Clinical trial NCT06128954
Conditions: Wilson's Disease
Sponsor: Orphalan
Start date: 2024-01-16; Completion date: 2024-02-16
Enrollment: 26 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
A randomised, open-label study evaluating the pharmacokinetics, safety, and tolerability of a new once daily dose of 900mg of TETA 4HCL by comparing it against the current marketed Cuprior® formulation (450mg trientine base, twice daily) in healthy male and female participants.

Detailed description:
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

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

At least 5 days and a maximum of 10 days between treatment period study drug administration

Objective: To evaluate the PK, safety, and tolerability of the new once daily TETA 4HCL formulation compared to the current marketed Cuprior® formulation.

Arms: arm 1: 1 x 900mg TETA 4HCl, new once daily formulation (3x300mg trientine base tablets as a single AM dose) arm 2: 2 x 450mg TETA 4HCl, Marketed Cuprior® formulation (6 x150mg trientine base tablets in two equally divided doses (450mg doses 8 hours apart)
Interventions: intervention 1: 900mg TETA 4HCl Once Daily Formulation intervention 2: 900mg TETA 4HCl Cuprior®
Intervention descriptions: intervention 1: 3x300mg trientine base tablets as a single AM dose intervention 2: 6 x150mg trientine base tablets in two equally divided doses

Protocol documents:
ICF_002.pdf: 
Sponsor: Orphalan SA 
Sponsor Study Code: ORPH-131-012 
RPL Study Code: C23030 
Regulatory Green Light sign off: 16 Jan 2024 
 
 
Effective From 17 Jan 2024 
C23030_ORPH-131-012_Informed Consent Form_V3.0_17Jan2024_GLSO_16Jan2024 
MW-TEM-3-1 PIS/ICF template 18 Sep 2023                                                                                                      Page 1 of 28 
 
Orphalan SA 
226 Boulevard Voltaire, 75011, Paris, France 
RPL ID Number:  
 
<INSERT VDB LABEL> 
Screening Number: 
 
 
Participant Information Sheet/Informed Consent Form 
 
Clinical Trial 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 
 
Protocol Number: 
 
 
ORPH-131-012 
 
IRAS ID:  
1009060 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dear Participant,  
We would like to invite you to take part in our clinical trial involving healthy participants. 
Joining the trial is entirely up to you, but before you decide, we would like you to understand 
why the clinical trial is done, what the clinical trial involves, and how we will use the 
information we collect about you.   
Please take time to read the following information carefully and discuss it with others if you 
like. Please ask us if there is anything that is not clear or if you would like more information.  
Once you have read this Participant Information Sheet, the Research Doctor will go through 
this information with you, to help you decide whether or not you would like to take part 
and answer any questions you may have. 


Sponsor: Orphalan SA 
Sponsor Study Code: ORPH-131-012 
RPL Study Code: C23030 
Regulatory Green Light sign off: 16 Jan 2024
Effective From 17 Jan 2024 
C23030_ORPH-131-012_Informed Consent Form_V3.0_17Jan2024_GLSO_16Jan2024 
MW-TEM-3-1 PIS/ICF template 18 Sep 2023    
Page 2 of 28 
Key trial Information 
Who is funding and 
conducting this trial? 
Orphalan SA (a pharmaceutical company based in France), also referred 
to as the Sponsor. 
Lead Research 
Doctor(s): 
Dr Thomas Ashdown & Dr Ulrike Lorch 
Trial Unit: 
Richmond Pharmacology, Ltd. 
1A Newcomen Street, London Bridge 
London, SE1 1YR, UK 
What does the 
investigational 
medicine do? 
Trientine tetrahydrochloride (TETA 4HCl) is a drug that is designed to treat 
Wilson’s disease and is approved in the UK. Wilson’s disease is caused by 
an excess of copper in the body. Although the body needs some copper to 
function properly, an excess of it can cause a build-up leading to damage 
of the liver and nervous system. TETA 4HCl attaches to copper in the body. 
This allows for the copper to be removed in the urine to lower the copper 
levels in the body. 
Why is the clinical 
trial being 
conducted? 
A TETA 4HCl tablet has already been approved for use in Wilson’s disease 
patients and is currently marketed in the UK under the name Cuprior®. 
Patients normally have to take their tablets 2-4 times a day. The Sponsor 
has created a new tablet, which contains more TETA 4HCl, which they 
believe patients will only have to take once a day. This trial will compare 
the new TETA 4HCl tablet to the currently approved Cuprior® tablet.  The 
trial will look at the levels of the drug in the blood after taking the different 
tablets (either once in the morning for the new tablet compared with 
morning and early afternoon for the currently approved tablet) and 
compare how safe and well tolerated the two different tablets are. 
How many 
participants are 
planned in this trial? 
Up to 26 healthy adult participants will take part in the trial. All 
participants will receive both the new TETA 4HCl tablet(s) and the 
approved Cuprior® tablet(s) at different visits at least 5 days apart. 
Who is allowed to 
take part in this 
trial? 
The Research Doctor will determine if you qualify to participate, but key 
requirements include that you: 
•
Are aged between 18 to 40 years old
•
Meet all inclusion criteria
•
Do not meet any of the exclusion criteria (conditions that are not
allowed)
More information about the inclusion/exclusion criteria and trial rules is 
given in sections 2 and 3. 
What is the expected 
duration of the trial? 
This clinical trial will take approximately 7 weeks including the screening 
period. 


Sponsor: Orphalan SA 
Sponsor Study Code: ORPH-131-012 
RPL Study Code: C23030 
 
Regulatory Green Light sign off: 16 Jan 2024 
 
 
Effective From 17 Jan 2024 
C23030_ORPH-131-012_Informed Consent Form_V3.0_17Jan2024_GLSO_16Jan2024 
MW-TEM-3-1 PIS/ICF template 18 Sep 2023                                                                                                      Page 3 of 28 
 
 
 
 
What is the purpose? 
The investigational drug used in this clinical trial is Trientine tetrahydrochloride (TETA 4HCl) which 
is a drug that is designed to treat Wilson’s disease.  
Wilson’s disease is an inherited disease (an illness that is passed on from both parents) where 
patients end up with too much copper in their bodies. This is a rare disease that affects less than 
2000 patients in the UK. Normally, the body needs some copper to function but with this disease, 
the copper isn’t processed properly. As a result, patients are unable to remove the copper, resulting 
in a gradual build-up in the body. This can then lead to liver damage and problems with the nervous 
system. TETA 4HCl attaches to the excess copper in the body and then it is removed in the urine.  
 
What will I have to 
do? 
 
You will be required to attend the trial unit for a screening visit, complete 
2 separate in-house stays (consisting of 4 days and 3 nights each) and 
attend a follow-up visit.  
 
You will be admitted to the unit on Day -1 for both in-house stays. On the 
dosing day (Day 1) of both stays, you’ll receive a dose of either the new 
TETA 4HCl tablet or Cuprior® (please refer to Figure 1). The number of 
tablets taken and how many times in the day will vary based on the type 
of tablet you are receiving. Half of the participants will take the new TETA 
4HCl tablets first, and then Cuprior®, after a certain period (known as the 
washout period which will be 5-10 days), ensuring the old drug is out of 
their system. The remaining participants will take the same tablets in the 
opposite order, as shown in Figure 1. 
 
For the duration of the clinical trial, you will undergo tests and procedures 
before and after the drug is administered as outlined in the Trial Calendar. 
Additionally, you will be asked to follow the trial rules and restrictions. 
This is for your safety. Some medicines, tobacco, alcohol, or supplements, 
might affect the way the trial drug is processed by your body. 
Are there risks to 
participating? 
There are potential risks (called side effects) such as allergic reactions, and 
soreness or pain from the blood draws. A Research Doctor will discuss the 
potential risks in detail with you.  
Is there a benefit to 
participating? 
The trial drug you will receive is being given to you for research purposes. 
You will not receive direct medical benefit. It is hoped that the information 
collected in this trial will help patients with Wilson’s disease in the future. 
Can I stop 
participating? 
You are free to stop participating in this trial at any time. Please notify a 
member of the research staff. You do not need to give a reason and it will 
not impact your future medical care.  
1. Summary of the clinical trial 


Sponsor: Orphalan SA 
Sponsor Study Code: ORPH-131-012 
RPL Study Code: C23030 
 
Regulatory Green Light sign off: 16 Jan 2024 
 
 
Effective From 17 Jan 2024 
C23030_ORPH-131-012_Informed Consent Form_V3.0_17Jan2024_GLSO_16Jan2024 
MW-TEM-3-1 PIS/ICF template 18 Sep 2023                                                                                                      Page 4 of 28 
A TETA 4HCl tablet has already been approved by the drug regulatory agencies for use in Wilson’s 
disease patients and is currently marketed under the name Cuprior®. Patients normally have to take 
this 2-4 times a day. The Sponsor have created a new tablet, which contains more TETA 4HCl, which 
they believe patients will only have to take once a day. The new TETA 4HCl tablet is not yet approved 
for use by the drug regulatory agencies. Therefore, it can only be used in research studies such as 
this one.  
 
What are the main aims? 
 
