Effects of Metformin on Hepatic Venous Pressure Gradient in Patients With Cirrhosis and Portal Hypertension

NCT06687265 | Recruiting Phase 2 DMC

• 1 other identifier: APHP230872
• Study Type: interventional
• Target: 76
• Locations: 1 country
• Sites: 1

Brief Summary

Portal hypertension (PHT) is defined by an elevated pressure gradient between the portal vein and the hepatic veins ≥ 5 mm Hg, and is the main vector of complications in cirrhosis. When the hepatic venous pressure gradient (HVPG) is ≥ 10 mm Hg, it is considered as a " clinically significant PHT ": ascites and oesophageal varices (EV) may occur. Above 12 mm Hg, there is a risk of variceal bleeding. Carvedilol, a non-selective beta-blocker (NSBB), is recommended in all the patients with cirrhosis and clinically significant PHT in order to prevent decompensation of cirrhosis. Nevertheless, 40 % of patients are NSBB non-responders, i.e. they do not show a significant decrease in HVPG. In addition, NSBB responders treated for primary prophylaxis have an incidence of variceal bleeding of approximately 10% per year, with a six-week mortality of 20%. Therefore, there is an unmet need for PHT in patients with cirrhosis who do not respond to NSBB, and also for an increase in efficacy in responders. In a randomised pilot study, Rittig et al. observed a mean change in HVPG of -2,9 mm Hg in 16 patients with cirrhosis and HVPG ≥ 12 mm Hg, not treated with NSBB, 90 minutes after ingestion of 1000 mg metformin. The study will be a prospective, national, multicentre, phase II, superiority comparative randomized (1:1) simple-blinded clinical trial with two parallel arms: metformin versus placebo. The main objective is to evaluate the effect of metformin versus placebo during 28 days on HVPG, in patients with cirrhosis and a HVPG ≥ 12 mm Hg already treated with carvedilol. Subjects randomized in the metformin group or placebo group will receive metformin ou placebo, one pill of 500 mg per os twice a day (one in the morning and one in the evening, during or at the end of the meal) for 28 days.

Conditions

Cirrhosis; Portal Hypertension Related to Cirrhosis

Keywords

cirrhosis; portal hypertension; metformin; hepatic venous pressure gradient; carvedilol

Outcome Measures

Primary Outcomes (1)

• effect of metformin versus placebo during 28 days on HVPG, in patients with cirrhosis and a HVPG ≥ 12 mm Hg already treated with carvedilol.

  HVPG measures before and after metformin or placebo treatment

  after 28 days of treatment

Secondary Outcomes (18)

• the rate of patients with a clinically significant improvement in HVPG

  after 28 days of treatment

• Change in cirrhosis severity MELD score

  after 28 days of treatment

• Change in cirrhosis severity Child-Pugh score

  after 28 days of treatment

• change in systemic haemodynamics

  after 28 days of treatment

• the tolerability of metformin in patients with cirrhosis and a HVPG ≥ 12 mm Hg

  after 28 days of treatment

Study Arms (2)

METFORMIN GROUP

EXPERIMENTAL

Drug: Metformin

PLACEBO GROUP

PLACEBO COMPARATOR

Drug: Placebo

Interventions

Metformin DRUG

one pill of 500 mg per os twice a day for 28 days.

METFORMIN GROUP

Placebo DRUG

one pill per os twice a day for 28 days.

PLACEBO GROUP

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• \- Age ≥ 18 years
• Written informed consent to participate in the study
• Medical insurance coverage
• For child-bearing aged women, contraception using oestroprogestative, progestative, intrauterine device, or mechanical contraception
• Diagnosis of cirrhosis based on a liver biopsy, or on clinical, biological, endoscopic, and radiological evidence
• Active cause of cirrhosis, or resolution (alcohol cessation, sustained virological response to direct-acting antiviral treatment for HCV, initiation of nucleoside/nucleotide analog treatment for HBV) for at least 6 months
• Child-Pugh A or B
• High likelihood of HVPG ≥ 12 mm Hg based on investigator's judgement, or on the following criteria:
• Investigator's judgement
• active cause of cirrhosis and:
• History of clinical ascites
• Or history of variceal bleeding
• Or liver stiffness by VCTE ≥ 35 kPa on carvedilol in the last two years
• or spleen stiffness by VCTE ≥ 55 kPa on carvedilol in the last two years
• or liver surface nodularity ≥ 2,9 in the last two years

You may not qualify if:

• Serum total bilirubin \> 50 µmol/L
• Prothrombin ratio \< 50 %
• Transaminases \> 5 ULN
• Need for at least one paracentesis for ascites fluid evacuation in the last 6 months
• Expected follow-up \< 3 months
• Known hypersensitivity to the active substance or any of the excipients
• History of lactic acidosis, diabetic acidocetosis, or diabetic precoma
• Ongoing condition that may lead to acute kidney injury or hypoxia: dehydration, severe infection, shock, cardiac decompensation, respiratory failure, or myocardial infarction within the past month
• Known hypersensitivity to all the iodin-containing contrast agents
• Known hypersensitivity to lidocaine for local anesthesia
• Known hypersensitivity to beta-lactam antibiotics if the patient has a history of valve replacement
• Alcohol consumption \> 14 units/week for women or \> 21 units/week for men, current or abstinent for less than 6 months
• Biliary cirrhosis
• Hepatocellular carcinoma with at least one nodule \> 3 cm in diameter, or more than 3 nodules
• Cholangiocarcinoma

Sponsors & Collaborators

• Assistance Publique - Hôpitaux de Paris: lead

Study Sites (1)

Facility Name: Beaujon hospital

Clichy, France, 92110, France

RECRUITING

Related Publications (1)

• Rittig N, Aagaard NK, Villadsen GE, Sandahl TD, Jessen N, Gronbaek H, George J. Randomised clinical study: acute effects of metformin versus placebo on portal pressure in patients with cirrhosis and portal hypertension. Aliment Pharmacol Ther. 2021 Aug;54(3):320-328. doi: 10.1111/apt.16460. Epub 2021 Jun 24.

  PMID: 34165199 BACKGROUND

MeSH Terms

Conditions

Fibrosis; Hypertension, Portal

Interventions

Metformin

Condition Hierarchy (Ancestors)

Pathologic Processes; Pathological Conditions, Signs and Symptoms; Liver Diseases; Digestive System Diseases

Intervention Hierarchy (Ancestors)

Biguanides; Guanidines; Amidines; Organic Chemicals

Central Study Contacts

LUCILE MOGA

CONTACT

01 71 11 46 69; lucile.moga@aphp.fr

PIERRE EMMANUEL RAUTOU

CONTACT

01 40 87 52 83; pierre-emmanuel.rautou@aphp.fr

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 31, 2024
• First Posted: November 13, 2024
• Study Start: March 10, 2025
• Primary Completion (Estimated): March 30, 2027
• Study Completion (Estimated): July 31, 2027
• Last Updated: April 13, 2025

Record last verified: 2024-11

Locations

FR (1)