<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT04407650</url>
  </required_header>
  <id_info>
    <org_study_id>264693</org_study_id>
    <nct_id>NCT04407650</nct_id>
  </id_info>
  <brief_title>Ursodeoxycholic Acid vs Metformin in Gestational Diabetes Mellitus</brief_title>
  <acronym>GUARD</acronym>
  <official_title>Randomised Controlled Trial of Gestational Treatment With Ursodeoxycholic Acid Compared to Metformin to Reduce Effects of Diabetes Mellitus</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>King's College London</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Guy's and St Thomas' NHS Foundation Trust</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>King's College London</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      GUARD is a Clinical Trial that wants to explore the impact of UDCA compared to metformin in&#xD;
      the treatment of GDM. The trial wants to recruit 158 women who are overweight or obese who&#xD;
      have been diagnosed with GDM, and require pharmacological treatment. Glucose control is our&#xD;
      primary measure.&#xD;
&#xD;
      Each year in the UK approximately 35,000 women develop diabetes during pregnancy, a condition&#xD;
      called gestational diabetes mellitus (GDM), which increases the risk of adverse outcomes for&#xD;
      both mother and child. Metformin, although unlicensed for used in pregnancy, is the most&#xD;
      commonly used first line pharmacological treatment. However, there is increasing concern&#xD;
      about its widespread use during pregnancy, because of its limited efficacy and because of&#xD;
      potential safety concerns. Other common treatments have not been shown to be superior.&#xD;
      Therefore, there is an unmet need for additional therapies.&#xD;
&#xD;
      Ursodeoxycholic acid (UDCA) is commonly used in pregnancy for the treatment of intrahepatic&#xD;
      cholestasis of pregnancy. It is currently not an established/licensed treatment for GDM.&#xD;
      However data from observational studies of women with cholestasis in pregnancy has flagged&#xD;
      this to be a potential effective treatment to control blood glucose levels in GDM.&#xD;
&#xD;
      The investigators will ask women to attend three study visits, which will coincide with the&#xD;
      time of their antenatal appointments. The trial aims to collect a range of clinical and&#xD;
      research blood samples, to measure quality of life and treatment satisfaction through two&#xD;
      questionnaires, and will will ask women to wear a continuous glucose monitor for three 10 day&#xD;
      periods.&#xD;
&#xD;
      There will be a number of optional assessments that participants will be offered. The primary&#xD;
      outcome will be the fasting blood glucose concentration at 36 weeks of gestation.&#xD;
&#xD;
      The investigators intend to carry out this study at 3 sites in the United Kingdom (Guy's and&#xD;
      St Thomas, Imperial College and Nottingham), and it has been funded by a J.P Moulton&#xD;
      Foundation grant.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      GUARD is a two-armed, randomised, controlled, open label multicentre clinical trial with&#xD;
      optional observational mechanistic study in a subgroup from each arm, comparing&#xD;
      Ursodeoxycholic Acid to Metformin (both oral BD). H0 is no difference in in maternal fasting&#xD;
      glucose at 36 weeks. HA is a difference of 6% (0.28mmol/L), consistent with previously&#xD;
      reported differences with UDCA treatment for non-alcoholic fatty liver disease (NAFLD). The&#xD;
      RCT design was chosen as the generally accepted way of demonstrating clinically important&#xD;
      effects of medical treatment, prior to their general acceptance into medical care. The open&#xD;
      label is due to the practical difficulty of matching the treatments, due to pill sizes and&#xD;
      different dosages.&#xD;
&#xD;
      At present it is known that not all women with GDM respond to oral metformin treatment. Some&#xD;
      women cannot tolerate the drug and it is ineffective in others. Many women are reluctant to&#xD;
      take insulin as this requires injections and is not without the risk of hypoglycaemia.&#xD;
      Therefore there is a need for additional oral treatments to improve glycaemic control. UDCA&#xD;
      is a reasonable drug to study as it has good safety data for use in pregnancy (due to studies&#xD;
      in women with cholestasis in pregnancy). If previous trials of women with cholestasis is was&#xD;
      shown to reduce insulin resistance. It also reduced umbilical cord lipid concentrations.&#xD;
      Therefore it is reasonable to compare UDCA to metformin as it may have an equivalent (or&#xD;
      better) impact upon glucose control and, if women with GDM have a similar response to those&#xD;
      with cholestasis in pregnancy, it could be associated with better outcomes for the baby, e.g.&#xD;
      improved umbilical cord blood lipids. As it has not been studied before The investigators do&#xD;
      not know if it will be effective, but the existing data suggest it is reasonable to study&#xD;