 
 
 
What are the key elements? 
In this trial, all participants will receive both treatments (new TETA 4HCl tablet and Cuprior® tablet). 
All eligible participants will be randomised (allocated to a treatment sequence by chance, like 
flipping a coin) as shown in Figure 1. Half of the participants will take the new TETA 4HCl tablets first 
and then after the washout period of 5-10 days, they will then take Cuprior® (this is treatment 
sequence 1). The remaining participants will receive treatment sequence 2, as shown below. The 
new TETA 4HCl tablet will be given as 3 tablets, once in the morning, with 240ml of water after 
overnight fasting. Cuprior® will be given as 3 tablets twice in the day, once in the morning after 
overnight fasting and 8 hours later in the afternoon, after a minimum of 2 hours of fasting. As this 
is an open-label trial, you and the research doctors will know what drug you are taking during each 
period.  
 
To assess the levels of TETA 4HCl and its breakdown products (metabolites) 
in the blood and how long they remain there (pharmacokinetics) and 
compare this with the currently approved marketed tablet (Cuprior®).     
To assess and compare the safety and tolerability of the new TETA 4HCl tablet 
with the approved Cuprior®. 
Figure 1. Randomisation Process 


Sponsor: Orphalan SA 
Sponsor Study Code: ORPH-131-012 
RPL Study Code: C23030 
 
Regulatory Green Light sign off: 16 Jan 2024 
 
 
Effective From 17 Jan 2024 
C23030_ORPH-131-012_Informed Consent Form_V3.0_17Jan2024_GLSO_16Jan2024 
MW-TEM-3-1 PIS/ICF template 18 Sep 2023                                                                                                      Page 5 of 28 
What are the possible benefits? 
The new TETA 4HCl tablet and Cuprior® medication that you will receive in this trial, are being given 
to you purely for research purposes. It is not intended that you will receive any benefit from them. 
Ultimately, it is current and future patients suffering from Wilson's disease that may benefit from 
this research. New, more effective, and convenient medicines can only be developed by performing 
research and we would like to thank you for considering participating in this clinical trial. 
 
What is the trial journey? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening  
Visit 
•
You will be required to attend a screening visit scheduled within 28 days 
before the first dosing day to ensure that you meet all of the trial eligibility 
criteria. 
•
Screening will be conducted over one day or may be divided into more than 
one day if necessary. 
Treatment 
Period 
•
Participation requires two in-house stays of 4 days and 3 nights. The in-
house stay may be extended, if necessary, for your clinical safety. 
•
You will be admitted to the unit on Day -1 of the first in-house stay (the day 
before the dosing). 
•
You will receive either the new TETA 4HCl tablets (3 tablets, once only) or 
Cuprior
® (6 tablets in two sittings over 24 hours) on Day 1 with 240ml of 
water.  
•
After dosing, you will be closely monitored by medically qualified staff and 
undergo standard safety assessments and blood samples to measure levels 
of the trial medicine in the body*. 
•
You will be discharged from the unit on Day 3. 
•
You will then return to the unit after the washout period (5-10 days 
between drug administration days) for the second in-house stay. This time 
you will receive the other drug.  
Follow-Up  
Visits 
•
You will be required to attend the unit for a follow-up visit on Day 7 of the 
second treatment period. 


Sponsor: Orphalan SA 
Sponsor Study Code: ORPH-131-012 
RPL Study Code: C23030 
 
Regulatory Green Light sign off: 16 Jan 2024 
 
 
Effective From 17 Jan 2024 
C23030_ORPH-131-012_Informed Consent Form_V3.0_17Jan2024_GLSO_16Jan2024 
MW-TEM-3-1 PIS/ICF template 18 Sep 2023                                                                                                      Page 6 of 28 
In total, you must be prepared to attend the trial unit on 4 occasions (unless the doctor requests 
further visits for safety reasons). You will only need to attend one follow-up visit unless the research 
doctor says otherwise.   
 
*The standard assessments that will be conducted during the clinical trial include safety blood and 
urine laboratory tests, vital signs, physical examinations, ECG (electrocardiogram – electrical heart 
recording), pharmacokinetics (measurement of medicine levels in the blood) and observations of 
any adverse events (side effects). 
 
Do I have to take part? 
Your participation in this clinical trial is voluntary, and you may withdraw your consent to take part 
at any time, without stating your reasons. 
 
Will my GP be involved? 
Yes, by signing a separate General Practitioner (GP)/Medical Practitioner Consent Form, you will 
give Richmond Pharmacology Ltd permission to contact your GP. This is so that your GP can tell 
Richmond Pharmacology Ltd if there is any reason why you should not take part in this Orphalan SA 
sponsored clinical trial or any future Richmond Pharmacology sponsored or conducted clinical trials. 
By signing the form, you are also giving Richmond Pharmacology permission to inform your GP of 
any abnormal results seen at screening or during the clinical trial. This is because your GP needs to 
be aware of any change in your health status. If a clinically significant abnormal result is identified, 
a study doctor will make every reasonable effort to contact you to thoroughly explain the findings 
and the potential implications. During this discussion, if you do not want your GP to be informed 
you must tell us. We will respect your wishes unless sharing the information is justified in the public 
interest. With respect to any other Richmond Pharmacology sponsored or conducted clinical trials 
that you may participate in, unless it is an Orphalan SA sponsored clinical trial, Orphalan SA shall 
have no responsibility or liability to you or Richmond Pharmacology regarding contacting, obtaining 
medical records and information from your GP, or otherwise communicating with your GP as 
outlined in the separate General Practitioner (GP)/Medical Practitioner Consent Form. 
 
 
 
 
You may be eligible to take part in this clinical trial if you: 
 
Are a male or female aged between 18 to 40 years.  
Weigh 50 kg or more and have a body mass index (BMI) of 18 to 25 kg/m2. 
2. Am I eligible for this clinical trial? 


Sponsor: Orphalan SA 
Sponsor Study Code: ORPH-131-012 
RPL Study Code: C23030 
 
Regulatory Green Light sign off: 16 Jan 2024 
 
 
Effective From 17 Jan 2024 
C23030_ORPH-131-012_Informed Consent Form_V3.0_17Jan2024_GLSO_16Jan2024 
MW-TEM-3-1 PIS/ICF template 18 Sep 2023                                                                                                      Page 7 of 28 
 
Are generally in good health based on screening examination, including medical history, 
physical examination, blood pressure, pulse rate, temperature, respiratory rate, ECG 
assessment, urine, and blood results. 
 
You will not be eligible to take part in this clinical trial if you: 
 
 
 
Have a medical history of any other illness, condition, or disease that in combination 
with the trial drug would pose a risk to your safety.  
Have any acute illness (e.g. vomiting, fever, diarrhoea) within 7 days of the first dosing 
day. 
Have had any major surgery or illness within 12 weeks before Day 1 dosing. 
Have any relevant drug allergies or a condition that may make you react badly to the 
drug that will be administered in this trial. 
Use prescription (excluding hormonal contraceptives or hormone replacement therapy) 
within 30 days of dosing or over-the-counter medications (including herbal remedies and 
supplements) within 14 days of dosing on Day 1.  
Have received another investigational medicine within 90 days before dosing on Day 1 
or exposure to more than 3 investigational medicines within 12 months of Day 1 dosing.  
Test positive for drugs of abuse/alcohol at screening or on day -1 of each period. 
Have a history of use of tobacco products within 6 months of screening or test positive 
for it at screening. 
Have donated or lost more than 450ml or more of blood or plasma within 16 weeks 
before the trial and or intend on donating blood within 16 weeks of the trial ending. 
Are pregnant or breastfeeding.  
Have a history of drug or alcohol abuse. 
 
 
 
You must be willing to adhere to the rules and restrictions stated below and attend each of the 
scheduled visits as detailed in the Trial Calendar. 
It is also important that you tell our clinical staff about any other medication you are taking before 
and during the clinical trial. In addition, you must tell the Research Doctor immediately if you or 
your partner become pregnant during the trial.  
 
3. What am I expected to do during the trial? 


Sponsor: Orphalan SA 
Sponsor Study Code: ORPH-131-012 
RPL Study Code: C23030 
 
Regulatory Green Light sign off: 16 Jan 2024 
 
 
Effective From 17 Jan 2024 
C23030_ORPH-131-012_Informed Consent Form_V3.0_17Jan2024_GLSO_16Jan2024 
MW-TEM-3-1 PIS/ICF template 18 Sep 2023                                                                                                      Page 8 of 28 
If you have a medical need to take any medications and your GP/another Doctor prescribes or 
advises you to take them, you should follow the medical advice. However, please inform the 
Research Doctor as soon as possible using the contact details on the Participant ID card that you will 
be given or the contact information in Section 10 of this document. 
 
Trial Rules 
Here is a list of things you must do during the clinical trial: 
 
Contraception  
 
If you are a female participant of childbearing potentiala: 
You must use a highly effective method of contraception 
during the trial period and for at least one complete 
menstrual cycle before dosing and for at least 1 month after 
the last dosing day of the trial.  
 
