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    Summary
    EudraCT Number:2017-002079-24
    Sponsor's Protocol Code Number:NL61855.018.17
    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:2017-06-26
    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 number2017-002079-24
    A.3Full title of the trial
    Targeting the secondary bile acid glycodeoxycholic acid as therapeutic strategy in type 2 diabetes mellitus.
    Het aangrijpen van het secundaire galzout glycodeoxycholaat als therapeutische strategie voor diabetes mellitus type 2.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    The effect of the secondary bile acid glycodeoxycholic acid as a therapy for diabetes.
    Het effect van het secundaire galzout glycodeoxycholaat als therapie voor diabetes.
    A.3.2Name or abbreviated title of the trial where available
    TRADE
    TRADE
    A.4.1Sponsor's protocol code numberNL61855.018.17
    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
    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 supportDutch Diabetes Research Foundation
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAcademic Medical Center
    B.5.2Functional name of contact pointM.R. Soeters principal investigator
    B.5.3 Address:
    B.5.3.1Street AddressMeibergdreef 9
    B.5.3.2Town/ cityAmsterdam
    B.5.3.3Post code1105 AZ
    B.5.3.4CountryNetherlands
    B.5.4Telephone number0031205666071
    B.5.5Fax number0031206917682
    B.5.6E-mailm.r.soeters@amc.uva.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 Ezetimibe
    D.2.1.1.2Name of the Marketing Authorisation holderMSD
    D.2.1.2Country which granted the Marketing AuthorisationUnited States
    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 nameEzetimibe
    D.3.2Product code Ezetimibe
    D.3.4Pharmaceutical form Film-coated 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
    Type 2 diabetes mellitus
    Type 2 diabetes mellitus
    E.1.1.1Medical condition in easily understood language
    Type 2 diabetes mellitus
    type 2 diabetes mellitus - type 2 suikerziekte
    E.1.1.2Therapeutic area Diseases [C] - Hormonal diseases [C19]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level LLT
    E.1.2Classification code 10045242
    E.1.2Term Type II diabetes mellitus
    E.1.2System Organ Class 100000004861
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To study the effects of gDCA on postprandial GLP-1 secretion, inflammation responses and hyperlipidemia in healthy lean male subjects and male T2D patients. The primary objective of phase 1 is to determine safety of long-term gDCA administration in healthy volunteers.

    E.2.2Secondary objectives of the trial
    The secondary objectives are to evaluate the effect of gDCA and ezetimibe on cholesterol elimination assessed as total faecal sterol concentration and plasma lipid profile/composition and the effect of different formulations on the gDCA bioavailability.
    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:
    - Ability to provide informed consent
    - Age: 18 years or older at the time of signing the informed consent
    - Male

    Specific inclusion criteria for the healthy lean subject group:
    - BMI between 18,5-25 kg/m2 or BMI between 25 and 30 kg/m2 with a waist circumference between between 79 cm and 94 cm
    - HOMA-IR index: ≤ 2.0 (measured as fasting insulin (pmol/L) x fasting glucose (mmol/L)) / 135)

    Specific inclusion criteria for the type 2 diabetes mellitus (T2D) patient group:
    - T2D treated with diet and/or medication only (medication not changed in the past 3 months)
    - HbA1c 53-64 mmol/mol
    - BMI above 25 kg/m2
    E.4Principal exclusion criteria
    A potential subject who meets any of the following criteria will be excluded from participation in this study:
    - Use of medication that interferes with bile acid metabolism (colesevelam, colestimide, ursodeoxycholic acid).
    - Diabetes treatment with dipeptidyl peptidase-4 inhibitors, GLP-1 receptor agonists or insulin
    - Hypercholesterolemia treatment with statins or fibrates unless on a stable dose for at least 3 months prior to screening
    - Use of nicotinic acid or derivates of nicotinic acid within 4 weeks prior to screening
    - Use of other drugs such as the following: vitamin K antagonists, ciclosporine, antacids containing aluminium hydroxide or aluminium oxide
    - Cholecystectomy
    - Gastro-intestinal disorders, including gallstone disease
    - Nefropathy checked by blood chemistry (creatinine, eGFR)
    - Liver disease checked by blood chemistry (ASAT, ALAT, GGT, AF, bilirubin)
    - Weight increase or decrease >10% in previous 3 months
    - Alcohol use >3 units/day
    - Tobacco use
    - XTC, cannabis, cocaine or opioids abuse
    - Likely to leave the study before its completion
    - Participation in other intervention studies
    E.5 End points
    E.5.1Primary end point(s)
    Phase 1
    The first phase of the study will be a pilot study where we investigate the metabolism and safety of long-term administration of gDCA compared to long-term administration of gDCA formulated in enteric-coated capsules (enteric-coated gDCA). In the past no safety study is performed or published investigating the metabolism of prolonged administration of (enteric-coated) glycine conjugated gDCA. Therefore we will include 20 healthy male volunteers in this phase. Ten subjects will receive 10 mg/kg/day gDCA for 30 days, the other group (N=10) will receive 10 mg/kg/day enteric-coated gDCA for 30 days. Subjects undergo a MMT at day 1, day 15 and day 30 in the AMC. After the last subject completed the study, the data will be analyses in the laboratory and discussed by the DSMB. After advise of the DSMB the project team will decide on phase 2.

