- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT05147090
Effects of Empagliflozin on Fibrosis and Cirrhosis in Chronic Hepatitis B
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
Status
Intervention / Treatment
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
Enrollment (Estimated)
Phase
- Phase 4
Contacts and Locations
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
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
Inclusion Criteria:
- Patients will be recruited if they have significant/advanced fibrosis or cirrhosis confirmed by MRE
Exclusion Criteria:
- decompensated cirrhosis (variceal bleeding, ascites, hepatic hydrothorax, hepatic encephalopathy),
- portal vein thrombosis,
- alcohol intake >20g within last 2 years,
- concurrent chronic liver disease (chronic hepatitis C infection, autoimmune hepatitis, Wilson's disease, hemochromatosis, primary biliary cholangitis, drug-induced),
- history of malignancy including hepatocellular carcinoma (HCC),
- pregnancy,
- contraindications to empagliflozin (estimated glomerular filtration rate (eGFR) <45mL/min/1.73m2, recurrent genitourinary tract infections, gangrene, allergy),
- contraindications to MRI (e.g., claustrophobia, implanted devices with ferromagnetic properties).
Study Plan
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:
|
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:
|
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
Sponsor
Collaborators
Investigators
- Principal Investigator: Ka Shing Cheung, MD, MPH, The University of Hong Kong
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Estimated)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Estimated)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Digestive System Diseases
- Pathologic Processes
- RNA Virus Infections
- Virus Diseases
- Infections
- Blood-Borne Infections
- Communicable Diseases
- Disease Attributes
- Liver Diseases
- Hepatitis, Viral, Human
- Hepadnaviridae Infections
- DNA Virus Infections
- Enterovirus Infections
- Picornaviridae Infections
- Chronic Disease
- Fibrosis
- Hepatitis B
- Hepatitis
- Hepatitis A
- Hepatitis B, Chronic
- Hepatitis, Chronic
- Liver Cirrhosis
- Hypoglycemic Agents
- Physiological Effects of Drugs
- Molecular Mechanisms of Pharmacological Action
- Sodium-Glucose Transporter 2 Inhibitors
- Empagliflozin
Other Study ID Numbers
- UW-21023
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
IPD Plan Description
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
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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