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    Summary
    EudraCT Number:2019-004651-36
    Sponsor's Protocol Code Number:GlibforCS
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2021-02-18
    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 number2019-004651-36
    A.3Full title of the trial
    Glibenclamide Treatment for Cantú syndrome
    Glibenclamide behandeling voor Cantú syndroom
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Treatment of Cantú syndrome
    Behandeling van Cantú syndroom
    A.3.2Name or abbreviated title of the trial where available
    Treatment of Cantú syndrome
    Behandeling van Cantú syndroom
    A.4.1Sponsor's protocol code numberGlibforCS
    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 SponsorAcademic Medical Center Amsterdam
    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 supportAcademic Medical Center Amsterdam
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAcademic Medical Center Amsterdam
    B.5.2Functional name of contact pointMieke van Haelst
    B.5.3 Address:
    B.5.3.1Street AddressMeibergdreef
    B.5.3.2Town/ cityAmsterdam
    B.5.3.3Post code1105 AZ
    B.5.3.4CountryNetherlands
    B.5.6E-mailm.vanhaelst@amsterdamumc.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 Glibenclamide Teva 5 mg, tabletten
    D.2.1.1.2Name of the Marketing Authorisation holderTeva
    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.3.4Pharmaceutical 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.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
    Cantú syndrome
    Cantú syndroom
    E.1.1.1Medical condition in easily understood language
    Cantú syndrome
    E.1.1.2Therapeutic area Body processes [G] - Genetic Phenomena [G05]
    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
    The principal aim of this proof-of-concept exploratory study is to determine whether a full randomised controlled trial to test glibenclamide in a large cohort of CS patients is justifiable and feasible and to optimize its design. We specifically intend to assess the efficacy and safety of glibenclamide in individuals with CS.
    Primary objective:
    To determine whether treating CS patients with glibencamide can reduce hypertrichosis. Thus, we will perform dermascopy before and after treatment to assess changes in the amount of hair follicle in predefined body areas as well as measure thickness, density and growth of hair.
    E.2.2Secondary objectives of the trial
    Secondary objectives involve safety, further evidence of efficacy and collecting of experience and data that can be used to optimize a subsequent pivotal study.
    1. We will determine safety of glibenclamide in CS patients. The main concern of treating CS patients with glibenclamide is that individuals who do not have diabetes are at risk to develop hypoglycemia.
    2. To determine efficacy of glibenclamide in reversing (I would use “reducing”) (i) cardiovascular abnormalities focusing on cardiomegaly, aortic dilation, tortuosity, high-state output and exercise intolerance, (ii) swelling/edema in the leg, (iii) distinctive facial features as described in Roessler et al. and (iv) further skin- and hair-related abnormalities associated with CS.
    2. To collect data for adequate sample size calculations for the primary outcome measures for use in a future full-scale phase II/III trial.
    3. To estimate treatment period, appropriate outcome measurements and effect size for future trial.
    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:
    1. As the majority of CS patients reveal a mutation in ABCC9 and we aim to create a homogenized study population, only, otherwise healthy, patients with a confirmed diagnosis of CS via molecular genetic testing, with a mutation in ABCC9 will be eligible.
    2. 16 years of age or older.
    3. No history of sulfonamides or thiazides allergies.
    E.4Principal exclusion criteria
    A potential subject who meets any of the following criteria will be excluded from participation in this study:
    1. All patients without a molecularly proven diagnosis of Cantú syndrome are excluded from this study.
    2. Patients with a history of a sulfonamides or thiazides allergy
    3. CS patients who are deemed poor candidates by the PI for the study based on additional medical concerns, not related to CS, including epilepsy, diabetes mellitus, intellectual deficit. As far as we are aware there are no cases in our cohort who are now suffering from additional medical concerns.
    4. Pregnant women.
    5. Patients with known G6PD deficiency.
    6. Patients with known chronic kidney or liver disease.
    E.5 End points
    E.5.1Primary end point(s)
    The primary outcome parameter of the exploratory study will be the mean change in the number of hair follicle per cm2 in predefined body areas affected with hypertrichosis (cheek, forehead, arm). Dermascopy pictures will be taken and evaluated using a computerized system (either Folliscope or Trichoscan). The system is able to pinpoint the area of interest, count the hairs and/or hair follicle present in this area as well as measure thickness, density and growth. Additionally, results can be compared over time.
