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    Summary
    EudraCT Number:2014-003408-65
    Sponsor's Protocol Code Number:
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2014-12-02
    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 ConcernedUK - MHRA
    A.2EudraCT number2014-003408-65
    A.3Full title of the trial
    Ulipristal acetate versus conventional management of heavy menstrual bleeding (HMB; including uterine fibroids): a randomised controlled trial and exploration of mechanism of action (UCON trial)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Comparison of drug ulipristal acetate with existing treatment of levonorgestrel-releasing intra-uterine system.
    A.3.2Name or abbreviated title of the trial where available
    UCON
    A.4.1Sponsor's protocol code number
    A.5.1ISRCTN (International Standard Randomised Controlled Trial) NumberISRCTN20426843
    A.5.4Other Identifiers
    Name:2014-003408-65Number:EudraCT
    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 of Edinburgh
    B.1.3.4CountryUnited Kingdom
    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 support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversity of Edinburgh
    B.5.2Functional name of contact pointProfessor Hilary Critchley
    B.5.3 Address:
    B.5.3.1Street Address47 Little France Crescent
    B.5.3.2Town/ cityEdinburgh
    B.5.3.3Post codeEH16 4TJ
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number01312426858
    B.5.5Fax number01312426441
    B.5.6E-mailhilary.critchley@ed.ac.uk
    B.Sponsor: 2
    B.1.1Name of SponsorNHS Lothian
    B.1.3.4CountryUnited Kingdom
    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 support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    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 Yes
    D.2.1.1.1Trade name Esmya
    D.2.1.1.2Name of the Marketing Authorisation holderGedeon Richter Plc.
    D.2.1.2Country which granted the Marketing AuthorisationHungary
    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 nameUlipristal acetate
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral 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 No
    D.IMP: 2
    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 Mirena
    D.2.1.1.2Name of the Marketing Authorisation holderBayer plc
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    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 nameLevonorgestrel-releasing intra-uterine system
    D.3.4Pharmaceutical form
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntrauterine 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 No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Heavy menstrual bleeding
    E.1.1.1Medical condition in easily understood language
    Heavy menstrual bleeding
    E.1.1.2Therapeutic area Diseases [C] - Female diseases of the urinary and reproductive systems and pregancy complications [C13]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.0
    E.1.2Level LLT
    E.1.2Classification code 10046784
    E.1.2Term Uterine fibroids
    E.1.2System Organ Class 100000004864
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.0
    E.1.2Level PT
    E.1.2Classification code 10027313
    E.1.2Term Menorrhagia
    E.1.2System Organ Class 10038604 - Reproductive system and breast disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Is UPA more effective at reducing the burden of HMB symptoms than LNG-IUS after 12 months of treatment?


    E.2.2Secondary objectives of the trial
    SECONDARY CLINICAL TRIAL OBJECTIVES:

    • Ascertain whether UPA use beyond 3 months and up to 12 months duration is associated with histological changes to the endometrium, and if so, whether this compromises safety.
    • Ascertain whether UPA is more effective than LNG-IUS in relation to menstrual blood loss, sexual activity, generic quality of life, satisfaction with treatment, patient reported adverse events, and compliance at 3, 6 and 12 months.
    • Determine the response to UPA and LNG-IUS treatment difference in the presence of uterine fibroids in terms of (i) alleviation of HMB and (ii) change in uterine/fibroid volume.


    MECHANISTIC SUB-STUDY OBJECTIVES:
    • To understand how UPA causes a reduction in menstrual bleeding and uterine/ fibroid volume in women with HMB, we will determine whether:
    • Administration of UPA alters endometrial cell function (proliferation, apoptosis, expression of steroid receptors, tumour suppressors or inflammatory mediators).
    • UPA reduces blood flo
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    UCON Mechanistic Sub-study:

    The sub-study has 2 components (i) MRI and (ii) endometrial biopsy.

    (i) MRI Sub-study:

    The aim of the 3T MRI substudy is to investigate the hypothesis that UPA will reduce blood flow and blood volume in the endometrium and myometrium in women with HMB. The research questions to be addressed will be:
    a. Does UPA reduce blood flow and blood volume, as measured by DCEMRI, in the endometrium, junctional zone, outer myometrium and fibroid tissue?
    b. Does UPA alter the volume fraction of the extracellular matrix in the above tissues, as measured by DCEMRI?
    c. Does UPA reduce uterine and fibroid volume, as measured by high resolution structural Magnetic Resonance Imaging (MRI).

