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    The EU Clinical Trials Register currently displays   43851   clinical trials with a EudraCT protocol, of which   7283   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

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    EudraCT Number:2022-003299-17
    Sponsor's Protocol Code Number:22-1005-CALCIFADE
    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:2023-01-18
    Trial results
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    A. Protocol Information
    A.1Member State ConcernedNetherlands - Competent Authority
    A.2EudraCT number2022-003299-17
    A.3Full title of the trial
    A randomized, placebo-controlled, double blind trial to study the effects of Etidronate on ectopic CALCIfication in FAhr’s Disease.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Treatment of patients with Fahr's disease with etidronate.
    A.3.2Name or abbreviated title of the trial where available
    CALCIFADE trial
    A.4.1Sponsor's protocol code number22-1005-CALCIFADE
    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 Utrecht
    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 supportHersenstichting
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversity Medical Center Utrecht
    B.5.2Functional name of contact pointClinical researcher
    B.5.3 Address:
    B.5.3.1Street AddressHeidelberglaan 100
    B.5.3.2Town/ cityUtrecht
    B.5.3.3Post code3584 CX
    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 No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameEtidronate
    D.3.2Product code Etidronate
    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. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. 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
    Fahr’s disease or sondrome is a neurodegenerative disease in which all patients present with bilateral vessel associated calcifications in the basal ganglia in the absence of other secondary causes of brain calcifications. The clinical penetration of Fahr's disease or syndrome is incomplete and heterogeneous comprising of neuropsychiatric signs, cognitive decline, and movement disorders. The symptoms start between 30 and 50 years and are (slowly) progressive.
    E.1.1.1Medical condition in easily understood language
    Patients with Fahr's disease or syndrome have calcifications in specific areas in the brain. This results in mobility problems, disturbed mental functions and/or psychiatric problems.
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10059626
    E.1.2Term Fahr's disease
    E.1.2System Organ Class 100000004850
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    1. To determine whether etidronate can halt or attenuate deterioration of cognitive functioning in patients with Fahr's disease or syndrome compared to placebo between baseline and 12 months after baseline.
    E.2.2Secondary objectives of the trial
    To determine whether etidronate can halt or attenuate deterioration of mobility, neuropsychiatric symptoms, dependence in activities of daily living, quality of life, and calcifications in the brain in patients with Fahr's disease or syndrome compared to placebo between baseline and 12 months after baseline.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Age of 18 years or over
    2. Clinical diagnosis of Fahr’s disease or syndrome. No international accepted diagnostic criteria for Fahr's disease or Fahr’s syndrome exist yet. It is diagnosed mostly based on the clinical presentation. For the present study the following criteria are used:
    a. Clinical symptoms consistent with a clinical diagnosis of Fahr’s disease or syndrome.
    b. Bilateral calcifications of the basal ganglia as seen on the CT scan of the head. To rule out basal ganglia calcifications due to aging, a CT based calcification score will be used as proposed by Nicolas et al. Calcification is graded from 0 (no calcification) to 5 (serious and confluent) in specific locations of the brain; lenticular, caudate, thalamus nuclei, subcortical white matter, cortex, cerebellar hemispheres, vermis, midbrain, pons, and medulla. The total calcification score (ranging from 0 to 80) is obtained by adding all location-specific points, where a score higher than the age-specific threshold points at PFBC.46

    Furthermore, the next criteria are supportive for the clinical diagnosis of PFBC:
    c. Frequently, the family history is consistent with autosomal dominant inheritance. A positive family history with at least one relative in the first or second degree with symptoms of PFBC is supportive for the clinical diagnosis of PFBC.
    d. The presence of a (likely) pathogenic mutation in one of the PFBC-related genes is supportive for the clinical diagnosis of PFBC. Mutations in up to now 4 known genes are associated with an autosomal dominant pattern of inheritance: SLC20A2 (OMIM#213600), XPR1 (OMIM#616413), PDGFB (OMIM#615483), and PDGFRB (OMIM#615007). Autosomal recessively inherited PFBC is associated with mutations in two genes: MYORG (OMIM#618317) and JAM2 (OMIM#618824).
