Effects of Empagliflozin on Fibrosis and Cirrhosis in Chronic Hepatitis B

December 6, 2023 updated by: The University of Hong Kong

Effects of Empagliflozin on Preventing Fibrosis and Cirrhosis Progression in Nucleos(t)Ide Analogue-treated Chronic Hepatitis B Patients With Significant/Advanced Fibrosis or Cirrhosis: a Randomized, Double-blind Placebo-controlled Trial

Chronic hepatitis B (CHB) affects 257million individuals worldwide. In 2017, it caused around 39.7 million cases of cirrhosis and 0.4 million cirrhosis-related deaths in 2017. However, there is no specific treatment for liver fibrosis/cirrhosis. Although nucleos(t)ide analogues (NAs) profoundly suppress viral replication, fibrosis/cirrhosis progression can still occur in NA-treated patients.

Sodium-glucose cotransporter type-2 (SGLT2) inhibitors are antidiabetic drugs that may prevent fibrosis/cirrhosis progression by reducing hepatic steatosis/inflammation, dampening renin-angiotensin aldosterone system (RAAS) activation, and reducing fluid retention, effects of which are independent of glycemic control. Clinical studies in diabetic patients show SGLT2 inhibitors reduce hepatis steatosis/inflammation, regress ascites (a cirrhotic complication), and improve liver function parameters and survival prognosis in terms of model for end-stage liver disease (MELD) score. There are currently no randomized controlled trials (RCTs) on role of SGLT2 inhibitors in preventing fibrosis/cirrhosis progression in CHB patients. Magnetic resonance elastography (MRE) and transient elastography (TE) are non-invasive techniques for liver stiffness measurement (LSM), although MRE is more accurate than TE.

The investigators propose a double-blind, randomized, placebo-controlled trial to compare effect of empagliflozin (an SGLT2 inhibitor) with placebo (1:1 ratio) in preventing fibrosis progression in both diabetic and non-diabetic NA-treated CHB patients with significant/advanced fibrosis or compensated cirrhosis. 108 patients will be randomly sampled from our pre-existing TE database. Empagliflozin 10mg daily will be given to treatment arm. Placebo pills will be manufactured identical in appearance to empagliflozin. Subjects will receive active or placebo pills for three years, and undergo clinical, anthropometric and laboratory assessments (at baseline, weeks 8, 16, and every 4 months thereafter). They will undergo LSM by TE at baseline, end of first, second and third year, and by MRE at baseline and end of third year. Primary outcome is difference in change to liver stiffness (measured by MRE) from baseline between the two groups at the end of third year.

The study results will determine whether SGLT2 inhibitors can prevent hepatic fibrosis/cirrhosis progression in NA-treated CHB patients.

Study Overview

Detailed Description

Chronic hepatitis B (CHB) affects 257million individuals worldwide. In 2017, it caused around 39.7 million cases of cirrhosis and 0.4 million cirrhosis-related deaths in 2017. However, there is no specific treatment for liver fibrosis/cirrhosis. Although nucleos(t)ide analogues (NAs) profoundly suppress viral replication, fibrosis/cirrhosis progression can still occur in NA-treated patients.

Sodium-glucose cotransporter type-2 (SGLT2) inhibitors are antidiabetic drugs that may prevent fibrosis/cirrhosis progression by reducing hepatic steatosis/inflammation, dampening renin-angiotensin aldosterone system (RAAS) activation, and reducing fluid retention, effects of which are independent of glycemic control. Clinical studies in diabetic patients show SGLT2 inhibitors reduce hepatis steatosis/inflammation, regress ascites (a cirrhotic complication), and improve liver function parameters and survival prognosis in terms of model for end-stage liver disease (MELD) score. Our preliminary data from a territory-wide electronic healthcare database shows SGLT2 inhibitors were associated with 58% reduction in risk of cirrhosis development over three years among CHB patients with diabetes (n=9,502). There are currently no randomized controlled trials (RCTs) on role of SGLT2 inhibitors in preventing fibrosis/cirrhosis progression in CHB patients. Magnetic resonance elastography (MRE) and transient elastography (TE) are non-invasive techniques for liver stiffness measurement (LSM), although MRE is more accurate than TE.

