Efficacy and Safety of Dapagliflozin in Patients With Non-alcoholic Steatohepatitis

Study Overview
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Brief Summary
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Patients with non-alcoholic fatty liver disease (NAFLD) are at increased risk of more aggressive liver disease; non-alcoholic steatohepatitis (NASH) and at a higher risk of death from cirrhosis, hepatocellular carcinoma and cardiovascular diseases. NAFLD is spreading as an epidemic in patients with metabolic syndrome. Its components include obesity, type 2 diabetes mellitus (T2DM) and dyslipidemia. The prevalence of NAFLD is likely to increase resulting in tremendous clinical, social and economic burdens. Unfortunately, there is no approved medication to treat patients with NASH-induced advanced fibrosis. Weight management is the first line of NASH treatment even in non-obese patients with at least 7% reduction of patient's weight. However, NASH patients need pharmacological treatment. Sodium glucose co-transporter (SGLT2) inhibitors demonstrated favorable effects on NAFLD without weight gain as an adverse event proposed by pioglitazone used for the same indication. SGLT2 inhibitors are able to reduce fatty liver content, as assessed by different imaging techniques, and improve biological markers of NAFLD, especially serum liver enzymes, in patients with or without T2DM. In addition, there are emerging data to suggest a mechanism beyond the reduction of body weight and hyperglycemia in patients with or without diabetes. This study aims to evaluate the efficacy and safety of SGLT2 inhibitors in NASH patients in comparison to pioglitazone. This is a randomized prospective parallel study, where all patients presented with NASH to the outpatient clinic in the National Hepatology and Tropical Medicine Research Institute, Cairo, Egypt; will be screened for specific inclusion and exclusion criteria. Diabetic and non-diabetic patients will be randomly assigned to receive one of two treatment modalities. The first arm will be the NASH patients receiving dapagliflozin and the second arm will be the NASH patients receiving pioglitazone for 24 weeks. Each group will have an equal number of diabetic and non-diabetic patients. All patients will be assessed for body composition, serum creatinine level, fasting blood glucose level, HbA1C, markers of insulin resistance (HOMA-IR), complete blood count, serum liver function tests, and NAFLD fibrosis score (NAS). Liver biopsy will be performed at baseline and at the end of the study and the total NAS score will be calculated. All patients will be assessed for any adverse drug reactions, and for their adherence by pill count method. Also, quality of life will be assessed for all patients using previously designed and validated questionnaire called Chronic Liver Disease Questionnaire (CLDQ).

Official Title
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Efficacy and Safety of Dapagliflozin Compared to Pioglitazone in Diabetic and Non-diabetic Patients With Non-alcoholic Steatohepatitis

Conditions
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Non-alcoholic Steatohepatitis