    E.4Principal exclusion criteria
    1. Unable or unwilling to sign an informed consent.
    2. Severe renal impairment (estimated creatinine clearance/eGFR of < 30 ml/min/1.73m2 calculated using CKD-EPI equation).
    3. Contraindication to receiving oral medication.
    4. Known abnormality of the esophagus that would interfere with the passage of the drug.
    5. Known sensitivity to etidronate.
    6. Pregnancy, women with an active pregnancy wish < 1 year, or women who are breastfeeding at the time of inclusion.
    7. Any other medical or social condition that, in the opinion 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.
    8. Use of bisphosphonate during last 5 years.
    9. Hypocalcemia (calcium <2,20 mmol/L)*.
    10. 25-OH vitamin D deficiency <35 nmol/L)*.
    *After correcting the hypocalcemia or vitamin D deficiency, a participant is again suitable for participation in the CALCIFADE trial, as long as the participant meets the inclusion criteria.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is the change in cognitive functioning in patients with Fahr's disease or syndrome treated with etidronate 20mg/kg compared to placebo between baseline and 12 months after baseline. Cognitive functioning is measured by means of a standardized neuropsychological test battery of global cognitive functioning and three cognitive domains; memory, attention and speed of information processing, and executive functioning.
    Overall cognitive functioning is assessed with the Montreal Cognitive Assessment (MoCA). Memory with the Rivermead Behavioral Memory Test Stories immediate and delayed recall, and with the Rey Complex Figure test immediate and delayed recall. Attention and speed of information processing with the third edition of the Wechsler Adult Intelligence Scale (WAIS-III) Digit Span Forward, Trail Making Test A, and Stroop I and II. Executive functioning with the WAIS-III Digit Span Backward, Trail Making Test B and Stroop III, semantic and letter fluency and social cognition with the FEEST.
    E.5.1.1Timepoint(s) of evaluation of this end point
    12 months after baseline
    E.5.2Secondary end point(s)
    The secondary endpoints are:
    1. To determine the change in mobility in patients with Fahr's disease or syndrome treated with etidronate 20 mg/kg compared to placebo between baseline and 12 months after baseline. The mobility symptoms are assessed with the condensed version of the Balance Evaluation Systems Test (Mini-BESTest), which is a composite test of gait and balance.
    2. To determine the change in neuropsychiatric symptoms in patients with Fahr's disease or syndrome treated with etidronate 20 mg/kg compared to placebo between baseline and 12 months after baseline. Neuropsychiatric symptoms are assessed with the Neuropsychiatric Inventory.
    3. To determine the change in dependence in activities of daily living in patients with Fahr's disease or syndrome treated with etidronate 20 mg/kg compared to placebo between baseline and 12 months after baseline. Daily functioning is assessed with the Katz-15 scale.
    4. To determine the change in quality of life in patients with Fahr's disease or syndrome treated with etidronate 20 mg/kg compared to placebo between baseline and 12 months after baseline. Quality of life is assessed with the 36-item Short Form Health Survey (SF-36).
    5. To determine the change in brain calcification volume compared in patients with Fahr's disease or syndrome treated with etidronate 20mg/kg compared to placebo as quantified in CT-scan between baseline and 12 months after baseline. Participants will be scanned on the IQon CT or CT7500 (Philips Healthcare) from skull base to vertex. Tube voltage will be 120kVp and the tube current will range depending on patient size. Only non-contrast CT will be used to slice thickness < 1 mm. Images will be visually assessed in bone setting (center: 300 Hounsfield Units – width: 1600 Hounsfield Units). Volume of the calcifications in the brain will be measured with standard software (Philips Intellispace Portal v11). Calcifications are defined as hyperdens lesions with a density above 130 Hounsfield Units. Care will be taken that all patients are scanned on the same scanner before and after treatment for all their investigations so that interscan differences can be avoided.
    E.5.2.1Timepoint(s) of evaluation of this end point
    12 months after baseline
    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. 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 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
    The end of the trial is the day of the last visit of the last subject undergoing the trial.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    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: 49
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 49
    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 state98
    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)
    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 Decision2023-01-18
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2023-03-20
    P. End of Trial
    P.End of Trial StatusOngoing
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