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    Summary
    EudraCT Number:2020-005949-16
    Sponsor's Protocol Code Number:202000894
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2021-10-21
    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 ConcernedNetherlands - Competent Authority
    A.2EudraCT number2020-005949-16
    A.3Full title of the trial
    A GnRH Agonist IN pre-menopausal women STudy to treat severe Polycystic Liver Disease
    Een GnRH Agonist IN pre-menopauzale vrouwen Studie om ernstige Polycysteuze Leverziekte te behandelen
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study into the efficacy and toleratability of leuprorelin by patients suffering from severe polycystic liver disease
    Een onderzoek naar de werkzaamheid en verdraagbaarheid van leuproreline bij patiënten met polycysteuze leverziekte en daardoor een sterk vergrote lever
    A.3.2Name or abbreviated title of the trial where available
    AGAINST-PLD
    A.4.1Sponsor's protocol code number202000894
    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 SponsorUniversity Medical Center Groningen
    B.1.3.4CountryNetherlands
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportZonMW
    B.4.2CountryNetherlands
    B.4.1Name of organisation providing supportAbbvie BV
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversity Medical Center Groningen
    B.5.2Functional name of contact pointCoordinating investigator
    B.5.3 Address:
    B.5.3.1Street AddressHanzeplein 1
    B.5.3.2Town/ cityGroningen
    B.5.3.3Post code9713GZ
    B.5.3.4CountryNetherlands
    B.5.4Telephone number0031503610772
    B.5.6E-mails.e.aapkes@umcg.nl
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleComparator
    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 Yes
    D.2.1.1.1Trade name Lucrin
    D.2.1.1.2Name of the Marketing Authorisation holderAbbvie BV
    D.2.1.2Country which granted the Marketing AuthorisationNetherlands
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameLucrin
    D.3.4Pharmaceutical form Solution for infusion in pre-filled syringe
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    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 Yes
    D.3.11.13.1Other medicinal product typeLeuprorelin
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Severe polycystic liver disease in female patients
    E.1.1.1Medical condition in easily understood language
    Large cystic livers in female patients
    E.1.1.2Therapeutic area Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level PT
    E.1.2Classification code 10048834
    E.1.2Term Polycystic liver disease
    E.1.2System Organ Class 10010331 - Congenital, familial and genetic disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10036045
    E.1.2Term Polycystic kidney
    E.1.2System Organ Class 10010331 - Congenital, familial and genetic disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10036046
    E.1.2Term Polycystic kidney, autosomal dominant
    E.1.2System Organ Class 10010331 - Congenital, familial and genetic disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 23.0
    E.1.2Level LLT
    E.1.2Classification code 10083939
    E.1.2Term Autosomal dominant polycystic liver disease
    E.1.2System Organ Class 10010331 - Congenital, familial and genetic disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The main objective of this study is to determine whether lowering estrogen and progesterone levels with leuproreline decreases liver growth rates in pre-menopausal women with severe PLD.
    E.2.2Secondary objectives of the trial
    Secondary objectives are to assess in these women the effect of leuproreline on PLD-related complaints, quality of life, tolerability and safety.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Female patients with PLD
    - Age 18 to 45 years
    - Very large height adjusted liver volume for age: 18-30 yr >2.0 L/m; 30-35 yr >2.2 L/m, 35-40 yr > 2.5 L/m and >40 years >3.0 L/m
    - Confirmed ongoing liver growth
    - Since somatostatin analogues are proven efficacious therapy for PLD at this time it is required that patients use a somatostatin analogue and still have liver growth (as mentioned above) or the patient has a specific reason not to use this medication (e.g. patient used a somatostatin analogue in the past, but had to stop it due to inefficacy or because they did not tolerate it, or they have a contra-indication for using somatostatin analogues)
    - Availability of at least 1 historical MRI or CT scan made between 5 to 1 years before baseline visit
    E.4Principal exclusion criteria
    - Post-menopausal status or (vasomotor) symptoms indicating upcoming menopause;
    - AMH measurement at screening < 0.3
    - Active desire to have pregancy;
    - Contra-indications for leuproreline, such as history of cardiovascular disease, history of osteoporosis or osteoporosis at the dexa-scan at screening;
    - Liver transplantation expected in the next 1.5 years
    - Use of estrogen or progesterone containing medication
    E.5 End points
    E.5.1Primary end point(s)
    The primary outcome is the livergrowth, in percent per year, calculated from BL till t=1.5 years, compared between the direct start groep (receiving leuproreline treatment in this period) and the delayed start group (serving as a control group).
    E.5.1.1Timepoint(s) of evaluation of this end point
    At the end of the trial, the primary outcome will be analyzed, using the calculated liver growth in percent per year during the first 18 months of the trial, compared between the direct start group and the delayed start group.
    E.5.2Secondary end point(s)
    1. Polycystic liver disease related complaints, using the validated PLD Questionnaire (8).
    The change in the score on the PLD Questionnaire (Δ PLD-Q score) will be compared between patients in the direct start group and the delayed start group after 18 months of treatment (Δ BL-18 months in the direct start group versus Δ BL-18 months in the delayed start group)


    2. Liver growth rate (in % per year) compared within individuals before start of treatment and during treatment (a paired analysis of growth rates; in the direct start group of historical growth versus growht during the frist 1.5 years of treatment, and in the delayed start group between the first 1.5 years of the trial without treatment and the next 1.5 years of the trial with treatment.


    Exploratory outcomes:
    - liver volume, compared between the direct and delayed start groep after 1.5 years
    - estrogen levels, compared at BL, 3 months after start treatment, 1.5 years, 21 months and 3 years
    - acute effects of the treatment, using the MRI scans 6 months after start of treatment
    - safety and toleratability, incidence of (serious) adverse events, bone-density measured using DEXA-scans, drop-out rate
    - Quality of life, assessed by het SF-36 and BD-II
    - menopause related complaints, assessed by the MENQOL-questionnaire

    In patients with polycystic kidney disease
    - growth rate of kidney volume in the first 1.5 years, compared between the direct start group and delayed start group
    - growth rate of kidney volumes, compared within individuals, before start of treatment and during treatment
    - acute effects of the treatment, using the MRI scans 6 months after start of treatment
    - change in renal function in the first 1.5 years between direct and delayed start group
    E.5.2.1Timepoint(s) of evaluation of this end point
    Endpoints will be evaluated if the last patient fulfulled the trial follow up. For a detailed description of outcomes please see E.5.2.1.
    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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    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 Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    At baseline, patients are randomized between direct or delayed start of treatment (after 1.5 years)
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Standard of care
    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 concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA5
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years5
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    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) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 36
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male No
    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 state18
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 18
    F.4.2.2In the whole clinical trial 36
    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)
    At the end of the study, but depending on the study site, patients will be allowed to continue leuproreline treatment on routine prescription, until study results are available. This is decided because the treatment can lead to menopause-related side effects, especially in the first months of treatment. If treatment would be stopped after the trial and restarted in case of positive trial results, patients experience these menopause symptoms two times.
    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 Decision2021-10-21
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-10-25
    P. End of Trial
    P.End of Trial StatusOngoing
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