Clinical trial NCT06364930: SGLT2i to Prevent of Liver Complications in Patients With CHB and Diabetes Mellitus
Official title: Sodium-glucose Co-transporter-2 Inhibitor (SGLT2i) to Prevent of Liver Complications in Patients With Chronic Hepatitis B and Diabetes Mellitus: a Double-blind, Randomised, Placebo-controlled Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Chronic Hepatitis B
Lead sponsor: Chinese University of Hong Kong
Sponsor class: OTHER
First posted: 2024-04-15
Enrollment: 412
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a five-year, double blinded, randomised trial of dapagliflozin versus placebo in patients with chronic hepatitis B and DM or IFG complicated with compensated advanced chronic liver disease (cACLD). 412 subjects will be recruited. Subject will be randomly assigned to receive dapagliflozin 10mg daily or dapagliflozin placebo one tablet daily for up to 5 years. After randomization, subject will be followed up at month 3, month 6 and then 6-monthly until 60 months (follow up ± 4 weeks from scheduled clinic visit is allowed). At each visit, drug compliance, physical examination, observed or reported adverse events will be assessed. 10ml of blood will be taken at each visit and transient elastography to assess fibrosis regression will be performed at 60th month or at withdrawal visit. You are discouraged to use (pegylated)-interferon, any other NA including lamivudine, adefovir, and telbivudine, another SGLT2i Empagliflozin (Jardiance), Dapagliflozin + Metformin XR (Xigduo).

Detailed description: Chronic hepatitis B virus (HBV) infection is a global health problem affecting approximately 234 million people worldwide; of those three-quarter come from the Asia-Pacific region.1 Up to 30%-40% of chronically infected persons will die of liver complications, including liver cancer and cirrhotic complications.2 The Global Burden of Disease Study 2016 revealed HBV as one of the top ten killers worldwide.3 Chronic HBV infection also represents a major global economic burden; with increasing socioeconomic costs.4 Majority of the liver complications and deaths is related to hepatocellular carcinoma (HCC) because of its high incidence rate and unfavourable clinical course.5

Sodium-glucose co-transporter-2 inhibitors (SGLT2i) is a potent antidiabetic agent that lowers blood glucose by inducing renal glycosuria.15 SGLT2i reduces cardiovascular and renal events by marked cardiac anti-fibrotic and anti-inflammatory effects,16 on top of dramatic weight reduction.6 A recent open-label, pilot study of nine patients with biopsy-proven non-alcoholic steatohepatitis (NASH) with type 2 DM received a SGLT2i (empagliflozin) 25 mg daily, for 24 weeks. SGLT2i led to histological improvement in steatosis, ballooning, and fibrosis, compared with historical placebo.7 SGLT2i also leads to more significant reduction of ALT.8 Several other randomised trials and cohort studies supported that SGLT2i also reduces liver fat content and liver fibrosis scores. SGLT2i has additional benefits on liver histology compared to other antidiabetic agents.8 The key pathways include control of hepatic inflammation and fibrosis, improvement of insulin resistance, and reduction of hepatic steatosis. The related mechanisms involve inflammatory parameters like high-sensitivity C-reactive protein, proinflammatory cytokines like interleukin-6 or TNF-alpha, reactive oxygen species and the inhibition of AMPc activation. The improvement was correlated with reductions in body weight, waist circumference and inflammatory parameters. The improvement was not correlated with changes in glucose control.9 All these favourable effects on liver have make it potentially useful to reduce liver complications.

Chronic hepatitis B is major cause of liver complications and death. Antiviral treatment with oral nucleos(t)ide analogues reduces but not abolish the risk of liver complications, especially in those with diabetes mellitus. Sodium-glucose co-transporter-2 inhibitors (SGLT2i) are promising in improving liver outcome in patients with chronic hepatitis B and diabetes mellitus. Our preliminary data provide strong plausibility that SGLT2i reduces the risk of liver complications. We are going to provide the definitive answer to this important clinical question through a randomised trial.

Eligibility criteria: Inclusion Criteria:

1. Patients with chronic hepatitis B on ETV, TDF or TAF monotherapy for at least 12 months.
2. Known or newly diagnosed type 2 diabetes mellitus (T2D), defined as HbA1c ≥5.7% or fasting blood sugar ≥5.6 mmol/L, or random blood sugar ≥11.1 mmol/L, or 2 hours sugar after oral glucose tolerance test ≥7.8 mmol/L.
3. Stable use of anti-diabetic drugs in the last three months.
4. Presence of compensated advanced chronic liver disease (cACLD) with liver stiffness measurement \>10.0 kPa, or significant portal hypertension (spleen stiffness measurement \> 41.3 kPa), or presence any sign of portal hypertension (e.g. splenomegaly, ascites, varices)
5. Aged 18 years old or above.
6. Written informed consent obtained.

Exclusion Criteria:

1. Patients with hepatitis C virus (HCV) infection as indicated by a positive antibody to HCV (anti-HCV) serology test.
2. Patients with history of cirrhotic complications or hepatocellular carcinoma
3. Patients with organ transplantation
4. Patients receiving a SGLT2i
5. Contraindications to SGLT2i due to renal insufficiency (GFR \< 45 mL/min/1.73m2)
6. Poor glycaemic control with HbA1c \>9.0%
7. Use of multiple anti-diabetic drugs (3 or more)
8. Change in anti-diabetic drugs in the last three months.
9. Serious medical illnesses or malignancy
10. Age \< 18 years
11. No patient consents

Primary outcomes:
measure: The primary endpoint is liver complications
timeFrame: 60 months
Secondary outcomes:
measure: Cardiovascular complications
timeFrame: 60 months
measure: change in liver stiffness measurement
timeFrame: 60 months
measure: change anthropometric parameters (body weight)
timeFrame: 60 months
measure: change anthropometric parameters (waist-hip ratio)
timeFrame: 60 months
Other outcomes:
Locations:
city: Hong Kong
country: Hong Kong
facility: Prince of Wales Hospital
Study officials:
affiliation: Chinese University of Hong Kong
name: Grace LH Wong, MD
role: PRINCIPAL_INVESTIGATOR
References:
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citation: Shrikrishnapalasuriyar N, Shaikh A, Ruslan AM, Sharaf G, Udiawar M, Price DE, Stephens JW. Dapagliflozin is associated with improved glycaemic control and weight reduction at 44 months of follow-up in a secondary care diabetes clinic in the UK. Diabetes Metab Syndr. 2020 May-Jun;14(3):237-239. doi: 10.1016/j.dsx.2020.03.007. Epub 2020 Mar 26.
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