    In particular, dynamic contrast EME enhanced MRI (DCEMRI) and high resolution structural MRI will be obtained in a subgroup of 20 women treated with UPA. DCEMRI, combined with pharmacokinetic modeling, yields quantitative estimates of physiological parameters, including tissue blood flow, blood volume fraction and endothelial permeability, as well as volume fraction of the extracellular extravascular space. The technique is well established as a marker of microvascular physiology in a wide range of pathologies and has recently been used, in a number of other studies, to measure regional and cyclical variation in the uterine tissue of 85 women with a range of uterine disorders.

    These data, in addition to those from our own unpublished pilot work confirm the feasibility of this technique in the uterus and provide a promising route to monitoring treatment response. Semiquantitative DCEMRI without pharmacokinetic modelling has previously been used for assessment of other fibroid treatments. Structural MRI provides high resolution images suitable for structural segmentation and radiological evaluation that, when combined with design based stereological analysis, yield accurate and precise measurements of uterine and fibroid volume for early assessment of treatment response.

    T2 weighted structural and DCEMRI using our established dynamic uterine acquisition protocol will be obtained using a dedicated research 3T clinical scanner (Magnetom Verio, Siemens AG) in a subgroup of 20 women in the UPA treatment group. Scanning will be performed at baseline, and at 6 and 12 months following commencement of treatment. Scans will take place during the secretory phase of the menstrual cycle. Structural images will be evaluated clinically by an experienced radiologist, and stereological analysis performed to determine the volumes of the uterus and of any fibroids. DCEMRI data will be analysed using the well-established adiabatic approximation to tissue homogeneity (AAHT) model, to generate pharmacokinetic maps of blood flow, blood volume and extracellular extravascular volume fraction; these will be used to extract representative values for endometrium, junctional zone, outer myometrium and fibroid tissue.

    (ii) Endometrial Biopsies Sub-Study:
    Analysis will be conducted on endometrial biopsies collected from women during the proliferative phase of a cycle prior to starting treatment and at 6 and 12 months, taken in a purposive sample of women (Edinburgh site; n=20). Endometrial tissue samples will be collected with a pipelle endometrial sampler. Our extensive experience of this method of endometrial sampling allows us to subdivide each tissue sample for detailed analysis. We will undertake the following analyses:
    a) Histology/cell specific protein expression. The tissue sample will be fixed in 70% neutral buffered formalin for 24 hours, and processed into paraffin wax using standardprotocols . Biopsy tissue may also be snap frozen for protein extraction for Western blotting.

