A Phase I, Single Centre, Randomised, Interventional, Open-Label, Cross-Over Study to Evaluate the Pharmacokinetics (PK) and the Safety and Tolerability of a Total Daily Dose of 900mg of TETA 4HCL, Comparing a New Once Daily TETA 4HCL Formulation (300mg) (3x300mg Trientine Base Tablets, OD) With the Current Marketed Cuprior® Formulation (150mg) (3x150mg Trientine Base Tablets, BD) in Adult Healthy Male and Female Participants
Phase: PHASE1
Conditions: Wilson's Disease
Sponsor: Orphalan

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CLINICAL TRIAL PROTOCOL 
Sponsor9s Reference Number: ORPH-131-012 
Richmond Pharmacology Trial Number: C23030 
IRAS Number: 1009060 
 
 
TITLE: 
A Phase I, Single Centre, Randomised, Interventional, Open-Label, Cross-Over 
Study to Evaluate the Pharmacokinetics (PK) and the Safety and Tolerability 
of a Total Daily Dose of 900mg of TETA 4HCL, Comparing a New Once Daily 
TETA 4HCL Formulation (300mg) (3x300mg Trientine Base Tablets, OD) with 
the Current Marketed Cuprior® Formulation (150mg) (3x150mg Trientine 
Base Tablets, BD) in Adult Healthy Male and Female Participants 
PHASE: 
Phase 1 
 
DRUG: 
Trientine tetrahydrochloride (TETA 4HCL) 
SPONSOR: 
Orphalan SA 
226 Boulevard Voltaire 
75011 Paris, France 
 
PRINCIPAL 
INVESTIGATOR: 
Dr Thomas Ashdown MBBCh BSc 
Associate Medical Director 
 
CO-PRINCIPAL 
INVESTIGATOR: 
Dr Ulrike Lorch MD FRCA FFPM 
Chief Medical Director 
 
TRIAL CENTRE: 
Richmond Pharmacology Ltd. 
1a Newcomen Street, London Bridge 
London 
SE1 1YR 
UK 
 
Telephone: 
+44 (0)20 7042 5800 
Fax: 
+44 (0)20 7378 9135 
 
Protocol Date: 
Version 2.0, 09/Jan/2024 
 
 
 
Information in this protocol is confidential and should not be disclosed, other than to those directly involved 
in the execution or the ethical/regulatory review of the trial, without written authorisation from Orphalan 
SA or its affiliates. 

Orphalan SA 
Protocol Ref: ORPH-131-012 
RPL Trial No C23030 
CONFIDENTIAL 
Version 2.0 
09-Jan-2024 
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Table of Contents 
PROTOCOL APPROVAL SIGNATURES ............................................................................................. 5 
INVESTIGATOR9S AGREEMENT....................................................................................................... 6 
TRIAL PERSONNEL .......................................................................................................................... 7 
LIST OF ABBREVIATIONS ................................................................................................................ 8 
TRIAL SYNOPSIS ............................................................................................................................ 11 
1. 
INTRODUCTION ................................................................................................................... 15 
1.1 
Background ...................................................................................................... 15 
1.2 
Current Treatment ........................................................................................................... 15 
1.3 
Study Rationale ................................................................................................................ 16 
2. 
TRIAL OBJECTIVES AND OUTCOMES ................................................................................... 17 
2.1 
Objectives ........................................................................................................................ 17 
3. 
TRIAL DESIGN ...................................................................................................................... 18 
3.1 
Overall trial design ........................................................................................................... 18 
3.1.1 
Choice of participants and dose rationale.................................................................... 18 
3.2 
Adaptive Protocol Features ............................................................................................. 22 
4. 
RISK MANAGEMENT ........................................................................................................... 23 
4.1 
Potential Benefits ............................................................................................................ 23 
4.2 
Potential Risks ................................................................................................................. 24 
4.2.1 
TETA 4HCL .................................................................................................................... 24 
4.2.2 
Investigator Site Facilities and Personnel ..................................................................... 24 
5. 
DECISION-MAKING RULES AND LIMITS .............................................................................. 25 
5.1 
Stopping Rules ................................................................................................................. 25 
5.1.1 
Individual Stopping Rules ............................................................................................. 25 
6. 
SELECTION AND WITHDRAWAL OF PARTICIPANTS ............................................................ 25 
6.1 
Replacement participants ................................................................................................ 25 
6.2 
Inclusion Criteria .............................................................................................................. 25 
6.3 
Exclusion Criteria ............................................................................................................. 26 
6.4 
Participant Restrictions .................................................................................................... 27 
6.5 
Criteria for withdrawal .................................................................................................... 28 

Orphalan SA 
Protocol Ref: ORPH-131-012 
RPL Trial No C23030 
CONFIDENTIAL 
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6.5.1 
Handling of Withdrawals .............................................................................................. 28 
7. 
TRIAL IMP AND CONCOMITANT TREATMENTS .................................................................. 29 
7.1 
Investigational Medicinal Products (IMPs): ..................................................................... 29 
7.1.1 
Labelling of IMPs .......................................................................................................... 29 
7.1.2 
Drug administration ..................................................................................................... 29 
7.1.3 
Storage of IMPs ............................................................................................................ 30 
7.1.4 
Drug Accountability ...................................................................................................... 30 
7.2 
Treatment Allocation ....................................................................................................... 30 
7.2.1 
Participant Randomisation ........................................................................................... 30 
8. 
TRIAL METHODOLOGY ........................................................................................................ 30 
8.1 
Order of Procedures ........................................................................................................ 30 
8.2 
Medical History ................................................................................................................ 31 
8.3 
Meals ............................................................................................................................... 31 
8.4 
Clinical Laboratory Assessments ...................................................................................... 31 
8.4.1 
Haematology, Biochemistry, and Coagulation ............................................................. 32 
8.4.2 
Serology ........................................................................................................................ 32 
8.4.3 
Pregnancy/FSH testing ................................................................................................. 33 
8.4.4 
Urinalysis ...................................................................................................................... 33 
8.4.5 
Drugs of Abuse ............................................................................................................. 33 
8.5 
Alcohol Breath Test.......................................................................................................... 33 
8.6 
Vital signs (blood pressure, pulse rate, respiratory rate, and tympanic temperature) . 33 
8.7 
Electrocardiographic (ECG) Measurements ..................................................................... 33 
8.7.1 
Recording of 12-lead ECGs ........................................................................................... 33 
8.8 
Physical Examination, Height, and Weight ...................................................................... 34 
8.9 
Pharmacokinetic Assessments ......................................................................................... 34 
8.9.1 
PK blood samples ......................................................................................................... 34 
8.10 
Volume of Blood Sampling .............................................................................................. 34 
8.11 
Adverse Events ................................................................................................................ 34 
8.11.1 
Definitions .................................................................................................................... 35 
8.11.2 
Assessment of Severity ................................................................................................ 36 
8.11.3 
Assessment of Causality ............................................................................................... 37 
8.11.4 
Eliciting and Recording of Adverse Events ................................................................... 38 
8.11.5 
Reporting of Serious Adverse Events ........................................................................... 38 
8.12 
Expedited Reports and Regulatory Requirements ........................................................... 39 
8.12.1 
Expectedness ................................................................................................................ 39 
8.12.2 
Regulatory Requirements ............................................................................................. 39 

Orphalan SA 
Protocol Ref: ORPH-131-012 
RPL Trial No C23030 
CONFIDENTIAL 
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8.13 
Pregnancy ....................................................................................................................... 40 
9. 
QUALITY ASSURANCE AND QUALITY CONTROL ................................................................ 40 
9.1 
Quality Assurance and Quality Control ........................................................................... 40 
9.2 
Monitoring ...................................................................................................................... 41 
10. STATISTICAL ANALYSIS ....................................................................................................... 41 
10.1 
Statistical Analysis Plan ................................................................................................... 41 
10.2 
Analysis sets .................................................................................................................... 41 
10.3 
Statistical analysis of safety ............................................................................................ 41 
10.4 
Pharmacokinetics ............................................................................................................ 42 
10.4.1 
Evaluation of Pharmacokinetic Parameters ................................................................ 42 
10.4.2 
Statistical Analysis on PK Parameters .......................................................................... 44 
10.5 
Handling of Missing and Incomplete Data ...................................................................... 44 
10.6 
Determination of sample size ......................................................................................... 44 
10.7 
Interim Analysis .............................................................................................................. 44 
11. DATA MANAGEMENT ........................................................................................................ 44 
11.1 
Case Report Forms ......................................................................................................... 45 
12. REGULATORY, ETHICAL AND STUDY OVERSIGHT CONSIDERATIONS................................ 45 
12.1.1 
Regulatory and Ethics Compliance .............................................................................. 45 
12.1.2 
Medicines and Healthcare products Regulatory Agency (MHRA) and Research Ethics 
Committee (REC) Approval .......................................................................................... 46 
12.1.3 
Indemnity/liability and insurance ............................................................................... 46 
12.1.4 
Protocol management and adherence ........................................................................ 46 
12.1.5 
End of trial notification and Clinical Trial Summary Results ........................................ 47 
12.1.6 
Documentation and retention of records ................................................................... 47 
12.1.7 
Informed consent ........................................................................................................ 47 
12.2 
Confidentiality ................................................................................................................ 47 
12.3 
Publication Policy............................................................................................................ 48 
13. REFERENCES ....................................................................................................................... 49 
14. APPENDIX 1 3 CONTRACEPTIVE REQUIREMENTS .............................................................. 50 

Orphalan SA 
Protocol Ref: ORPH-131-012 
RPL Trial No C23030 
CONFIDENTIAL 
Version 2.0 
09-Jan-2024 
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PROTOCOL APPROVAL SIGNATURES 
Version 2.0, Dated 09-Jan-2024 
Sponsor9s Approval 
This protocol has been approved by Orphalan SA. 
Sponsor9s Signatory: 
 
 
 
Name: 
 
 
Signature: 
Dr Omar Kamlin MD FRACP FRCPCH DMedSci 
Senior Medical Director 
 
 
 
 
Date: 
 
DD-MMM-YYYY 
 
 
09-JAN-2024 
 
 
 
 
 
8fd277ee3637472fb281 
Omar Kamlin 

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Orphalan SA 
Protocol Ref: ORPH-131-012 
RPL Trial No C23030 
 
CONFIDENTIAL 
Version 2.0 
09-Jan-2024 
RJCHM ND 
Phar111acoh1gy 
 
 
INVESTIGATOR'S AGREEMENT 
 
I have read this Orphalan SA Protocol No. ORPH-131-012: 
 
A Phase I, Single Centre, Randomised, lnterventional, Open-Label, Cross-Over Study to Evaluate the 
Pharmacokinetics (PK) and the Safety and Tolerability of a Total Daily Dose of 900mg of TETA 4HCL, 
Comparing a New Once Daily TETA 4HCL Formulation (300mg) (3x300mg Trientine Base Tablets, OD) 
with the Current Marketed Cuprior Formulation (150mg) (3x150mg Trientine Base Tablets, BD) in 
Adult Healthy Male and Female Participants 
 
 
I have fully discussed the objectives of this trial and the contents of this protocol with the Orphalan SA 
representative. 
I understand that the information in this protocol is confidential and should not be disclosed, other 
than to those directly involved in the execution or the ethical/regulatory review of the trial, without 
written authorisation from Orphalan SA. It is, however, permissible to provide information to a 
participant to obtain consent. 
I agree to conduct this trial according to this protocol and to comply with its requirements, subject to 
ethical and safety considerations and guidelines, and to conduct the trial in accordance with ICH 
guidelines on GCP and with the applicable regulatory requirements. 
I understand that OrphaIan SA may decide to suspend or prematurely terminate the trial at any time 
for any reason as described in the Master Service Agreement (MSA) or Work Order with the clinical 
trial site; such a decision will be communicated to me in writing. Conversely, should I decide to 
withdraw from execution of the trial I will communicate my intention immediately in writing to 
Orphalan SA. 
 
Principal Investigator: 
Dr Thomas Ashdown MBBCh BSc 
/ 
s;gnaturec  bk- 
-- 
., 
 ,..- 
 
 
 
 
 
Date: 
 
Co-Principal Investigator: 
Dr Ulrike Lorch MD FRCA FFPM 
 
 
Signature: 
Date: 
10 ;)mu zoz<;- 

Orphalan SA 
Protocol Ref: ORPH-131-012 
RPL Trial No C23030 
CONFIDENTIAL 
Version 2.0 
09-Jan-2024 
C23030_ORPH-TRIUMPH-3_CSP v2.0_09Jan2024.docx 
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Page 7 of 51 
 
 
 
 
TRIAL PERSONNEL 
Sponsor9s Representative 
Carla Bennett 
Principal Clinical Research Manager 
 
Sponsor9s Medical Contact 
Dr Omar Kamlin MD FRACP FRCPCH DMedSci 
Senior Medical Director 
 
Sponsor site 
Orphalan SA 
226 Boulevard Voltaire 
75011 Paris, France 
 
Principal Investigator 
Dr Thomas Ashdown MBBCh BSc 
Associate Medical Director 
Phone: +44 (0)20 7042 5800 
e-mail: t.ashdown@richmondpharmacology.com 
 
Co-Principal investigator 
Dr Ulrike Lorch MD FRCA FFPM 
Chief Medical Director 
Phone: +44 (0)20 7042 5800 
E-mail: u.lorch@richmondpharmacology.com 
 
Trial Site 
Richmond Pharmacology Ltd. 
1a Newcomen Street, London Bridge, 
London SE1 1YR, UK 
Clinical Laboratory 
The Doctor9s Laboratory 
The Halo Building, 1 Mabledon Place 
London, WC1H 9AX, UK 
 
Bioanalytical Laboratory 
QPS Netherlands B.V. 
 
Data Management 
Richmond Pharmacology Ltd. 
Statistics 
Richmond Pharmacology Ltd. 
Qualified Person 
Vittoria Ardissone 
Pharmacovigilance 
Richmond Pharmacology Ltd. 
Medical Writing 
Richmond Pharmacology Ltd. 

Orphalan SA 
Protocol Ref: ORPH-131-012 
RPL Trial No C23030 
CONFIDENTIAL 
Version 2.0 
09-Jan-2024 
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Page 8 of 51 
 
 
 
 
LIST OF ABBREVIATIONS 
For the purposes of this protocol, 8Investigator9 refers to the Principal Investigator or their delegate. 
 
