Ursodeoxycholic Acid vs Metformin in Gestational Diabetes Mellitus (GUARD)

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.

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.

Study Overview

• Status: Recruiting
• Conditions: Gestational Diabetes
• Intervention / Treatment: Drug: Metformin; Drug: Ursodeoxycholic Acid

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.

• Study Type: Interventional
• Enrollment (Anticipated): 158
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Jennifer Crook, Trial Manager; Phone Number: 53378 00442071887188; Email: Jennifer.Crook@gstt.nhs.uk
• Study Contact Backup: Name: Holly Lovell, Midwife; Email: holly.lovell@gstt.nhs.uk

Study Locations

• United Kingdom
  • London, United Kingdom, SE1 7EH
    • Recruiting
    • Guy'S and St Thomas' Nhs Foundation Trust
    • Contact: Catherine Williamson; Email: catherine.williamson@kcl.ac.uk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 45 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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, intrapartum and postpartum care at the participating centre (i.e. not planning to move before delivery).

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 >48 mmol/mol or ≥6.5% during current pregnancy (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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Metformin; Oral 1000 mg BD	Drug: Metformin; 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
Experimental: Ursodeoxycholic acid; Oral 500 mg BD	Drug: Ursodeoxycholic Acid; 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Glycaemic control	Maternal fasting glucose concentration in blood sample	Gestational week 36

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)	Gestational week 36
Biomedical outcomes: continuous glucose monitoring	Glucose metabolism control measured by continuous glucose monitors to establish whether continuous glucose monitoring gives more informative overall assessment of maternal glycaemic control	Baseline (week 28), Follow up 1 (week 32), Follow up 2 (week 36)
Biomedical outcomes: 1,5-anhydroglucitol	Glucose metabolism control measured by serum concentrations of 1,5-anhydroglucitol	Baseline (week 28), Follow up 1 (week 32), Follow up 2 (week 36)
Biomedical outcomes: glucose control by HbA1c	Glucose metabolism control measured by HbA1c concentration	Baseline (week 28), Follow up 2 (week 36)
Biomedical outcomes: lipids	Lipid metabolism assessed by blood triglyceride, total cholesterol, calculated LDL-cholesterol, HDL-cholesterol and free fatty acid concentrations, all in mmol/L	Follow up 2 (week 36)
Biomedical analyses: bilirubin	Maternal liver function tests: bilirubin	Follow up 2 (week 36)
Biomedical analyses: ALT	Maternal liver function tests: ALT	Follow up 2 (week 36)
Biomedical analyses: bile acids	Maternal liver function tests: bile acids	Follow up 2 (week 36)
Biomedical analyses: CRP	Maternal liver function tests: C reactive protein	Follow up 2 (week 36)
Clinical maternal outcomes: insulin	Proportion of women requiring insulin treatment (time until treatment and dose)	From enrolment to birth
Clinical maternal outcomes: weight	Maternal weight change	Follow up 2 (week 36) compared to first trimester
Maternal vascular responses (I)	maternal pulse wave velocity (PWV)	Follow up 1 (week 32), Follow up 2 (week 36)
Maternal vascular responses (II)	systolic and diastolic blood pressure	Follow up 1 (week 32), Follow up 2 (week 36)
Maternal vascular responses (III)	central arterial pressure (cP)	Follow up 1 (week 32), Follow up 2 (week 36)
Maternal vascular responses (IV)	Augmentation index (AIx)	Follow up 1 (week 32), Follow up 2 (week 36)
Blood loss	Estimated blood loss during birth	Delivery
Neonatal outcomes: mode of birth	Amongts all participants, caesarean section (elective & emergency), assisted vaginal birth and spontaneous vaginal delivery numbers will be measured	Delivery
Neonatal outcomes: gestational age	Gestational age at birth	Delivery
Neonatal outcomes: apgar scores	Apgar scores at 5 minutes post birth	Delivery
Neonatal outcomes: shoulder dystocia	Occurrence of shoulder dystocia	Delivery
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	Delivery
Neonatal outcomes: morbidity	Treatment for neonatal hypoglycaemia, neonatal jaundice, respiratory distress or birth trauma	Delivery
Neonatal outcomes: rate of special care unit admission.	Neonatal intensive care and special care unit admission (duration of hospital stay)	28 days post delivery
Stillbirth and neonatal death	Occurrence of stillbirth and neonatal death	Delivery
Biomedical neonatal outcomes	Cord blood C-peptide, triglyceride, total cholesterol, calculated LDL-cholesterol, HDL-cholesterol and free fatty acid concentrations all in mmol/L	Delivery

Collaborators and Investigators

• Sponsor: King's College London
• Collaborators: Guy's and St Thomas' NHS Foundation Trust
• Investigators: Principal Investigator: Catherine Williamson, CI, King's College London

Publications and helpful links

General 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.

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2021
• Primary Completion (Anticipated): January 31, 2023
• Study Completion (Anticipated): June 30, 2023

Study Registration Dates

• First Submitted: May 14, 2020
• First Submitted That Met QC Criteria: May 26, 2020
• First Posted (Actual): May 29, 2020

Study Record Updates

• Last Update Posted (Actual): August 19, 2022
• Last Update Submitted That Met QC Criteria: August 17, 2022
• Last Verified: March 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Pregnancy Complications; Diabetes Mellitus; Diabetes, Gestational; Hypoglycemic Agents; Physiological Effects of Drugs; Gastrointestinal Agents; Cholagogues and Choleretics; Metformin; Ursodeoxycholic Acid
• Other Study ID Numbers: 264693

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No