    b) Gene analyses. Tissue will be collected in RNAlater for subsequent extraction of RNA and downstream analysis using qRTPCR (Taqman) or Illumina arrays.
    E.3Principal inclusion criteria
    • Aged 18 years or over
    • Menstrual bleeding at intervals of 21-42 days that she perceives to be heavy and troublesome
    • Willing to receive medical treatment with either UPA or LNG-IUS
    • Willing to undergo two pelvic ultrasounds
    • If allocated to UPA, willing and eligible to undergo two endometrial biopsies with the possibility of a third and fourth (i.e. up to four biopsies)
    • If allocated to UPA mechanistic sub-study, willing and eligible to undergo three biopsies with the possibility of a fourth and fifth (i.e. up to five biopsies). If ‘No’ may be randomised to RCT if UPA endometrial biopsy consent given
    • Willing to use barrier contraception if allocated to UPA
    • Given written informed consent
    • Willing and eligible to undergo up to three magnetic resonance imaging scans? If allocated to UPA, mechanistic sub-study only. If ‘No’ may still be randomised to RCT
    E.4Principal exclusion criteria
    • Post-menopausal
    • A >14 week fibroid uterus and/or cavity length >11 cm confirmed by ultrasound scan
    • Submucosal fibroids >2cm diameter confirmed by ultrasound scan
    • Contraindications to UPA or LNG-IUS
    • Intention to continue current use of current use of Cytochrome P450 (CYP3A4) inhibitors
    • Intention to continue current use of current use of Cytochrome P450 (CYP3A4) inducers (e.g. Phenytoin, carbamazepine, rifampicin, St John’s Wort)
    • Intention to continue current use of P-glycoprotein substrates (e.g. digoxin)
    • A past, current or suspected diagnosis of endometrial hyperplasia or neoplasia
    • Severe hepatic impairment
    • Epilepsy managed with carbamazepine, phenytoin
    • Significant renal impairment
    • Pregnant
    • Current plans to become pregnant within 12 months
    • Currently breastfeeding
    • Severe asthma that is not sufficiently controlled by oral glucocorticoids
    • Past or current known history of with uterine, cervical, ovarian or breast cancer.
    • Current use of progestagen-releasing intrauterine device (except if allocated within UCON)
    • Intention to continue regular use of Mefenamic acid
    • Intention to continue regular use of Tranexamic acid
    • Intention to continue regular use of GnRH analogues
    • Intention to continue regular use of Progestagen-only contraceptive
    • Intention to continue regular use of any combined oral contraceptive pills
    • Intention to continue regular use of hormonal replacement therapy
    E.5 End points
    E.5.1Primary end point(s)
    The primary outcome measure is the conditon-specific Menorrhagia Multi-Attribute Scale (MMAS) designed and validated to capture the impact of HMB on women’s day-to-day life.Summary scores range from 0 (not affected) to 100 (worst affected). The primary time point for analysis will be at 12 months.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Validated Menorrhagia Multi-attribute Assessment Scale (MMAS)
    to assess impact of HMB on women’s life, measured at 12 months. This is now an accepted primary outcome for randomised trials of interventions to improve HMB.
    E.5.2Secondary end point(s)
    SECONDARY CLINICAL OUTCOMES INCLUDE:
    Satisfaction, Surgical intervention (hysterectomy or endometrial ablation), menstrual blood loss, menstrual regularity, pain, fibroid symptom and quality of life, sexual activity and compliance will be assessed at 3, 6 and 12 months. Endometrial biopsy at 12 months for exclusion of pre-malignant or other pathology.

    MECHANISTIC OUTCOMES (subset of UPA group only):
    Study of impact of UPA on cell fate including markers of steroid responsiveness, inflammation, survival and proliferation and complemented with imaging of the uterus using high resolution Magnetic Resonance Imaging (MRI) of the uterine matrix and fibroids and Dynamic Contrast Enhanced (DCE-MRI) to measure uterine perfusion.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Satisfaction, menstrual blood loss, menstrual regularity, pain, fibroid symptom and quality of life, sexual activity and compliance will be assessed at 3, 6 and 12 months. Endometrial biopsy at 12 months for exclusion of pre-malignant or other pathology.

    MECHANISTIC OUTCOMES (subset of UPA group only):
    Study of impact of UPA on cell fate including markers of steroid responsiveness, inflammation, survival and proliferation and complemented with imaging of the uterus using high resolution Magnetic Resonance Imaging (MRI) of the uterine matrix and fibroids and Dynamic Contrast Enhanced (DCE-MRI) to measure uterine perfusion. Measured up to 18 months.
    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 Yes
    E.6.13.1Other scope of the trial description
    Mechanistic sub-study
    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 Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    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 No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Medication: levonorgestrel-releasing intra-uterine system
    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 concerned5
    E.8.5The trial involves multiple Member States No
    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
    For UPA, satisfactory resolution of any PAEC changes confirmed by endometrial biopsy, at 15 or 18 months post-randomisation. For LNG-IUS, completion of the 12 months follow-up questionnaire by last patient. Whilst women may retain the LNG-IUS for up to 5 years - this is beyond the end of the trial participation.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months11
    E.8.9.1In the Member State concerned days30
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months11
    E.8.9.2In all countries concerned by the trial days30
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1Number of subjects for this age range: 0
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) No
    F.1.1.6.1Number of subjects for this age range: 0
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 219
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 1
    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 No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    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 state220
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 220
    F.4.2.2In the whole clinical trial 220
    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)
    The LNG-IUS will be prescribed according to its licenced indication and can be retained for up to 5 years before replacement. There will be no provision of UPA beyond the end of the patients trial participation.

    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2014-12-19
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-08-26
    P. End of Trial
    P.End of Trial StatusOngoing
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
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