Abbreviation 
Explanation 
ABPI 
Association of the British Pharmaceutical Industry 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
AR 
Adverse Reaction 
BHCG 
Beta-hCG 
BMI 
Body Mass Index 
BP 
Blood Pressure 
CI 
Confidence Interval 
CRF 
Case Report Form 
CSP 
Clinical Study Protocol 
CSR 
Clinical Study Report 
CV 
Coefficient of Variation 
DHP 
Data Handling Protocol 
DSUR 
Development Safety Update Report 
ECG 
Electrocardiogram 
ET 
Early Termination 
eGFR 
Estimated Glomerular Filtration Rate 
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulation 
GMP 
Good Manufacturing Practice 
HBsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus 
HIV 
Human Immunodeficiency virus 
HR 
Heart Rate 

Orphalan SA 
Protocol Ref: ORPH-131-012 
RPL Trial No C23030 
CONFIDENTIAL 
Version 2.0 
09-Jan-2024 
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IB 
Investigators Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IMP 
Investigational Medicinal Product 
LFT 
Liver Function Test 
LLOQ 
Lower Limit of Quantification 
MSA 
Master Service Agreement 
MTS 
Master Treatment Schedule 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
QC 
Quality Control 
QP 
Qualified Person 
RP 
Research Physician 
RPL 
Richmond Pharmacology Ltd 
RSI 
Reference Safety Information 
SAP 
Statistical Analysis Plan 
SAE 
Serious Adverse Event 
SAR 
Suspected Adverse Reaction 
SD 
Standard Deviation 
SmPC 
Summary of Product Characteristics 
SOA 
Schedule of Assessments 
SOC 
System Organ Class 
SOM 
Study Operations Manual 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TETA 
Trientine 
TETA 2HCL 
Trientine Dihydrochloride 
TETA 4HCL 
Trientine Tetrahydrochloride 

Orphalan SA 
Protocol Ref: ORPH-131-012 
RPL Trial No C23030 
CONFIDENTIAL 
Version 2.0 
09-Jan-2024 
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ULN 
Upper Limit of Normal 
WD 
Wilson9s Disease 
WOCBP 
Women Of Childbearing Potential 

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Orphalan SA 
CONFIDENTIAL 
Protocol Ref: ORPH-131-012 
Version 2.0 
RPL Trial No C23030 
09-Jan-2024 
 
TRIAL SYNOPSIS 
Protocol Reference: ORPH-131-012 Study drugs: TETA 4HCl 
Title of the study: A Phase I, Single Centre, Randomised, Interventional, Open-Label, Cross-Over Study to Evaluate the 
Pharmacokinetics (PK) and the Safety and Tolerability of a Total Daily Dose of 900mg of TETA 4HCL, Comparing a New Once 
Daily TETA 4HCL Formulation (300mg) (3x300mg Trientine Base Tablets, OD) with the Current Marketed Cuprior® 
Formulation (150mg) (3x150mg Trientine Base Tablets, BD) in Adult Healthy Male and Female Participants 
Principal Investigator: Dr Thomas Ashdown MBBCh BSc 
Co 3 Investigator: Dr Ulrike Lorch MD FRCA FFPM 
Study centre: 
Richmond Pharmacology Ltd., 1A Newcomen Street, London Bridge, London SE1 1YR, UK 
Study parts: N/A 
Clinical phase: Phase 1 
Objectives 
Endpoints 
Statistical analyses 
Primary 
To evaluate and compare the plasma 
PK parameters of TETA 4HCL and its 
two 
main 
metabolites 
(N1- 
acetyltriethylenetetramine 
(MAT) 
and 
N1, 
N10- 
diacetyltriethylenetetramine (DAT)) 
following administration of a total 
daily dose of 900mg TETA 4HCL, 
comparing the new once daily TETA 
4HCL 
formulation 
(3x300mg 
trientine base tablets, OD) with the 
current 
marketed 
Cuprior® 
formulation, 
(3x150mg 
trientine 
base tablets, BD) in healthy adult 
male and female participants. 
PK parameters derived by non- 
compartmental methods including 
maximum 
observed 
plasma 
concentration (Cmax), time to reach 
maximum 
plasma 
concentration 
(tmax), area under the plasma 
concentration-time curve from time 
zero to last detectable plasma 
concentration (AUC0-t), area under 
the 
plasma 
concentration-time 
curve from time zero to 24 hours 
plasma concentration (AUC0-24), 
area 
under 
the 
plasma 
concentration-time curve from time 
zero extrapolated to infinite (AUC0- 
¥), apparent total plasma clearance 
(CL/F), 
apparent 
volume 
of 
distribution during the terminal 
phase (Vz/F), terminal elimination 
rate constant (»z), and terminal 
elimination half-life (t1/2). 
″ 
″ 
″ 
Plasma concentrations will be listed 
and summarised by time point. 
Individual and arithmetical mean 
plasma concentration vs time curves 
for each analyte which includes all 
treatments will be produced on both 
linear/linear and log10/linear scales. 
The PK parameters will be listed for 
each participant and summarized for 
each 
treatment 
group 
using 
descriptive statistics (N - the number 
of participants, arithmetic mean, SD 
- standard deviation, CV - coefficient 
of 
variation, 
geometric 
mean, 
median, minimum, maximum). 
For comparability of the two 
products the geometric mean, ratio 
of geometric means, confidence 
intervals 
(CI) 
including 
their 
logarithmic transformation together 
with the coefficient of variation for 
the within-participant variability will 
be summarised. In case a gender 
effect is noticeable, gender will be 
added as an additional term in the 
PK model, and all PK analyses will be 
presented per gender as well. 

Orphalan SA 
Protocol Ref: ORPH-131-012 
RPL Trial No C23030 
CONFIDENTIAL 
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Secondary 
To  compare  the  safety  and ″ 
The  incidence,  severity,  and 
″ 
″ 
Adverse 
Events 
(AE), 
Serious 
Adverse Events (SAEs), vital signs, 
ECG 
parameters, 
and 
clinical 
laboratory data will be listed and 
summarised 
using 
descriptive 
statistics. 
All AEs will be summarised and 
listed by using System Organ Class 
(SOC) and Preferred Term (PT) 
assigned to the event using Medical 
Dictionary for Regulatory Activities 
(MedDRA). 
Furthermore, 
these 
events will be summarised by the 
maximum intensity. The number of 
participants who experienced drug- 
related AEs will also be summarised. 
Any SAEs and/or AEs that led to 
withdrawal will be summarised and 
listed. 
tolerability of the two TETA 4HCL 
relationship 
of 
Treatment- 
tablet formulations. 
Emergent Adverse Events (TEAEs). 
″ 
Proportion of participants with 
clinically significant changes in 
laboratory 
safety 
tests 
(haematology, 
biochemistry, 
coagulation, and urinalysis). 
″ 
Proportion of participants with 
morphological  and/or  rhythm 
abnormalities 
on 
electrocardiogram (ECG). 
″ 
Proportion of participants with 
clinically significant changes in 
vital 
signs 
(systolic 
blood 
pressure, diastolic blood pressure 
and pulse rate). 
Study design 
This is a single centre, phase I, randomized, controlled trial with a crossover design to evaluate the pharmacokinetics (PK), 
safety, and tolerability of a new once daily TETA 4HCL formulation (300mg) (3x300mg trientine base tablets, OD) 
compared to the current marketed Cuprior® formulation (150mg) (3x150mg trientine base tablets, BD) in adult healthy 
male and female participants. 
Participants: 26 healthy participants will be enrolled to ensure 24 participants complete the study, with a balanced gender 
split. 
Treatment: Participants will be randomized to receive either the new or the current formulation of the drug, and then 
switch to the other formulation after a period of time (see study flow chart below). 
To remain in line with current EU SmPC and US PIL, being: 
- 
EU daily dose range of 450-975 mg of trientine base 
- 
US daily dose range of 150-1500mg trientine base 
the following treatments will be administered according to the treatment allocation schedule below: 
A: 900mg TETA 4HCl once a day / new formulation = 3 tablets of 300mg trientine base as a single dose 
B: 900mg TETA 4HCl marketed Cuprior formulation = 6 tablets of 150mg trientine base in two equally divided doses 
Patients will be randomised in a 1:1 ratio to either one of the following sequences: 
Treatment Sequence 
Period 1 
Period 2 
Sequence 1 
Treatment A 
Treatment B 
Sequence 2 
Treatment B 
Treatment A 

Orphalan SA 
Protocol Ref: ORPH-131-012 
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Assessments: Participants will be assessed for eligibility criteria and will be monitored closely throughout the study. 
Assessments will be performed during the study and at the end of the study follow-up visit. 
Duration: The duration of the study will be up to approximately 7 weeks, from screening to follow-up: 
- 
Screening will take place between days -28 and -2 
- 
In-house period from D-1 to D3 with dosing on D1 of each treatment period 
- 
Follow-up will take place on D7 of Treatment Period 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Objective: To evaluate the PK, safety, and tolerability of the new once daily TETA 4HCL formulation compared to the 
current marketed Cuprior® formulation. 
 
Main criteria for inclusion: 
″ 
Age: 18 to 40 years 
″ 
Body weight: g 50 kg 
″ 
BMI: 18.0 to 25.0 kg/m2 
″ 
Health: Generally healthy, with no clinically significant illnesses or surgeries in the past 12 weeks 
″ 
Willingness to comply with trial procedures and restrictions 
Participants must also be able to provide written informed consent before participating in the trial. 
 
Main criteria for exclusion: 
 
″ 
Significant current or recurrent disease 
″ 
Acute significant disease or illness within 7 days before the start of the trial 
″ 
Clinically significant deviations in blood tests 
″ 
An estimated glomerular filtration rate (eGFR) of less than 60 ml/min/1.73m2 
″ 
Positive test for alcohol, drugs of abuse, hepatitis B surface antigen (HBsAg), hepatitis C antibody (HCV Ab), or 
human immunodeficiency virus antibody (HIV Ab) 
″ 
Pregnant or breastfeeding women 
″ 
History or regular use of tobacco or other nicotine-containing products within 6 months before the start of the 
trial 
″ 
Treatment with an investigational drug within 90 days or 5 half-lives (whichever is longer) or exposure to more 
than 3 investigational drugs within 12 months of first study drug administration 
″ 
Use of prescription medication (excluding female hormonal contraception or hormone replacement therapy) 

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within 30 days or 5 half-lives (whichever is longer) prior to first study drug administration, or use of over-the- 
counter (OTC) medication (including multivitamin, herbal, or homeopathic preparations; Paracetamol use f2g 
per day is permitted) during the 14 days or 5 half-lives of the drug (whichever is longer) before first study drug 
administration 
″ 
History of sensitivity/allergy to the study medications or components thereof (mannitol, colloidal anhydrous 
silica, glycerol dibehenate or magnesium-stearate) 
″ 
Donation or loss of 450 mL or more of blood or plasma within 16 weeks prior to first trial medication 
administration or intention to donate blood in the 16 weeks after completing the trial 
″ 
An inability to follow a standardised diet and meal schedule or inability to fast, as required during the trial 
″ 
Participants deemed to have difficult veins for cannulation/blood draws 
These exclusion criteria are designed to protect the safety of participants and to ensure that the results of the trial are 
accurate and reliable. 

Orphalan SA 
Protocol Ref: ORPH-131-012 
RPL Trial No C23030 
CONFIDENTIAL 
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1. 
INTRODUCTION 
1.1 
Background 
Wilson9s Disease (WD) is an autosomal recessive life-threatening disorder caused by a mutation in the 
gene that codes for the ATP7B transport protein located on Chromosome 131. The ATP7B protein 
mediates the binding of copper molecules to apoceruloplasmin in hepatocytes, forming ceruloplasmin, 
which can then safely transport the bound copper to its intended sites. In addition, the ATP7B protein 
also serves to transport excess copper from the hepatocytes into the bile for subsequent biliary 
excretion, therefore also permitting the safe elimination of excess copper. Such copper transport 
systems are essential, as although copper is fundamental for cellular function, free copper is toxic and 
causes cellular damage. 
 
Pathogenic mutations in the ATP7B gene result in pathological copper accumulation, causing a wide 
spectrum of symptoms. WD presents symptomatically at any age, with the majority between 5 and 35 
years2. Hepatic symptoms are the initial clinical manifestation in about 40-50% of WD patients. The 
hepatic dysfunction symptoms are highly variable, ranging from enlargement of the liver, or 
asymptomatic biochemical abnormalities, to overt cirrhosis or acute hepatic failure3. 
 
Neurologic or neuropsychiatric manifestations of WD typically present later than liver disease, most 
commonly in the third decade of life, but can also be present in childhood. There are a range of 
presenting neurologic abnormalities which are initially present in 40350% of patients4. They include 
Parkinson9s-like akinetic-rigid syndrome, pseudosclerosis with tremor, ataxia, and dystonic syndrome. 
Neuropsychiatric abnormalities can also develop, most frequently in patients who also display 
neurological dysfunction, thus reflecting their Central Nervous System origin. These most commonly 
include personality changes and mood disturbances, particularly depression, but they may also 
manifest as impulsiveness, disinhibition, paranoia, or poor school performance. 
 
Dietary control of copper intake is not sufficient and pharmacological treatments are therefore 
needed. 
 
1.2 
Current Treatment 
Treatment is primarily aimed at removing copper that has accumulated in organ tissue and preventing 
the accumulation of further copper. This is achieved with potent chelator therapies which extract 
copper from the tissues and promote copper excretion. Traditionally, D-penicillamine has been the 
first line chelation agent. However, approximately a third of patients cannot tolerate long-term D- 
penicillamine treatment due to side effects2. 
 
Trientine, also referred to as triethylene tetramine (TETA), is an organic compound with the formula 
[CH2NHCH2CH2NH2]2. In Europe, trientine has been predominantly used as a second-line chelator, for 
those unable to tolerate D-penicillamine. The use of Trientine for treating WD is well established and 
supported by extensive literature. The primary mechanism of action of trientine is the formation of a 
stable molecular complex with copper, which is then excreted in the urine. Trientine prevents copper 
accumulation in tissues by increasing the urinary excretion of copper and reducing copper levels in the 
liver and kidney5,6. In addition, trientine may bind to copper in the gut and reduce copper absorption. 
Most orally ingested trientine is not absorbed but excreted unchanged in the faeces. The 5 to 18% that 
is systematically absorbed in humans is reported to display extensive tissue distribution, with high 
levels of distribution to the liver and kidneys7,8. Systemically absorbed trientine is extensively 

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metabolised, with acetylation into two major metabolites, N1-acetyltriethylenetetramine (MAT) and 
N1,N10-diacetyltriethylenetetramine (DAT). Trientine and its metabolites are rapidly excreted in the 
urine, although low levels of trientine can still be detected in the plasma after 20 hours9, there is no 
evidence of accumulation. Evidence suggests that steady state concentrations are achieved with 
regular administration of trientine at recommended dose levels10. 
 
