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Gestational DiabetesPhase 4GUARDNCT04407650

Ursodeoxycholic Acid vs Metformin in Gestational Diabetes Mellitus

A Phase 4 study testing Metformin and Ursodeoxycholic Acid in people with Gestational Diabetes, run by King's College London at 1 site in United Kingdom.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial summary

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. Read more about this study

Who is it for?
Ages 16 to 45 years, women only
Conditions the study is for
Gestational Diabetes
What is being tested?
Metformin and Ursodeoxycholic Acid
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
55 participants
Where
1 siteUnited Kingdom
Study dates
18 Jun 2021to 29 May 2025
Phase
Phase 4
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 16 to 45 years
  • Women only
  • No healthy volunteers
  • Child, Adult

Who may be able to join

  • 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).
  • Overweight or obese (Booking BMI ≥25 kg/m2)
  • Planned antenatal, intrapartum and postpartum care at the participating centre (i.e. not planning to move before delivery).

Who cannot join

  • Unwilling/unable to give written informed consent and comply with the requirements of the study protocol
  • Multiple pregnancies (twins, triplets etc) in current pregnancy
  • Congenital anomaly on ultrasound requiring fetal medicine input
  • Previous diagnosis of diabetes outside pregnancy
  • HbA1c at booking >48 mmol/mol or ≥6.5% during current pregnancy (if available)
  • 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.
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  • 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.
  • Not fluent in English and absence of interpreter or translation services (ie telephone translation services)
  • 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.
  • Known allergy/hypersensitivity/intolerance to the active substance or excipients, or patients taking any medications which are contraindicated as per IMP SmPC

Trial locations and contacts

1 site in 1 country.

United Kingdom1 site
  • Guy's and St Thomas' NHS Foundation Trust

    London, SE1 7EH

Other trials in United Kingdom

About this study

Official title: Randomised Controlled Trial of Gestational Treatment With Ursodeoxycholic Acid Compared to Metformin to Reduce Effects of Diabetes Mellitus

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.

Read more

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.

Read the detailed description

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.

Being tested
Metformin, Ursodeoxycholic Acid
Medical subject headings
Diabetes, Gestational

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • MetforminDrug

    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
  • Ursodeoxycholic AcidDrug

    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
Study groups in NCT04407650
Study groupRoleWhat they receive
MetforminActive comparatorOral 1000 mg BD
Receives: Drug: Metformin
Ursodeoxycholic acidExperimentalOral 500 mg BD
Receives: Drug: Ursodeoxycholic Acid

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Glycaemic Control

    Maternal fasting glucose concentration in blood sample

    Measured: Gestational week 36

Secondary outcomes (18)
  1. Acceptability

    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)

    Measured: Gestational week 36

  2. Biomedical Outcomes: Glucose Control by HbA1c

    Glucose metabolism control measured by HbA1c concentration - change in Hba1c from 28 weeks to 36 weeks' gestation measured

    Measured: Baseline (gestational week 28), Follow up 2 (gestational week 36)

  3. Biomedical Outcomes: Lipids

    Lipid metabolism assessed by blood triglycerides in mmol/L

    Measured: Follow up 2 (gestational week 36)

  4. Biomedical Analyses: Bilirubin

    Maternal liver function tests: bilirubin

    Measured: Follow up 2 (gestational week 36)

  5. Biomedical Analyses: ALT

    Maternal liver function tests: ALT

    Measured: Follow up 2 (gestational week 36)

  6. Biomedical Analyses: Bile Acids

    Maternal liver function tests: bile acids

    Measured: Follow up 2 (gestational week 36)

  7. Biomedical Analyses: CRP

    Maternal liver function tests: C reactive protein

    Measured: Follow up 2 (gestational week 36)

  8. Clinical Maternal Outcomes: Insulin

    Proportion of women requiring insulin treatment

    Measured: From enrolment to birth (up to 16 weeks total duration, 0 weeks postnatal)

  9. Clinical Maternal Outcomes: Weight

    Maternal weight change across the duration of pregnancy - weight at 36 weeks minus that in the first trimester

    Measured: Follow up 2 (gestational week 36) compared to first trimester

  10. Blood Loss

    Estimated blood loss during birth

    Measured: Delivery

  11. Neonatal Outcomes: Mode of Birth

    Amongst all participants, caesarean section (elective \& emergency), assisted vaginal birth and spontaneous vaginal delivery numbers will be measured

    Measured: Delivery

  12. Neonatal Outcomes: Apgar Scores

    Apgar scores at 5 minutes post birth, count of the number with Apgar score <7. The Apgar score is a standard tool universally used to assess the neonate in the majority of birth settings - no modifications to this were made (see DOI: 10.1542/peds.2015-2651); it involves scoring 5 aspects of the neonate with 0,1 or 2, and summating all numbers to give a total score out of 10. Aspects scored are breathing, colour, heart rate, reflexes and tone.

    Measured: Delivery

  13. Neonatal Outcomes: Shoulder Dystocia

    Occurrence of shoulder dystocia recorded at time of birth. Shoulder dystocia is the bony impaction of the fetal shoulder on the maternal pelvis, and is defined by the need to perform maneuvers to assist birth of the baby.

    Measured: Delivery

  14. Neonatal Outcomes: Weight

    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

    Measured: Delivery

  15. Neonatal Outcomes: Morbidity

    Treatment for neonatal hypoglycaemia, neonatal jaundice, respiratory distress or birth trauma

    Measured: Delivery

  16. Neonatal Outcomes: Rate of Special Care Unit Admission.

    Neonatal intensive care and special care unit admission (duration of hospital stay)

    Measured: 28 days post delivery

  17. Stillbirth and Neonatal Death

    Occurrence of stillbirth or neonatal death

    Measured: Delivery

  18. Neonatal Outcomes: Gestational Age

    Gestational age at birth - recorded in whole gestational weeks

    Measured: Delivery

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted29 May 2020
  2. Study start18 Jun 2021
  3. Primary completion3 Oct 2024
  4. Study completion29 May 2025

Why it stopped: CTIMP randomised part of the study was halted early due to difficulty to recruit sufficient participants.

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 4
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Model description
Pilot Phase 4 Randomised Controlled Trial
Masking
None (open label)
Enrolment
55 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04407650
Sponsor's protocol ID
264693
Acronym
GUARD
Status last verified
Apr 2026
First submitted
14 May 2020
Last updated
28 Oct 2026
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No: CTIMP aspect of trial terminated early; nested substudy was exploratory and not appropriate for IPD meta-analysis

Publications

  • Lovell H, Mitchell A, Ovadia C, Pitrelli N, Briley A, Singh C, Marschall HU, Cruickshank K, Murphy H, Seed P, Williamson C. A multi-centered trial investigating gestational treatment with ursodeoxycholic acid compared to metformin to reduce effects of diabetes mellitus (GUARD): a randomized controlled trial protocol. Trials. 2022 Jul 19;23(1):571. doi: 10.1186/s13063-022-06462-y.

    PubMed 35854327

Questions about this trial

What is this clinical trial studying?

A Phase 4 study testing Metformin and Ursodeoxycholic Acid in people with Gestational Diabetes, run by King's College London at 1 site in United Kingdom.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 3 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 28 Oct 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 28 Oct 2026). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Glycaemic Control (time frame: Gestational week 36). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04407650, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 28 Oct 2026.

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