Highly effective methods of contraception include: 
• Combined (oestrogen- and progestogen-containing) 
contraceptives (e.g., oral pill, vaginal rings, and patches) 
• Progestogen-only contraceptives (e.g., oral pills, 
injections, and implants) 
• Intrauterine hormone-releasing systems (placed in the 
uterus and slowly release a low dose of hormones) 
• Intrauterine device (hormonal or copper) 
• Bilateral tubal occlusion (surgical blocking of the 
fallopian tubes) 
• Infertile male partner (e.g. vasectomised, bilateral 
orchidectomy or any other reason with documented 
evidence) 
• Sexual abstinenceb  
 
a Women of childbearing potential are defined as women 
who are fertile following menarche (the first occurrence of 
menstruation) until becoming postmenopausal, unless 
permanently sterile. Permanent sterilisation methods 
include hysterectomy, bilateral salpingectomy (surgical 
removal 
of 
the 
fallopian 
tubes), 
and 
bilateral 
oophorectomy (surgical removal of the ovaries). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Sponsor: Orphalan SA 
Sponsor Study Code: ORPH-131-012 
RPL Study Code: C23030 
 
Regulatory Green Light sign off: 16 Jan 2024 
 
 
Effective From 17 Jan 2024 
C23030_ORPH-131-012_Informed Consent Form_V3.0_17Jan2024_GLSO_16Jan2024 
MW-TEM-3-1 PIS/ICF template 18 Sep 2023                                                                                                      Page 9 of 28 
b Sexual abstinence is considered a highly effective method 
only if defined as refraining from heterosexual intercourse. 
If abstinence is your preferred and usual lifestyle before 
starting the trial, you will be asked to refrain from 
intercourse from one complete menstrual cycle before the 
first dosing until 1 month after the last dose in the trial and 
be exempt from contraception. 
 
If you are a female of non-childbearing potential: 
You do not require contraception. Confirmation of post-
menopausal state will be undertaken by blood testing at 
the unit. 
If you are a male participant: 
You must agree to the following during the trial duration 
and for at least 1 month after the last dose of the trial 
medicine: 
a. Be abstinent from heterosexual intercourse with 
female partners of childbearing potential.  
 
OR 
 
b. Use a male condom (during intercourse with a female 
partner of childbearing potential to prevent the transfer 
of trial medicine to the female partner or foetus/baby, 
and they should also be advised to use a highly effective 
method of contraception), this is still required even if 
you are infertile (e.g. vasectomised, permanently sterile 
following bilateral orchidectomy (removal of both 
testicles), or any other documented cause of infertility). 
Meals 
You will receive standardised meals, served at scheduled 
times throughout your in-patient stay. You are required to 
consume all your meals. These meals may contain meat and 
provision for diets that are either meat-free or free from 
certain meats is not available as part of this clinical trial. 
 
 


Sponsor: Orphalan SA 
Sponsor Study Code: ORPH-131-012 
RPL Study Code: C23030 
 
Regulatory Green Light sign off: 16 Jan 2024 
 
 
Effective From 17 Jan 2024 
C23030_ORPH-131-012_Informed Consent Form_V3.0_17Jan2024_GLSO_16Jan2024 
MW-TEM-3-1 PIS/ICF template 18 Sep 2023                                                                                                      Page 10 of 28 
You will be required to fast overnight before dosing. Once 
you have been dosed on Day 1, you will be required to fast 
for one hour (no water for this hour too). For the dosing of 
Cuprior®, participants will need to have fasted for 2 hours 
before the second dose and for 1 hour after. 
Unit rules 
You will be required to observe and adhere to the unit rules 
during your in-house stay as stated in the Volunteer Charter 
and Unit Rules (unit regulations). 
 
 
Trial Restrictions 
Here is the list of things you must not consume or do during the clinical trial: 
 
Smoking 
(tobacco and/or 
nicotine-
containing 
products) 
You must not use tobacco and/or nicotine-containing 
products within 6 months before the dosing day and until 
trial completion/last visit.  
 
Richmond Pharmacology is a non-smoking site and smoking 
is not allowed anywhere on the grounds. 
 
Alcohol 
You must not consume alcohol within 48 hours before the 
dosing on Day 1 (of both dosing periods) and 48 hours 
before the follow-up visit. 
 
Strenuous 
physical activity 
You may not participate in strenuous physical activity 48 
hours before screening, admission, and follow-up visit.  
 
Strenuous physical activity means more than your normal 
regime, but you can discuss this further with the Research 
Doctor if you are unsure about what this means. You should 
not start new physical training activities during the trial 
until completion.  
 
Prescription or 
over-the-
counter 
medication  
You must not use any prescriptions (excluding hormonal 
contraception or hormone replacement therapy) within 30 
days before the dosing day and throughout the trial. Over-
the-counter 
medications 
(including 
remedies 
and 
supplements) must not be used for 14 days before the 
dosing day 1 and until trial completion (last visit). 
 
Exceptions: Paracetamol ≤ 2 g per day (but the research 
doctor should still be notified). 
 
 


Sponsor: Orphalan SA 
Sponsor Study Code: ORPH-131-012 
RPL Study Code: C23030 
 
Regulatory Green Light sign off: 16 Jan 2024 
 
 
Effective From 17 Jan 2024 
C23030_ORPH-131-012_Informed Consent Form_V3.0_17Jan2024_GLSO_16Jan2024 
MW-TEM-3-1 PIS/ICF template 18 Sep 2023                                                                                                      Page 11 of 28 
Caffeine- or 
Xanthine-
containing 
products  
 
You must not consume caffeine or xanthine-containing 
products (for example: coffee, tea, cola drinks and energy 
drinks) for 48 hours before the dosing day and each 
follow-up visit. 
 
Blood and 
plasma 
donation 
You are not allowed to donate blood or plasma within 16 
weeks before the dosing day until 16 weeks after the trial 
completion (last visit).  
 
Energy drinks 
You must not consume any energy drinks containing 
taurine or glucuronolactone (e.g., Red Bull) within 48 
hours before the dosing day and each follow-up visit.  
 
Recreational 
drugs 
Under no circumstances are you allowed to take drugs of 
abuse for the duration of the clinical trial. This could lead 
to unpredictable risks, which can seriously damage your 
health. 
 
 
Please note that this is not an exhaustive list of the eligibility criteria. The Research Doctor will 
discuss this with you in detail. 
 
 
 
 
All participants will receive both the new TETA 4HCl tablets and the approved Cuprior®. Both 
planned doses provide a total daily dose of 900mg of TETA 4HCl : 
 
 
  
 
 
 
 
 
 
 
 
              4. What happens at dosing? 
Cuprior® 
6 tablets of 150mg divided into two doses (3 tablets in 
the morning and three tablets in the afternoon) 
 
New TETA 4HCl tablet 
3 tablets of 300mg given once in the morning 


Sponsor: Orphalan SA 
Sponsor Study Code: ORPH-131-012 
RPL Study Code: C23030 
 
Regulatory Green Light sign off: 16 Jan 2024 
 
 
Effective From 17 Jan 2024 
C23030_ORPH-131-012_Informed Consent Form_V3.0_17Jan2024_GLSO_16Jan2024 
MW-TEM-3-1 PIS/ICF template 18 Sep 2023                                                                                                      Page 12 of 28 
 
 
Below is the summary of the tests and procedures you will have performed during the trial after you 
have provided written informed consent. Please refer to the Trial Calendar for more information on 
which tests and procedures are performed during each of your trial visits. 
 
COVID-19 & Influenza test You will be required to have a throat and/or nasal swab 
for COVID-19 and influenza screening before you enter 
the unit, and once daily during your inhouse stays. In 
addition, a check of your health records to confirm you 
are fully vaccinated against COVID-19.  
 
General health, 
symptoms, and medical 
history 
You will be asked questions to gather a full medical 
history including questions about past or present 
medical 
problems 
or 
surgeries, 
allergies 
to 
medications, your activity level, smoking status, 
alcohol, and tobacco consumption as well as 
information on age, gender, and race.  
 
Throughout the trial, the staff will regularly ask 
questions about your health. We will also record any 
adverse events (side effects) you may have during the 
trial. 
 
Physical examination 
A Research Doctor will perform a physical examination 
(medical check) to assess your body systems. 
 
 
 
Height, weight, and BMI 
The trial staff will measure your height, weight, and 
BMI.  
 
Electrocardiograph (ECG) 
This trial staff will regularly check how well the heart is 
functioning. This will be done by placing small sticky 
pads on your chest, shoulder, and hips. The pads are 
connected by wires to a machine that will measure the 
electrical activity of your heart. Before each ECG you 
need to lie down for at least 10 minutes.  
 
5. What type of tests and procedures will be done? 


Sponsor: Orphalan SA 
Sponsor Study Code: ORPH-131-012 
RPL Study Code: C23030 
 
Regulatory Green Light sign off: 16 Jan 2024 
 
 
Effective From 17 Jan 2024 
C23030_ORPH-131-012_Informed Consent Form_V3.0_17Jan2024_GLSO_16Jan2024 
MW-TEM-3-1 PIS/ICF template 18 Sep 2023                                                                                                      Page 13 of 28 
Vital signs 
 
The trial staff will regularly check your vital signs 
including blood pressure, pulse, body temperature, 
and breathing rate.  
 
Urine samples 
Urine samples will be collected to: 
• Test for drugs of abuse 
• Check your general health. 
• Check if you are of childbearing potential and to 
check if you are pregnant (females only).  
• Check nicotine levels 
 
 Blood samples 
Blood samples will be collected to: 
• Check if you are of childbearing potential and to 
check if you are pregnant (females only).  
• Check your general health (safety blood samples) 
• Measure the pharmacokinetic properties of the 
trial drug. 
 
Alcohol breath test 
A breath test will be performed to test for alcohol. 
 
Trial drug administration 
At each dosing timepoint, you will be given three 
tablets which you must swallow with 240ml of water. 
You will be asked to take the medication at an exact 
time and have a mouth inspection to ensure you have 
taken the medication.  
 