Trientine tetrahydrochloride (TETA 4HCl) is a formulation of trientine that was developed to be stable 
at room temperature, unlike the previous Trientine compound, Trientine hydrochloride (TETA 2HCL). 
A TETA 4HCL tablet, containing 150 mg of trientine base, has previously received marketing 
authorisation in the EU, UK, and further afield under the tradename of Cuprior®. Cuprior® is licensed 
for the treatment of WD in adults, adolescents, and children aged g 5 years intolerant to D- 
penicillamine therapy. Additionally, TETA 4HCl has received marketing authorisation in USA in 2022 
under the tradename CuvriorTM for a converse indication, the treatment of adults with stable WD 
tolerant to D-penicillamine. 
 
1.3 
Study Rationale 
As in all chronic diseases, medication compliance, adherence and persistence are key parameters to 
improve prognosis, but unfortunately are often suboptimal. In WD, available data concerning 
medication adherence and persistence are limited. However, periods of non-adherence and low 
persistence have been shown to be associated with significant progression of disease11,12,13. 
All current treatments for WD require a multiple daily dosing posology, combined with the 
requirement to administer each dose on an empty stomach, at least one hour before meals or two 
hours after meals and at least one hour apart from any other medicinal product, food, or milk. These 
challenging requirements, along with pill/capsule burden (number/size) have been identified as the 
key obstacles to adherence for WD patients14. In a prospective study14, 139 Wilson disease patients 
were assessed for adherence using the Morisky medication adherence scale. The study revealed a 
significant low rate of adherence in the majority of patients, with only 21% maintaining high adherence 
and with 47% and 32% of patients exhibiting medium and low treatment adherence, respectively. 
 
To address the challenge of adherence, compliance, and persistence in WD, Orphalan SA have 
developed a new TETA 4HCL tablet formulation, which contains 300mg trientine base, intended for 
once daily dose administration. This is a hybrid medicine based on the reference medicine, Cuprior® 
(TETA 4HCL)15. This new hybrid medicine contains twice as much trientine base per tablet compared 
to Cuprior®, and will aid once daily dosing. The formulations are compared in Table 1. 
 
Table 1: Drug Formulation Properties 
Cuprior® 
New Formulation 
Appearance 
Yellow film coated scored tablet 
Yellow film coated scored tablet 
Active compound 
Trientine base, mg 
Excipients 
TETA 4HCL 
TETA 4HCL 
150 
300 
Mannitol 
Colloidal anhydrous silica 
Glycerol dibehenate 
Mannitol 
Colloidal anhydrous silica 
Glycerol dibehenate 
Magnesium-stearate 
Film-coating 
Opadry AMB II 88A120000 Yellow 
Opadry AMB II 88A120000 Yellow 
 
 
This study aims to assess the pharmacokinetics and safety and tolerability of a total daily dose of 
900mg of TETA 4HCL, comparing the new once daily TETA 4HCL formulation (3x300mg trientine base 
tablets, OD) with the current marketed Cuprior® formulation, administered 3x150mg trientine base 
tablets administered twice a day in healthy adult male and female participants. Current recommended 

Orphalan SA 
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initial doses of TETA 4HCl in Europe are between 450mg and 975mg of trientine base, administered in 
two to four divided doses and titrated to clinical response. Some literature has supported a once daily 
dosing regimen but there is a paucity of pharmacokinetic data to support this. 
 
Exploring the PK profile of once daily TETA 4HCL administration will be used to support a once daily 
dosing regimen in patients. This reduction in treatment burden will increase overall therapeutic 
compliance, and ultimately lead to better clinical outcomes for patients with WD. 
 
2. 
TRIAL OBJECTIVES AND OUTCOMES 
2.1 
Objectives 
 
Primary 
Objectives 
Endpoints 
Statistical analyses 
To evaluate and compare the 
plasma concentration of TETA 4HCL 
(active moiety, TETA) and its two 
main 
metabolites 
 (N1- 
acetyltriethylenetetramine 
(MAT) 
and 
 
N1, 
N10- 
diacetyltriethylenetetramine (DAT)) 
following administration of a total 
daily dose of 900mg TETA 4HCL, 
comparing the new once daily TETA 
4HCL 
formulation 
(3x300mg 
trientine base tablets, OD) with the 
current 
marketed 
Cuprior® 
formulation, (3x150mg trientine 
base tablets, BD) in healthy adult 
male and female participants. 
PK parameters derived by non- 
compartmental methods including: 
area under the plasma concentration- 
time curve from time zero to last 
detectable 
plasma 
concentration 
(AUC0-t), area under the plasma 
concentration-time curve from time 
zero 
to 
24 
hours 
plasma 
concentration (AUC0-24), area under 
the plasma concentration-time curve 
from time zero extrapolated to 
infinite (AUC0-¥), maximum observed 
plasma concentration (Cmax), time to 
reach 
maximum 
plasma 
concentration (tmax), apparent total 
plasma clearance (CL/F), apparent 
volume of distribution during the 
terminal 
phase 
(Vz/F), 
terminal 
elimination rate constant (»z), and 
terminal elimination half-life (t1/2). 
″ Plasma concentrations will be listed 
and summarised by time point. 
Individual and arithmetical mean 
plasma concentration vs time curves 
for each analyte which includes all 
treatments will be produced on both 
linear/linear and log10/linear scales. 
″ The PK parameters will be listed for 
each participant and summarized for 
each 
treatment 
group 
using 
descriptive statistics (N - the number 
of participants, arithmetic mean, SD 
- standard deviation, CV - coefficient 
of 
variation, 
geometric 
mean, 
median, minimum, maximum). 
″ 
For 
comparability 
of 
the 
two 
products the geometric mean, ratio 
of geometric means, confidence 
intervals 
(CI) 
including 
their 
logarithmic transformation together 
with the coefficient of variation for 
the within-participant variability will 
be summarised. In case a gender 
effect is noticeable, gender will be 
added as an additional term in the PK 
model, and all PK analyses will be 
presented per gender as well. 
Secondary 
Objectives 
Endpoints 
Statistical analyses 
To compare the safety and 
tolerability of the two TETA 4HCL 
tablet formulations. 
″ 
The incidence, severity, and 
relationship of Treatment- 
Emergent Adverse Events 
(TEAEs). 
″ 
Proportion of participants with 
clinically significant changes in 
laboratory safety tests 
(haematology, biochemistry, 
coagulation, and urinalysis). 
″ 
Adverse Events (AE), Serious 
Adverse Events (SAEs), vital signs, 
ECG parameters, and clinical 
laboratory data will be listed and 
summarised using descriptive 
statistics. 
″ 
All AEs will be summarised and 
listed by using System Organ Class 
(SOC) and Preferred Term (PT) 
assigned to the event using Medical 

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″ 
Proportion of participants with 
morphological and/or rhythm 
abnormalities on 
electrocardiogram (ECG). 
″ 
Proportion of participants with 
clinically significant changes in 
vital signs (systolic blood 
pressure, diastolic blood 
pressure and pulse rate). 
Dictionary for Regulatory Activities 
(MedDRA). Furthermore, these 
events will be summarised by the 
maximum intensity. The number of 
participants who experienced drug- 
related AEs will also be summarised. 
Any SAEs and/or AEs that led to 
withdrawal will be summarised and 
listed. 
 
 
3. 
TRIAL DESIGN 
 
3.1 
Overall trial design 
This is a phase I, single centre, randomised, interventional, open-label, cross-over study to evaluate 
the PK, safety, and tolerability of a total daily dose of 900mg of TETA 4HCL, comparing the new once 
daily TETA 4HCL formulation (3x300mg trientine base tablets, OD) with the current marketed Cuprior® 
formulation (3x150mg trientine base tablets, BD) in adult healthy male and female participants. 
 
3.1.1 
Choice of participants and dose rationale 
This study will enrol 26 healthy participants composed of both male and female participants who have 
met all the eligibility criteria. 26 participants will be enrolled to ensure 24 participants complete the 
study. Enrolment will target a balanced gender split, with a maximal 60:40 gender split accepted. 
All women of childbearing potential (WOCBP) will undergo a serum beta human chorionic 
gonadotropin (³-HCG) pregnancy test at screening and a urinary pregnancy test on D-1 of the 
treatment periods. Women that are breastfeeding will be excluded from participating in the 
study. Post-menopausal females will undergo FSH testing at screening to confirm menopausal 
status. 
A total daily dose of 900mg trientine base has been selected as this aligns with the approved Cuprior® 
indication of 450-975mg initial total daily doses. A previous PK study, in which healthy participants 
received high and low doses of TETA formulations, observed no change in the safety profile with 
increasing dose level16. 
 
The overall trial design is depicted in Figure 1. 

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Figure 1: Study flow chart 
 
The study will be conducted at a single site in the UK. Each participant will receive verbal and written 
information before signing the Informed Consent Form (ICF) prior to any screening procedures taking 
place. Participants will undergo screening (D-28 to D-2) to assess eligibility. Enrolled participants will 
undertake two inpatient treatment periods, separated by an intermediate washout period (at least 5 
days and a maximum of 10 days between study drug administration). At each treatment period, 
participants will be admitted to the unit on D-1 and will be discharged on the morning of D3. On D1 of 
the first treatment period, participants will be randomised (1:1) to one of two treatment sequences, 
as described in Table 2. Study drug administration will occur on D1. 
 
Table 2: Treatment Sequences 
 
Treatment Sequence 
Period 1 
Period 2 
Sequence 1 
Treatment A 
Treatment B 
Sequence 2 
Treatment B 
Treatment A 
Treatment A: 900mg TETA 4HCl, new once daily formulation (3x300mg trientine base tablets as a single 
AM dose). 
Treatment B: 900mg TETA 4HCl, Marketed Cuprior® formulation (6 x150mg trientine base tablets in 
two equally divided doses (450mg doses 8 hours apart). 
Participants will return to the unit for an outpatient, end of study follow-up visit on D7 of treatment 
period 2. All assessments performed during the study are detailed in the study schedule of assessments 
(Table 3 & 4). The total duration of the study (including the screening period) is approximately 7 weeks. 

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Table 3: Schedule of Assessments 
 
Period 
Screening 
Treatment period 1 
Treatment period 2a 
Follow-up Visit/ End 
of Study 
Procedure 
(allowable window) 
D-28 
to 
D-2 
D-1 
D1 
D2 
D3 
D-1 
D1 
D2 
D3 
D7 
(+/-2d) 
Informed consent b 
x 
Demographic data 
x 
Body weight/height/BMI c 
x 
x 
x 
x 
12-lead ECG d 
x 
x 
x 
x 
Vital signs e 
x 
x 
x 
x 
x 
x 
x 
x 
Medical/Surgical history and 
prior medication 
x 
Smoking history 
x 
Physical examination f 
x 
x 
x 
x 
x 
x 
Urine drugs of abuse screen 
x 
x 
x 
Breath alcohol test 
x 
x 
x 
Haematology/Biochemistry 
/Coagulation g 
x 
x 
x 
x 
x 
x 
Serology (HIV 1 & 2, Hep B & C) 
x 
Urinalysis 
x 
x 
x 
x 
x 
x 
Urine Cotinine test 
x 
Pregnancy testing (females) h 
x 
x 
x 
x 
FSH i 
x 
Inclusion/Exclusion criteria j 
x 
x 
Check-in 
x 
x 
Check-out 
x 
x 
Non-residential visit 
x 
x 
Randomisation 
x 
Study drug administration a,k 
x 
x 
Meals l 
x 
x 
x 
x 
x 
x 
x 
x 
PK blood sampling m 
x 
x 
x 
x 
x 
x 
COVID-19/Influenza testing n 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
AE recording/concomitant 
medication o 
Throughout 
a. 
The study drug administration between treatment periods will be at least 5 days and a maximum of 10 days 
(Washout period). 
b. 
Study procedures will not occur until informed consent is completed. Participants will not be reconsented if they 
are rescreening for the trial. 
c. 
Height will be measured at Screening only. 
d. 
12-lead ECGs (triplicate) will be measured after at least 10 minutes rest in supine position. 

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e. 
Vital signs (respiratory rate, tympanic temperature, blood pressure and heart rate) will be measured after at least 
5 minutes rest in supine position. D1 vital signs will be performed 2 hours prior to AM dosing and at H6. 
f. 
Full physical examination will be carried out at screening and EOS visits, symptom directed physical examination 
will be performed at other time-points. 
g. 
D2 samples to be taken at H24. 
h. 
Serum pregnancy test will be performed at screening. A urine pregnancy test will be performed at all other time- 
points. 
i. 
FSH test will only be performed at screening on post-menopausal women to confirm post-menopausal status. 
j. 
Inclusion and exclusion criteria will be assessed at screening and treatment period 1 D-1. Participants will be 
assessed on treatment period 2 D-1 to ensure the participant has not had any significant changes to their health 
with may preclude further dosing. 
k. 
The study drug will be administered on Day 1 with 240ml water. The order of the treatment sequence is 
determined by the randomisation schedule. 
l. 
Detailed D1 timings are provided in Table 4. 
m. Timings of PK samples are detailed on Table 4. 
n. 
COVID-19/influenza point of care testing will be carried out as per the site9s latest COVID-19 Infection Control 
Guidelines and pre-entry algorithms. 
o. 
AEs and concomitant medications will be collected at each visit from the time of consent until the end of study 
visit, and daily during study residency. 

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Table 4: Schedule of assessments (cont.) 
 