      UDCA. As there is the option of treatment with insulin for women that do not have acceptable&#xD;
      glucose control when taking UDCA (as there is for metformin) both drugs are used with an&#xD;
      acceptable alternative treatment if they are not sufficiently effective at achieving&#xD;
      glycaemic control.&#xD;
&#xD;
      The investigators plan recruitment to last for 18-24 months, and a further 12 months to allow&#xD;
      for close out activities.&#xD;
&#xD;
      According to sample size calculations, enrolling 158 participants will provide sufficient&#xD;
      statistical power to detect the primary outcome, and allow for a 20% withdrawal rate. An&#xD;
      additional 40 participants will be enrolled onto GUARD MEC to serve as controls for this part&#xD;
      of the research. Participants will be identified following their OGTT appointment and&#xD;
      approached by the diabetes nurse or the study midwife, ideally when they receive dietary and&#xD;
      lifestyle education. Interdepartment co-operation will be required.&#xD;
&#xD;
      The Independent Data Monitoring Committee (IDMC) will review outcomes after 25% of the&#xD;
      participants have given birth. Data will be monitored by the IDMC at intervals to ensure the&#xD;
      interest of participants and validity of data is safeguarded. Most of the outcomes are&#xD;
      clinical samples, objective measurements and patient questionnaires. As such researcher bias&#xD;
      should have a minimal impact on the reporting. Should this be identified, it will be&#xD;
      escalated to the Trial Steering Committee for decision.&#xD;
&#xD;
      An observational sub-study called GUARD MEC will be conducted. 40 GUARD participants, plus&#xD;
      other two other control groups (20 women with GDM who do not require pharmacological&#xD;
      treatment, and 20 healthy pregnant women), will be invited to participate in the optional&#xD;
      study, which will involve eating a specific breakfast in hospital and collecting blood&#xD;
      samples at 4 timepoints.&#xD;
&#xD;
      Monitoring of this trial is performed to ensure compliance with Good Clinical Practice, and&#xD;
      scientific integrity is managed and oversight retained by the King's Health Partners Clinical&#xD;
      Trials Office (KHP-CTO) Quality Team. A study specific monitoring plan has been developed by&#xD;
      the KHP-CTO on the basis of a risk assessment. The KHP-CTO will carry out on-site monitoring&#xD;
      to undertake source data verification checks and confirm that records are being appropriately&#xD;
      maintained by the PI and pharmacy teams.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">July 1, 2021</start_date>
  <completion_date type="Anticipated">June 30, 2023</completion_date>
  <primary_completion_date type="Anticipated">January 31, 2023</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>Pilot Phase 4 Randomised Controlled Trial</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Glycaemic control</measure>
    <time_frame>Gestational week 36</time_frame>
    <description>Maternal fasting glucose concentration in blood sample</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Acceptability</measure>
    <time_frame>Gestational week 36</time_frame>
    <description>To assess the acceptability of UDCA compared to metformin using the Diabetes Treatment Satisfaction Questionnaire GB-DTSQs_Jul94 with scales ranging from 6 (increased satisfaction/acceptability) - 0 (dissatisfaction)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Biomedical outcomes: continuous glucose monitoring</measure>
    <time_frame>Baseline (week 28), Follow up 1 (week 32), Follow up 2 (week 36)</time_frame>
    <description>Glucose metabolism control measured by continuous glucose monitors to establish whether continuous glucose monitoring gives more informative overall assessment of maternal glycaemic control</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Biomedical outcomes: 1,5-anhydroglucitol</measure>
    <time_frame>Baseline (week 28), Follow up 1 (week 32), Follow up 2 (week 36)</time_frame>
    <description>Glucose metabolism control measured by serum concentrations of 1,5-anhydroglucitol</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Biomedical outcomes: glucose control by HbA1c</measure>
    <time_frame>Baseline (week 28), Follow up 2 (week 36)</time_frame>
    <description>Glucose metabolism control measured by HbA1c concentration</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Biomedical outcomes: lipids</measure>
    <time_frame>Follow up 2 (week 36)</time_frame>
    <description>Lipid metabolism assessed by blood triglyceride, total cholesterol, calculated LDL-cholesterol, HDL-cholesterol and free fatty acid concentrations, all in mmol/L</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Biomedical analyses: bilirubin</measure>
    <time_frame>Follow up 2 (week 36)</time_frame>
    <description>Maternal liver function tests: bilirubin</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Biomedical analyses: ALT</measure>