Intervention / Treatment
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* Drug: Dapagliflozin 10Mg Tab
* Drug: Pioglitazone 30 mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age range 18-65 years. Liver biopsy confirming NASH within 6 months. For diabetic patients, the patients should be with stable glycemic control defined as HbA1C <10%. Exclusion Criteria: Active viral hepatitis (HBV, HCV). Child Pugh B or C cirrhosis. Alcohol consumption in the past six months. A history of alcoholic liver disease. Secondary causes of steatohepatitis. Autoimmune hepatitis. Celiac disease. Hemochromatosis or Wilson's disease. Drug induced liver injury (DILI) or patient with history of taking medication(s) that may cause fatty liver (e.g., tamoxifen, valproic acid, amiodarone, methotrexate, steroids, oral contraceptives). Obstructive biliary disease. Serum alanine aminotransferase (ALT) more than 2.5 folds of UNL. History of serious hypersensitivity to dapagliflozin or pioglitazone or any component of the formulation. Pregnancy and breastfeeding. Renal impairment (eGFR <45 mL/minute/1.73 m2), end-stage renal disease (ESRD), or patients on dialysis. Having any medical condition that would affect metabolism (i.e., known hyperthyroidism or hypothyroidism). Hypopituitarism. Patients with Type 1 diabetes. Starvation. Serious medical disease with likely life expectancy less than 5 years. Participation in other clinical trial in the 30 days before enrollment. Patients who are unwilling or unable to give informed consent. Patients on statins. Heart failure defined as New York Heart Association (NYHA) class III or IV. Recent initiation or change of antidiabetic drugs that influence liver fat including thiazolidinediones, glucagon like peptide 1 receptor agonists or any SGLT2 inhibitor.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Diabetic Group 1<br>25 diabetic patients will be prescribed on dapagliflozin 10 mg - once daily (OD) - to be taken orally (PO) for 24 weeks | Drug: Dapagliflozin 10Mg Tab<br>* Dapagliflozin 10 mg, administered orally and to be prescribed for diabetic and non-diabetic patients with NASH for 24 weeks; in comparison to pioglitazone.<br>|
| Active Comparator: Diabetic Group 2<br>25 diabetic patients will be prescribed on Pioglitazone 30 mg - once daily (OD) - to be taken orally (PO) for 24 weeks | Drug: Pioglitazone 30 mg<br>* Pioglitazone 30 mg, administered orally and to be prescribed for diabetic and non-diabetic patients with NASH for 24 weeks; as an active control and standard of care treatment.<br>|
| Experimental: Non-diabetic Group 1<br>25 non-diabetic patients will be prescribed on dapagliflozin 10 mg - once daily (OD) - to be taken orally (PO) for 24 weeks. | Drug: Dapagliflozin 10Mg Tab<br>* Dapagliflozin 10 mg, administered orally and to be prescribed for diabetic and non-diabetic patients with NASH for 24 weeks; in comparison to pioglitazone.<br>|
| Active Comparator: Non-diabetic Group 2<br>25 non-diabetic patients will be prescribed on Pioglitazone 30 mg - once daily (OD) - to be taken orally (PO) for 24 weeks | Drug: Pioglitazone 30 mg<br>* Pioglitazone 30 mg, administered orally and to be prescribed for diabetic and non-diabetic patients with NASH for 24 weeks; as an active control and standard of care treatment.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| NAFLD activity score (NAS) | Reduction of at least 2 points in NAFLD activity score (NAS) in 2 histological categories without worsening of fibrosis according to results of liver biopsy. | Baseline and 24th week | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| NAFLD activity score (NAS) | Resolution of total NAS defined as absence of NASH. Improvement in at least 1 point in any of steatosis, inflammation, ballooning and fibrosis scores. Higher score means worse outcome. | Baseline and 24th week | 
| NAFLD fibrosis score (NFS) | Change in NAFLD fibrosis score (NFS) (lower score means better outcome). | Baseline and 24th week | 
| Fibro-controlled attenuated parameter (fibro CAP) | Improvement of fibro-controlled attenuated parameter (fibro CAP) | Baseline and 24th week | 
| Serum Alanine Transaminase level (ALT) | Change in ALT serum level as inflammatory markers of NASH | Baseline, 12th and 24th week | 
| Serum Aspartate Aminotransferase level (AST) | Change in AST serum level as inflammatory markers of NASH | Baseline, 12th and 24th week | 
| Serum Alkaline Phosphatase level (ALP) | Change in ALP serum level as inflammatory markers of NASH | Baseline, 12th and 24th week | 
| Serum Gamma-glutamyl Transferase level (GGT) | Change in GGT serum level as inflammatory markers of NASH | Baseline, 12th and 24th week | 
| Serum total and direct bilirubin. | Change in levels of serum total and direct bilirubin. | Baseline, 12th and 24th week | 
| Waist circumference | Change in waist circumference | Baseline, 6th, 12th, 18th and 24th week | 
| Body weight | Change in body weight | Baseline, 6th, 12th, 18th and 24th week | 
| Visceral and subcutaneous abdominal fat | Change in visceral and subcutaneous abdominal fat using abdominal ultrasound (US) | Baseline and 24th week | 
| Lipid profile | Change in serum lipids | Baseline, 12th and 24th week | 
| Glycated hemoglobin (HbA1C) | Change in HbA1C level for patients with T2DM | Baseline, 12th and 24th week | 
| Fasting blood glucose level | Change in fasting blood glucose for patients with T2DM | Baseline, 12th and 24th week | 
| Insulin resistance (HOMA-IR) |  | Baseline, 12th and 24th week | 
| Quality of life Questionnaire (quality of life assessment) | Change in health-related quality of life scores using chronic liver disease questionnaire (CLDQ) | Baseline and 24th week | 
| Drugs adverse events | Assessment of safety by reporting any adverse events | Baseline, 3rd, 6th, 12th, 18th and 24th week. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Dapagliflozin, SGLT2 inhibitors, NASH, Efficacy, Safety, Liver biopsy, Pioglitazone, Fatty Liver, NAFLD activity score