Timepoint 
Treatment A 
Treatment B 
Generic 
Study 
Day 
Time (h) 
Dose 
administration 
PK 
sampling 
(plasma) 
Dose 
administration 
PK 
sampling 
(plasma) 
Mealsa 
Fastingb 
D1 
Pre-dose 
x 
x 
x 
0 
x 
x 
x 
0.5 
x 
x 
x 
1 
x 
x 
x 
1.25 
x 
x 
1.5 
x 
x 
2 
x 
x 
3 
x 
x 
4 
x 
x 
5 
x 
x 
x 
6 
x 
x 
x 
8 
x 
x 
xc 
x 
8.5 
x 
x 
9 
x 
9.25 
x 
9.5 
x 
10 
x 
11 
x 
12 
x 
x 
x 
13 
x 
14 
x 
x 
16 
x 
x 
20 
x 
D2 
24 
x 
x 
36 
x 
x 
D3 
48 
x 
x 
a. 
D1 meals for both treatment periods will be identical and will follow the scheduled times above. D2/D3 meals 
will follow the standard timings of the research unit and are not described in this table. 
b. 
Participants will be fasted overnight (minimum 8 hours) prior to H0 dose administration. Participants will be 
fasted for at least 2 hours prior to H8. Participants will be nil by mouth for 1 hour following all study drug 
administrations. 
c. 
H8 PK sample must be taken just before (within 10mins) the second treatment B dose. 
 
 
3.2 
Adaptive Protocol Features 
This trial incorporates adaptive protocol features which may be implemented at the discretion of the 
investigator. These adaptive protocol features and their limits are described Table 5. 

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Table 5: Adaptive Protocol Features 
 
Additional safety 
assessments 
1. Additional safety assessments may be performed 
on an individual participant if it is considered 
clinically necessary by the Site Investigator on a 
case-by-case basis. 
2. Additional safety assessments may refer to either: 
a. an increased number of the same safety 
assessments planned in the existing 
Schedule of Assessments. 
b. additional parameters (specific tests) on 
assessments 
already 
scheduled 
e.g., 
troponin tests on safety blood samples. 
c. 
additional safety tests requiring additional 
blood/urine sample collections or other 
clinical procedures e.g., ultrasound scans. 
3. Specialist referrals (e.g., to a cardiologist) may be 
made (and may include all relevant assessments 
and investigations) if it is considered clinically 
necessary and agreed by the Principal Investigator 
(PI) and Sponsor (unless considered an acute 
emergency by site PI), on a case-by-case basis. 
I. 
The maximum blood volume for 
scheduled assessments is given in 
Section 8.10. This maximum may only 
be exceeded if additional unscheduled 
blood samples/ investigations are 
performed as necessary to ensure the 
safety of the individual participant. 
II. 
A maximum number of specialist 
referrals 
for 
individuals 
will 
be 
determined on a case-by-case basis and 
cannot be pre-defined as investigations 
will be performed as necessary to 
ensure the safety of the individual 
participants. 
Screening 
1. Screening assessments performed (prior to 
signing the ICF for this study) at Richmond 
Pharmacology on participants screened (but not 
randomized) for another study or screening for a 
generic protocol can be used for this study to 
avoid unnecessary tests/repeats. 
I. 
The 
assessments 
must 
meet 
protocol criteria (e.g., the method 
to be used). 
II. 
The assessments must be performed 
within the protocol defined Screening 
window (Day -28 to -2). 
Replacement of 
withdrawn 
participants 
1. 
Withdrawn participants can be replaced at the 
discretion of the Sponsor and the Investigator. 
The eligible replacement participant(s) will be 
enrolled into the same treatment sequence as 
the original participant(s) and will complete both 
treatment periods and the end of study visit as 
per the schedule of assessments. Evaluable data 
from the withdrawn participant will be included 
in the analysis as appropriate. 
I. 
Participants will only be replaced to fulfil 
a total of 24 participants completing the 
study. 
II. 
Trial stopping rules apply to all 
participants. 
 
 
4. 
RISK MANAGEMENT 
4.1 
Potential Benefits 
TETA 4HCL will be given to healthy participants for research purposes only. It is not anticipated that 
participants will receive any medical benefit apart from a general health examination. 

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4.2 
Potential Risks 
4.2.1 
TETA 4HCL 
Potential risks are expected to be similar to the reference medicine, Cuprior® (150mg trientine base 
per tablet). The Cuprior®SmPC reports the following adverse reactions: iron deficiency anaemia, 
sideroblastic anaemia, nausea, duodenitis, colitis (including severe colitis), skin rash, pruritus, 
erythema and urticaria. Potential risks will be closely monitored for as part of the safety evaluations 
being performed in this trial. The risk mitigation measures are summarised in Table 6. 
 
Table 6: Potential risks and mitigation strategies per target system 
 
Target System 
Effect 
Risk Mitigation 
Haematological 
system 
1) 
Iron Deficiency 
Anaemia 
2) 
Sideroblastic Anaemia 
1) 
Participants with clinically significant haematological pathology or 
laboratory abnormalities (in the opinion of the investigator) will be 
excluded from participation. 
2) 
Safety bloods, including a full blood count, will be taken at regular 
intervals highlighted in the schedule of assessments. 
3) 
Adverse events will be collected throughout the study. 
Gastrointestinal 
system 
1) 
Nausea 
2) 
Duodenitis 
3) 
Colitis 
1) 
Participants with clinically significant gastrointestinal pathology 
(in the opinion of the investigator) will be excluded from 
participation. 
2) 
Safety bloods tests will be taken at regular intervals highlighted 
in the schedule of assessments. 
3) 
Adverse events will be collected throughout the study. 
Cutaneous and 
Mucosal 
1) 
Skin rashes 
2) 
Pruritis 
3) 
Erythema 
4) 
Urticaria 
1) 
Participants with clinically significant dermatological pathology (in 
the opinion of the investigator) will be excluded from 
participation. 
2) 
Physical examination will be performed at Screening and post 
dose to monitor for cutaneous and mucosal reactions. 
3) 
Adverse events will be collected throughout the study. 
 
4.2.1.1 
Summary 
TETA 4HCL has a relatively well-established safety profile, as Cuprior® received marketing authorisation 
in 2017 and previous formulations of trientine have been used in the UK since 1985. Some of the known 
side effects (iron deficiency anaemia, sideroblastic anaemia) relate to chronic dosing and the long-term 
chelation of other metals (i.e., iron, zinc etc.). This is unlikely to occur when healthy participants receive 
single doses. In applying the above risk management strategies, the overall risk to participants in this 
trial is considered low. 
 
4.2.2 
Investigator Site Facilities and Personnel 
This trial will be conducted in a specialised early phase Clinical Pharmacology Unit with onsite 
resuscitation equipment and medication, in addition to access to an acute hospital with Critical Care 
facilities. The trial is conducted by an experienced PI and well trained medical and technical staff with 
ample experience in the conduct of early phase clinical trials. 
The trial is designed to closely monitor, treat, and communicate potential expected adverse reactions 
as well as potential unexpected adverse events. 

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5. 
DECISION-MAKING RULES AND LIMITS 
5.1 
Stopping Rules 
If either of the following scenarios occur, study enrolment and dosing will be suspended immediately: 
″ 
If g1 participant experiences a serious AE that is considered at least possibly related to the IP. 
 
″ 
If g2 participants experience severe non-serious AEs that are considered at least possibly 
related to the IP, independent of within or not within the same system organ class (SOC). 
 
″  If the Sponsor or Investigator considers there to be an unfavourable benefit-risk ratio based 
on emerging safety data. 
If, following consultation between the PI and the Sponsor, it is considered appropriate to restart 
enrolment/dosing in the remaining participants, a substantial amendment will be submitted to the 
Medicines and Healthcare Products Regulatory Agency (MHRA) for restarting the study. 
5.1.1 
Individual Stopping Rules 
 
In addition to the stopping rules described in 5.1, any participant who has received a dose of IMP and 
is scheduled to receive further doses of IMP, will not receive any further doses of IMP if either of the 
following occur: 
 
″ 
If the participant experiences a severe non-serious AE that is considered at least possibly 
related to the IP. 
″ 
If the investigator or sponsor considers there to be any other factor which may jeopardise the 
safety of the individual participant. 
6. 
SELECTION AND WITHDRAWAL OF PARTICIPANTS 
6.1 
Replacement participants 
 
Additional participants may be recruited to replace any withdrawn participants, in order to ensure 
that 24 participants complete the study. Participant replacement is detailed in the Adaptive Protocol 
Features (Table 5). 
 
6.2 
Inclusion Criteria 
Participants must meet all the following criteria to be eligible for enrolment in this study: 
1. Ability to provide written, personally signed, and dated informed consent to participate in the 
trial, in accordance with the ICH Good Clinical Practice (GCP) Guideline E6 (R2) (2016) and 
applicable regulations, before any study-specific procedure is performed. 
2. Male or female aged g18 to f40 years at the date of signing informed consent which is defined 
as the beginning of the Screening Period. This inclusion criterion will only be assessed at the 
Screening Visit. 
3. Body weight g 50 kg and body mass index (BMI) of 18.0 to 25.0 (inclusive) kg/m2 at Screening. 
4. Healthy as defined by: 

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a. The absence of clinically significant illness and surgery within twelve weeks prior to dosing. 
b. The absence of clinically significant history of neurological, endocrine, cardiovascular, 
respiratory, haematological, immunological, psychiatric, gastrointestinal, renal, hepatic, 
and metabolic disease. 
5. Satisfactory medical assessment with no clinically significant or relevant abnormalities as 
determined by medical history, physical examination, vital signs, 12-lead ECG, and clinical 
laboratory evaluation (haematology, biochemistry, coagulation, and urinalysis) that is 
reasonably likely to interfere with the participant's participation in or ability to complete the 
trial as assessed by the Investigator. 
6. Participants must agree to adhere to a contraceptive method defined in Appendix 1. 
7. An understanding, ability, and willingness to fully comply with trial procedures and restrictions. 
 
6.3 
Exclusion Criteria 
Participants will be excluded from enrolment in this study if they meet any of the following criteria: 
1. Any significant current or recurrent disease (e.g., cardiovascular, haematological, 
dermatological, neurological, endocrine, immunological, renal, hepatic, respiratory, or 
gastrointestinal or other conditions). 
2. Acute significant disease or illness (e.g., vomiting, fever, diarrhoea) within 7 days before study 
Day 1 of Treatment period 1. 
3. Any clinically significant deviations in haematology, biochemistry, or coagulation parameters 
at screening. Repeat testing is permitted at the discretion of the investigator. 
4. An estimated Glomerular Filtration Rate (eGFR) <60 ml/min/1.73m2 at screening. 
5. Positive test result for alcohol at Screening or Day -1 of each treatment period. 
6. History of drug abuse or excessive alcohol intake. Excessive alcohol intake is defined as regular 
consumption of more than 14 units of alcohol per week. 
7. Positive test result for drugs of abuse at Screening or Day -1 of each treatment period. 
8. Positive test for Hepatitis B surface antigen (HBsAg), Hepatitis C antibody (HCV Ab), or human 
immunodeficiency virus antibody (HIV Ab) at Screening. 
9. Female participants who are pregnant (including a positive pregnancy test at Screening and on 
Day-1 of each Period) or breastfeeding. 
10. History or regular use of tobacco in any form (e.g., smoking or chewing) or other nicotine- 
containing products in any form (e.g., gum, patch, electronic cigarettes) within 6 months 
prior to Screening. 
11. Positive urine cotinine level at screening. 
12. Treatment with an investigational drug within 90 days or 5 half-lives (whichever is the longer) 
or exposure to more than 3 investigational drugs within 12 months of first study drug 
administration. 
13. Has used any of the following: 
Prescription medication (excluding female hormonal contraception or hormone replacement 
therapy) within 30 days or 5 half-lives (whichever is longer) prior to first study drug 
administration. 
OR 

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Over the counter (OTC) medication (including multivitamin, herbal, or homeopathic 
preparations; (Paracetamol use f2g per day is permitted)) during the 14 days or 5 half-lives of 
the drug (whichever is longer) before first study drug administration. 
14. History of sensitivity/allergy to the study medications or components thereof (mannitol, 
colloidal anhydrous silica, glycerol dibehenate or magnesium-stearate). 
15. Donation or loss of 450 mL or more of blood or plasma within 16 weeks prior to first trial 
medication administration or intention to donate blood in the 16 weeks after completing the 
trial. 
16. An inability to follow a standardised diet and meal schedule or inability to fast, as required 
during the trial. 
17. Participants deemed to have difficult veins for cannulation/blood draws. 
 
 
6.4 
Participant Restrictions 
 
Participants will have to comply with the restrictions described in Table 7. 
Table 7: Participant Restrictions 
 
Items 
participants 
must 
not 
consume or do: 
When participants must stop: 
When participants can re-start: 
Tobacco in any form (e.g., smoking 
or chewing) or other nicotine- 
containing products in any form 
(e.g., 
gum, 
patch, 
electronic 
cigarettes) 
From 
six 
months 
prior 
to 
screening. 
After trial completion. 
Meals/snacks/water 
During the inpatient stays, only 
the meals/drinks provided by the 
trial personnel will be allowed. 
Standard meals will be provided at 
set times as stated in the trial plan, 
and meals should be completed 
each time. 
After discharge from the unit. 
Caffeine-containing or Xanthine- 
containing products 
48 hours before the planned trial 
drug administrations and follow- 
up visit. 
After trial completion. 
Energy drinks or drinks containing 
taurine, glucuronolactone (e.g., 
Red Bull) 
48 hours before the planned first 
trial drug administration and each 
out-patient/ follow-up visit. 
After trial completion. 
Alcohol 
48 hours before the planned trial 
drug administrations and follow- 
up visit. 
After trial completion. 
Strenuous 
physical 
activity. 
(Participants should not start new 
48 hours before admissions and 
follow-up visit. 
After trial completion. 

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Items 
participants 
must 
not 
consume or do: 
When participants must stop: 
When participants can re-start: 
physical training activities during 
the trial until trial completion) 
Any 
prescription 
medication 
(excluding 
female 
hormonal 
contraception 
or 
hormone 
replacement therapy) 
30 days or 5 half-lives (whichever 
is longer) before the planned first 
trial drug administration. 
After trial completion. 
N.B: If participants have a medical 
need to take any medication or 
have any medications prescribed 
to them by a doctor, they should 
follow the medical advice but 
inform the Investigator as soon as 
possible afterwards. Participants 
should be informed not to stop 
taking any medication that has 
been prescribed by their GP or 
other doctor. 
Any over the counter (OTC) 
medication (Paracetamol use f2g 
per day is permitted). 
14 days or 5 half-lives (whichever 
is longer) before the planned first 
trial drug administration. 
Blood and plasma donation 
16 weeks before the planned first 
trial drug administration. 
16 weeks after trial completion. 
 