    E.5.1.1Timepoint(s) of evaluation of this end point
    At baseline and every 3 months after glibenclamide intake.
    E.5.2Secondary end point(s)
    Secondary outcome parameters will include parameters of safety and efficacy of glibenclamide in treating cardiovascular, lymphatic, facial and dermatological effects of this condition. Based on our data from natural history studies collected over the past 5 years, we have identified a number of clinical characteristics whose possible reduction we intend to investigate during chronic exposure to glibenclamide.
    1. Hypoglycemic events (safety parameter)
    The prevalence of dose-related minor and major hypoglycemic events will be assessed. Patients will be provided with a continuous glucose sensor and instructed by a specialized nurse how to handle in case of low blood glucose and recognize hypoglycemic symptoms. They will upload their 24h glucose profiles daily during the 2x2 weeks run-in period and weekly thereafter. Hypoglycemia will be categorized as follows (EMA 2012): documented symptomatic hypoglycemia (blood glucose <3.9 mmol/L), asymptomatic hypoglycemia (blood glucose <3.9 mmol/L), severe hypoglycemia (requiring assistance from another person), relative hypoglycemia (blood glucose > 3.9 mmol/L).
    2. Change from baseline in cardiovascular abnormalities
    Cardiovascular abnormalities will be evaluated by MRI, echocardiography, 24-hour heart rhythm monitoring and standard cardiac exercise test.
    3. Changes from baseline in swelling/edema in the leg
    Edema will be measured applying method of Kuhnke (Kuhnke & Asdonk, 1986) where measurement of leg circumference by tape will be taken at the malleolar level and every 4 cm for eight leg segments.
    4. Change from baseline in facial abnormalities
    3D images of the face will be taken and analyzed using dense surface modelling and closest mean classification as described in Roessler et al. (2020)
    5. Changes from baseline in dermatological abnormalities
    We will take clinical photographs of body parts with hypertrichosis, collect hair samples and take a scalp/forehead biopsy as described in Ohko et al. (2020). Patient satisfaction with hair growth and frequency of shaving necessary will be measured by asking patients to fill in a questionnaire including a Likert scale.
    6. Change from baseline in skin-related phenotypes
    During a physical exam, we will take clinical photographs of body parts revealing key skin abnormalities seen in CS. Clinical pictures will be blindly evaluated by specialists to give qualitative scores.
    7. Changes from baseline in vital signs
    Heart rate, systolic (sitting down) and diastolic (standing up) blood pressure will be measured.
    8. Anthropometric measurements.
    We will measure height, weight and head size during every visit.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Definition: t0: baseline, t1: after 1 month of treatment

    - Mean change from baseline in cardiovascular abnormalities: t0 and t9
    - Mean change from baseline in swelling/edema in the leg: t0, t3, t6, t9
    - Mean change from baseline in facial abnormalities: t0, t9
    - Mean change from baseline in skin-related phenotypes: t0-t9
    - Mean change from baseline in vital signs: t0-t9
    - Mean change in incidence of hypoglycemic events: t0-t9
    - Anthropometric measurements: t0-t9
    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) Yes
    E.7.1.1First administration to humans Yes
    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 No
    E.8.1.1Randomised No
    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 No
    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 No
    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
    Patients will take glibenclamide for 9 months.
    Patients who do not tolerate glibenclamide treatment due to hypoglycemia or other side effects will be withdrawn from the study.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years0
    E.8.9.1In the Member State concerned months9
    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 Yes
    F.1.1Number of subjects for this age range: 1
    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: 1
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 6
    F.1.3Elderly (>=65 years) No
    F.1.3.1Number of subjects for this age range: 0
    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 state7
    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)
    If the subjects are showing benefit from the medication and are not experiencing side effects, we intend to continue medication through an extension study.
    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 Decision2021-02-18
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-05-21
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2023-11-21
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