 
Additional blood test 
You must also agree to an additional blood test being performed before the start of the clinical trial 
to test for HIV 1 and 2, Hepatitis B, and Hepatitis C. If you are found to have a positive result, the 
Research Doctor will contact you and explain the results to you, and we will inform your GP (if 
applicable). We may request a repeat blood test to be done to confirm the diagnosis. Please note 
that you will not be able to participate in this clinical trial if you test positive for HIV, Hepatitis B, or 
Hepatitis C or refuse to allow the collection of blood for these tests. 
Blood volume 
The total volume of blood that will be taken over the duration of the clinical trial will be less than 
350mL, approximately 70 teaspoons. This includes any additional blood samples that may be 
undertaken for safety reasons and to ensure the quality of the clinical trial data. 


Sponsor: Orphalan SA 
Sponsor Study Code: ORPH-131-012 
RPL Study Code: C23030 
 
Regulatory Green Light sign off: 16 Jan 2024 
 
 
Effective From 17 Jan 2024 
C23030_ORPH-131-012_Informed Consent Form_V3.0_17Jan2024_GLSO_16Jan2024 
MW-TEM-3-1 PIS/ICF template 18 Sep 2023                                                                                                      Page 14 of 28 
COVID-19 procedures and precautions 
Please note that you will be required to have a throat/nasal swab for COVID-19 and influenza at 
regular intervals i.e., before entry to the Richmond Pharmacology Unit and ad-hoc (as required) 
during your in-house stay. Please also note Public Health England will be notified within 72 hours if 
you test positive for SARS-CoV-2, in line with our legal duty. By signing this consent, you are allowing 
us to also use your anonymised COVID-19 test results for research purposes.  
 
Wearing of face masks at the unit:  
Coronavirus (Covid-19) usually spreads by droplets from coughs, sneezes, and speaking. These 
droplets can also be picked up from surfaces if you touch a surface and then your face without 
washing your hands first. This is why social distancing, regular hand hygiene, and covering coughs 
and sneezes are so important in controlling the spread of the virus.  
 
The best available scientific evidence is that, when used correctly, wearing a face 
covering may reduce the spread of coronavirus droplets in certain circumstances, helping 
to protect others. 
 
During your time with us at Richmond Pharmacology, you will be required to wear a face mask at all 
times whilst in the unit. This may change based on our current COVID-19 policy.   
 
Possible changes:  
The COVID-19 pandemic is an ongoing global healthcare crisis and Richmond Pharmacology is 
constantly adapting our health and safety measures in line with the latest scientific evidence and 
Government guidance. You will be fully informed of any changes to our health and safety policy, 
including the requirement to wear face masks and other personal protective equipment as soon as 
practically possible. 
 
 
 
 
The trial drug may cause some side effects. You may experience none, some, or all of those 
described below. Should you develop any new symptoms of an illness or become unwell during the 
trial, you will be examined by a Research Doctor, which may involve additional safety tests (including 
urine and blood tests, vital signs, and ECGs). The Research Doctor will perform a clinical assessment 
and ensure your condition is managed appropriately. This may involve taking additional medication 
or having a procedure. The risks and benefits of any additional treatment will be explained to you. 
You may be referred to a hospital or another clinical care setting for further management if, in the 
6. What are the possible risks and discomforts of taking part in the 
trial? 


Sponsor: Orphalan SA 
Sponsor Study Code: ORPH-131-012 
RPL Study Code: C23030 
 
Regulatory Green Light sign off: 16 Jan 2024 
 
 
Effective From 17 Jan 2024 
C23030_ORPH-131-012_Informed Consent Form_V3.0_17Jan2024_GLSO_16Jan2024 
MW-TEM-3-1 PIS/ICF template 18 Sep 2023                                                                                                      Page 15 of 28 
opinion of the Research Doctor, your condition cannot be safely managed within the Richmond 
Pharmacology unit. This includes referrals for private specialists or general practitioner 
assessments.  
 
The new TETA 4HCl tablet, is similar to the reference medicine, Cuprior® (contains TETA 4HCl as the 
active drug), which has been used to treat Wilson's disease since 2017. Cuprior® has some possible 
side effects, including: 
Common (1 in a 100 to 1 in 10 people) 
• 
Nausea (sickness) 
 
Uncommon (1 in 1000 to 1 in 100 people) 
• 
Sideroblastic anaemia (low red blood cell levels when the body has enough iron but it is not 
being used) 
• 
Skin rash 
• 
Pruritus (itchy skin) 
• 
Erythema (redness of the skin) 
 
Not known (cannot be estimated from the current data) 
• 
Iron deficiency anaemia (low red blood cell levels due to not enough iron) 
• 
Duodenitis (inflammation of the small intestine) 
• 
Colitis (inflammation of the bowel) 
• 
Urticaria (hives) 
 
The trial team is taking steps to manage these risks, including: 
• 
Excluding participants with any underlying medical conditions that could make them more 
at risk of suffering from side effects. 
• 
Monitoring participants closely. 
• 
Taking safety blood tests and performing physical examinations at regular intervals. 
 
We believe the side effects of the new TETA 4HCl tablet will be very similar to Cuprior® as they both 
contain the same active drug (TETA 4HCl). Although unlikely, because the new TETA 4HCl tablet has 
not been tested in humans before, there may be side effects that we cannot predict. However, for 
the duration of the trial, all side effects will be collected, and the data will be analysed to compare 
the safety profile of the established TETA 4HCl tablets with the new TETA 4HCl tablets. 
 
Richmond Pharmacology Ltd is a specialist clinical trials unit that regularly conducts trials where 
drugs are given to people for the first time. There are trained doctors and clinical staff on-site and 
procedures in place (approved by the authorities) to deal with side effects that arise. 
Risks associated with pregnancy and breastfeeding 
 
If you are a woman of childbearing potential: 


Sponsor: Orphalan SA 
Sponsor Study Code: ORPH-131-012 
RPL Study Code: C23030 
 
Regulatory Green Light sign off: 16 Jan 2024 
 
 
Effective From 17 Jan 2024 
C23030_ORPH-131-012_Informed Consent Form_V3.0_17Jan2024_GLSO_16Jan2024 
MW-TEM-3-1 PIS/ICF template 18 Sep 2023                                                                                                      Page 16 of 28 
• You must not plan to become pregnant during the trial as nothing is known about the effect of 
the trial drug on pregnancy, breastfeeding, or an unborn foetus.  
• You must use a highly effective method of contraception during the trial and for 1 month after 
the last dose of the trial drug. Please refer to ‘Acceptable methods of contraception’ (Section 3: 
What am I expected to do during the trial?) for more information. 
 
The Research Doctor will discuss contraception with you, and you will be asked to have pregnancy 
tests during the trial. If you think you may have become pregnant during the trial you must tell the 
Research Doctor immediately. If you are pregnant or breastfeeding, you will not be able to 
participate in the trial. If you become pregnant during the trial, you must tell your Research Doctor 
immediately so we can help decide on appropriate action. We would discuss referral for specialist 
counselling on the possible risks to your unborn baby and arrangements will be made to monitor 
the health of both you and your unborn baby. The Research Doctor will collect information about 
your pregnancy and the health of you and your baby. 
 
If you are a man whose partner is of childbearing potential: 
• You must use barrier contraception from screening and for at least 1 month after the last 
dose of the trial drug. This is still required even if you are infertile (e.g. vasectomised, 
permanently sterile following bilateral orchidectomy (removal of both testicles), or any other 
documented cause of infertility). Female partners of male participants are advised to use 
highly effective contraception (detailed in Section 3: What am I expected to do during the 
trial?) during the trial and for 1 month after the last dose. This is to stop the transfer of the 
trial drug to your partner, foetus, or baby, as we do not know if TETA 4HCl is safe for an 
unborn baby. 
 
If you think your partner may have become pregnant during the trial tell the Research Doctor 
immediately. If your partner becomes pregnant, she will be asked to sign and date a separate 
informed consent form for her permission to collect information about the pregnancy and its 
outcome. 
 
Risks associated with trial procedures: 
 
Blood pressure  
Blood pressure will be measured using an inflatable cuff 
which will be placed on your arm. You may experience 
mild discomfort in your arm whilst the cuff is inflated.  
 
 
 
Blood sampling 
During the trial, blood will be drawn for testing. You may 
experience discomfort and/or soreness when the needle 
is inserted and removed, and a small bruise may appear. 
Very rarely, a vein can become blocked, or a small nerve 
injury can occur, resulting in numbness and pain. If this 
occurs, it typically will resolve with time. There may be 
other side effects such as fainting, redness, bleeding, or 
infection.  
 
 
 
 


Sponsor: Orphalan SA 
Sponsor Study Code: ORPH-131-012 
RPL Study Code: C23030 
 
Regulatory Green Light sign off: 16 Jan 2024 
 
 
Effective From 17 Jan 2024 
C23030_ORPH-131-012_Informed Consent Form_V3.0_17Jan2024_GLSO_16Jan2024 
MW-TEM-3-1 PIS/ICF template 18 Sep 2023                                                                                                      Page 17 of 28 
 
The clinical staff may decide to use a cannula (a small 
plastic tube) placed in your arm using a small needle 
because it allows several blood samples to be taken 
without having to insert a needle each time. This cannula 
may remain in place for 24 hours following your dose of 
the trial medicine, after which it will be removed. As with 
all uses of a cannula, there is a small chance of infection, 
but every medical precaution will be taken to prevent 
this from happening. 
 
