E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
Wilson's disease is an autosomal recessive genetic disorder in which copper accumulates in tissues; this manifests as neurological or psychiatric symptoms and liver disease. |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10047988 |
E.1.2 | Term | Wilson's disease |
E.1.2 | System Organ Class | 100000004850 |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective is to evaluate the efficacy of WTX101 for 24 weeks on non-ceruloplasmin-bound copper (NCC) levels adjusted for molybdenum (Mo) plasma concentration in newly diagnosed Wilson Disease (WD) patients aged 18 and older with NCC levels within or above the normal reference range at the time of enrolment.
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E.2.2 | Secondary objectives of the trial |
- Establish the safety and tolerability of individualised dosing of WTX101 over the course of the study period - Evaluate: change in and time to normalisation of NCC levels adjusted for Mo plasma concentration; the effects of WTX101 on neurological status using the UWDRS (neurological subscore; parts I, II and III); the effects of WTX101 on psychiatric status using M.I.N.I. Tracking; the global effects of WTX101 on clinical symptoms as assessed by the Investigators on the CGI scale items 1 (severity of illness) and 2 (global improvement); the effects of WTX101 on the following QoL / PRO endpoint measures: EQ5D, MAQ-8 and the TSQM, the effects of WTX101 on hepatic measures - Analyse copper endpoints (exchangeable copper, speciation profiling, and 24-hour urinary copper) - Collect PK data on WTX101 in this patient population based on the measurement of plasma total Mo - Evaluate the durability, and establish long-term safety and efficacy of WTX101 in a 12 month Extension Phase |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Patients must meet all of the following criteria to be eligible for enrolment in this study: 1. Willing and able to give informed consent for participation in the study. 2. Male or female patients, aged 18 years or older as of signing the ICF. 3. Able to understand and willing to comply with study procedures, restrictions and requirements, as judged by the Investigator. 4. Newly established diagnosis of Wilson Disease by Leipzig-Score 4 (Ferenci et al 2003) documented by testing as outlined in 2012 EASL WD Clinical Practice Guidelines. 5. NCC levels above the normal reference range (0.8-2.3 μM). 6. Willing to undergo 48 hour washout from current Wilson Disease treatment. 7. Adequate venous access to allow collection of a number of blood samples. 8. Willing to avoid intake of foods and water with high concentrations of copper throughout the duration of the study. 9. Females of childbearing potential will be included if they are either sexually inactive (abstinent) for 14 days prior to the first WTX101 dose continuing through 28 days after the last WTX101 dose, or using one of the following highly effective birth control methods: a. intrauterine device (IUD) (without Cu); b. surgical sterilization of the partner (vasectomy for 6 months minimum); c. combined (estrogen or progestogen containing) hormonal contraception associated with the inhibition of ovulation (either oral, intravaginal, or transdermal); d. progestogen only hormonal contraception associated with the inhibition of ovulation (either oral, injectable, or implantable); e. intrauterine hormone releasing system (IUS); f. bilateral tubal occlusion. 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 study treatments. In this trial abstinence is only acceptable if in line with the subjects preferred and usual lifestyle. Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhoea method (LAM) are not acceptable methods of contraception. As well, female condom and male condom should not be used together. 10. Females of childbearing potential agree to remain sexually inactive or to keep the same birth control method for at least 28 days following the last dose. 11. A female of non-childbearing potential must have undergone one of the following sterilization procedures at least 6 months prior to the first WTX101 dose: a. hysteroscopic sterilization; b. bilateral tubal ligation or bilateral salpingectomy; c. hysterectomy; d. bilateral oophorectomy; or be postmenopausal with amenorrhea for at least 1 year prior to the first WTX101 dose and follicle stimulating hormone (FSH) serum levels consistent with postmenopausal status. 12. A non-vasectomized male subject agrees to use a condom with spermicide or abstain from sexual intercourse during the study until 90 days beyond the last dose of study medication and the female partner agrees to comply with inclusion 9 or 11. For a vasectomized male who has had his vasectomy 6 months or more prior to study start, it is required that they use a condom during sexual intercourse. A male who has been vasectomized less than 6 months prior to study start must follow the same restrictions as a non- vasectomized male. 