E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Primary Sclerosing Cholangitis (PSC) is a slowly progressing chronic cholestatic liver disease of assumed autoimmune, but finally unidentified etiology, characterized by a chronic inflammatory and fibro-obliterative destruction of extra-, and intrahepatic bile ducts. The disease is characterized by diffuse inflammation, fibrosis, and strictures of the intra- and/or extrahepatic bile ducts with an impaired biliary secretion of potentially aggressive bile fluid often leading to cirrhosis. |
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E.1.1.1 | Medical condition in easily understood language |
Primary Sclerosing Cholangitis (PSC) is a slowly progressing chronic liver disease characterized by changes in the gall ducts inside and/or outside the liver, such as narrowing or enlargement. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Digestive System Diseases [C06] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10036732 |
E.1.2 | Term | Primary sclerosing cholangitis |
E.1.2 | System Organ Class | 10019805 - Hepatobiliary disorders |
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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 |
To show the superiority of norursodeoxycholic acid (norUDCA) compared to placebo in the treatment of Primary Sclerosing Cholangitis (PSC) with regard to prevention of disease progression. |
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E.2.2 | Secondary objectives of the trial |
To study safety and tolerability (Adverse Events, laboratory parameters) of norUDCA, To assess quality of life.
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Amendment No. 8 (Open-Label Extension Phase) V1.0 dated 24.11.2021
Rationale: Due to the lack of effective medical treatment for Primary Sclerosing Cholangitis (PSC), patients completing their approximately 4-year study period of the trial would be left without any treatment. This open-label extension (OLE) phase is an option for treatment continuation for patients who are completing or already have completed the double-blind extension (DBE) phase prior to the overall study completion. Eligible patients for the OLE phase are especially those who showed improved laboratory values during the double-blind (DB) and DBE phase. But even patients with stable or deteriorated laboratory values are eligible for an OLE phase participation and could benefit from treatment continuation. Furthermore the OLE phase will provide resilient longitudinal data on safety and efficacy in the treatment with norursodeoxycholic acid (NCA).
Study design: Patients who completed the DBE phase will be asked to enter the OLE phase. All patients irrespective of their previous treatment group will receive the same number of capsules (verum only) as used during the DBE phase. A prolongation of the OLE treatment phase is established in those countries where patients are completing the DBE phase (192 weeks of treatment) early 2024 and where a parallel PK study is established (Austria, Germany and Finland).
Study drug OLE-phase: Week 193 – 336: 6x 250 mg NCA capsules = 1500 mg NCA OD in the morning.
Study duration: The OLE phase of this study lasts up to 132 weeks (approx. 2.5 years) and follows the DBE phase of the study. For those patients who consent to participate in the OLE phase, the last study visit of the DBE phase (V22) is also the first visit of the OLE phase.
Inclusion Criteria for the OLE phase: 1. Signed additional informed consent for OLE phase 2. DBE phase completed with Visit 22
Study Centres: It is intended that the continuation of the trial as OLE phase will take place at approximately 50 centers in Europe in 10 countries whose patients have completed their approximately 4-year study period (Austria, Germany, Denmark, Finland, France, Hungary, Netherlands, Norway, Sweden and UK). A prolongation of the OLE treatment phase is established in those countries where patients are completing the DBE phase (192 weeks of treatment) early 2024 and where a parallel PK study is established (Austria, Germany and Finland).
Sample Size: The calculated sample size for the OLE phase is approximately 110 patients who have completed the DBE phase (192 weeks of treatment).
Project Time Schedule: The OLE phase started in March 2022 and is expected to end in December 2024. The OLE phase has no impact on overall study project timelines. Estimated end of the study (DBE phase) is March 2026.
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E.3 | Principal inclusion criteria |
1. Signed informed consent. 2. Males or females. 3. Verified PSC. 4. Liver biopsy available. 8. Women of child-bearing potential, i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile, who are sexually active have to apply a highly effective method of birth Control with a low failure rate (i.e., less than 1% per year) when used constantly and correctly such as combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal or transdermal), progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable or implantable), intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, vasectomized partner, or sexual abstinence (only accepted as a highly effective contraceptive measure if it is the usual and preferred lifestyle of the patient), throughout the treatment period and for four weeks following the last dose of study drug. Hormonal methods other than levonorgestrel containing devices or medroxyprogesterone injections should be supplemented with use of a male condom. Women of non-childbearing potential may be included if surgically sterile or post-menopausal for at least 2 years. The investigator is responsible for determining whether the patient has this adequate birth control for study participation.
Inclusion Criteria for the open-label extension (OLE) phase: 1. Signed additional informed consent for OLE phase 2. DBE phase completed with Visit 22
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E.4 | Principal exclusion criteria |
1. History or presence of other concomitant liver diseases including. 4. Secondary causes of Sclerosing Cholangitis 11. Total bilirubin > 4.0 mg/dL (> 68 μmol/L) at screening or baseline. 13.Any known relevant infectious disease (e.g., active tuberculosis, AIDS defining diseases). 14.Abnormal renal function 15. Thyroid-stimulating hormone (TSH) > ULN at screening (elevated levels [4.2-10 μU/mL] are acceptable if fT4 is measured and within the normal range). 16. Any severe concomitant cardiovascular, renal, endocrine, or psychiatric disorder, which in the opinion of the investigator might have an influence on the patient's compliance or on the interpretation of the results, or patient with atrial fibrillation or any disorder which in the opinion of the investigator may affect the patient's safety. 17.Any active malignant disease. 18.Known intolerance/hypersensitivity to study drug, or drugs of similar chemical structure or pharmacological profile. 19.Well-founded doubt about the patient's cooperation. 20.Existing or intended pregnancy or breast-feeding. 21.Participation in another clinical trial within the last 30 days prior to screening visit. 22.Patients who have an absolute contraindication for liver biopsy. 23.Imprisoned persons, persons admitted to nursing homes, persons under legal guardianship, and persons not able to express their consent (e.g. due to mental impairment). |
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E.5 End points |
E.5.1 | Primary end point(s) |
Partial normalization of s-ALP and no worsening of disease stage as determined by the Ludwig stage.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Partial normalization of s-ALP and no worsening of disease stage as determined by the modified Nakanuma score at the week 96 visit compared to baseline as key secondary endpont. Liver stiffness, fibrosis stage, liver histology, dominant strictures, quality of life as other secondary endpoints. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | No |
E.6.7 | Pharmacodynamic | No |
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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
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 | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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 | 24 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 58 |
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 |
Switzerland |
Russian Federation |
United Kingdom |
Austria |
Belgium |
Czechia |
Denmark |
Finland |
France |
Germany |
Hungary |
Italy |
Lithuania |
Netherlands |
Norway |
Poland |
Spain |
Sweden |
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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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last visit of the last subject |
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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 | 8 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 8 |
E.8.9.2 | In all countries concerned by the trial months | 6 |