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    Summary
    EudraCT Number:2019-002880-82
    Sponsor's Protocol Code Number:GUARD
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:GB - no longer in EU/EEA
    Date on which this record was first entered in the EudraCT database:2020-06-02
    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 number2019-002880-82
    A.3Full title of the trial
    Randomised controlled trial of Gestational treatment with Ursodeoxycholic Acid compared to Metformin to Reduce effects of Diabetes mellitus
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Comparison of Ursodeoxycholic Acid to Metformin to treat women with Gestational Diabetes Mellitus.
    A.3.2Name or abbreviated title of the trial where available
    GUARD
    A.4.1Sponsor's protocol code numberGUARD
    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 SponsorKing's College London
    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 supportJon Moulton Foundation
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationKing’s College London
    B.5.2Functional name of contact pointProfessor Catherine Williamson
    B.5.3 Address:
    B.5.3.1Street AddressDivision of Women and Children’s Health
    B.5.3.2Town/ cityLondon
    B.5.3.3Post codeSE1 1UL
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number020 7848 6350 / 020 7848 6014
    B.5.6E-mailcatherine.williamson@kcl.ac.uk
    B.Sponsor: 2
    B.1.1Name of SponsorGuy’s and St Thomas NHS Foundation Trust
    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 supportJon Moulton Foundation
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationGuy’s and St Thomas NHS Foundation Trust
    B.5.2Functional name of contact pointProfessor Catherine Williamson
    B.5.3 Address:
    B.5.3.1Street AddressDivision of Women and Children’s Health
    B.5.3.2Town/ cityLondon
    B.5.3.3Post codeSE1 1UL
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number020 7848 6350 / 020 7848 6014
    B.5.6E-mailcatherine.williamson@kcl.ac.uk
    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 Ursofalk 500mg film-coated tablets
    D.2.1.1.2Name of the Marketing Authorisation holderDr. Falk Pharma UK Ltd
    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 nameUrsofalk 500mg film-coated tablets
    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.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 Metformin 500mg Tablets BP
    D.2.1.1.2Name of the Marketing Authorisation holderMedley Pharma Limited
    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 nameMetformin 500mg Tablets BP
    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
    Gestational Diabetes Mellitus
    E.1.1.1Medical condition in easily understood language
    High blood glucose in pregnant women
    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 21.1
    E.1.2Level LLT
    E.1.2Classification code 10018210
    E.1.2Term Gestational diabetes mellitus
    E.1.2System Organ Class 100000004868
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    We would like to assess how well ursodeoxycholic acid works at controlling glucose levels in overweight or obese women with gestational diabetes mellitus, compared to metformin, which is the most commonly used treatment.
    E.2.2Secondary objectives of the trial
    - We would like to see how each treatment changes the lipid metabolism of both mothers and babies.
    - We would like to find out if the new treatment is well accepted by women.
    - We will conduct continuous glucose monitoring. We would like to assess if the information produced by this device offers a more informative assessment to the single glucose test.
    - We would like to measure the impact on blood vessels and blood pressure as this may affect the health of women with GDM.
    - We would like to compare adverse outcomes in the pregnancy and fetus.

    We are also conducting a mechanistic sub-study which intends to look at the gut microbiome of different groups, to assess how these medicines affect the hormonal system, glucose and lipid composition.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    GUARD MEC (Mechanistic) V1.0

    We want to assess whether UDCA and metformin differentially alter gut microbiome and whether this is associated with a change in endocrine signalling, serum glucose levels and lipid composition.

    158 participants will be recruited for GUARD and 40 additional controls for GUARD MEC. Total of 198 participants.
    E.3Principal inclusion criteria
    1. Women between 16 and 45 years of age with GDM diagnosed at 26+0 to 30+6 weeks’ gestation in accordance with the NICE guidelines (one or more glucose concentrations of ≥5.6 mmol/l fasting or ≥7.8 mmol/l 2 hours after a standard 75g OGTT, and requiring pharmacological treatment).
    2. Overweight or obese (Booking BMI ≥25 kg/m2)
    3. Planned antenatal, birth intrapartum and postpartum care at the participating centre (i.e. not planning to move before delivery).

