Metformin in Intrahepatic Cholestasis of Pregnancy (METRIC)

• ClinicalTrials.gov Identifier: NCT03056274
• Recruitment Status: Unknown
• First Posted: February 17, 2017
• Last Update Posted: July 26, 2018
• Sponsor: Epsom and St Helier University Hospitals NHS Trust
• Collaborators: King's College Hospital NHS Trust; Medway NHS Foundation Trust
• Information provided by (Responsible Party): Epsom and St Helier University Hospitals NHS Trust

Study Description

Brief Summary:

This is a pilot study aimed at comparing the effect of metformin versus ursodeoxycholic acid in women with intrahepatic cholestasis in pregnancy. The study will be conducted in three NHS hospital sites, over an 18 month period.

Condition or disease	Intervention/treatment	Phase
Intrahepatic Cholestases; Pregnancy Complications	Drug: Metformin; Drug: Ursodeoxycholic Acid	Phase 2; Phase 3

Detailed Description:

Intrahepatic cholestasis is a condition that affects pregnant women. It is characterised by itching, usually in the third trimester of pregnancy and is associated with an increase in the liver enzymes and bile salts. This can be associated with maternal and neonatal morbidity, and rarely perinatal mortality.

The investigators propose to assess and compare the effect of Metformin versus Ursodeoxycholic acid on lowering liver enzymes and bile salts, improving maternal morbidity and improving neonatal outcomes.

This study is a pilot study that will be conducted at 3 NHS hospital sites where patients will randomly assigned to receive either Metformin or Ursodeoxycholic acid. There will be 20 patient in each arm. Recruitment will commence in February 2017 and will run for an 18 month period.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 40 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Participant)
• Primary Purpose: Treatment
• Official Title: METformin in Intrahepatic Cholestasis of Pregnancy (METRIC) Study
• Estimated Study Start Date: January 2019
• Estimated Primary Completion Date: June 2019
• Estimated Study Completion Date: September 2019

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Metformin arm; Metformin	Drug: Ursodeoxycholic Acid; Ursodeoxycholic acid (UDCA) is used to treat gallstones and primary biliary cirrhosis. UDCA is also used to treat obstetric cholestasis (OC), a liver condition that occurs specifically in pregnancy.; Other Name: Destolit®, Urdox®, Ursofalk®, Ursogal®
Active Comparator: Ursodeoxycholic acid; Ursodeoxycholic acid	Drug: Metformin; Metformin Hydrochloride (HCl) Tablets, is an oral antihyperglycemic drug used in the management of type 2 diabetes; Other Name: Glucophage

Outcome Measures

Primary Outcome Measures :

1. Normalisation of maternal serum concentration of bile salts and liver enzymes [ Time Frame: From date of randomisation to date of delivery assessed up to 26 weeks ]
   Normalisation of Bile acids and liver enzymes - both parameters are the cornerstone for a diagnosis of intrahepatic cholestasis. They have been separated into two outcomes due to to the different laboratory indices of measurement. Results will be aggregated together to report number of patients with abnormal results
2. Normalisation of maternal serum concentration of liver enzymes [ Time Frame: From date of randomisation to date of delivery assessed up to 26 weeks ]
   Normalisation of liver enzymes Alanine transaminase Aspartate transaminase Bilirubin (total) Gamma glutamyl transferase Results will be aggregated together to report the number of patients with abnormal liver enzymes

Secondary Outcome Measures :

1. Fetal outcomes [ Time Frame: From date of randomisation to date of delivery assessed up to 26 weeks ]
   Perinatal death
2. Fetal outcomes [ Time Frame: From date of randomisation to date of delivery assessed up to 26 weeks ]
   Preterm delivery
3. Fetal outcomes [ Time Frame: Immediately upon delivery date ]
   Respiratory distress syndrome
4. Fetal outcomes [ Time Frame: Immediately upon delivery date ]
   Birth weight (g)
5. Fetal outcomes [ Time Frame: Immediately upon delivery date ]
   Birth weight percentile
6. Fetal outcomes [ Time Frame: Immediately upon delivery date ]
   Gestational age at delivery

Other Outcome Measures:

1. Fetal outcomes [ Time Frame: Immediately upon delivery date ]
   Presence of meconium
2. Fetal outcomes [ Time Frame: Immediately upon delivery date ]
   APGAR score at 5 minutes
3. Fetal outcomes [ Time Frame: Immediately upon delivery date ]
   Umbilical arterial pH at birth
4. Maternal outcomes [ Time Frame: From date of randomisation to date of delivery assessed up to 26 weeks ]
   Symptoms (itch) - assessed by questionnaire at clinic visits
5. Maternal outcomes [ Time Frame: From date of randomisation to date of delivery assessed up to 20 weeks ]
   Maximum dose of medication required
6. Maternal outcomes [ Time Frame: From date of randomisation to date of delivery assessed up to 20 weeks ]
   Gestational diabetes
7. Maternal outcomes [ Time Frame: From date of randomisation to date of delivery assessed up to 26 weeks ]
   Postpartum haemorrhage
8. Maternal outcomes [ Time Frame: From date of randomisation to date of delivery assessed up to 20 weeks ]
   Mode of delivery
9. Maternal outcomes [ Time Frame: From date of randomisation to date of delivery assessed up to 26 weeks ]
   Liver failure

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. 20+0 to 40 weeks' gestation on day of randomisation
2. Itching with a raised serum bile acid above the upper limit of normal
3. Normal anomaly scan at 20 weeks
4. Aged 18 years or over
5. Able to give written informed consent
6. No known pre-existing liver disease

Exclusion Criteria:

1. Decision already made for delivery within the next 48 hours
2. Known allergy to any component of the ursodeoxycholic acid or metformin tablets
3. Patients already on metformin for other conditions

Contacts and Locations

Contacts

Contact: Hassan Shehata, FRCPI, FRCOG; 01372 735735 ext 6887; hassan.shehata@esth.nhs.uk

Contact: Amanda Ali, MRCPI, MRCOG; amandaha.ali@gmail.com

Sponsors and Collaborators

Epsom and St Helier University Hospitals NHS Trust

King's College Hospital NHS Trust

Medway NHS Foundation Trust

Investigators

• Principal Investigator: Hassan Shehata, FRCPI, FRCOG; Epsom & St Helier University Trust

More Information

Publications of Results:

Elfituri A, Ali A, Shehata H. Managing Recurring Obstetric Cholestasis With Metformin. Obstet Gynecol. 2016 Dec;128(6):1320-1323.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Walker KF, Chappell LC, Hague WM, Middleton P, Thornton JG. Pharmacological interventions for treating intrahepatic cholestasis of pregnancy. Cochrane Database Syst Rev. 2020 Jul 27;7:CD000493. doi: 10.1002/14651858.CD000493.pub3.

• Responsible Party: Epsom and St Helier University Hospitals NHS Trust
• ClinicalTrials.gov Identifier: NCT03056274
• Other Study ID Numbers: RVR
• First Posted: February 17, 2017
• Last Update Posted: July 26, 2018
• Last Verified: January 2018

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• 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

Keywords provided by Epsom and St Helier University Hospitals NHS Trust:

Metformin; Ursodeoxycholic acid; Outcomes

Additional relevant MeSH terms:

Cholestasis; Cholestasis, Intrahepatic; Pregnancy Complications; Bile Duct Diseases; Biliary Tract Diseases; Digestive System Diseases; Liver Diseases; Metformin; Ursodeoxycholic Acid; Hypoglycemic Agents; Physiological Effects of Drugs; Cholagogues and Choleretics; Gastrointestinal Agents