ECG 
 
Minor skin irritation could develop from the adhesive 
used on the pads. Before the pads are applied, the skin 
needs to be cleaned. We may need to shave/clip small 
patches of your hair in these areas. Like plasters, these 
sticky pads may be uncomfortable to remove and in 
rare cases may cause some skin irritation. 
 
 
 
 
 
 
Day -28 to -2 (Screening) 
1 or more visits 
In-person Clinic Visit(s) 
 
 
 
 
If you have already carried out screening assessments for another trial at Richmond Pharmacology, 
this informed consent form will allow us to use those results in this trial to avoid repeat procedures. 
 
Day -1 
Day 1 
Day 2 
Day 3  
In-house Treatment Periods 
Overnight stay 
7. Trial Calendar 


Sponsor: Orphalan SA 
Sponsor Study Code: ORPH-131-012 
RPL Study Code: C23030 
 
Regulatory Green Light sign off: 16 Jan 2024 
 
 
Effective From 17 Jan 2024 
C23030_ORPH-131-012_Informed Consent Form_V3.0_17Jan2024_GLSO_16Jan2024 
MW-TEM-3-1 PIS/ICF template 18 Sep 2023                                                                                                      Page 18 of 28 
  
 
 
 
There will be a washout period of 5-10 days (between treatment doses) before the 2nd in-house 
period. The in-house Treatment Period calendar will be the same for when you return for the 
second in-house visit.  
 
 
 
In recognition of the time and effort involved in taking part in this clinical trial, you will be paid 
£833.33 on completion of the clinical trial, once follow-up results are confirmed, checked by the 
Research Doctor, and confirmed there are no safety issues. i.e., the Research Doctor considers your 
participation in the clinical trial to be completed.  
 
We want you to cooperate with us to achieve the objectives of the clinical trial, so if you are dosed, 
We will give you a compliance payment of £416.67 for your satisfactory compliance with this 
document (Participant Information/Informed Consent Form), the Richmond Pharmacology 
Volunteer Charter and all unit rules (unit regulations). However, the compliance payment is issued 
at the discretion of Richmond Pharmacology, meaning Richmond Pharmacology may not pay these 
monies if there is a justified reason not to do so within the terms of the contract with you the 
participant. 
The total amount that you could be paid for the clinical trial is £1,250.00. Payment will be made to 
you up to 21 working days after completion of the clinical trial. You will be paid for the time you give 
up for the clinical trial site and this payment is only for time and NOT linked to risk or inconvenience. 
Therefore, payment is proportional to the time you spend on the clinical trial i.e., payment may be 
Day 7 (Follow up) 
In-person Clinic Visit(s) 
 
 
 
 
8. How will I be reimbursed? 


Sponsor: Orphalan SA 
Sponsor Study Code: ORPH-131-012 
RPL Study Code: C23030 
 
Regulatory Green Light sign off: 16 Jan 2024 
 
 
Effective From 17 Jan 2024 
C23030_ORPH-131-012_Informed Consent Form_V3.0_17Jan2024_GLSO_16Jan2024 
MW-TEM-3-1 PIS/ICF template 18 Sep 2023                                                                                                      Page 19 of 28 
reduced or increased depending on your duration in the clinical trial (if you are required to attend 
the unit for fewer or more days than stated in the Clinical Trial Plan). You should not view 
participation in this clinical trial as equivalent to employment and under no circumstances should 
you participate in more than one clinical trial at a time.  
 
Please note that the clinical trial payment includes travel expenses. 
If you are dosed with the trial drug and are required to attend the unit for a repeat test (outside of 
scheduled or requested visits prolonging your participation in the clinical trial) you will be paid £80 
for a day visit or £100 for an overnight visit plus a contribution towards your travel expense of £20. 
This is applicable for each visit (i.e., in addition to the visits above) that you are required to attend. 
If you are withdrawn from the clinical trial for any reason, either voluntarily or non-voluntarily, you 
will be reimbursed for your time according to Table 1 below. 
 
REASON for WITHDRAWAL 
RE-
IMBURSEMENT 
COMPLIANCE 
PAYMENT 
Unwell/Illness related to the clinical trial 
or medicines* 
Pro-rata** 
Full 
Unwell/Illness unrelated to clinical trial or 
medicine * 
Pro-rata** 
Full 
Entire clinical trial stopped 
Pro-rata** 
Full 
Non-compliance or voluntary withdrawal 
None 
None 
Table 1: Withdrawal reimbursement plan  
*As judged by the Research Doctor. 
**Calculated according to the actual time spent in the clinical trial in relation to the total clinical 
trial period. 
 
For admission and to make sure that we start the clinical trial with the right number of participants, 
we will book more participants than will be dosed. The decision as to who is included on Day 1 of 
the clinical trial will be decided by the Research Doctor who will take into account your past medical 
history and the availability and quality of your medical history. The amount you will be paid if you 
are admitted yet not dosed is £150. 
Should you not wish to receive payment for this clinical trial, then we suggest that you nominate a 
charity of your choice, and we will arrange for a donation of the amounts that would otherwise be 
due to you.  


Sponsor: Orphalan SA 
Sponsor Study Code: ORPH-131-012 
RPL Study Code: C23030 
 
Regulatory Green Light sign off: 16 Jan 2024 
 
 
Effective From 17 Jan 2024 
C23030_ORPH-131-012_Informed Consent Form_V3.0_17Jan2024_GLSO_16Jan2024 
MW-TEM-3-1 PIS/ICF template 18 Sep 2023                                                                                                      Page 20 of 28 
It is your responsibility to manage your own tax affairs. Information on how the clinical trial 
payments may impact your tax responsibilities can be found on the following website: 
www.hmrc.gov.uk/manuals/eimanual/eim71105.htm. For any further information, please 
contact your local tax office.  
 
 
Trial termination 
If the clinical trial stops or if you decide to withdraw from the clinical trial early, you understand that 
we will keep the information about you that we have already obtained and that we can process this 
information in accordance with the clinical trial protocol and this Informed Consent Form. 
Please refer to Appendix 2 for more information. 
The Research Doctor may also decide to remove you from the clinical trial due to illness, side effects, 
new information on the trial drug or if you are not following the clinical trial rules and restrictions. 
In addition, the Sponsor may end your participation in the clinical trial at any time without your 
consent. You are strongly advised to attend a follow-up visit if you do not continue with the clinical 
trial for any reason, this is for your safety.  
New information 
Sometimes during a research project, new information becomes available about the 
treatment/investigational drug that is being studied. If this happens, the Research 
Doctor will tell you about it and discuss with you whether you want to continue in the 
clinical trial. If you decide to withdraw, the Research Doctor will make arrangements to continue 
your care if this proves necessary.  
If you decide to continue in the clinical trial, you will be asked to sign an addendum to the version 
of the consent form you previously signed. On receiving new information, the Research Doctor 
might consider it to be in your best interests to withdraw you from the clinical trial.  
Richmond Pharmacology and the Sponsor reserve the right to terminate your participation in the 
clinical trial, at any time without your consent. 
 
 
 
 
 
 
9. What could change during the trial? 


Sponsor: Orphalan SA 
Sponsor Study Code: ORPH-131-012 
RPL Study Code: C23030 
 
Regulatory Green Light sign off: 16 Jan 2024 
 
 
Effective From 17 Jan 2024 
C23030_ORPH-131-012_Informed Consent Form_V3.0_17Jan2024_GLSO_16Jan2024 
MW-TEM-3-1 PIS/ICF template 18 Sep 2023                                                                                                      Page 21 of 28 
 
 
Any complaint about the way you have been treated during the clinical trial or any possible harm 
you may suffer will be addressed. Reimbursement will be available for any injury attributable to the 
administration of the investigational drug or any clinical intervention or procedure within the clinical 
trial. Detailed information is given in Appendix 1.  
WHO SHOULD I CONTACT FOR MORE INFORMATION OR IF I HAVE QUESTIONS? 
If you have a question, concern, or complaint about any part of this study, then you should contact 
our Volunteer recruitment team who will do their best to help or connect you to the study doctor 
or a member of the study team to ensure that your queries are discussed and adequately addressed. 
 
Name: Volunteer Recruitment team 
Phone: +44 (0) 207 042 5800 Monday – Friday: 08h00 – 19h00. 
 
Additionally, the Research Doctor and his/her staff will be pleased to help if you have any further 
questions about this clinical trial. Should you have any urgent questions or experience a side effect, 
a member of staff is contactable on one of the telephone numbers below 24 hours a day. 
 
A side effect is any illness, symptom or discomfort you develop at any time during the clinical trial. 
The illness/symptom might be related to the clinical trial, or it might be something completely 
unrelated like a cold or a headache or an injury. However, you must let us know about all of these 
events, even if you think that they might not be serious or important.  
Prior to leaving the unit after you have been dosed, you will be provided with a Participant ID Card. 
You should always carry this card while you are involved in the clinical trial. The Participant ID Card 
contains your details (Richmond Pharmacology ID, forename, surname, and date of birth along with 
the clinical trial code C23030 and the following information (in italics). 
 
 
 
 
 
 
10. What if there is a problem? 
I am currently participating in a clinical trial. I may be taking an investigational 
medicine. In case of an emergency, please contact Richmond Pharmacology. 
 
