Clinical trial NCT05147090: Effects of Empagliflozin on Fibrosis and Cirrhosis in Chronic Hepatitis B
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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Chronic Hepatitis b
NAFLD
Cirrhosis
Fibrosis, Liver
Empagliflozin
SGLT2 Inhibitors
Lead sponsor: The University of Hong Kong
Sponsor class: OTHER
Collaborators: name: Research Grant Council
First posted: 2021-12-07
Enrollment: 106
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Eligible subjects will be randomly allocated to either the empagliflozin group or placebo group (i.e. control group)
Primary purpose: TREATMENT

Brief 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.

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.

Eligibility criteria: 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).

Primary outcomes:
measure: Change in liver stiffness (measured by MRE)
timeFrame: week 156
Secondary outcomes:
measure: Remission of significant/advanced fibrosis and cirrhosis
timeFrame: week 156
measure: Progression of significant/advanced fibrosis to cirrhosis (measured by MRE)
timeFrame: week 156
measure: Progression to decompensated cirrhosis
timeFrame: week 156
measure: Change in liver stiffness (measured by transient elastography)
timeFrame: week 26, 52, 104 and 156
measure: Change in fat content (measured by transient elastography)
timeFrame: week 26, 52, 104 and 156
measure: Changes of alanine aminotransferase (ALT)
timeFrame: week 26, 52, 104 and 156
measure: Changes of aspartate aminotransferase (AST)
timeFrame: week 26, 52, 104 and 156
measure: Changes of alkaline phosphatase (ALP)
timeFrame: week 26, 52, 104 and 156
measure: Changes of gamma glutamyl transferase (GGT)
timeFrame: week 26, 52, 104 and 156
measure: Changes of fasting glucose
timeFrame: week 26, 52, 104 and 156
measure: Changes of haemoglobin A1c (HbA1c)
timeFrame: week 26, 52, 104 and 156
measure: Changes of total cholesterol
timeFrame: week 26, 52, 104 and 156
measure: Changes of low density lipoprotein (LDL)
timeFrame: week 26, 52, 104 and 156
measure: Changes of high density lipoprotein (HDL)
timeFrame: week 26, 52, 104 and 156
measure: Changes of body weight
timeFrame: week 26, 52, 104 and 156
measure: Changes of body mass index (BMI)
timeFrame: week 26, 52, 104 and 156
measure: Changes of waist circumference
timeFrame: week 26, 52, 104 and 156
measure: Changes of systolic blood pressure
timeFrame: week 26, 52, 104 and 156
measure: Changes of diastolic blood pressure
timeFrame: week 26, 52, 104 and 156
Other outcomes:
Locations:
city: Hong Kong
country: Hong Kong
facility: The University of Hong Kong/Queen Mary Hospital
state: Hong Kong, China
Study officials:
affiliation: The University of Hong Kong
name: Ka Shing Cheung, MD, MPH
role: PRINCIPAL_INVESTIGATOR
References: