Effects of Empagliflozin on Fibrosis and Cirrhosis in Chronic Hepatitis B

Cirrhosis Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05147090
• Other study ID #: UW-21023
• Status: Recruiting
• Phase: Phase 4
• Start date: January 2, 2022
• Est. completion date: December 31, 2025

Study information

• Verified date: December 2023
• Source: The University of Hong Kong
• Contact: Ka Shing Cheung, MD, MPH
• Phone: 22556979
• Email: cks634[@]hku.hk
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 106
• Est. completion date: December 31, 2025
• Est. primary completion date: December 31, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

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).

Related Conditions & MeSH terms

• Chronic Hepatitis b
• Cirrhosis
• Fibrosis
• Fibrosis, Liver
• Hepatitis
• Hepatitis A
• Hepatitis B
• Hepatitis B, Chronic
• Hepatitis, Chronic
• Liver Cirrhosis
• NAFLD

Intervention

Drug:
• Empagliflozin 10 MG
Empagliflozin 10mg daily
• Placebo pills
Identical in appearance to empagliflozin 10mg daily

Locations

Country	Name	City	State
Hong Kong	The University of Hong Kong/Queen Mary Hospital	Hong Kong	Hong Kong, China

Sponsors (2)

Lead Sponsor	Collaborator
The University of Hong Kong	Research Grant Council

Country where clinical trial is conducted

Hong Kong, 

Outcome

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