    Phase 2
    At the second phase we include 10 T2D male patients. The 10 T2D patients will receive 10 mg/kg/day gDCA or enteric-coated gDCA. The dosage and which form of gDCA (normal or enteric-coated) will be based on the results of the pilot study (phase 1) regarding safety. Subjects undergo a MMT at day 1, day 15 and day 30 in the AMC.

    Phase 3
    In the third (final) phase we want to include 10 T2D male patients. The 10 T2D patients receive 10 mg/kg/day (enteric-coated) gDCA and 20 mg ezetimibe per day for 30 days. Subjects undergo a MMT at day 1, day 15 and day 30 in the AMC.


    The safety of long term administration of (enteric-coated) gDCA will be established in the pilot study by the appearance of (S)AE’s (phase 1).

    The effect of gDCA and enteric-coatedenteric-coated gDCA treatment (phase 1 and 2) on:

    - GLP-1 and insulin levels (expressed as (incremental) AUC)
    - Inflammatory responses (IL-ß, IL-6, TNF-α and leukocyte differentiation)
    - Postprandial hyperlipidaemia (LDL-C, HDL-C, triglycerides, ApoB, ApoA1)

    The effect of (enteric-coated) gDCA in combination with ezetimibe (phase 3) on:
    - Postprandial hyperlipidaemia (LDL-C, HDL-C, triglycerides, ApoB, ApoA1)
    - Cholesterol elimination assessed as total faecal sterol concentration (faecal neutral sterol concentration (FNS) + faecal bile acid concentration)
    E.5.1.1Timepoint(s) of evaluation of this end point
    Visit 1: Day 1: baseline mixed meal test
    Visit 2: Day 15: second mixed meal test
    Visit 3: Day 31: third mixed meal test
    E.5.2Secondary end point(s)
    • Bile acid metabolism
    - CA, CDCA, DCA, LCA and conjugates, FGF19,C4)
    • Glucoregulatory and gut hormones
    - Glucose, glucagon and c-peptide
    • Resting energy expenditure
    - Basal metabolic rate - kcal/kg/day, protein-, carbohydrate- and fat oxidation)
    • Body composition (% fat mass and lean mass)
    • Microbiome
    - Gut microbiota composition
    • Appetite
    - Visual analogue scale scores + quantity of food consumed
    •Total faecal sterol concentration
    - FNS + faecal bile acid concentration
    • Bioavailability/pharmacokinetic parameters
    - Clearance, volume of distribution, absorption rate, mean residence time, elimination half-life between gDCA and enteric-coated gDCA.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Visit 1: Day 1: baseline mixed meal test + stool sampling
    Visit 2: Day 15: second mixed meal test + stool sampling
    Visit 3: Day 31: third mixed meal test + stool sampling
    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 Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence Yes
    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) No
    E.7.4Therapeutic use (Phase IV) Yes
    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.8.2.4Number 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
    LVLS
    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: 40
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 40
    F.2 Gender
    F.2.1Female No
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers Yes
    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 state40
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 40
    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)
    After the study is finished T2D patients will continu their regular follow-up appointments and examinations as before the trial.
    Na het einde van de studie zullen de patienten hun reguliere behandeling hervatten in de vorm van controle afspraken en onderzoeken zoals voor de studie.
    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 Decision2017-06-26
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-01-22
    P. End of Trial
    P.End of Trial StatusOngoing
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