    Eligibility criteria for GUARD MEC is included in the protocol in section 19.
    E.4Principal exclusion criteria
    1. Unwilling/unable to give written informed consent and comply with the requirements of the study protocol
    2. Multiple pregnancies (twins, triplets etc) in current pregnancy
    3. Congenital anomaly on ultrasound requiring fetal medicine input
    4. Previous diagnosis of diabetes outside pregnancy
    5. HbA1c at booking of current pregnancy of >48 mmol/mol or ≥6.5% (if available)
    6. Significant pre-pregnancy comorbidities that increase risk in pregnancy, for example renal failure, severe liver disease, transplantation, cardiac failure, psychiatric conditions requiring in-patient admission (within previous year) in the opinion of the responsible clinician or the CI.
    7. Significant co-morbidity in the current pregnancy, nephropathy (estimated GFR <60ml/min), other physical or psychological conditions likely to interfere with the conduct of the study and/or interpretation of the trial results in the opinion of the responsible clinician or the CI.
    8. Not fluent in English and absence of interpreter or translation services (ie telephone translation services)
    9. Participating in another intervention study where the results could influence GDM-related endpoints, in the opinion of the responsible clinician or the CI, or participation in a CTIMP during current pregnancy.
    10. Known allergy/hypersensitivity/intolerance to the active substance or excipients or patients taking any medications which are contraindicated as per IMP SmPC (as per Section 5.7 of the protocol).

    Eligibility criteria for GUARD MEC is included in the protocol in section 19.
    E.5 End points
    E.5.1Primary end point(s)
    Maternal fasting glucose concentration at 36 weeks' gestation measured with a blood sample
    E.5.1.1Timepoint(s) of evaluation of this end point
    Week 36 of gestation
    E.5.2Secondary end point(s)
    - Quality of Life assessment (EQ-5D-5L) at baseline and Follow up 2, and treatment satisfaction scores at Follow up 2.

    - Biomedical and clinical maternal outcomes:
    1. Glucose metabolism at baseline, follow up 1 and 2 assessed by:
    a) Continuous glucose monitoring (CGM) to assess glycaemic control. This will determine the percentage time spent within target (glucose levels 3.9-7.8mmol/L), percentage time spent above target (>7.8mmol/l and ≥6.7mmol/l), time spent below target (≤3.5 and ≤3.0 mmol/l), measures of glucose variability including glucose standard variation (SD), co-efficient of variation (CV), frequency and duration of glycaemic excursions measured by the area under the curve (AUC) for the pre-specified glucose thresholds.
    b) Serum concentrations of 1,5-anhydroglucitol; a novel marker of short-term glycaemia 4,43
    c) HbA1c concentration; a conventional marker of medium-term glycaemia
    2. Lipid metabolism at Follow up 2 assessed by blood triglyceride, total cholesterol, calculated LDL-cholesterol, HDL-cholesterol and free fatty acid concentrations
    3. Biochemical analysis of maternal blood for liver function tests at Follow up 2 (ALT, bilirubin, ALP), bile acids, C reactive protein (including highly sensitive analyses)
    4. Proportion of women requiring insulin treatment (time until treatment and total dose of insulin required)
    5. Maternal gestational weight change at 36 weeks compared to weight at first trimester screening visit.
    6. Measurement of vascular responses at Follow up 1 and 2, including: i) maternal pulse wave velocity (PWV), with systolic and diastolic blood pressure, ii) central arterial pressure (cP), and iii) augmentation index (AIx)
    7. Estimated blood loss at time of delivery.

    - Biomedical and clinical neonatal outcomes at birth:
    1. Mode of birth (rates of caesarean section (CS),(elective & emergency), assisted vaginal birth and spontaneous vaginal delivery (SVD)
    2. Gestational age at birth
    3. Apgar scores @ 5 minutes post birth
    4. Occurrence of shoulder dystocia
    5. Cord blood C-peptide, triglyceride, total cholesterol, calculated LDL-cholesterol, HDL-cholesterol, free fatty acid concentrations and lipid composition by mass spectrometry
    6. Infant birth weight (customised birth weight percentile51, proportion of babies born large for gestational age (LGA), proportion of babies born small for gestational age (SGA)
    7. Neonatal morbidity (treatment for neonatal hypoglycaemia, neonatal jaundice, respiratory distress or birth trauma)
    8. Neonatal intensive care and special care unit admission (duration of hospital stay)
    9. Stillbirth and neonatal death
    E.5.2.1Timepoint(s) of evaluation of this end point
    All endpoints will be measured at 32 and 36 week's of gestation, and at birth.
    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 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.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 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 Yes
    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) Yes
    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 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 concerned3
    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 will be defined as database lock, once all recruits have completed all the study related visits, and the data has been entered in the eCRF and cleaned.
    In our experience, database lock in a multi-centre study can be a very long process, which leaves very limited time to submit the final study report. This allows us more time to prepare the analysis and engage with the relevant committees and PPIs before we submit our reports.
    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 months0
    E.8.9.1In the Member State concerned days1
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days1
    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: 158
    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) Yes
    F.1.1.6.1Number of subjects for this age range: 198
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 158
    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 No
    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 No
    F.3.3.3Pregnant women Yes
    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 state158
    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)
    Once women give birth, their GDM dissapears. Any follow up required will be provided as per standard of care.
    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 Decision2020-05-05
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-05-05
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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