6.5 
Criteria for withdrawal 
 
The investigator or designee may withdraw a participant from the trial if the participant: 
″ 
Is in violation of the protocol, which may jeopardize the trial results or represent a risk to the 
participant 
″ 
Has an AE warranting withdrawal 
″ 
Becomes pregnant 
″ 
Use of/need for a prohibited medication which in the opinion of the sponsor or investigator 
may jeopardize the trial results or represent a risk to the participant 
″ 
Requests to be withdrawn from the trial (participant withdrawal of consent) 
″ 
Is found to be considerably non-compliant with the protocol-required dosing visits 
″ 
In the investigator9s opinion, is unable to continue trial participation 
″ 
Is withdrawn from the trial upon the request of sponsor, including if sponsor terminates the 
trial. 
 
6.5.1 
Handling of Withdrawals 
In the event a participant withdraws or is withdrawn from the trial, the investigator will inform the 
sponsor immediately. If there is a medical reason for withdrawal, the participant will remain under the 
supervision of the investigator for protocol-specified safety follow up procedures. 
Should any of the participants be withdrawn from the trial (by the investigator and/or sponsor) after 
being dosed, all the relevant assessments in relation to last dose should be completed as per protocol. 
The investigator and/or sponsor may decide to perform additional (or less) assessments in accordance 
with Table 53 Adaptive Protocol Features. 
Should a participant withdraw themselves from the trial, every effort should be made to conduct a 
complete Early Termination (ET) visit at an appropriate time-point. The procedures required for the 
8Last Visit9 should be performed at this visit. The investigator and/or sponsor may request additional 
(or less) assessments in accordance with Table 53 Adaptive Protocol Features, with the participant9s 

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agreement. 
A participant who fails to return for final evaluation will be contacted by the site in an attempt to have 
the participant comply with the protocol in accordance with the site SOPs. 
 
When a participant withdraws from the trial, the primary reason for discontinuation must be recorded 
in the appropriate section of the case report form (CRF). 
 
7. 
TRIAL IMP AND CONCOMITANT TREATMENTS 
The trial treatments are categorised and described below. 
An Investigational Medicinal Product (IMP) is defined as a pharmaceutical form of an active substance 
or placebo being tested or used as a reference in a clinical trial, including products already with a 
marketing authorisation but used or assembled (formulated or packaged) in a way different from the 
authorised form, or when used for an unauthorised indication, or when used to gain further 
information about the authorised form. 
″ The term <test IMP= is used to indicate only the experimental product under trial or 
development. Note: This term is more specific than <investigational medicinal product= which 
includes comparators and placebos. 
″ The term <reference IMP= is used to indicate any medicinal product being used as a 
comparator or reference substance (including placebo). Note: This term is more specific than 
<investigational medicinal product= which includes the experimental product and placebos. 
 
7.1 
Investigational Medicinal Products (IMPs): 
 
The following IMPs will be used in this trial: 
″ 
Cuprior® 150 mg film-coated tablets [Reference IMP] 
″ 
TETA 4HCL new once daily formulation 300mg tablets [Test IMP] 
 
Bulk Test IMP will be supplied and QP certified by Orphalan SA or their contractor. Reference IMP will 
be obtained by Richmond Pharmacology through an approved Richmond Pharmacology supplier. Prior 
to being used on the clinical trial, the IMPs will be re-packaged and prepared by Richmond 
Pharmacology9s clinical trials pharmacy. The packaged and prepared individual participant doses will 
be certified and dispensed by the site9s pharmacy staff. 
 
7.1.1 
Labelling of IMPs 
 
The labelling of the trial drugs will be in compliance with Good Manufacturing Practice (GMP) 
specifications, as described in The Rules Governing Medicinal Products in the European Union, Volume 
4, Annex 13, Investigational Medicinal Products, and any other or local applicable regulations. 
Sample label(s) will be submitted to the UK health authorities according to the submission 
requirements. 
 
7.1.2 
Drug administration 

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The two TETA 4HCL tablet (Oral) formulations tested in this study will be administered to participants 
with 240 mL of water. 
Study drug administration will be performed by a Research Physician and the details of dosing will be 
recorded in the CRF. The dosing will be verified by another member of the investigator9s staff. Detailed 
instructions for dose administration will be included in the SOM. 
 
7.1.3 
Storage of IMPs 
IMP will be stored in accordance with the labelling instructions as defined in the IMPD. The IMPs will 
be stored securely in a temperature-controlled pharmacy with authorised access only. 
 
7.1.4 
Drug Accountability 
 
The designated pharmacy staff at the clinical trial site will maintain accurate records of receipt and the 
condition of all trial drugs, including dates of receipt. In addition, accurate records will be kept by the 
pharmacy staff of when and how much trial drug is dispensed and used by each participant in the trial. 
Any reason for departure from the protocol dispensing regimen must also be recorded. 
Drug accountability records and inventory will be available for verification by the sponsor or designee. 
At the completion of the trial, there will be a final reconciliation of all trial drugs. 
Trial drug must not be used for any purpose other than the present trial. Remaining trial drug will be 
returned to the sponsor or its agent or its destruction arranged by the clinical trial site according to 
applicable regulations and only after receipt of written authorization from the sponsor. 
 
7.2 
Treatment Allocation 
 
7.2.1 
Participant Randomisation 
 
All participants in this trial will be assigned to a treatment regimen according to a randomisation 
schedule generated by a statistician. Eligible participants will be randomly assigned on D1 to one of 
the two treatment sequences (1:1 ratio) detailed in Table 2. 
Details regarding the unique screening and participant number allocation will be included in the SOM. 
 
8. 
TRIAL METHODOLOGY 
8.1 
Order of Procedures 
 
Order of Procedures / Priorities: 
When multiple assessments occur at a specific timepoint, PK blood sampling takes priority (takes 
precedence over ECG and vital sign measurements) and is to be scheduled at the exact time point 
defined in the Schedule of Assessments. During the In-house Period, the order of procedures should 
be ECG, Vital Signs, Blood Samples including PK, and Meal. Should there be any delay to procedures, 
PK sample timings should be prioritized above the order of procedures. 

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Scheduling time windows: 
The permitted time windows are set out in the Data Handling Protocol for scheduling time windows 
(DHP STW) and factored into the design of the Master Treatment Schedule (MTS). 
 
 
Protocol deviations: 
Where the time of clinical assessment deviates from the scheduling time window in the DHP STW, this 
will be considered a protocol deviation. These deviations will be identified, classified (minor, major, 
critical), and managed in accordance with the DHP STW. 
8.2 
Medical History 
All clinically significant medical history (including any significant surgical history) must be reviewed and 
recorded on the CRF for each participant. Each participant9s full medical history will be obtained 
through direct questioning, medical assessment at Screening and GP Health Care Form review. 
 
Any changes to medical history occurring during the Screening Period and prior to first study drug 
administration on Day 1 will be documented. 
 
8.3 
Meals 
Dosing day (D1) meals will be identical across treatment periods. Meals will be provided at the 
timepoints dictated in Table 3 & 4 . Meals will consist of the following: 
• 
Breakfast (1 hour post AM dose) 
• 
Lunch (5 hours post AM dose) 
• 
Dinner (12 hours post AM dose) 
• 
Snack (14 hours post AM dose) 
 
Meals for the non-dosing inpatient days will be served as below, following the standard timings of the 
research unit: 
• 
Breakfast (following the morning procedures) 
• 
Lunch 
• 
Dinner 
• 
Snack 
 
 
8.4 
Clinical Laboratory Assessments 
Laboratory parameters to be measured are presented in Table 8. 

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Table 8: Laboratory parameters 
 
Haematology 
Biochemistry 
Urinalysis 
″ 
Platelets 
″ 
Haemoglobin (Hb) 
″ 
Haematocrit 
″ 
White blood cells 
″ 
Neutrophils cell count 
″ 
Eosinophils cell count 
″ 
Basophils cell count 
″ 
Lymphocytes cell count 
″ 
Monocytes cell count 
″ 
Red blood cells 
″ 
Mean cell haemoglobin (MCH) 
″ 
Mean 
corpuscular 
haemoglobin 
concentration (MCHC) 
″ 
Mean corpuscular volume (MCV) 
″ 
HbA1c* 
″ 
Aspartate aminotransferase (AST) 
″ 
Alanine aminotransferase (ALT) 
″ 
Alkaline phosphatase (ALP) 
″ 
Urea 
″ 
Gamma GT 
″ 
Total bilirubin 
″ 
Direct bilirubin 
″ 
Creatinine 
″ 
eGFR* 
″ 
Total Serum Proteins 
″ 
Albumin 
″ 
Creatine kinase 
″ 
Sodium 
″ 
Potassium 
″ 
Calcium 
″ 
Corrected calcium 
″ 
Magnesium 
″ 
Chloride 
″ 
Leukocytes 
″ 
Nitrite 
″ 
Urobilinogen 
″ 
Protein 
″ 
pH 
″ 
Blood 
″ 
Specific gravity 
″ 
Ketones 
″ 
Bilirubin 
″ 
Glucose 
″ 
Urine microscopy** 
″ 
Urine pregnancy test*** 
 
 
 
 
 
 
 
 Coagulation 
 ″ 
Bicarbonate 
 Urine Screen for Drugs of Abuse 
 
″ 
aPTT 
″ 
PT (or INR in patient studies) 
″ 
Fibrinogen 
″ 
INR 
 
 Serology* 
 
″ 
Hepatitis B surface antigen (HBsAg) 
″ 
Hepatitis B core antibody (anti-HBC IgG 
+ IgM, if IgG positive) 
″ 
Hepatitis C antibody (anti-HCV) 
″ 
HIV I and II antibodies 
″ 
Amylase 
″ 
Total cholesterol 
″ 
Triglycerides 
″ 
Serum pregnancy test*** 
″ 
FSH*/*** 
″ 
Benzodiazepines 
″ 
Opiates 
″ 
Amphetamines 
″ 
Methadone 
″ 
Cocaine 
″ 
Cannabinoids 
″ 
Barbiturates 
″ 
Cotinine* 
 
* Only measured at screening. 
**Only if urinalysis demonstrates one of the following: positive nitrites, positive leucocytes, >trace protein or blood (unless female and 
menstruating,). Microscopy may be requested at the discretion of the investigator outside of the aforementioned parameters. 
*** Pregnancy test for pre-menopausal women only; FSH for post-menopausal women only. 
 
 
8.4.1 
Haematology, Biochemistry, and Coagulation 
 
Blood samples for determination of biochemistry, haematology and coagulation parameters will be 
taken at the times given in the Schedule of Assessments (Table 3 & 4). The date and time of collection 
will be recorded on the appropriate CRF pages. The analyses will be done using routine methods. eGFR 
will be calculated using the CKD-EPI (2009) equation. Further details will be described in the SOM. 
Laboratory values outside the reference limits, which are suspected to be of any clinical significance, 
will be repeated. Participants in whom the suspected clinical significance is confirmed on repeated 
sampling will either not be included or, if already included, may be withdrawn from further 
participation in the trial and/or followed-up until normalisation or for as long as the Investigator 
considers necessary. 
 
8.4.2 
Serology 
 
Serology will be performed at Screening as detailed in the Schedule of Assessments (Table 3 & 4). At 
the screening visit all participants will be tested for the parameters listed in Table 8. 

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If a participant is found to be confirmed positive in any of these tests, they will be referred for further 
examination/treatment and will not be included in the trial, except for participants with a confirmed 
positive anti-HBc IgG and negative anti-HBc IgM and negative HBsAg, indicative of natural immunity 
due to a past infection without active chronic or acute infection. 
8.4.3 
Pregnancy/FSH testing 
Serum pregnancy tests will be performed on WOCBP at screening. A urine pregnancy test will be 
performed at all other time-points, as per the schedule of assessments. Additional pregnancy tests 
may be performed if pregnancy is suspected. Participants who are pregnant will not be eligible for 
study participation. 
FSH test will only be performed at screening on post-menopausal women to confirm post-menopausal 
status. 
 
8.4.4 
Urinalysis 
 
Urine samples for determination of urinalysis parameters will be taken at the times given in the 
Schedule of assessments. If deemed necessary, based on a clinically significant abnormal test, 
microscopic examination of urine will be performed. 
 
8.4.5 
Drugs of Abuse 
 
Urine will be tested for the drugs of abuse as described in the Schedule of assessments. If a participant 
fails the drug abuse screen, they will be excluded from the trial. A repeat drug screen can be done 
where methodological reasons are believed to have led to a false positive. If participants are suspected 
to be positive due to medication e.g., flu/cold remedies, they may undergo a repeat drug screen. A 
urine Cotinine will also be assessed at screening. 
 
8.5 
Alcohol Breath Test 
An alcohol breath test will be done using an alcometer as described in the Schedule of Assessments. If 
a participant tests positive to the test they will be excluded from the trial. 
 
8.6 
Vital signs (blood pressure, pulse rate, respiratory rate, and tympanic temperature) 
 
Vital signs will be measured at the time points as detailed in the Schedule of Assessments. Blood 
pressure and pulse rate will be measured in supine position after the participant has rested 
comfortably for at least 5 minutes using automated blood pressure monitors. Respiratory rate will be 
measured by manual counting for one minute. Temperature will be measured using tympanic 
thermometers. Detailed methodology will be provided in the SOM. 
 
8.7 
Electrocardiographic (ECG) Measurements 
 
8.7.1 
Recording of 12-lead ECGs 
 
12-lead ECGs will be recorded at the time-points described in Schedule of assessments. 12-lead ECG 
recordings will be made after the participants have been resting in a supine position for at least 10 

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minutes. At each time point, the ECG will be recorded in triplicate, to reduce variance and improve the 
precision of measurement. Detailed methodology will be provided in the SOM. 
 
8.8 
Physical Examination, Height, and Weight 
 
The physical examination performed at screening and at the end of trial visit will include an assessment 
of the following: general appearance, skin, eyes, ears, nose, neck, lymph nodes, throat, heart, lungs, 
abdomen, musculoskeletal system and extremities. A symptom-directed physical examination will be 
conducted at all other visits as needed based on reported signs and symptoms. The timings of the 
physical examinations are described in the Schedule of Assessments. 
Height will be measured in centimetres and weight in kilograms. Measurements should be taken with 
participants wearing light clothing and without shoes using calibrated scales for all measurements. BMI 
will be calculated from the height and weight. Full details will be described in the SOM. 
 