Richmond Pharmacology Ltd                       0207 042 5800 
1A Newcomen Street                                 Monday – Friday: 08h00-19h00 
London Bridge  
SE1 1YR                                                   079 7942 2946 
      24 hour Medical emergency (for any    
                                                               medical concerns) 
www.richmondpharmacology.com 
www.trials4us.co.uk 


Sponsor: Orphalan SA 
Sponsor Study Code: ORPH-131-012 
RPL Study Code: C23030 
 
Regulatory Green Light sign off: 16 Jan 2024 
 
 
Effective From 17 Jan 2024 
C23030_ORPH-131-012_Informed Consent Form_V3.0_17Jan2024_GLSO_16Jan2024 
MW-TEM-3-1 PIS/ICF template 18 Sep 2023                                                                                                      Page 22 of 28 
The medically responsible person at Richmond Pharmacology is Dr Thomas Ashdown (Richmond 
Pharmacology Associate Medical Director) whose contact details are: 
Dr Thomas Ashdown   
 t.ashdown@richmondpharmacology.com                       0207 042 5800 
 
 
Will my taking part in the clinical trial be kept confidential? 
Yes. By signing this form, you consent to the Research Doctor and his/her staff at 
Richmond Pharmacology, the Sponsor Orphalan, regulatory authorities, and the 
Ethics Committee collecting, storing, transferring, and processing your personal 
data, including the following: your date of birth, your sex, your race or ethnic origin, 
personal data on your physical or mental health or condition and any other personal 
data obtained during your participation in the clinical trial or as a result of any follow-up 
assessments. Please refer to Appendix 2 for more information.  
What will happen to any samples I give? 
Samples 
Processing and Analysis 
Retention 
Blood and urine 
(safety)  
Processed and analysed by a 
laboratory within the UK on an 
ongoing basis during the clinical 
trial. These samples will not have 
your personal details on them; 
however, they will be coded in a 
way that is linked to you (see 
Appendix 2). 
These samples will be retained 
for a maximum of three months 
to perform all tests described in 
the clinical trial protocol, after 
which they will be destroyed. 
Blood for 
pharmacokinetics 
 
Processed and analysed by a 
laboratory within the EU on an 
ongoing basis during the clinical 
trial. These samples will not have 
your personal details on them; 
however, they will be coded in a 
way that is linked to you (see 
Appendix 2). 
These samples will be retained 
until the clinical trial has been 
closed to perform all tests 
described in the clinical trial 
protocol, incl. e.g., inspection 
related 
confirmatory 
re-
analysis, after which they will be 
destroyed. 
 
The samples will not be used for any other research that you have not consented to on this form.     
 
Please contact the Research Doctor at any time if you require more detailed explanations about this. 
 
11. Privacy and confidentiality 


Sponsor: Orphalan SA 
Sponsor Study Code: ORPH-131-012 
RPL Study Code: C23030 
 
Regulatory Green Light sign off: 16 Jan 2024 
 
 
Effective From 17 Jan 2024 
C23030_ORPH-131-012_Informed Consent Form_V3.0_17Jan2024_GLSO_16Jan2024 
MW-TEM-3-1 PIS/ICF template 18 Sep 2023                                                                                                      Page 23 of 28 
 
The protocol has been produced by Richmond Pharmacology and reviewed by Orphalan SA. This 
clinical trial has been approved by the Medicines and Healthcare Products 
Regulatory Agency (MHRA) which is the regulatory authority in the UK.  
 
To protect your interests the clinical trial has been looked at by an independent group of people 
called a Research Ethics Committee. This clinical trial has been reviewed and given a favourable 
opinion by NRES Committee Berkshire B Ethics Committee (IRAS ID: 1009060).  
 
This clinical trial is regulated by both national and international guidelines. Richmond Pharmacology 
Ltd is under the inspection of the MHRA ensuring that the quality of our clinical trial is to acceptable 
standards. According to Good Clinical Practice (GCP) guidelines, UK law and other relevant legal, 
regulatory, and scientific guidelines your clinical trial data must be stored and made accessible for 
at least 25 years after either drug development stops OR after the last approval of a marketing 
authorisation in a country where GCP applies. Results of the trial will be published on 
clinicaltrials.gov within 1 year of the trial finishing. For further information, please contact Richmond 
Pharmacology on the details above. 
 
 
Thank you for considering taking part in this clinical trial. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12. Who has reviewed this clinical trial? 


Sponsor: Orphalan SA 
Sponsor Study Code: ORPH-131-012 
RPL Study Code: C23030 
 
Regulatory Green Light sign off: 16 Jan 2024 
 
 
Effective From 17 Jan 2024 
C23030_ORPH-131-012_Informed Consent Form_V3.0_17Jan2024_GLSO_16Jan2024 
MW-TEM-3-1 PIS/ICF template 18 Sep 2023                                                                                                      Page 24 of 28 
RPL Number:  
 
<INSERT VDB LABEL> 
Screening Number: 
 
Informed Consent Form 
 
Clinical Trial 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 
 
Please read the following statements and put your short signature in the box to 
show that you have read and understood them and that you agree with them. 
Please 
provide 
short 
signature 
in each 
box 
1   
I confirm that I have received verbal information on the above clinical trial, 
and I understand and have read the Participant Information dated 
17/Jan/2024, Version 3.0 and have had the opportunity to ask questions and 
any questions I asked have been answered to my satisfaction.  
 
2   
I understand that my participation is voluntary and that I am free to withdraw 
at any time, without giving any reason, without my medical care or legal rights 
being affected. I am aware of any risks associated with withdrawal from the 
clinical trial before the end. 
 
3   
I understand that sections of any of my medical notes and clinical trial-specific 
records may be looked at by responsible individuals from the sponsor or from 
regulatory authorities where it is relevant to my taking part in the clinical trial. 
I give permission for these individuals to have access to my records. 
 
4   
By signing this consent form, I agree that my personal data, including 
photographs (this would only be applicable when monitoring possible side 
effects and will be taken in such a way as to prevent disclosure of my identity) 
and data relating to my physical or mental health or condition, and race or 
ethnic origin, may be collected and processed as described in the information 
sheet for the clinical trial.  
 
5   
I acknowledge that some of my samples may be sent outside the UK for 
analysis; where they have data protection laws which may be different than 
what is found in the UK; and I accept that the transferred samples will not be 
covered under the Human Tissue Act (the laws that govern and protect the 
collection, storage, use and disposal of human tissue in the UK).  
 
 


Sponsor: Orphalan SA 
Sponsor Study Code: ORPH-131-012 
RPL Study Code: C23030 
 
Regulatory Green Light sign off: 16 Jan 2024 
 
 
Effective From 17 Jan 2024 
C23030_ORPH-131-012_Informed Consent Form_V3.0_17Jan2024_GLSO_16Jan2024 
MW-TEM-3-1 PIS/ICF template 18 Sep 2023                                                                                                      Page 25 of 28 
RPL Number:   
<INSERT VDB LABEL> 
Screening Number: 
 
6   
I give my consent for my General Practitioner (GP) to be contacted and 
informed of my participation on the clinical trial and of any significant, 
abnormal results seen at screening or during the clinical trial. 
 
7   
I 
understand 
I 
will 
receive 
a 
copy 
of 
this 
Participant 
Information/Informed Consent Form. 
 
8   
I understand that the general outcome and results of this clinical trial, 
will be posted to clinicaltrials.gov within 1 year of this trial finishing.  
 
9   
I confirm that I voluntarily consent to participate in this clinical trial. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Sponsor: Orphalan SA 
Sponsor Study Code: ORPH-131-012 
RPL Study Code: C23030 
 
Regulatory Green Light sign off: 16 Jan 2024 
 
 
Effective From 17 Jan 2024 
C23030_ORPH-131-012_Informed Consent Form_V3.0_17Jan2024_GLSO_16Jan2024 
MW-TEM-3-1 PIS/ICF template 18 Sep 2023                                                                                                      Page 26 of 28 
RPL Number:   
 
<INSERT VDB LABEL> 
Screening Number: 
 
Participant: 
 
The Research Doctor supervising this clinical trial has given me an explanation of the nature, purpose 
and likely duration of the clinical trial, and what I will be expected to do. I have also been advised 
about any possible discomfort and ill effects on my health or well-being which may result from my 
participation. 
 
I understand that if I withdraw from the clinical trial at any time and for any reason, the information 
that I have provided will be kept and will continue to be used, transferred, and processed. 
 
I have been given the opportunity to question the Research Doctor on all aspects of the clinical trial 
and have understood the advice and information given to me. I understand that the information for 
participants in its current version number 3.0 dated 17/Jan/2024 which has been handed out to 
me forms part of this written informed consent. 
 
____________________             ___________________      |__|__|.|__|__|__|.|__|__|__|__|  |__|__|:|__|__|     
 Signature of Participant 
    Full Name                                       Date (DD/MMM/YYYY)                           Time (24 HOUR CLOCK) 
 
 
 
 
 
 
 
Observer: 
Observer to signature of the participant and to the fact that they have read the document and freely 
given their consent. 
 
____________________        _________________             |__||__|.|__|__|__|.|__|__|__|__| |__|__|:|__|__| 
Signature of Observer 
    Full Name                                     Date (DD/MMM/YYYY)                            Time (24 HOUR CLOCK) 
 
Research Doctor: 
I confirm that I have explained to the participant the nature, purpose, and possible hazards of these 
procedures, and therefore sign on behalf of Richmond Pharmacology. 
 