The novelty of utilizing "drug repositioning" by changing role of SGLT2 inhibitors in treating diabetes mellitus (DM) to preventing fibrosis/cirrhosis progression in CHB deserves exploration. We propose a double-blind, randomized, placebo-controlled trial to compare effect of empagliflozin (an SLGT2 inhibitor) with placebo (1:1 ratio) in reducing liver stiffness in both diabetic and non-diabetic NA-treated CHB patients with significant/advanced fibrosis or compensated cirrhosis. 108 patients will be randomly sampled from our pre-existing TE database. Empagliflozin 10mg daily will be given to treatment arm. Placebo pills will be manufactured identical in appearance to empagliflozin. Subjects will receive active or placebo pills for three years, and undergo clinical, anthropometric and laboratory assessments (at baseline, weeks 8, 16, and every 4 months thereafter). They will undergo LSM by TE at baseline, end of first, second and third year, and by MRE at baseline and end of third year. Primary outcome is difference in change to liver stiffness (measured by MRE) from baseline between the two groups at the end of third year. Secondary outcomes are remission of advanced fibrosis/cirrhosis, progression of advanced fibrosis to cirrhosis, improvement of laboratory results (liver transaminases, ferritin, glucose, lipid profiles) and anthropometric measurements.

The study results will determine whether SGLT2 inhibitors can prevent hepatic fibrosis/cirrhosis progression in NA-treated CHB patients.

Study Type

Interventional

Enrollment (Estimated)

106

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

  • Name: Ka Shing Cheung, MD, MPH
  • Phone Number: 852 22556979
  • Email: cks634@hku.hk

Study Locations

    • Hong Kong, China
      • Hong Kong, Hong Kong, China, Hong Kong, 852
        • Recruiting
        • The University of Hong Kong/Queen Mary Hospital
        • Contact:
          • Ka Shing Cheung, MD, MPH
          • Phone Number: 852 22553632
          • Email: cks634@hku.hk

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 80 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Patients will be recruited if they have significant/advanced fibrosis or cirrhosis confirmed by MRE

Exclusion Criteria:

  1. decompensated cirrhosis (variceal bleeding, ascites, hepatic hydrothorax, hepatic encephalopathy),
  2. portal vein thrombosis,
  3. alcohol intake >20g within last 2 years,
  4. concurrent chronic liver disease (chronic hepatitis C infection, autoimmune hepatitis, Wilson's disease, hemochromatosis, primary biliary cholangitis, drug-induced),
  5. history of malignancy including hepatocellular carcinoma (HCC),
  6. pregnancy,
  7. contraindications to empagliflozin (estimated glomerular filtration rate (eGFR) <45mL/min/1.73m2, recurrent genitourinary tract infections, gangrene, allergy),
  8. contraindications to MRI (e.g., claustrophobia, implanted devices with ferromagnetic properties).

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Empagliflozin group
Empagliflozin 10mg daily for 156 weeks
Empagliflozin 10mg daily
Other Names:
  • empagliflozin
Placebo Comparator: Placebo group
Placebo pills (identical in appearance to empagliflozin 10mg) daily for 156 weeks
Identical in appearance to empagliflozin 10mg daily
Other Names:
  • placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in liver stiffness (measured by MRE)
Time Frame: week 156
difference in change to liver stiffness from baseline between the two groups at the end of year 3 as measured by MRE
week 156