    <time_frame>Follow up 2 (week 36)</time_frame>
    <description>Maternal liver function tests: ALT</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Biomedical analyses: bile acids</measure>
    <time_frame>Follow up 2 (week 36)</time_frame>
    <description>Maternal liver function tests: bile acids</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Biomedical analyses: CRP</measure>
    <time_frame>Follow up 2 (week 36)</time_frame>
    <description>Maternal liver function tests: C reactive protein</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical maternal outcomes: insulin</measure>
    <time_frame>From enrolment to birth</time_frame>
    <description>Proportion of women requiring insulin treatment (time until treatment and dose)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical maternal outcomes: weight</measure>
    <time_frame>Follow up 2 (week 36) compared to first trimester</time_frame>
    <description>Maternal weight change</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Maternal vascular responses (I)</measure>
    <time_frame>Follow up 1 (week 32), Follow up 2 (week 36)</time_frame>
    <description>maternal pulse wave velocity (PWV)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Maternal vascular responses (II)</measure>
    <time_frame>Follow up 1 (week 32), Follow up 2 (week 36)</time_frame>
    <description>systolic and diastolic blood pressure</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Maternal vascular responses (III)</measure>
    <time_frame>Follow up 1 (week 32), Follow up 2 (week 36)</time_frame>
    <description>central arterial pressure (cP)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Maternal vascular responses (IV)</measure>
    <time_frame>Follow up 1 (week 32), Follow up 2 (week 36)</time_frame>
    <description>Augmentation index (AIx)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Blood loss</measure>
    <time_frame>Delivery</time_frame>
    <description>Estimated blood loss during birth</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Neonatal outcomes: mode of birth</measure>
    <time_frame>Delivery</time_frame>
    <description>Amongts all participants, caesarean section (elective &amp; emergency), assisted vaginal birth and spontaneous vaginal delivery numbers will be measured</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Neonatal outcomes: gestational age</measure>
    <time_frame>Delivery</time_frame>
    <description>Gestational age at birth</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Neonatal outcomes: apgar scores</measure>
    <time_frame>Delivery</time_frame>
    <description>Apgar scores at 5 minutes post birth</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Neonatal outcomes: shoulder dystocia</measure>
    <time_frame>Delivery</time_frame>
    <description>Occurrence of shoulder dystocia</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Neonatal outcomes: weight</measure>
    <time_frame>Delivery</time_frame>
    <description>Infant birth weight will be collected to analyse the percentage proportion of babies born large for gestational age and proportion of babies born small for gestational age</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Neonatal outcomes: morbidity</measure>
    <time_frame>Delivery</time_frame>
    <description>Treatment for neonatal hypoglycaemia, neonatal jaundice, respiratory distress or birth trauma</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Neonatal outcomes: rate of special care unit admission.</measure>
    <time_frame>28 days post delivery</time_frame>
    <description>Neonatal intensive care and special care unit admission (duration of hospital stay)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Stillbirth and neonatal death</measure>
    <time_frame>Delivery</time_frame>
    <description>Occurrence of stillbirth and neonatal death</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Biomedical neonatal outcomes</measure>
    <time_frame>Delivery</time_frame>
    <description>Cord blood C-peptide, triglyceride, total cholesterol, calculated LDL-cholesterol, HDL-cholesterol and free fatty acid concentrations all in mmol/L</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">158</enrollment>
  <condition>Gestational Diabetes</condition>
  <arm_group>
    <arm_group_label>Metformin</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Oral 1000 mg BD</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Ursodeoxycholic acid</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Oral 500 mg BD</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Metformin</intervention_name>
    <description>Patients will be randomized to each intervention using minimisation:&#xD;
BMI category (Overweight/Obese),&#xD;
Previous history of GDM,&#xD;
Disease severity (baseline fasting glucose ≤6.2 or &gt;6.2),&#xD;
Recruitment centre</description>
    <arm_group_label>Metformin</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ursodeoxycholic Acid</intervention_name>
    <description>Patients will be randomized to each intervention using minimisation:&#xD;
BMI category (Overweight/Obese),&#xD;
Previous history of GDM,&#xD;
Disease severity (baseline fasting glucose ≤6.2 or &gt;6.2),&#xD;
Recruitment centre</description>
    <arm_group_label>Ursodeoxycholic acid</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Women between 16 and 45 years of age with GDM diagnosed at 26+0 to 30+6 weeks'&#xD;
             gestation in accordance with the NICE guidelines (one or more glucose concentrations&#xD;
             of ≥5.6 mmol/l fasting or ≥7.8 mmol/l 2 hours after a standard 75g OGTT, and requiring&#xD;
             pharmacological treatment).&#xD;
&#xD;
          2. Overweight or obese (Booking BMI ≥25 kg/m2)&#xD;
&#xD;
          3. Planned antenatal, intrapartum and postpartum care at the participating centre (i.e.&#xD;
             not planning to move before delivery).&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Unwilling/unable to give written informed consent and comply with the requirements of&#xD;
             the study protocol&#xD;
&#xD;
          2. Multiple pregnancies (twins, triplets etc) in current pregnancy&#xD;
&#xD;
          3. Congenital anomaly on ultrasound requiring fetal medicine input&#xD;
&#xD;
          4. Previous diagnosis of diabetes outside pregnancy&#xD;
&#xD;
          5. HbA1c at booking &gt;48 mmol/mol or ≥6.5% during current pregnancy (if available)&#xD;
&#xD;
          6. Significant pre-pregnancy comorbidities that increase risk in pregnancy, for example&#xD;
             renal failure, severe liver disease, transplantation, cardiac failure, psychiatric&#xD;
             conditions requiring in-patient admission (within previous year) in the opinion of the&#xD;
             responsible clinician or the CI.&#xD;
&#xD;
          7. Significant co-morbidity in the current pregnancy, nephropathy (estimated GFR&#xD;
             &lt;60ml/min), other physical or psychological conditions likely to interfere with the&#xD;
             conduct of the study and/or interpretation of the trial results in the opinion of the&#xD;
             responsible clinician or the CI.&#xD;
&#xD;
          8. Not fluent in English and absence of interpreter or translation services (ie telephone&#xD;
             translation services)&#xD;
&#xD;
          9. Participating in another intervention study where the results could influence&#xD;
             GDM-related endpoints, in the opinion of the responsible clinician or the CI, or&#xD;
             participation in a CTIMP during current pregnancy.&#xD;
&#xD;
         10. Known allergy/hypersensitivity/intolerance to the active substance or excipients, or&#xD;
             patients taking any medications which are contraindicated as per IMP SmPC&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <gender_based>Yes</gender_based>
    <gender_description>Only pregnant people allowed study entry, irrespective of gender indentity</gender_description>
    <minimum_age>16 Years</minimum_age>
    <maximum_age>45 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Catherine Williamson, CI</last_name>
    <role>Principal Investigator</role>
    <affiliation>King's College London</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Jennifer Crook, Trial Manager</last_name>
    <phone>00442071887188</phone>
    <phone_ext>53378</phone_ext>
    <email>Jennifer.Crook@gstt.nhs.uk</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Holly Lovell, Midwife</last_name>
    <email>holly.lovell@gstt.nhs.uk</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Guy's and St Thomas' NHS Foundation Trust</name>
      <address>
        <city>London</city>
        <zip>SE1 7EH</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Catherine Williamson</last_name>
      <email>catherine.williamson@kcl.ac.uk</email>
    </contact>
  </location>
  <location_countries>
    <country>United Kingdom</country>
  </location_countries>
  <verification_date>March 2022</verification_date>
  <study_first_submitted>May 14, 2020</study_first_submitted>
  <study_first_submitted_qc>May 26, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">May 29, 2020</study_first_posted>
  <last_update_submitted>August 17, 2022</last_update_submitted>
  <last_update_submitted_qc>August 17, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">August 19, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Diabetes, Gestational</mesh_term>
    <mesh_term>Diabetes Mellitus</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Metformin</mesh_term>
    <mesh_term>Ursodeoxycholic Acid</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>March 11, 2020</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/50/NCT04407650/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04407650
org study id: 264693
nct id: NCT04407650
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
is us export: No
GUARD is a Clinical Trial that wants to explore the impact of UDCA compared to metformin in
      the treatment of GDM. The trial wants to recruit 158 women who are overweight or obese who
      have been diagnosed with GDM, and require pharmacological treatment. Glucose control is our
      primary measure.

      Each year in the UK approximately 35,000 women develop diabetes during pregnancy, a condition
      called gestational diabetes mellitus (GDM), which increases the risk of adverse outcomes for
      both mother and child. Metformin, although unlicensed for used in pregnancy, is the most
      commonly used first line pharmacological treatment. However, there is increasing concern
      about its widespread use during pregnancy, because of its limited efficacy and because of
      potential safety concerns. Other common treatments have not been shown to be superior.
      Therefore, there is an unmet need for additional therapies.

      Ursodeoxycholic acid (UDCA) is commonly used in pregnancy for the treatment of intrahepatic
      cholestasis of pregnancy. It is currently not an established/licensed treatment for GDM.
      However data from observational studies of women with cholestasis in pregnancy has flagged
      this to be a potential effective treatment to control blood glucose levels in GDM.

      The investigators will ask women to attend three study visits, which will coincide with the
      time of their antenatal appointments. The trial aims to collect a range of clinical and
      research blood samples, to measure quality of life and treatment satisfaction through two
      questionnaires, and will will ask women to wear a continuous glucose monitor for three 10 day
      periods.

      There will be a number of optional assessments that participants will be offered. The primary
      outcome will be the fasting blood glucose concentration at 36 weeks of gestation.

      The investigators intend to carry out this study at 3 sites in the United Kingdom (Guy's and
      St Thomas, Imperial College and Nottingham), and it has been funded by a J.P Moulton
      Foundation grant.
GUARD is a two-armed, randomised, controlled, open label multicentre clinical trial with
      optional observational mechanistic study in a subgroup from each arm, comparing
      Ursodeoxycholic Acid to Metformin (both oral BD). H0 is no difference in in maternal fasting
      glucose at 36 weeks. HA is a difference of 6% (0.28mmol/L), consistent with previously
      reported differences with UDCA treatment for non-alcoholic fatty liver disease (NAFLD). The
      RCT design was chosen as the generally accepted way of demonstrating clinically important
      effects of medical treatment, prior to their general acceptance into medical care. The open
      label is due to the practical difficulty of matching the treatments, due to pill sizes and
      different dosages.

      At present it is known that not all women with GDM respond to oral metformin treatment. Some
      women cannot tolerate the drug and it is ineffective in others. Many women are reluctant to
      take insulin as this requires injections and is not without the risk of hypoglycaemia.
      Therefore there is a need for additional oral treatments to improve glycaemic control. UDCA
      is a reasonable drug to study as it has good safety data for use in pregnancy (due to studies
      in women with cholestasis in pregnancy). If previous trials of women with cholestasis is was
      shown to reduce insulin resistance. It also reduced umbilical cord lipid concentrations.
      Therefore it is reasonable to compare UDCA to metformin as it may have an equivalent (or
      better) impact upon glucose control and, if women with GDM have a similar response to those
      with cholestasis in pregnancy, it could be associated with better outcomes for the baby, e.g.
      improved umbilical cord blood lipids. As it has not been studied before The investigators do
      not know if it will be effective, but the existing data suggest it is reasonable to study
      UDCA. As there is the option of treatment with insulin for women that do not have acceptable
      glucose control when taking UDCA (as there is for metformin) both drugs are used with an
      acceptable alternative treatment if they are not sufficiently effective at achieving
      glycaemic control.

      The investigators plan recruitment to last for 18-24 months, and a further 12 months to allow
      for close out activities.

      According to sample size calculations, enrolling 158 participants will provide sufficient
      statistical power to detect the primary outcome, and allow for a 20% withdrawal rate. An
      additional 40 participants will be enrolled onto GUARD MEC to serve as controls for this part
      of the research. Participants will be identified following their OGTT appointment and
      approached by the diabetes nurse or the study midwife, ideally when they receive dietary and
      lifestyle education. Interdepartment co-operation will be required.

      The Independent Data Monitoring Committee (IDMC) will review outcomes after 25% of the
      participants have given birth. Data will be monitored by the IDMC at intervals to ensure the
      interest of participants and validity of data is safeguarded. Most of the outcomes are
      clinical samples, objective measurements and patient questionnaires. As such researcher bias
      should have a minimal impact on the reporting. Should this be identified, it will be
      escalated to the Trial Steering Committee for decision.

      An observational sub-study called GUARD MEC will be conducted. 40 GUARD participants, plus
      other two other control groups (20 women with GDM who do not require pharmacological
      treatment, and 20 healthy pregnant women), will be invited to participate in the optional
      study, which will involve eating a specific breakfast in hospital and collecting blood
      samples at 4 timepoints.

      Monitoring of this trial is performed to ensure compliance with Good Clinical Practice, and
      scientific integrity is managed and oversight retained by the King's Health Partners Clinical
      Trials Office (KHP-CTO) Quality Team. A study specific monitoring plan has been developed by
      the KHP-CTO on the basis of a risk assessment. The KHP-CTO will carry out on-site monitoring
      to undertake source data verification checks and confirm that records are being appropriately
      maintained by the PI and pharmacy teams.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Pilot Phase 4 Randomised Controlled Trial
primary purpose: Treatment
masking: None (Open Label)
measure: Glycaemic control
time frame: Gestational week 36
description: Maternal fasting glucose concentration in blood sample
measure: Acceptability
time frame: Gestational week 36
description: To assess the acceptability of UDCA compared to metformin using the Diabetes Treatment Satisfaction Questionnaire GB-DTSQs_Jul94 with scales ranging from 6 (increased satisfaction/acceptability) - 0 (dissatisfaction)
measure: Biomedical outcomes: continuous glucose monitoring
time frame: Baseline (week 28), Follow up 1 (week 32), Follow up 2 (week 36)
description: Glucose metabolism control measured by continuous glucose monitors to establish whether continuous glucose monitoring gives more informative overall assessment of maternal glycaemic control
measure: Biomedical outcomes: 1,5-anhydroglucitol
time frame: Baseline (week 28), Follow up 1 (week 32), Follow up 2 (week 36)
description: Glucose metabolism control measured by serum concentrations of 1,5-anhydroglucitol
measure: Biomedical outcomes: glucose control by HbA1c
time frame: Baseline (week 28), Follow up 2 (week 36)
description: Glucose metabolism control measured by HbA1c concentration
measure: Biomedical outcomes: lipids
time frame: Follow up 2 (week 36)
description: Lipid metabolism assessed by blood triglyceride, total cholesterol, calculated LDL-cholesterol, HDL-cholesterol and free fatty acid concentrations, all in mmol/L
measure: Biomedical analyses: bilirubin
time frame: Follow up 2 (week 36)
description: Maternal liver function tests: bilirubin
measure: Biomedical analyses: ALT
time frame: Follow up 2 (week 36)
description: Maternal liver function tests: ALT
measure: Biomedical analyses: bile acids
time frame: Follow up 2 (week 36)
description: Maternal liver function tests: bile acids
measure: Biomedical analyses: CRP
time frame: Follow up 2 (week 36)
description: Maternal liver function tests: C reactive protein
measure: Clinical maternal outcomes: insulin
time frame: From enrolment to birth
description: Proportion of women requiring insulin treatment (time until treatment and dose)
measure: Clinical maternal outcomes: weight
time frame: Follow up 2 (week 36) compared to first trimester
description: Maternal weight change
measure: Maternal vascular responses (I)
time frame: Follow up 1 (week 32), Follow up 2 (week 36)
description: maternal pulse wave velocity (PWV)
measure: Maternal vascular responses (II)
time frame: Follow up 1 (week 32), Follow up 2 (week 36)
description: systolic and diastolic blood pressure
measure: Maternal vascular responses (III)
time frame: Follow up 1 (week 32), Follow up 2 (week 36)
description: central arterial pressure (cP)
measure: Maternal vascular responses (IV)
time frame: Follow up 1 (week 32), Follow up 2 (week 36)
description: Augmentation index (AIx)
measure: Blood loss
time frame: Delivery
description: Estimated blood loss during birth
measure: Neonatal outcomes: mode of birth
time frame: Delivery
description: Amongts all participants, caesarean section (elective & emergency), assisted vaginal birth and spontaneous vaginal delivery numbers will be measured
measure: Neonatal outcomes: gestational age
time frame: Delivery
description: Gestational age at birth
measure: Neonatal outcomes: apgar scores
time frame: Delivery
description: Apgar scores at 5 minutes post birth
measure: Neonatal outcomes: shoulder dystocia
time frame: Delivery
description: Occurrence of shoulder dystocia
measure: Neonatal outcomes: weight
time frame: Delivery
description: Infant birth weight will be collected to analyse the percentage proportion of babies born large for gestational age and proportion of babies born small for gestational age
measure: Neonatal outcomes: morbidity
time frame: Delivery
description: Treatment for neonatal hypoglycaemia, neonatal jaundice, respiratory distress or birth trauma
measure: Neonatal outcomes: rate of special care unit admission.
time frame: 28 days post delivery
description: Neonatal intensive care and special care unit admission (duration of hospital stay)
measure: Stillbirth and neonatal death
time frame: Delivery
description: Occurrence of stillbirth and neonatal death
measure: Biomedical neonatal outcomes
time frame: Delivery
description: Cord blood C-peptide, triglyceride, total cholesterol, calculated LDL-cholesterol, HDL-cholesterol and free fatty acid concentrations all in mmol/L
arm group label: Metformin
arm group type: Active Comparator
description: Oral 1000 mg BD
arm group label: Ursodeoxycholic acid
arm group type: Experimental
description: Oral 500 mg BD
intervention type: Drug
intervention name: Metformin
description: Patients will be randomized to each intervention using minimisation:
BMI category (Overweight/Obese),
Previous history of GDM,
Disease severity (baseline fasting glucose ≤6.2 or >6.2),
Recruitment centre
arm group label: Metformin
intervention type: Drug
intervention name: Ursodeoxycholic Acid
description: Patients will be randomized to each intervention using minimisation:
BMI category (Overweight/Obese),
Previous history of GDM,
Disease severity (baseline fasting glucose ≤6.2 or >6.2),
Recruitment centre
arm group label: Ursodeoxycholic acid
criteria: 
gender: Female
gender based: Yes
gender description: Only pregnant people allowed study entry, irrespective of gender indentity
minimum age: 16 Years
maximum age: 45 Years
healthy volunteers: No
last name: Catherine Williamson, CI
role: Principal Investigator
affiliation: King's College London
last name: Jennifer Crook, Trial Manager
phone: 00442071887188
phone ext: 53378
email: Jennifer.Crook@gstt.nhs.uk
last name: Holly Lovell, Midwife
email: holly.lovell@gstt.nhs.uk
facility: 
status: Recruiting
contact: 
country: United Kingdom
responsible party type: Sponsor
mesh term: Diabetes, Gestational
mesh term: Diabetes Mellitus
mesh term: Metformin
mesh term: Ursodeoxycholic Acid
sharing ipd: No
provided document: 