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 study treatments. In this trial abstinence is only acceptable if in line with the subjects preferred and usual lifestyle. Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhoea method (LAM) are not acceptable methods of contraception. As well, female condom and male condom should not be used together. 10. Females of childbearing potential agree to remain sexually inactive or to keep the same birth control method for at least 28 days following the last dose. 13. If male, agrees not to donate sperm from the first WTX101 dose until 90 days after dosing. |
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E.4 | Principal exclusion criteria |
1. Treatment for greater than 24 months for Wilson Disease with chelation therapy (i.e.penicillamine, trientine hydrochloride) or zinc therapy. 2. Decompensated hepatic cirrhosis. 3. Model for End-Stage Liver Disease (MELD) score > 11. 4. Modified Nazer score > 6 (Dhawan et al. Liver Transplant 2005). 5. GI bleed within past 6 months. 6. ALT > 5x upper limit of normal (ULN). 7. Marked neurological disease requiring either nasogastric (NG) feeding or intensive in-patient medical care. 8. Severe anaemia with a haemoglobin < 9 mg/dL. 9. Participation in a clinical trial of an experimental or unapproved/unlicensed therapy at the same time or within the 4 weeks prior to this study. 10. History of seizure activity within 6 months of study start. 11. Pregnant (or women who are planning to become pregnant) or lactating women. 12. Known sensitivity to WTX101, WTX101 excipients (anhydrous di-calcium phosphate, anhydrous sodium carbonate), any of the ingredients contained in WTX101, PPIs or to related compounds. 13. Active infection with hepatitis B virus (positive hepatitis B surface antigen) or C virus (patients with positive hepatitis C antibody result would require confirmation of active disease with a positive hepatitis C polymerase chain reaction (PCR) test), seropositivity for human immunodeficiency virus (HIV). 14. Any disability acquired from trauma or another illness that, in the opinion of the Investigator, could interfere with evaluation of disability due to WD. 15. Previous treatment with tetrathiomolybdate. 16. Major systemic disease or other illness that would, in the opinion of the Investigator, compromise patient safety or interfere with the collection or interpretation of study results. 17. In the opinion of the Investigator, the patient is likely to be non-compliant or uncooperative during the study. 18. Any deviation in laboratory values that are confirmed on re-examination to be clinically significant by the Investigator that would jeopardise the safety of the patient or impact the validity of the study results. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Non-ceruloplasmin-bound copper (NCC) levels adjusted for molybdenum (Mo) plasma concentration
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Evaluation is done over a period of 24 weeks |
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E.5.2 | Secondary end point(s) |
- Change in NCC levels adjusted for Mo plasma concentration - Time to normalisation of NCC adjusted for Mo plasma concentration - Change in exchangeable copper during 24 weeks of treatment - Change in speciation profiling (Mo, Cu and protein complex profiling with SEC) during 24 weeks of treatment - Change in 24-hour urinary copper during 24 weeks of treatment - Changes in hepatic measures (ALT, AST, INR and bilirubin) - Changes in neurological status using the UWDRS (neurological subscore; parts I, II and III) and additionally: - Number of patients that deteriorate = increase ≥ 4 (part III of neurological sub-score) or increase ≥ 1 (part II of neurological sub- score). - Number of patients that improve = decrease ≥ 4 (part III of neurological sub-score) or decrease ≥ 1 (part II of neurological sub- score). - Changes in psychiatric status using M.I.N.I. Tracking - Changes in the global effects of WTX101 on clinical symptoms assessed by the Investigators on the CGI scale items 1 (severity of illness) and 2 (global improvement) - Absolute changes in QOL / PRO measures EQ5D, MAQ-8, TSQM - Pharmacokinetic (PK) data based on measurement of plasma total molybdenum (Mo) - Durability and long term efficacy of WTX101 in a 12 month Extension Phase. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Evaluation is done over a period of 24 weeks. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 3 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Austria |
Germany |
Poland |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 17 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 12 |