8.9 
Pharmacokinetic Assessments 
 
8.9.1 
PK blood samples 
For timing of individual samples refer to the Schedule of Assessments. The date and time of collection 
will be recorded on the appropriate CRF. 
Plasma samples for determination of PK parameters of TETA 4HCL (active moiety, TETA) and its two 
main metabolites (N1-acetyltriethylenetetramine (MAT) and N1, N10-diacetyltriethylenetetramine 
(DAT)) will be analysed by QPS Netherlands B.V. using a validated method. Full details of the analytical 
methods used will be described in a separate bioanalytical report. All sample handling procedures, 
including the time of each sample collection, collection tube details, the time of placement into frozen 
storage (at the end of the sample workup), and the date of transfer or shipment of the samples to the 
responsible analyst will be documented in detail in the SOM and Laboratory Manual. 
 
8.10 
Volume of Blood Sampling 
 
The maximum total blood volume collected from participants participating in this study will not exceed 
350 mL overall. The NHS blood donation policy at the time of completion of this protocol 
(https://www.blood.co.uk/who-can-give-blood/) states that women can give 470 mL of blood every 
16 weeks. Therefore, the 350 mL permitted in this study is approximately consistent with current 
clinical practice. 
 
8.11 
Adverse Events 
The collection, evaluation and reporting of adverse events/reactions arising from this clinical trial will 
be performed in accordance with: 
″ Detailed guidance on the collection, verification and presentation of adverse event/reaction 
reports arising from clinical trials on medicinal products for human use (8CT-39) (2011/C 
172/01). 
″  International Conference on Harmonization (ICH) harmonised tripartite guideline on clinical 
safety data management: <Definitions and standards for expedited reporting= E2A. 
″  ICH harmonised tripartite guideline on development safety update report: E2F. 
″  ICH guideline E2F <Note for guidance on development safety update reports (DSUR)=. 

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All AEs will be collected from the signing of the ICF until the end of study visit. Investigators are not 
obligated to actively seek AEs or SAEs after conclusion of the study participation. 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 treatment or study 
participation, the Investigator must promptly notify the Sponsor or designee. 
8.11.1 
Definitions 
 
Adverse Event 
In accordance with the International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) E2A guideline Definitions and Standards for Expedited Reporting, 
an Adverse Event (AE) is any untoward medical occurrence or clinical investigation that is temporally 
associated with the use of a medicinal product or medical device which does not necessarily have a 
causal relationship with this treatment. An AE can therefore be any unfavourable and unintended sign 
(including an abnormal laboratory finding), symptom or disease, temporally associated with the use of 
a pharmaceutical product, whether or not considered to be related to the pharmaceutical product or 
device. 
A clinical laboratory abnormality will be reported as an AE/SAE if deemed to be clinically significant by 
the Investigator. Examples that may suggest clinical significance include: 
″ 
Accompanied by clinical symptoms. 
″ 
Leading to a change in treatment with IMP (e.g., dose modification, interruption, 
permanent discontinuation). 
″ 
The abnormality suggests a disease and/or organ toxicity. 
″ 
The abnormality is of a degree that requires active management (e.g., discontinuation of 
IMP, more frequent follow-up assessments, further diagnostic investigation). 
″ 
Any laboratory result abnormality fulfilling the criteria for an SAE will also be reported. 
 
Serious Adverse Event 
A Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, at any dose: 
″  Results in death. 
″  Is life-threatening: the term "life-threatening" in the definition of "serious" refers to an event 
in which the participant was at immediate risk of death at the time of the event; it does not 
refer to an event which hypothetically might have caused death if it were to worsen or become 
more severe). 
″ 
Requires inpatient hospitalisation or prolongation of existing hospitalisation. 
″ 
Results in persistent or significant disability/incapacity. 
″ 
Results in a congenital abnormality, or birth defect. 
″  Is an important medical event: Medical events that may not result in death, be life-threatening, 
or require hospitalisation may be considered serious when, based on appropriate medical 
judgment, they may jeopardise the participant and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. Examples of such events 
are intensive treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in inpatient hospitalisation, or the development of 
drug dependency or drug abuse. 

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″ Participants with DILI defined as AST or ALT g 3 × ULN; total bilirubin g 2 × ULN; absence of 
biliary obstruction/cholestasis (alkaline phosphatase < 2 × ULN) and no other explanation for 
the findings (e.g., viral hepatitis, chronic or acute liver disease, administration of concomitant 
hepatotoxic drug) must be reported as an SAE. 
 
Adverse Reactions 
An Adverse Reaction (AR) is a response to a medicinal product which is noxious and unintended, and 
which occurs at any dose. The term <reaction= means that a causal relationship between a medicinal 
product and an adverse event is at least a reasonable possibility, i.e., the relationship cannot be ruled 
out. 
 
A Serious Adverse Reaction (SAR) is any adverse reaction (i.e., at least a reasonable possibility of a 
causal relationship with the medicinal product) that fulfils the criteria of seriousness, as defined above. 
A Suspected Unexpected Serious Adverse Reaction (SUSAR) is a serious adverse reaction that is 
unexpected. The 8expectedness9 of a serious adverse reaction is assessed in the light of the reference 
safety information. 
The Reference Safety Information (RSI) is a list of medical events that defines which reactions are 
expected for the IMP being administered to clinical trial participants, and do not require expedited 
reporting to the Competent Authority. It is contained within a specific section of the Investigator9s 
Brochure (IB) for non-marketed products and Summary of Product Characteristics (SmPC) for marketed 
products. 
8.11.2 
Assessment of Severity 
Adverse events should be graded according to Table 9 below. 
Changes in the severity of an AE/SAE should be documented to allow for assessment of the duration 
of the event at each level of severity. AEs/SAEs characterised as intermittent require documentation 
of the start and end of each incidence. 
Adverse event severity and seriousness are assessed independently. 8Severity9 characterizes the 
intensity of an AE. 8Serious9 is a regulatory definition and serves as a guide to the Sponsor for defining 
regulatory reporting obligations (see above definition of SAE). 
 
Table 9: Categorical grading of AE/SAEs 
 
Grade 
Global clinical assessment & application of grading to a diagnosis 
Mild 
Overall clinical condition is asymptomatic, or symptomatic with all the following 
characteristics: 
″  No or minimal interference with usual social and/or functional activities. 
″ No impact, or minimal impact (e.g., of short duration or a return to normal 
status without intervention), upon usual self-care activities. 
″ Deviation from reference range for the population and from the participant9s 
clinically determined physiological baseline has no clinical impact and does not 
signal potential safety concern or unanticipated clinical risk. 
″  The condition is reversible to baseline within an anticipated timeframe. 

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Grade 
Global clinical assessment & application of grading to a diagnosis 
″ Intervention or treatment is either not indicated or indicated only to increase 
participant9s sense of wellbeing and comfort, but not due to safety concerns or 
risk. 
Moderate 
Overall clinical condition is asymptomatic or is symptomatic with no or minimal 
impact on usual self-care activities and one or more of the following characteristics: 
″  Greater than minimal interference with usual social & functional activities. 
″ Deviation from reference range for the population and from the participant9s 
baseline has clinical impact, but there is no acute safety concern or 
unanticipated risk. However, should the condition persist and/or occur more 
frequently, it could signal a potential safety concern or unanticipated risk and 
should therefore be monitored. 
″  Reversibility of the condition to baseline condition takes longer than desirable 
or anticipated, impacting on the participant9s wellbeing beyond the mere 
severity of the condition. 
″ Further medical assessment, intervention or treatment indicated to increase 
participant9s sense of wellbeing and comfort and to accelerate recovery and/or 
to prevent worsening. 
Severe 
Overall clinical condition is asymptomatic or is symptomatic with one or more of 
the following characteristics: 
″  Significant impact on usual self-care activities. 
″  Inability to perform usual social & functional activities. 
″ The deviation from reference range for the population and from the 
participant9s baseline has significant clinical impact, it is an acute safety 
concern or unanticipated risk and requires close and continuous monitoring. 
″  The reversibility of the condition to baseline condition takes significantly longer 
than desirable or anticipated, with significant impact on the participant9s 
wellbeing. 
″ Intervention or treatment essential to treat the acute manifestations and to 
prevent worsening. 
″  Life-threatening or Fatal 
 
8.11.3 
Assessment of Causality 
 
The Investigator must assess, and document, the relationship of each AE/SAE to the IMP. Alternative 
causes, such as underlying disease(s), concomitant therapy, and other risk factors, as well as the 
temporal relationship of the event to IMP administration must be assessed. The Investigator will also 
consult the Investigator9s Brochure (IB)/SmPC in their assessment. 
The Investigator should also comment on the source document whether an AE/SAE is not related to 
the study treatment but is related to study participation (e.g., study procedures, wash-out periods 
etc.). AEs where a causal relationship between IMP and the AE is at least a reasonable possibility, are 
referred to as ARs. 
Causality should be documented before the initial transmission of the SAE data to the Sponsor or 
Designee. The Investigator may change their opinion of causality with follow-up information and send 
an SAE follow-up report with the updated causality assessment. 
The causal relationship of the AE/SAE will be assessed by the Investigator as either 8Related9 or 8Not 
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Related: The available evidence suggests there is a reasonable possibility that the AE/SAE is caused by 
the IMP. The occurrence of the AE cannot be explained by other causative factors, but can be explained 
by the pharmacological effect of the IMP such as: 
″ 
Temporal relationship to IMP exposure. 
″ 
Event is known to be associated with the IMP drug class. 
″ 
Event improved on discontinuation or dose reduction of IMP. 
″ 
Event reoccurred on re-challenge of IMP. 
″ 
Biological plausibility. 
″ 
Other (must be specified). 
Not Related: There is no reasonable possibility that the IMP caused the AE/SAE. The occurrence of 
the AE can be explained by other causative factors, such as: 
″ 
Event attributed to concomitant medication (provide details of the concomitant medication). 
″ 
No reasonably temporal relationship associated with IMP administration. 
″ 
Event is expected in the study indication and/or target population. 
″ 
Negative de-challenge and/or negative re-challenge. 
″ 
Other (must be specified). 
 
8.11.4 
Eliciting and Recording of Adverse Events 
 
All (serious and non-serious) adverse events detected by the investigator or spontaneously notified by 
the participant at each visit/examination must be reported on the appropriate pages of the CRF. The 
following information should be reported for each adverse event, whether or not it can be attributed 
to study drug: 
″ 
Description of adverse event 
″ 
Date of onset/Stop date 
″ 
Characteristics of the event (seriousness, intensity) 
″ 
Actions taken (treatment required, or dose adjustments must be reported in the CRF) 
″ 
Outcome 
″ 
Relationship with study drug (causality assessment) and/or study participation 
 
When an AE/SAE occurs, the Investigator will attempt to establish a diagnosis of the event based on 
signs, symptoms, and/or other clinical information/documentation. Where feasible, the diagnosis will 
be documented as the AE/SAE. If a diagnosis is not available, each sign/symptom may be reported as 
a separate AE/SAE. If a diagnosis subsequently becomes available, this should be recorded, replacing 
the original entry(s) where appropriate. All relevant AE/SAE information must be recorded and filed in 
the CRF. SAEs will be recorded on the SAE form and filed in the CRF. 
 
All AEs and SAEs will be followed until satisfactory resolution, until baseline level is reached, or until 
the SAE is considered by the Investigator to be chronic or the patient is stable, as appropriate, or the 
investigator considers it medically justifiable to terminate the follow-up. The reason(s) will be recorded 
in the CRF when the AE follow-up is terminated. 
 
8.11.5 
Reporting of Serious Adverse Events 
All AEs and SAEs must be reported regardless of the relationship to the study treatment. If an SAE 
occurs, the Investigators will take appropriate action immediately and will strive to identify the 
cause(s) of the events. Investigators should not delay the reporting of a suspected SAE to obtain 

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additional information. Any additional information, if collected, can be reported to the Sponsor or its 
designee as a follow-up to the initial report. 
 
All SAEs/SUSARs will be notified by the Investigator to the Sponsor within 24 hours of awareness by 
email to: 
 
E-mail: adverseeventreporting@orphalan.com 
Phone: +356 99 966 819 
 
Further follow-up SAE reports and any supplemental information will be provided as and when new 
information becomes available. 
The Sponsor will also perform an evaluation of all SAEs prior to their finalization and/or reporting. 
SUSARs will be notified to the MHRA and to the relevant REC(s) by Orphalan or its representatives 
within 7 days for fatal and life-threatening SUSARs or 15 days all other SUSARs. 
Detailed reporting procedures will be outlined in the Pharmacovigilance Safety Management Plan. 
 
 
8.12 
Expedited Reports and Regulatory Requirements 
 
8.12.1 
Expectedness 
The RSI for TETA 4HCL states that iron deficiency anaemia is an expected serious adverse reaction. 
However, given this is a healthy participant trial, there are no expected serious adverse reactions. All 
serious adverse reactions will be treated as unexpected and will be reported as SUSARs. 
 
Prompt notification by the Investigator to the Sponsor or designee of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of patients and the safety of a study 
treatment under clinical investigation are met. 
 
8.12.2 
Regulatory Requirements 
The Sponsor has a legal responsibility to notify the MHRA about the safety of a study treatment under 
clinical investigation. The Sponsor will comply with UK regulatory requirements relating to safety 
reporting to the MHRA, Institutional Review Boards (IRB)/IEC, and Investigators. 
 
Suspected unexpected serious adverse reactions (SUSARs) will be notified to the MHRA by Sponsor or 
designee and to the relevant REC through combined review by Sponsor or designee within 7 (for fatal 
and life-threatening SUSARs) or 15 days (all other SUSARs), and forwarded to Investigators as 
necessary. 
Annual safety reporting through combined review to the REC and MHRA will be in agreement with ICH 
guideline E2F <Note for guidance on development safety update reports (DSUR)=. 
Investigators will be informed in writing of any new or emerging safety information as it becomes 
available. Notification of safety information to Investigators will be performed in accordance with the 
Pharmacovigilance Safety Management Plan. 