 
____________________          ___________________        |__|__|.|__|__|__|.|__|__|__|__| |__|__|:|__|__|           
Signature of Research Doctor         Full Name                                    Date (DD/MMM/YYYY)                           Time (24 HOUR CLOCK) 
 
 
 
Richmond Pharmacology Limited | 1a Newcomen Street | London Bridge  
SE1 1YR | Tel: 02070425800 
 
 
 
 
 


Sponsor: Orphalan SA 
Sponsor Study Code: ORPH-131-012 
RPL Study Code: C23030 
 
Regulatory Green Light sign off: 16 Jan 2024 
 
 
Effective From 17 Jan 2024 
C23030_ORPH-131-012_Informed Consent Form_V3.0_17Jan2024_GLSO_16Jan2024 
MW-TEM-3-1 PIS/ICF template 18 Sep 2023                                                                                                      Page 27 of 28 
Appendix 1 – What to do if there is a problem 
 
1. If you suffer any side effects or injury, notify the Research Doctor immediately so that you can 
receive appropriate medical treatment.   
2. If you suffer injury caused directly by participation in the clinical trial, the sponsoring company 
Orphalan SA will pay you compensation in accordance with the Association of British 
Pharmaceutical 
Industry 
Clinical 
Trial 
Compensation 
Guidelines 
2014 
[compensation_guidelines_2014.pdf (abpi.org.uk)]. A copy can be provided to you. 
3. Any dispute or disagreement as to the application of clause 2 and above shall be referred to an 
arbitrator to be agreed between yourself and the sponsor. If you and the Sponsor cannot agree 
on the identity of an arbitrator, the President of the Royal College of Physicians of London will 
be invited to appoint an arbitrator with the power to consult a barrister of 10 years standing on 
any issue of law including the amount of damages to be paid.  
4. The agreement to pay compensation shall be construed in accordance with English law and 
subject to the clause 3 above, the English courts shall have sole jurisdiction over any dispute 
which may arise out of it. 
5. You are not being asked to give up any of your legal rights by agreeing to take part in this clinical 
trial.  
Both Richmond Pharmacology and Orphalan SA have insurance policies in place for insuring 
against claims for their alleged liability.  
 
 
 
 
 
 
 
 
 
 
 


Sponsor: Orphalan SA 
Sponsor Study Code: ORPH-131-012 
RPL Study Code: C23030 
 
Regulatory Green Light sign off: 16 Jan 2024 
 
 
Effective From 17 Jan 2024 
C23030_ORPH-131-012_Informed Consent Form_V3.0_17Jan2024_GLSO_16Jan2024 
MW-TEM-3-1 PIS/ICF template 18 Sep 2023                                                                                                      Page 28 of 28 
Appendix 2 – Use of Personal Data 
How will we use information about you?  
We will need to use information from you, from your medical records, and your GP for this 
research project.  
This information will include your Initials,  
• NHS number, 
• Name, 
• Contact details, 
• Medical/health information,  
• Year of birth,  
• Race and ethnicity,  
• Demographic information, 
• Back-up family/emergency contact details.  
People will use this information to do the research or to check your records to make sure that the 
research is being done properly. People who do not need to know who you are will not be able to 
see your name or contact details. Your data will have a code number instead.  We will keep all 
information about you safe and secure.  
Some of your information will be sent to France. They must follow our rules about keeping your 
information safe. Once we have finished the study, we will keep some of the data so we can check 
the results. We will write our reports in a way that no-one can work out that you took part in the 
study. 
What are your choices about how your information is used? 
• You can stop being part of the study at any time, without giving a reason, but we will keep 
information about you that we already have.  
• We need to manage your records in specific ways for the research to be reliable. This means 
that we won’t be able to let you see or change the data we hold about you.  
Where can you find out more about how your information is used? 
You can find more about how we use your information:  
• 
at www.hra.nhs.uk/information-about-patients/ 
• 
on the HRA leaflet available from www.hra.nhs.uk/patientdataandresearch OR a printed 
version can be provided. 
• 
by asking one of the research team 
• 
by sending an email to  DPO@richmondpharmacology.com (Site’s Data Protection Officer), 
or (dataprivacy@orphalan.com) 
• 
by ringing us on +44 56 0375 0073 (Sponsor’s Data Protection officer). 

Prot_SAP_000.pdf: 
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MW-TEM-1-1 CSP Study Protocol 
Page 1 of 51 
 
 
 
 
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 
C23030_ORPH-TRIUMPH-3_CSP v2.0_09Jan2024.docx 
MW-TEM-1-1 CSP Study Protocol 
Page 2 of 51 
 
 
 
 
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 
Version 2.0 
09-Jan-2024 
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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 
Version 2.0 
09-Jan-2024 
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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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Page 5 of 51 
 
 
 
 
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 
MW-TEM-1-1 CSP Study Protocol 
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 
C23030_ORPH-TRIUMPH-3_CSP v2.0_09Jan2024.docx 
MW-TEM-1-1 CSP Study Protocol 
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 
Version 2.0 
09-Jan-2024 
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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 
RPL Trial No C23030 
CONFIDENTIAL 
Version 2.0 
09-Jan-2024 
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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. 


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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 


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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 

SAP_001.pdf: 
Statistical Analysis Plan
 
 
 
C23030 ORPH-131-012 SAP Final v1.0 31Jan2024_Redacted             
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SPONSOR’S REFERENCE NUMBER: ORPH-131-012 
IRAS NUMBER: 1009060 
RICHMOND STUDY CODE: C23030 
STATISTICAL ANALYSIS PLAN  
 
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 (3x300mg 
Trientine Base Tablets, OD) with the Current Marketed Cuprior® Formulation (3x150mg 
Trientine Base Tablets, BD) in Adult Healthy Male and Female Participants
FINAL VERSION 1.0, 31JAN2024 
 
 
 
Issued by: S. Melikyan 
 
 
 
          
Richmond Pharmacology  
 
 
 
 
Senior Biostatistician  
Date...........................   Signature...................... 
 
 
Reviewed by: D. Djumanov 
 
 
 
Richmond Pharmacology  
 
 
 
 
Director of Data Science Date...........................   Signature...................... 
 
 
Reviewed by: Saqib Mir 
Richmond Pharmacology  
 
 
 
 
Medical Writing 
 
Date...........................   Signature...................... 
 
 
Reviewed by: Thomas Ashdown  
 
Richmond Pharmacology  
 
 
 
 
PI/SubI 
 
 
Date...........................   Signature...................... 
 
 
Reviewed by: Carla Bennett 
 
 
 
Orphalan 
 
 
 
 
 
Clinical Research Manager  Date...........................   Signature...................... 
 
 


Statistical Analysis Plan
 
 
 
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Contents 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................... 3 
1. 
INTRODUCTION .............................................................................. 3 
2.1 
Trial objectives ............................................................................... 4 
2.2 
Endpoints ...................................................................................... 4 
3. 
TRIAL DESIGN .................................................................................. 5 
3.1 Overall Trial Design ........................................................................... 5 
3.2 
Sample Size ................................................................................... 6 
4. STATISTICAL ANALYSES ......................................................................... 6 
4.1 General Notes for Statistical Analyses ................................................... 6 
4.2 
Interim Analysis ............................................................................. 7 
4.3 
Analysis Sets ................................................................................. 7 
4.4 
Subject Disposition ......................................................................... 8 
4.5 
Demographic Characteristics............................................................. 8 
4.6 
Inclusion and Exclusion Criteria ......................................................... 8 
4.7 
Protocol Deviations ......................................................................... 8 
4.8 
Medical and Surgical History ............................................................. 8 
4.9 
Trial Drug Administration ................................................................. 9 
4.10 Prior and Concomitant Medications .................................................... 9 
4.11 Safety Analysis ............................................................................... 9 
4.11.1 Adverse Events .......................................................................... 9 
4.11.2 Laboratory Data ....................................................................... 10 
4.11.3 Vital Signs ............................................................................... 10 
4.11.4 Physical Examination ................................................................ 10 
4.11.5 Electrocardiograms ................................................................... 11 
4.11.6 Other assessments ................................................................... 11 
4.13 Pharmacokinetic Data ..................................................................... 11 
4.13.1 Statistical Analysis on PK Parameters ........................................... 13 
4.14 Methods for Withdrawals, Missing Data and Outliers ............................ 13 
 
 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
or Specialist 
Term 
Explanation 
AE 
Adverse Event 
β-HCG
Beta-hCG, beta human chorionic gonadotropin
BD
Twice daily
BMI
Body Mass Index
CI
Confidence Interval
CV
Coefficient Of Variation
DAT
N1, N10-diacetyltriethylenetetramine
DRM
Data Review Meeting
ECG 
Electrocardiogram 
H
High
HR
Heart rate
IMP
Investigational Medicinal Product
L
Low
LLOQ
Lower Limit Of Quantification
MAT
N1-acetyltriethylenetetramine
MedDRA
Medical Dictionary for Regulatory Activities
OD
Once daily
PK 
Pharmacokinetic(s) 
Richmond
Richmond Pharmacology Ltd
SAP
Statistical Analysis Plan
SD
Standard Deviation
SOC
System Organ Class
TETA
Trientine
TEAE
Treatment-Emergent Adverse Event
WOCBP
Women Of Childbearing Potential
 
 
1. 
INTRODUCTION 
The purpose of this Statistical Analysis Plan (SAP) is to define the variables and 
provide details of the planned analysis for addressing the objectives of this trial. 
The protocol dated 23 Nov 2023, version 1.1 was used to prepare this SAP. 
Statistical analysis and reporting will be performed by Richmond Pharmacology 
(Richmond) as described within this SAP.  
 
