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    Summary
    EudraCT Number:2016-003367-19
    Sponsor's Protocol Code Number:NUC-5/PSC
    National Competent Authority:Austria - BASG
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2017-06-27
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedAustria - BASG
    A.2EudraCT number2016-003367-19
    A.3Full title of the trial
    Double-blind, randomized, placebo-controlled, phase III study comparing norursodeoxycholic acid capsules with placebo in the treatment of primary sclerosing cholangitis
    Doppelblinde, randomisierte, placebo-kontrollierte Phase III-Studie zum Vergleich von nor-Ursodeoxycholsäure-Kapseln vs. Placebo bei der Behandlung von primär sklerosierender Cholangitis
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to compare norursodeoxycholic acid with placebo in the treatment of primary sclerosing cholangitis
    A.4.1Sponsor's protocol code numberNUC-5/PSC
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorDr. Falk Pharma GmbH
    B.1.3.4CountryGermany
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportDr. Falk Pharma GmbH
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationDr. Falk Pharma GmbH
    B.5.2Functional name of contact pointDepartment of Clinical Research
    B.5.3 Address:
    B.5.3.1Street AddressLeinenweberstrasse 5
    B.5.3.2Town/ cityFreiburg
    B.5.3.3Post code79108
    B.5.3.4CountryGermany
    B.5.4Telephone number004976115140
    B.5.5Fax number00497611514377
    B.5.6E-mailzentrale@drfalkpharma.de
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/14/1288
    D.3 Description of the IMP
    D.3.1Product nameNorursodeoxycholic acid
    D.3.4Pharmaceutical form Capsule
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNNorucholic acid
    D.3.9.1CAS number 99697-24-2
    D.3.9.2Current sponsor codeNorUDCA
    D.3.9.3Other descriptive nameNorursodeoxycholic acid, NCA
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number250
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboCapsule
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical 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.
    E.1.1.1Medical 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.
    E.1.1.2Therapeutic area Diseases [C] - Digestive System Diseases [C06]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level LLT
    E.1.2Classification code 10036732
    E.1.2Term Primary sclerosing cholangitis
    E.1.2System Organ Class 10019805 - Hepatobiliary disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main 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.
    E.2.2Secondary objectives of the trial
    To study safety and tolerability (Adverse Events, laboratory parameters) of norUDCA,
    To assess quality of life.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full 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.
    E.3Principal 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
    E.4Principal 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).
    E.5 End points
    E.5.1Primary end point(s)
    Partial normalization of s-ALP and no worsening of disease stage as determined by the Ludwig stage.

    E.5.1.1Timepoint(s) of evaluation of this end point
    Visit 2 and Visit 14
    E.5.2Secondary 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.
    E.5.2.1Timepoint(s) of evaluation of this end point
    week 96
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    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.8.4.1Number of sites anticipated in Member State concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA58
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If 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
    E.8.7Trial 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
    last visit of the last subject
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years8
    E.8.9.1In the Member State concerned months2
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years8
    E.8.9.2In all countries concerned by the trial months6
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 50
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 50
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 210
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 40
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state25
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 210
    F.4.2.2In the whole clinical trial 300
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    For all patients, treatment decisions after study end (after V22, or in case of premature withdrawal during DB phase: after V14) are at the discretion of the respective investigator.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2017-07-26
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-08-01
    P. End of Trial
    P.End of Trial StatusOngoing
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