or high. In case of multiple values by visit, the value furthest from the upper/lower 
boundary of the normal range will be selected. For each parameter the worst treatment-
emergent category will be tabulated by parameter and by period.  
The pre-calculated CRF Modified Nazer score will only be summarized as a continuous 
variable. 
Urine pregnancy test results (for those females of child bearing potential) will be 
summarized as a categorical binary variable.  
Data will be presented according to treatment arm, and for visits in the Penicillamine 
Baseline Period only, overall. 
9.6 Vital Signs 
Descriptive statistics of systolic and diastolic blood pressure, heart rate, respiration rate 
and body temperature will be presented by visit. Both absolute values and change from
 baseline (only for post-randomization periods) will be presented. In case of multiple 
measurements by visit, the latest measurement will be used for baseline, the highest for 
post-baseline measures. 
10. References 
Ala Aftab, Aliu Ermal, Schilsky Michael L. Prospective Pilot Study of a Single Daily Dosage 
of Trientine for the Treatment of Wilson Disease. Dig Dis Sci 2015;60:1433-1439. 
Freedman LS, White SJ. On the Use of Pocock and Simon's Method for Balancing Treatment 
Numbers over Prognostic Factors in the Controlled Clinical Trial. Biometrics 1976;32:691-
694. 
Pocock SJ, Simon R. Sequential Treatment Assignment with Balancing for Prognostic 
Factors in the Controlled Clinical Trial. Biometrics 1975;31:103-115. 
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