 
 


Statistical Analysis Plan
 
 
 
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Trial OBJECTIVES AND ENDPOINTS 
2.1 
Trial objectives 
Primary 
 
To evaluate and compare the plasma Pharmacokinetic (PK) parameters of 
TETA 
4HCL 
(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. 
Secondary 
 
To compare the safety and tolerability of the two TETA 4HCL tablet 
formulations. 
 
2.2 
Endpoints 
Primary 
 
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-inf), apparent total plasma 
clearance (CL/F), apparent volume of distribution during the terminal phase 
(Vz/F), terminal elimination rate constant (λz), and terminal elimination half-
life (t1/2). 
Secondary 
• 
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).  
• 
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). 
 
 
 


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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. 
 
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 (β-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 
level.  
 
The overall trial design is depicted in Figure 1. 
 
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 prior to 


Statistical Analysis Plan
 
 
 
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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 1: 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 in protocol. The total duration of the study 
(including the screening period) is approximately 7 weeks. 
 
3.2 
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. 
In the study 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. 
4. STATISTICAL ANALYSES 
4.1 General Notes for Statistical Analyses  
Statistical analysis and reporting will be performed by Richmond. 


Statistical Analysis Plan
 
 
 
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In general, descriptive statistics for continuous variables will include number of non-
missing values (n), arithmetic mean, standard deviation (SD), median, minimum, 
and maximum.  
Categorical variables will be summarized using frequency counts and percentages.  
For all tables, descriptive statistics for minimum and maximum will be presented 
with the same decimal digits as the original data, and with 1 more decimal place 
than the original data for mean and median; SD will be reported with 2 more decimal 
places than the original data.  
To increase the readability of the TFLs the treatments will be abbreviated as  
A: 900mg TETA 4HCl, new once daily formulation (3x300mg trientine base tablets 
as a single AM dose). 
B: 900mg TETA 4HCl, Marketed Cuprior® formulation (6 x150mg trientine base 
tablets in two equally divided doses (450mg doses 8 hours apart). 
Listings and baseline data and Adverse event (AE) tables will be presented by 
treatment sequence AB, BA and Overall (where applicable). The analyses will be 
presented by treatment group (A and B), with pre-dose data presented under the 
treatment A. 
All collected data will be presented in by-subject listings. Listings will be ordered by 
treatment sequence and subject number and will include all randomized subjects. 
Unless otherwise stated, baseline will be defined as the last non-missing value prior 
to first administration of trial drug. Changes from baseline values will be calculated 
as the post-baseline assessment value minus the baseline value. Only observed 
values from scheduled time points will be used to create summary tables. 
If repeated measurements are made at a time point, the first scheduled value will 
be used for summary analysis, unless otherwise stated in relevant section of this 
SAP. 
Deviations from the planned analyses will be described in the final clinical study 
report. 
  
4.2 
Interim Analysis 
No interim analysis is planned for this trial. 
 
4.3 
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. 
 


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Safety set 
The Safety set will consist of all randomised participants who received at least one 
dose of the Investigational Medicinal Product (IMP) or Approved Product (150mg). 
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. 
 
4.4 
Subject Disposition  
All subjects will be included in the summary of subject disposition. This will present 
the overall number of subjects, the frequency and percentage of subjects 
randomized and treated, and who completed or discontinued from the trial, along 
with reason for discontinuation.  
Furthermore, the number and percentage of subjects in each analysis set will be 
tabulated. Discontinued subjects will be listed. Subject assignment to analysis sets 
will be listed. Screen Failures will not be listed or included in summary tables. 
 
4.5 
Demographic Characteristics 
Individual participant demographics (age, gender, ethnicity and race) and body 
measurement data (height, weight, and body mass index (BMI)) at screening will 
be listed. These demographic characteristics and measurements will be summarised 
by treatment group and overall, using the safety analysis set. Other baseline 
characteristics will be listed only. 
 
4.6 
Inclusion and Exclusion Criteria 
The inclusion and exclusion criteria text will be listed, as well as failed eligibility 
criteria for each randomised subject, if any. 
 
4.7 
Protocol Deviations 
The final review of protocol deviations will be performed at the DRM prior to 
database lock. The protocol deviations will be listed. 
 
4.8 
Medical and Surgical History 
Medical and Surgical history data will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA) dictionary Version 26.1 (or higher) and listed 
individually. Surgical history data will be listed separately. Medical and Surgical 
history data will be summarised using frequency and percentage by SOC and 
preferred term. 


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4.9 
Trial Drug Administration 
Trial drug administration data including treatment details and date-time of 
administration will be listed by subject. 
 
4.10 Prior and Concomitant Medications 
All prior and concomitant medications will be coded using the World Health 
Organization Drug Dictionary version Sep 2023 (or higher) and will be listed 
individually. The frequency and percentage of prior and concomitant medications 
will be summarized by Anatomical Therapeutic Chemical and Preferred Name. 
Separate tables will be given for prior and concomitant medications. Prior 
medications are defined as those for which the end date and time is prior to the 
date, and time of first trial drug administration. Concomitant medications are 
defined as those with start date and time on or after the date and time of first trial 
drug administration and those with start date and time prior to the first trial drug 
administration but with end date and time on or after the date and time of first trial 
drug administration. 
If medication dates are incomplete and it is not clear whether the medication was 
concomitant, it will be assumed to be concomitant. 
 
4.11 Safety Analysis 
Safety analyses will be performed on the safety set, unless otherwise stated.  
Safety analyses will include an analysis of all AEs, ECGs, clinical laboratory data, 
vital sign measurements and physical examination results and will be presented 
using descriptive statistics. No formal statistical analysis will be performed. 
 
4.11.1 Adverse Events 
A Treatment Emergent Adverse Event (TEAE) is defined as any adverse event which 
commences or any worsening of pre-existing conditions after the start of 
administration of trial drug. AEs with unknown start date/time will be assumed to 
be treatment-emergent unless the end date/time is known to be before the first 
administration of trial drug. 
AE data will be listed and TEAEs summarised using descriptive statistics: the number 
(and percentage) of participants who experienced any AEs and the number of AE 
episodes will be summarized for each dose. All AEs will be summarized and listed 
by using the System Organ Class (SOC) and Preferred Term assigned to the event 
using the 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. 
Subjects having multiple AEs within a category (e.g., overall, SOC and Preferred 
Term) will be counted once in that category. In each table, SOC and Preferred Term 


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will be presented in descending order of overall incidence rate (alphabetical order 
will be used in case of equal rates).  
 
4.11.2 Laboratory Data 
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. 
The scheduled lab value will be used for summary analysis if repeated 
measurements are made at any time point.  
For summary statistics, a lab value with “<” will be replaced with a numeric value 
by removing the “<” sign. In the listings, the values will be displayed as originally 
reported by the laboratory. 
Serology, Urine cotinine, Pregnancy and Follicle-stimulating hormone tests will be 
listed only under a combined listing. 
 
4.11.3 Vital Signs 
Vital signs data (Systolic Blood Pressure, Diastolic Blood Pressure, Pulse rate, 
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. 
Normal ranges for the relevant parameters are presented below: 
Parameter 
Normal Range 
Systolic Blood Pressure (Supine) 
90–140 mmHg 
Diastolic Blood Pressure (Supine)  
40–90mmHg  
Pulse Rate (supine) 
40–100 bpm 
Temperature (tympanic)  
35-38°C  
Respiratory Rate
8 – 20 breaths per min
 
4.11.4 Physical Examination 
The full and symptom directed physical examination data will be listed only and 
include an assessment of the following: general appearance, skin, eyes, ears, nose, 


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neck, lymph nodes, throat, heart, lungs, abdomen, musculoskeletal system and 
extremities. 
 
4.11.5 Electrocardiograms 
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.  
Reference ranges for ECGs are as follows: 
 
Parameter
Normal Range
Heart Rate (Supine)  
40-100 bpm  
PR Interval 
120–210 ms 
QRS duration  
≤120 ms  
QTcF 
≤450 ms (Males) ≤470 ms (Females)
 
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. 
 
4.11.6 Other assessments 
The meal times will be listed only. 
 
4.13 Pharmacokinetic Data 
Non-compartmental analysis will be used for estimation of pharmacokinetic 
parameters.  
The following pharmacokinetic parameters will be calculated for of trientine and its 
two main metabolites (N1-acetyltriethylenetetramine (MAT) and N1, N10-
diacetyltriethylenetetramine (DAT)): 
 


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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 
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 of 
trientine 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 the lower limit of quantification (LLOQ) prior 
to the first quantifiable concentration will be set to zero. Samples with 
concentrations below LLOQ after the first quantifiable concentration will be set to 
‘missing’ and omitted from the analysis. Other pharmacokinetic parameters will be 
calculated according to standard equations.  
In the determination of λz (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 ≥ 0.8, and  
 
%AUCextrap < 0.20. 
If these conditions are not met, the PK parameter will be flagged in the listings 
(together with the ones dependent on λz, 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. 


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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 
 
4.13.1 Statistical Analysis on PK Parameters  
Plasma concentrations will be listed and summarised by time point (N - the number 
of participants, n – 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. 
 
4.14 Methods for Withdrawals, Missing Data and Outliers 
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.