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8.13 
Pregnancy 
 
Pregnancy in itself, is not regarded as an AE, unless there is a suspicion that investigational product 
may have interfered with the effectiveness of a contraceptive medication. However, complications of 
pregnancy and abnormal outcomes of pregnancy are AEs and may meet criteria for an SAE. 
Complications of pregnancy and abnormal outcomes of pregnancy, such as ectopic pregnancy, 
spontaneous abortion, intrauterine foetal demise, neonatal death, or congenital anomaly, would meet 
the criteria of an SAE and therefore should be reported as an SAE as detailed above. Elective abortions 
without complications should not be handled as an AE. 
If a female participant becomes pregnant during participation in the study, the participant must be 
withdrawn from study treatment, and the Investigator must report the pregnancy to the Sponsor or 
designee within 24 hours of being notified of the pregnancy. Details of the pregnancy will be recorded 
on the pregnancy reporting form. The pregnancy should be followed by the Investigator until 
completion. At the completion of the pregnancy, the Investigator will document the outcome of the 
pregnancy. If additional follow-up is required, the investigator will be requested to provide the 
information. 
If a male participant9s female partner becomes pregnant while the participant was being treated or 
exposed to trial drug, consent must be obtained from the partner of the participant and the 
Investigator must report the pregnancy to Sponsor or designee using the Pregnancy Reporting Form. 
The participant partner should be followed until the outcome of the pregnancy is known. Male 
participants may continue in the trial if an accidental pregnancy of their female partner occurs despite 
adequate contraception. If additional follow-up of the female partner is required, the investigator will 
be requested to provide the information. 
The pregnancy must be submitted to Sponsor or designee within 24 hours of awareness via the 
following: 
E-mail: adverseeventreporting@orphalan.com 
Phone: +356 99 966 819 
 
9. 
QUALITY ASSURANCE AND QUALITY CONTROL 
 
9.1 
Quality Assurance and Quality Control 
 
An inspection of this trial may be carried out by regulatory agencies. Such audits/inspections can occur 
at any time during or after completion of the trial. If an audit or inspection occurs, the PI and Richmond 
Pharmacology agree to allow the auditor/inspector direct access to all relevant documents and to 
allocate staff time to the auditor/inspector to discuss any findings or relevant issues. 
Quality Control (QC) procedures at the Richmond Pharmacology will be implemented to ensure data 
recorded into the CRFs are accurate. QC checks will be carried out on an ongoing basis and according 
to the relevant SOPs. Records of QC checks will be documented and available for review. 
Trial documents routinely undergo QC to ensure their accuracy before being use and/or sent to the 
sponsor. The Richmond Pharmacology staff member providing the QC checks the documents and notes 
any findings/comments on the QC record form. QC checks will be carried out on an ongoing basis 
throughout the trial and according to the relevant SOPs. Records of QC checks will be documented and 
available for review. 

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9.2 
Monitoring 
 
All aspects of the trial will be carefully monitored by the sponsor, or designee, for compliance with 
applicable government regulations with respect to Good Clinical Practice (GCP) and current standard 
operating procedures. 
The monitoring of this trial will be performed by the sponsor9s monitor(s) or a designee in accordance 
with the principles of GCP as laid out in the International Conference on Harmonisation (ICH) Good 
Clinical Practice Guideline E6(R2) (2016). 
The clinical monitor, as a representative of the sponsor, has an obligation to follow the trial closely. 
The monitor will maintain current knowledge of the trial through observation, review of trial records 
and source documentation, and discussion of the conduct of the trial with the investigator and staff. 
Further details will be described in the SOM. 
 
10. 
STATISTICAL ANALYSIS 
 
10.1 
Statistical Analysis Plan 
 
A statistical analysis plan (SAP) containing detailed statistical methodology will be written and signed 
off before the DB hard lock. The plan may be updated to reflect adaptive features of the trial as 
appropriate. 
 
10.2 
Analysis sets 
 
The analysis of data will be based on different analysis sets according to the purpose of analysis. 
Participant eligibility for each analysis set will be finalised before the DB hard lock. A participant who 
withdraws prior to the last planned observation in a trial period will be included in the analyses up to 
the time of discontinuation. 
Safety set 
The Safety set will consist of all randomised participants who received at least one dose of the IMP. 
The safety set will be used for the safety analyses. 
 
PK set 
The PK set will consist of those participants in the safety set who have sufficient blood samples taken 
for at least one of the PK variables to be calculated. The PK set will be used for the PK analyses. 
 
10.3 
Statistical analysis of safety 
Individual participant demographics (age, gender, and race) and body measurement data (height, 
weight, and BMI) at screening will be listed. These demographic characteristics and body 
measurements will be summarised by treatment group and overall, using the safety analysis set. Other 
baseline characteristics will be listed only. 
AE data will be listed and summarised using descriptive statistics: the number (and %) of participants 
who had any AEs, and the number of AE episodes will be summarised for each dose. All AEs will be 
summarised and listed by using system organ class (SOC) and preferred term (PT) assigned to the event 
using Medical Dictionary for Regulatory Activities (MedDRA). Furthermore, these events will be 
summarised by the maximum intensity. The number of participants who had drug-related AEs will also 
be summarised. Any SAEs and/ or AEs that led to withdrawal will be summarised and listed. 

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Vital signs data (SBP, DBP, HR, Temperature, Respiratory rate) will be listed and summarised, along 
with changes from baseline, using descriptive statistics (mean, median, standard deviation, minimum, 
maximum). Out-of-reference-range values will be flagged as high (H) or low (L) and as being clinically 
relevant or not: the number of participants presenting out-of-range and clinically relevant values will 
be summarised. 
All safety clinical laboratory data will be listed. Laboratory test results outside of the applicable range 
will be flagged as high (H) or low (L) and as being clinically relevant or not. The number of participants 
presenting out-of-range and clinically relevant values will be summarised. The quantitative laboratory 
data, along with changes from baseline will be summarised using descriptive statistics (mean, median, 
standard deviation, minimum, maximum). Change from baseline values at each assessment will be 
calculated as the assessment value minus the baseline value. The qualitative urinalysis data will be 
listed only. 
All ECG data (PR, QRS, QT, QTcB, QTcF and HR) and overall ECG evaluation will be listed with comments. 
Out-of-reference-range values will be flagged. ECG data, along with changes from baseline will be 
summarised using descriptive statistics (mean, median, standard deviation, minimum, maximum). 
Furthermore, categorical analysis of QTcF data will be presented as follows: 
″ 
Absolute QTcF interval prolongation 
- 
QTcF interval > 450 ms 
- 
QTcF interval > 480 ms 
- 
QTcF interval > 500 ms 
″ 
Change from baseline in QTcF interval 
- 
QTcF interval increases from baseline > 30 ms 
- 
QTcF interval increases from baseline > 60 ms 
The number of participants presenting out-of-range and clinically relevant values will be summarised. 
 
10.4 
Pharmacokinetics 
10.4.1 
Evaluation of Pharmacokinetic Parameters 
 
Non-compartmental analysis will be used for estimation of pharmacokinetic parameters. 
The following pharmacokinetic parameters will be calculated for TETA 4HCL (active moiety, TETA)and 
its 
two 
main 
metabolites 
(N1-acetyltriethylenetetramine 
(MAT) 
and 
N1, 
N10- 
diacetyltriethylenetetramine (DAT)): 
 
Cmax 
Maximal plasma concentration 
Ctrough 
Plasma concentration prior to next dose 
tmax 
Time at which the maximum plasma concentration occurs 
t1/2 
Terminal elimination half-life 
AUC0-t 
Area under the plasma concentration curve from time zero up to the last 
quantifiable concentration 
AUC0-24 
Area under the plasma concentration curve from time zero to 24 hours 

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AUC0-inf 
Area under the plasma concentration-time curve from time 0 extrapolated to 
infinite time 
%AUCextrap 
Percentage of AUC that is due to extrapolation from last to infinity 
CL/F 
Apparent total plasma clearance 
Vz/F 
Apparent volume of distribution during the terminal phase 
Rac 
Accumulation ratio based on AUC0-inf and Cmax after the first and the last dose 
 
The individual plasma concentration data and the actual time for IMP administration and blood 
sampling will be used in the derivation of the PK parameters for TETA 4HCL (active moiety, TETA) and 
its two main metabolites (N1-MAT and N1, N10-DAT). If there is any doubt in the actual time a sample 
was taken, then the scheduled time will be used. 
AUC0-t and AUC0-inf will be calculated using the linear/log trapezoidal method, applying the linear 
trapezoidal rule up to Cmax and the log trapezoidal rule for the remainder of the curve. Samples below 
limit of quantification (LOQ) prior to the first quantifiable concentration will be set to zero. Samples 
with concentrations below LOQ after the first quantifiable concentration will be set to 8missing9 and 
omitted from the analysis. Other pharmacokinetic parameters will be calculated according to standard 
equations. 
In the determination of »z (and AUC0-inf), the following conditions should be met: 
″ 
A minimum of at least 3 data points in the terminal elimination phase, in which Cmax is not 
included; 
″ 
The Adj-Rsq should be g 0.8, and 
″ 
%AUCextrap < 20%. 
 
If these conditions are not met, the PK parameter will be flagged in the listings (together with the 
ones dependent on »z, such as t1/2, CL/F and Vz/F) and they may be excluded from the summary 
statistics. The decision to include these parameters will be based on the decision of the Sponsor with 
input from the pharmacokineticist. 
 
The following flags/footnotes may be applied to the pharmacokinetic parameters: 
 
Flag 
Footnote 
a 
Rsq of regression was <0.8 
b 
Period used for regression analysis was less than 2-fold the calculated half-life 
c 
Extrapolated portion of AUC0-inf >20% 
d 
Insufficient post-Cmax data points for estimation of lambda-z 
e 
Entire profile BLQ, no pharmacokinetic parameters could be calculated 
f 
Regression line could not be fitted 
 
Details will be provided in SAP. 

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10.4.2 
Statistical Analysis on PK Parameters 
 
Plasma concentrations will be listed and summarised by time point (N - the number of participants, n 
3 the number of samples, n(LLOQ) - the number of samples <LLOQ, arithmetic mean, SD - standard 
deviation, CV - coefficient of variation, geometric mean, median, minimum, maximum). Individual and 
arithmetical mean plasma concentration vs time curves for each analyte which includes all treatments 
will be produced on both linear/linear and log10/linear scales. 
The PK parameters will be listed for each participant and summarized for each treatment group using 
descriptive statistics (N - the number of participants, arithmetic mean, SD - standard deviation, CV - 
coefficient of variation, geometric mean, median, minimum, maximum). 
For comparability of the two products the geometric mean, ratio of geometric means, confidence 
intervals (CI) including their logarithmic transformation together with the coefficient of variation for 
the within-participant variability will be summarised. In case a gender effect is noticeable, gender will 
be added as an additional term in the PK model, and all PK analyses will be presented per gender as 
well. 
Details will be provided in SAP. 
 
10.5 
Handling of Missing and Incomplete Data 
 
Unrecorded values will be treated as missing. The appropriateness of the method(s) for handling 
missing data may be reassessed at the data review prior to database lock. 
 
10.6 
Determination of sample size 
Formal sample size calculation for the comparison between the two treatments was performed 
based on a 2´2 crossover design. A sample size of 24 participants was selected to reach 91% power to 
infer that the mean difference is not 0. In comparison a sample size of 22 participants will reach 88% 
power based on two-sided t-test. This calculation was based on an actual mean difference of 1 and 
the square root of the within mean square error of 1 between test and reference formulations. 
 
10.7 
Interim Analysis 
 
No interim analyses are planned. 
 
11. 
DATA MANAGEMENT 
 
Data Management will be performed by the Data Management department of Richmond 
Pharmacology. The data management process will be described in detail in the Data Handling Protocol 
(DHP). 
The Richmond Pharmacology Data Management department will be responsible for developing and 
maintaining the DHP; setting-up and validating the clinical trial database; programming validation 
checks; entering data into the clinical trial database; reviewing data for accuracy, completeness, and 
consistency between the CRF and the database; and verifying adherence to the clinical pharmacology 
trial protocol and the DHP. 
Clinical data queries will be generated and resolved according to the DHP. Clinical data queries are 
resolved with the assistance of Richmond Pharmacology clinical staff. 

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After all clinical data queries are resolved, final error rate is confirmed, and QC checks are acceptable 
the database will be locked. 
Medical coding will be performed by Richmond DM. AEs, diagnoses from Medical History and 
procedures from Surgical History will be classified according to MedDRA. Concomitant medication will 
be coded using WHODRUG. 
SAEs in the clinical database will be reconciled with the safety database. 
Standard datasets are extracted from the final trial database and transferred to statistician for analysis. 
11.1 
Case Report Forms 
 
A source data agreement will be signed by the sponsor and investigator to define what constitutes 
source data for all types of data captured. 
Case Report Forms will be used to record data in the trial. Data should be recorded legibly onto the 
CRFs in black ballpoint pen. Correction fluid or covering labels must not be used. 
The monitor will check data at the monitoring visits to the trial site. The PI will ensure by delegation 
that the data in the CRFs are accurate, complete, and legible. 
Data from the completed CRFs will be entered into Richmond 9s clinical trial database and validated 
under the direction of the Data Manager. Screening failures (participants who signed consent to take 
part in the trial but were not randomised) as well as admission data for Reserves will not be entered 
into the clinical trial database. Any missing, impossible (inconsistent with human life), or inconsistent 
recordings in the CRFs will be queried to the PI and be documented for each individual participant 
before clean file status is declared. 
 
 
12. 
REGULATORY, ETHICAL AND STUDY OVERSIGHT CONSIDERATIONS 
 
12.1.1 
Regulatory and Ethics Compliance 
 
The study will be conducted in accordance with the protocol and with the following: 
- 
Consensus ethical principles derived from international guidelines including the World Medical 
Assembly (Helsinki 1964) and subsequent amendments 
- 
Applicable ICH Good Clinical Practice (GCP) Guidelines 
- 
Applicable laws and regulations 
 
The procedures set out in this clinical study protocol are designed to ensure that Orphalan SA and any 
third party to whom aspects of the trial management or monitoring have been delegated abide by the 
principles of the current ICH GCP guideline on the conduct, evaluation, and documentation of this 
study, as described in ICH Topic E6 (Guideline for GCP). The study will also be carried out according to 
all applicable international and national regulatory requirements. 
Visits to investigator sites will be conducted by representatives of Orphalan SA to inspect trial data, 
participants9 medical records, and CRFs in accordance with current ICH GCP E6 guidelines and the 
respective local and national government regulations and guidelines. Records and data may 
additionally be reviewed by auditors or by competent authorities. 
 
The investigator must undertake to perform the study in accordance with ICH GCP Guidelines, and the 
applicable MHRA regulatory requirements. 

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It is the investigator9s responsibility to ensure that adequate time and appropriate resources are 
available at the trial site prior to commitment to participate in this trial. The investigator should also 
be able to estimate or demonstrate a potential for recruiting the required number of suitable 
participants within the agreed recruitment period. 
 
