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    Summary
    EudraCT Number:2021-000434-34
    Sponsor's Protocol Code Number:UMCU-VASC-CO-003
    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:2021-12-17
    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 number2021-000434-34
    A.3Full title of the trial
    A placebo-controlled, double-blind randomized trial evaluating the effect of etidronate in young patients with pseudoxanthoma elasticum on ectopic mineralization.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    TEMP-PREVENT: The prevention of systemic ectopic mineralization in pseudoxanthoma elasticum
    A.3.2Name or abbreviated title of the trial where available
    TEMP-PREVENT
    A.4.1Sponsor's protocol code numberUMCU-VASC-CO-003
    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 Centre Utrecht
    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 supportDioraphte
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversity Medical Centre Utrecht
    B.5.2Functional name of contact pointWilko Spiering
    B.5.3 Address:
    B.5.3.1Street AddressHeidelberglaan 100
    B.5.3.2Town/ cityUtrecht
    B.5.3.3Post code3508 CA
    B.5.3.4CountryNetherlands
    B.5.6E-mailw.spiering@umcutrecht.nl
    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 Etidronate
    D.2.1.1.2Name of the Marketing Authorisation holderUNI-PHARMA KLEON TSETIS PHARMACEUTICAL LABORATORIES S.A
    D.2.1.2Country which granted the Marketing AuthorisationGreece
    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 nameEtidronate
    D.3.4Pharmaceutical form Capsule
    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.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboTablet
    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
    Pseudoxanthoma elasticum
    E.1.1.1Medical condition in easily understood language
    Pseudoxanthoma elasticum
    E.1.1.2Therapeutic area Not possible to specify
    MedDRA Classification
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To determine if 24 months of treatment with etidronate halts the progression of arterial calcification in the legs and carotid siphons.
    E.2.2Secondary objectives of the trial
    To determine if 24 months of treatment with etidronate , compared with placebo, affects
    functional ophthalmological measurements, such as visual acuity and contrast sensitivity.
    the progression of normalized reflectivity in Bruch’s membrane as measured with SD-optical coherence tomography,.
    structural ophthalmological measurements, on fundus photography, (infrared (IR) and autofluorescence (FAF)) and OCT-angiography (OCTA).
    the intracranial velocity pulsatility index as measured with MRI.
    the progression of elastin degradation and of calcification in skin biopsies
    inorganic pyrophosphate an desmosine.
    vascular measurements (carotid intima-media thickness, pulse wave velocity on ultrasound, ankle brachial index, 6 minue walking test and WELCH questionnaire)
    occurrence of major adverse cardiovascular events.
    Changes in cognitive functioning.
    reported quality of life.
    safety measures: changes in plasma calcium, phosphate and number of anti-VEGF injections used.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    In order to be eligible to participate in this study, a subject must meet all of the following criteria:
    - Be between 18 years and 50 years.
    - Have a definitive diagnosis of PXE according to the Plomp criteria, which confirm a diagnosis of PXE when at least two (or more) criteria not belonging to the same category (skin, eye, genetic) are met:
    1. Skin
    a. Yellowish papules and/or plaques on the lateral side of the neck and/or flexural areas of the body or
    b. Increase of morphologically altered elastin with fragmentation, clumping and calcification of elastic fibers in a skin biopsy taken.
    2. Eye
    a. Peau d'orange of the retina or
    b. One or more angioid streaks (AS), each at least as long as one disk diameter. When in doubt, fluorescein or indocyanine green angiography of the fundus is needed for confirmation.
    3. Genetics
    a. A pathogenic mutation of both alleles of the ABCC6 gene or
    b. A first-degree relative (parent, sibling or child) who meets independently the diagnostic criteria for definitive PXE
    E.4Principal exclusion criteria
    A potential subject who meets any of the following criteria will be excluded from participation in this study:
    1. Patients that are unable or unwilling to sign for informed consent.
    2. Pregnant, lactating, or fertile women who might wish to become pregnant within three years.
    3. Patients with an estimated glomerular filtration rate below 30 ml/min/1.73m2 according to the CKD-EPI equation.30
    4. Patients with a known abnormality of the oesophagus that would interfere with passage of the drug (e.g. oesophagus stenosis).
    5. Patients with chronic diarrhoea (> 1 month).
    6. Patients with osteomalacia.
    7. Patients with hypocalcaemia (calcium <2.20 mmol/L corrected for albumin)*
    8. Patients with a vitamin D deficiency (<30 nmol/L)*
    9. Patients that used a bisphosphonate in the last 5 years
    10. Patients with known sensitivity to etidronate.
    11. Any other medical or social condition that, at the discretion of the Principal Investigator, might put the subject at risk of harm during the study or might adversely affect the interpretation of the study data.
    * After correction a patient is again suitable for participation, as long as inclusion criteria are met.
    E.5 End points
    E.5.1Primary end point(s)
    Total calcification score measured on low dose CT in the legs and carotid siphons.
    E.5.1.1Timepoint(s) of evaluation of this end point
    24 months
    E.5.2Secondary end point(s)
    1. changes in functional ophthalmological measurements, such as visual acuity .
    2. normalized reflectivity in Bruch’s membrane as measured with SD-optical coherence tomography.
    3. structural ophthalmological measurements on fundus photography (infrared, autofluorescence and OCT-angiography).
    4. increased pulsatility index of the intracranial carotid arteries and middle cerebral arteries on 7T MRI
    5. elastin degradation and of calcification in the skin in skin biopsies
    6. levels of plasma levels of inorganic pyrophosphate compared to placebo.
    7. progression of systemic elastin degradation products, as measured via plasma levels of desmosin, compared to placebo.
    8. arterial calcification in legs and siphons, as measured with computed tomography, compared to placebo.
    9. increased carotid intima media thickness, as measured with ultrasound with a linear array transducer
    10. arterial stiffness, as measured by pulse wave analysis and velocity using a Doppler-ultrasound, compared to placebo.
    11. peripheral artery disease measured by the ankle brachial index, the WELCH questionnaire and the six-minute walking test.
    12. occurrence of major cardiovascular events (stroke, TIA, myocardial infarction or cardiovascular death) events compared to placebo.
    13. improved reported quality of life, as measured with the EQ-5D compared to placebo.
    14. differences in safety measures: changes in plasma calcium, phosphate, ASAT, ALAT, eGFR measured via laboratory assessment, and number of anti-VEGF injections used.
    15. Difference in functioning on cognitive testing compared to placebo after 24 months.
    E.5.2.1Timepoint(s) of evaluation of this end point
    All secondary endpoints have a timepoint of 24 months, except for the reflectivity of Bruchs membrane on SD-OCT, this will be measured after 12 months as well as after 24 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 No
    E.6.5Efficacy No
    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 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 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 Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    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
    End of the trial is after the 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 years2
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days
    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: 76
    F.1.3Elderly (>=65 years) No
    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 state76
    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)
    Currently there is no treatment available ofr patients with pseudoxanthoma elasticum. After the trial they will stop using etidronate (or placebo), and follow usual preventative care provided by their medical specialist(s).
    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 Decision2023-04-12
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-12-16
    P. End of Trial
    P.End of Trial StatusOngoing
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