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Remission of significant/advanced fibrosis and cirrhosis
Time Frame: week 156
Remission of advanced fibrosis and cirrhosis (defined as a decrease in 1 fibrosis stage using MRE) at the end of year 3
week 156
Progression of significant/advanced fibrosis to cirrhosis (measured by MRE)
Time Frame: week 156
Progression of significant/advanced fibrosis to cirrhosis (as defined by MRE) at the end of year 3
week 156
Progression to decompensated cirrhosis
Time Frame: week 156
Progression to decompensated cirrhosis (ascites, variceal bleeding and/or hepatic encephalopathy) at the end of year 3
week 156
Change in liver stiffness (measured by transient elastography)
Time Frame: week 26, 52, 104 and 156
Difference in serial changes to liver stiffness from baseline between the two groups (LSM measured by transient elastography)
week 26, 52, 104 and 156
Change in fat content (measured by transient elastography)
Time Frame: week 26, 52, 104 and 156
Difference in serial changes to liver fat content from baseline between the two groups (CAP measured by transient elastography)
week 26, 52, 104 and 156
Changes of alanine aminotransferase (ALT)
Time Frame: week 26, 52, 104 and 156
Changes of ALT at week 26, 52, 104 and 156
week 26, 52, 104 and 156
Changes of aspartate aminotransferase (AST)
Time Frame: week 26, 52, 104 and 156
Changes of AST at week 26, 52, 104 and 156
week 26, 52, 104 and 156
Changes of alkaline phosphatase (ALP)
Time Frame: week 26, 52, 104 and 156
Changes of ALP at week 26, 52, 104 and 156
week 26, 52, 104 and 156
Changes of gamma glutamyl transferase (GGT)
Time Frame: week 26, 52, 104 and 156
Changes of GGT at week 26, 52, 104 and 156
week 26, 52, 104 and 156
Changes of fasting glucose
Time Frame: week 26, 52, 104 and 156
Changes of fasting glucose at week 26, 52, 104 and 156
week 26, 52, 104 and 156
Changes of haemoglobin A1c (HbA1c)
Time Frame: week 26, 52, 104 and 156
Changes of HbA1c at week 26, 52, 104 and 156
week 26, 52, 104 and 156
Changes of total cholesterol
Time Frame: week 26, 52, 104 and 156
Changes of total cholesterol at week 26, 52, 104 and 156
week 26, 52, 104 and 156
Changes of low density lipoprotein (LDL)
Time Frame: week 26, 52, 104 and 156
Changes of LDL at week 26, 52, 104 and 156
week 26, 52, 104 and 156
Changes of high density lipoprotein (HDL)
Time Frame: week 26, 52, 104 and 156
Changes of HDL at week 26, 52, 104 and 156
week 26, 52, 104 and 156
Changes of body weight
Time Frame: week 26, 52, 104 and 156
Changes of body weight at week 26, 52, 104 and 156
week 26, 52, 104 and 156
Changes of body mass index (BMI)
Time Frame: week 26, 52, 104 and 156
Changes of BMI at week 26, 52, 104 and 156
week 26, 52, 104 and 156
Changes of waist circumference
Time Frame: week 26, 52, 104 and 156
Changes of waist circumference at week 26, 52, 104 and 156
week 26, 52, 104 and 156
Changes of systolic blood pressure
Time Frame: week 26, 52, 104 and 156
Changes of systolic blood pressure at week 26, 52, 104 and 156
week 26, 52, 104 and 156
Changes of diastolic blood pressure
Time Frame: week 26, 52, 104 and 156
Changes of diastolic blood pressure at week 26, 52, 104 and 156
week 26, 52, 104 and 156

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Collaborators

Investigators

  • Principal Investigator: Ka Shing Cheung, MD, MPH, The University of Hong Kong

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

January 2, 2022

Primary Completion (Estimated)

December 31, 2025

Study Completion (Estimated)

December 31, 2025

Study Registration Dates

First Submitted

November 22, 2021

First Submitted That Met QC Criteria

December 6, 2021

First Posted (Actual)

December 7, 2021

Study Record Updates

Last Update Posted (Estimated)

December 7, 2023

Last Update Submitted That Met QC Criteria

December 6, 2023

Last Verified

December 1, 2023

More Information

Terms related to this study

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

IPD Plan Description

Individual participant data (IPD) will be made available in the form of excel files upon request by other researchers

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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