The investigator will maintain a record of appropriately qualified persons to whom the investigator has 
delegated significant trial-related tasks. An up-to-date copy of the curriculum vitae for the investigator, 
sub-investigator(s), and essential trial staff will be provided to Orphalan SA (or designee) before 
starting the trial. 
Agreement with the final Clinical Trial Report will be documented by the dated signature of the PI, in 
compliance with compliance with UK Statutory Instrument and ICH E3. 
12.1.2 
Medicines and Healthcare products Regulatory Agency (MHRA) and Research Ethics 
Committee (REC) Approval 
 
Orphalan SA (or delegate) will ensure that MHRA requirements are met before the start of the trial. 
 
It is the responsibility of the PI to submit this CSP, the informed consent document (approved by 
Orphalan SA), relevant supporting information, and all types of participant recruitment information to 
the REC and MHRA for combined review, and all must be approved prior to the start of participant 
screening. In addition, advertisements must be approved by the REC and MHRA prior to use at the site. 
Prior to implementing changes in the trial, Orphalan SA and the REC and MHRA must also approve any 
substantial amendments to the CSP and corresponding updates to informed consent documents. For 
non-substantial protocol amendments (that do not require regulatory approval) and subsequent 
updates of the ICF all changes will be done in agreement with Orphalan SA and Richmond 
Pharmacology. 
 
12.1.3 
Indemnity/liability and insurance 
 
Orphalan SA will adhere to the recommendations of the Association of British Pharmaceutical Industry 
(ABPI) Guidelines. A copy of the Indemnity document will be supplied to the investigator before trial 
initiation. 
Orphalan SA will ensure that suitable insurance cover is in place prior to the start of the trial. An 
insurance certificate will be supplied to Richmond Pharmacology. 
 
12.1.4 
Protocol management and adherence 
 
All protocols and amendments will be prepared by Orphalan SA and/or Richmond Pharmacology. If it 
becomes necessary to issue a protocol amendment during the course of the trial, Orphalan SA will 
notify the investigator and collect documented Investigator Agreement to the amendment. 
The PI and delegates must adhere to the CSP as detailed in this document. The PI will be responsible 
for including only those participants who have met CSP eligibility criteria. The PI will be required to 
sign an investigator Agreement to confirm acceptance and willingness for themselves and delegates 
to comply with the CSP. 

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12.1.5 
End of trial notification and Clinical Trial Summary Results 
 
Richmond Pharmacology on behalf of Orphalan SA will submit an end of trial notification to the MHRA 
within 90 days of the end of the trial in accordance with UK statutory requirements. The PI will be 
responsible for submitting these to the REC and MHRA through combined review within 90 days of the 
end of the trial. 
 
For the purposes of this notification, the end of the trial will be defined as last participant, last visit. 
Orphalan SA or its delegate will post result-related information from this clinical trial to 
Clinicaltrials.gov (which is considered as the submission of a summary of the clinical trial report) and 
send a confirmatory email to the MHRA, within one year of the end of the complete trial to the 
competent authority of the Member State concerned as required by the regulatory requirement and 
to comply with the Community guideline on Good Clinical Practice. Richmond Pharmacology on behalf 
of Orphalan SA will submit a summary of the clinical trial report to the concerned REC via combined 
review. 
 
12.1.6 
Documentation and retention of records 
After completion of the trial, all essential records relating to the trial will be kept in an orderly 
manner and securely by the PI in a secure file and/or electronically, in compliance with ICH Good 
Clinical Practice Guideline E6(R2) (2016). The data will be available for inspection by Orphalan SA or 
their representatives. Essential documents must be retained for 25 years after the final marketing 
approval in an ICH region or at least 25 years have elapsed since the formal discontinuation of 
clinical development of Orphalan SA. The PI or delegate must contact Orphalan SA before destroying 
any trial-related documentation and it is the responsibility of Orphalan SA to inform the investigative 
site of when these documents can be destroyed. In addition, all participant records and other 
source documentation will be kept for a longer period if required by the applicable regulatory 
requirements. 
 
12.1.7 
Informed consent 
 
The informed consent is a process by which a participant voluntarily confirms his/her willingness to 
participate in a clinical trial. It is the responsibility of the PI or delegate to obtain written informed 
consent from participants. All consent documentation must be in accordance with applicable 
regulations and the ICH Good Clinical Practice Guideline E6 (R2) (2016). Each participant is requested 
to sign the ICF after they have received and read the written participant information and received an 
explanation of what the trial involves, including but not limited to: the objectives, potential benefits 
and risk, inconveniences, and the participant9s rights and responsibilities. Signed ICFs must remain on 
file and must be available for verification by Trial Monitors at any time. Another signed original of the 
ICF must be given to the participant or the participant9s legally authorized representative. The PI or 
delegate will submit ICFs to the REC via combined review and provide the sponsor with copies of the 
REC approved consent forms, and the REC written approval, prior to the start of the trial. 
 
12.2 
Confidentiality 
 
For the purposes of this Section 12.4, <Applicable Data Protection Law= shall mean (a) the Data 
Protection Act 2018; (b), the UK GDPR (as defined in Section 3(10) of the Data Protection Act 2018) 
and (c) the General Data Protection Regulation ((EU) 2016/679) as applicable, and any applicable 
legislation introduced in the UK. 

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Data collected during this trial may be used to support the development, registration, or marketing of 
medicinal product. Orphalan SA will control all data collected during the trial and will abide by the 
Applicable Data Protection Law. For the purpose of the Applicable Data Protection Law, Orphalan SA 
will be the data controller. To the extent that Richmond Pharmacology processes personal data on 
behalf of Orphalan SA, in relation to such data Richmond Pharmacology shall only act in accordance 
with the terms of this protocol and Orphalan SA9s reasonable written instructions and Richmond 
Pharmacology shall take appropriate technical and organisational measures against the unauthorised 
or unlawful processing of such personal data. 
After participants have consented to take part in the trial, their medical records and the data collected 
during the trial will be reviewed by Orphalan SA and/or its representatives. These records and data 
may, in addition, be reviewed by the following: independent auditors who validate the data on behalf 
of Orphalan SA; national or local regulatory authorities, and the REC which gave its approval for this 
trial to proceed. 
 
Although participants will be known by a unique number, their date of birth will also be collected by 
Richmond Pharmacology and used to assist Orphalan SA to verify the accuracy of the data, for example, 
that the results of trial assessments are assigned to the correct participant. The results of this trial 
containing the unique number, date of birth, and relevant medical information including ethnicity may 
be recorded and transferred to and used in other countries throughout the world. If personal data is 
transferred outside the UK, Richmond Pharmacology will ensure applicable data transfer mechanisms 
are in place to ensure the data receives essentially equivalent protection as are applicable in the UK. 
The purpose of any such transfer would be to support regulatory submissions made by Orphalan SA in 
such countries. The Parties agree to comply with the relevant provisions of the Applicable Data 
Protection Law and any directions issued by the UK Information Commissioner9s Office in its processing 
of such Personal Data. All nominative information in the participant9s medical record will be kept 
strictly confidential. Nominative information shall mean the name, the address and all other personally 
identifiable information associated with a participant9s name. Orphalan SA access to participant9s data 
shall be performed in such a way that no participant could be identified by such data. 
If there are any contradictions in terms of confidentiality requirements, the requirements of Applicable 
Data Protection Law will prevail. 
 
To the extent that Richmond Pharmacology9s processes personal data on behalf of Orphalan SA, the 
terms are dictated in the MSA. 
 
12.3 
Publication Policy 
 
Orphalan SA reserves the right to publish the trial's results independently, as they deem necessary 
for regulatory, scientific or commercial purposes. Richmond Pharmacology may also publish the 
trial's results, provided it is done in good faith and in collaboration with Orphalan SA. Richmond 
Pharmacology agrees to obtain Orphalan SA9s written approval for such publications or presenting 
trial results at scientific meetings and both parties are encouraged to work together to achieve timely 
and meaningful dissemination of findings. 

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13. 
REFERENCES 
 
1. Petrukhin, K., et al. "Mapping, cloning and genetic characterization of the region containing 
the Wilson disease gene." Nature genetics 5.4 (1993): 338-343. 
2. European Association For The Study Of The Liver. "EASL clinical practice guidelines: Wilson9s 
disease." Journal of hepatology 56.3 (2012): 671-685. 
3. Pfeiffer, Ronald F. "Wilson's disease." Seminars in neurology. Vol. 27. No. 02. Copyright© 2007 
by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA., 2007. 
4. Yarze, Joseph C., et al. "Wilson's disease: current status." The American journal of 
medicine 92.6 (1992): 643-654. 
5. Iseki, Ken, et al. "Comparison of disposition behavior and de0coppering effect of 
triethylenetetramine in animal model for Wilson's disease (long0evans cinnamon rat) with 
normal Wistar rat." Biopharmaceutics & drug disposition 13.4 (1992): 273-283. 
6. Hayashi, Masanobu, et al. "Inhibitory effects of trientine, a copper-chelating agent, on 
induction of DNA strand breaks in kidney cells of Long-Evans Cinnamon (LEC) 
rats." Experimental animals 54.5 (2005): 403-412. 
7. Gibbs, K. R. "The metabolism of trientine: animal studies, in Orphan Diseases and Orphan 
Drugs (Scheinberg IH and Walshe JM eds) pp 33342." (1986). 
8. Lu, Jun, et al. "Pharmacokinetics, pharmacodynamics, and metabolism of triethylenetetramine 
in healthy human participants: an open0label trial." The Journal of Clinical Pharmacology 50.6 
(2010): 647-658. 
9. Cuprior® Summary of Product Characteristics (available on 
https://www.medicines.org.uk/emc/product/10100/smpc - consulted in Oct/2023) 
10. Pfeiffenberger, Jan, et al. "The steady state pharmacokinetics of trientine in Wilson disease 
patients." European Journal of Clinical Pharmacology 74 (2018): 731-736. 
11. MaseCbas, Wojciech, et al. "Persistence with treatment for Wilson disease: a retrospective 
study." BMC neurology 19 (2019): 1-6. 
12. Beinhardt, Sandra, et al. "Long-term outcomes of patients with Wilson disease in a large 
Austrian cohort." Clinical gastroenterology and hepatology 12.4 (2014): 683-689. 
13. Guillaud, Olivier, et al. "Long term results of liver transplantation for Wilson9s disease: 
experience in France." Journal of hepatology 60.3 (2014): 579-589. 
14. Jacquelet, Elodie, et al. "Adherence to treatment, a challenge even in treatable metabolic 
rare diseases: A cross sectional study of Wilson's disease." Journal of Inherited Metabolic 
Disease 44.6 (2021): 1481-1488. 
15. Generic and hybrid medicines (European Medicines Agency) 3 available on 
https://www.ema.europa.eu/en/human-regulatory/marketing-authorisation/generic-hybrid- 
medicines (consulted in Oct/2023) 
16. Trientine tetrahydrochloride tablets (TETA 4HCl) Investigator9s Brochure 
17. Committee for Medicinal Products for Human Use (CHMP) 3 European Medicines Agency 
(available on https://www.ema.europa.eu/en/committees/committee-medicinal-products- 
human-use-chmp; consulted in Oct/2023) 

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14. 
APPENDIX 1 3 CONTRACEPTIVE REQUIREMENTS 
 
The contraceptive requirements for this trial have been created in coordination with the Clinical Trials 
Facilitation and Coordination Group (CTFG) <Recommendations related to contraception and 
pregnancy 
testing 
in 
clinical 
trials= 
guideline. 
This 
is 
based 
on 
possible 
human 
teratogenicity/fetotoxicity and no known genotoxicity17. The SmPC for Cuprior® has no specified 
contraceptive requirements. 
Participants must agree to adhere to one of the following contraceptive methods to be eligible for trial 
enrolment (inclusion criteria 6): 
 
a. Female participants of non-childbearing potential (WNCBP): Defined as either 
postmenopausal (evidence of menopause based on a combination of amenorrhea for at 
least one year and increased serum follicle-stimulating hormone (FSH) level [> 30 IU/L]), or 
surgical sterilization (evidence of hysterectomy and/or bilateral oophorectomy). 
CONTRACEPTION REQUIRED: None 
b. Female participants of childbearing potential (WOCBP) who anticipate being sexually active 
with a male during the trial (from one complete menstrual cycle prior to the initial dosing 
until 1 month after the last dose in the study): 
CONTRACEPTION REQUIRED: Highly effective contraception must start one complete 
menstrual cycle prior to the first day of dosing and continue until 1 month after the last 
study dose. Highly effective contraception methods for WOCBP include: 
″ Combined i.e. (oestrogen- and progestogen-containing) hormonal contraception 
associated with inhibition of ovulation: 
o oral 
o Intravaginal 
o transdermal 
″  Progestogen-only hormonal contraception associated with inhibition of ovulation 
o oral 
o injectable 
o implantable 
″  Intrauterine hormone-releasing system (IUS) 
″  Intrauterine device (IUD) 
″  Bilateral tubal occlusion 
″ Infertile male partner (e.g., vasectomised, permanently sterile following bilateral 
orchidectomy, or any other documented cause of infertility) 
c. Female participants of childbearing potential (WOCBP) who agree to remain abstinent for 
the duration of the study (from one complete menstrual cycle prior to the first dosing until 
1 month after the last dose in the study): 
CONTRACEPTION REQUIRED: Abstinence (N.B. sexual abstinence is considered a highly 
effective method only if defined as refraining from heterosexual intercourse during the 

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entire period of risk associated with the trial treatments. The reliability of sexual abstinence 
needs to be evaluated in relation to the duration of the clinical trial and the preferred and 
usual lifestyle of the participant. Calendar, symptothermal and post-ovulation methods of 
contraception are not considered to be equivalent to abstinence). 
d. Male participants, who agree to remain abstinent for the duration of the study (from first 
dosing until 1 month after the last dose in the study): 
CONTRACEPTION REQUIRED: Abstinence (N.B. sexual abstinence is considered a highly 
effective method only if defined as refraining from heterosexual intercourse during the 
entire period of risk associated with the trial treatments. The reliability of sexual abstinence 
needs to be evaluated in relation to the duration of the clinical trial and the preferred and 
usual lifestyle of the participant). 
If the situation changes post-dose during the trial, participants must use a condom. 
e. Male participants, who anticipate being sexually active during the trial period (from initial 
dosing until 1 month after the last study drug administration) with a woman who is either 
a WOCBP, a woman who is pregnant and/or breast feeding: 
CONTRACEPTION REQUIRED: From the first day of dosing until 1 month after the last study 
drug administration . Acceptable methods are: 
″ 
Male condom