Clinical trial NCT05254626: Efficacy and Safety of Dapagliflozin in Patients with Non-alcoholic Steatohepatitis
Official title: Efficacy and Safety of Dapagliflozin Compared to Pioglitazone in Diabetic and Non-diabetic Patients with Non-alcoholic Steatohepatitis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Non-alcoholic Steatohepatitis
Keywords: Dapagliflozin
SGLT2 inhibitors
NASH
Efficacy
Safety
Liver biopsy
Pioglitazone
Fatty Liver
NAFLD activity score
Lead sponsor: Cairo University
Sponsor class: OTHER
First posted: 2022-02-24
Enrollment: 100
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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).


Eligibility criteria: 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.

Primary outcomes:
measure: Histological Features (Liver Biopsy)
timeFrame: Baseline and 24th week
Secondary outcomes:
measure: NAFLD fibrosis score
timeFrame: Baseline and 24th week
measure: Fibrosis Index Based on 4 factors
timeFrame: Baseline and 24th week
measure: Fibro-controlled attenuated parameter (fibro CAP)
timeFrame: Baseline and 24th week
measure: Serum Alanine Transaminase level (ALT)
timeFrame: Baseline, 12th and 24th week
measure: Serum Aspartate Aminotransferase level (AST)
timeFrame: Baseline, 12th and 24th week
measure: Serum Alkaline Phosphatase level (ALP)
timeFrame: Baseline, 12th and 24th week
measure: Serum Gamma-glutamyl Transferase level (GGT)
timeFrame: Baseline, 12th and 24th week
measure: Serum total and direct bilirubin.
timeFrame: Baseline, 12th and 24th week
measure: Waist circumference
timeFrame: Baseline, 3rd, 6th, 12th, 18th and 24th week
measure: Body weight
timeFrame: Baseline, 3rd, 6th, 12th, 18th and 24th week
measure: Lipid profile
timeFrame: Baseline, 12th and 24th week
measure: Glycated hemoglobin (HbA1C)
timeFrame: Baseline, 12th and 24th week
measure: Fasting blood glucose level
timeFrame: Baseline, 3rd, 6th, 12th, 18th and 24th week
measure: Insulin resistance (HOMA-IR)
timeFrame: Baseline, 12th and 24th week
measure: Quality of life Questionnaire (quality of life assessment)
timeFrame: Baseline and 24th week
measure: Drugs adverse events
timeFrame: Baseline, 3rd, 6th, 12th, 18th and 24th week
Other outcomes:
measure: Serum creatinine
timeFrame: Baseline, 3rd, 6th, 12th, 18th and 24th week
measure: Estimated glomerular filtration rate (eGFR)
timeFrame: Baseline, 3rd, 6th, 12th, 18th and 24th week
Locations:
city: Cairo
country: Egypt
facility: National Hepatology and Tropical Medicine Research Institute
Study officials:
affiliation: Clinical Pharmacy Department - Faculty of Pharmacy - Cairo university
name: Nirmeen A. Sabry
role: PRINCIPAL_INVESTIGATOR
References: