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

• ClinicalTrials.gov Identifier: NCT05254626
• Recruitment Status: Recruiting
• First Posted: February 24, 2022
• Last Update Posted: May 9, 2023
• Sponsor: Cairo University
• Information provided by (Responsible Party): Nirmeen Ahmed Sabry, Cairo University

Study Description

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).

Condition or disease	Intervention/treatment	Phase
Non-alcoholic Steatohepatitis	Drug: Dapagliflozin 10Mg Tab; Drug: Pioglitazone 30 mg	Phase 4

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 100 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Efficacy and Safety of Dapagliflozin Compared to Pioglitazone in Diabetic and Non-diabetic Patients With Non-alcoholic Steatohepatitis
• Actual Study Start Date: August 1, 2022
• Estimated Primary Completion Date: January 2024
• Estimated Study Completion Date: August 2025

Arms and Interventions

Arm	Intervention/treatment
Experimental: Diabetic Group 1; 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; Dapagliflozin 10 mg, administered orally and to be prescribed for diabetic and non-diabetic patients with NASH for 24 weeks; in comparison to pioglitazone.
Active Comparator: Diabetic Group 2; 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; 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.
Experimental: Non-diabetic Group 1; 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; Dapagliflozin 10 mg, administered orally and to be prescribed for diabetic and non-diabetic patients with NASH for 24 weeks; in comparison to pioglitazone.
Active Comparator: Non-diabetic Group 2; 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; 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.

Outcome Measures

Primary Outcome Measures :

1. NAFLD activity score (NAS) [ Time Frame: Baseline and 24th week ]
   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.

Secondary Outcome Measures :

1. NAFLD activity score (NAS) [ Time Frame: Baseline and 24th week ]
   1. Resolution of total NAS defined as absence of NASH.
   2. Improvement in at least 1 point in any of steatosis, inflammation, ballooning and fibrosis scores.

   Higher score means worse outcome.

2. NAFLD fibrosis score (NFS) [ Time Frame: Baseline and 24th week ]
   Change in NAFLD fibrosis score (NFS) (lower score means better outcome).
3. Fibro-controlled attenuated parameter (fibro CAP) [ Time Frame: Baseline and 24th week ]
   Improvement of fibro-controlled attenuated parameter (fibro CAP)
4. Serum Alanine Transaminase level (ALT) [ Time Frame: Baseline, 12th and 24th week ]
   Change in ALT serum level as inflammatory markers of NASH
5. Serum Aspartate Aminotransferase level (AST) [ Time Frame: Baseline, 12th and 24th week ]
   Change in AST serum level as inflammatory markers of NASH
6. Serum Alkaline Phosphatase level (ALP) [ Time Frame: Baseline, 12th and 24th week ]
   Change in ALP serum level as inflammatory markers of NASH
7. Serum Gamma-glutamyl Transferase level (GGT) [ Time Frame: Baseline, 12th and 24th week ]
   Change in GGT serum level as inflammatory markers of NASH
8. Serum total and direct bilirubin. [ Time Frame: Baseline, 12th and 24th week ]
   Change in levels of serum total and direct bilirubin.
9. Waist circumference [ Time Frame: Baseline, 6th, 12th, 18th and 24th week ]
   Change in waist circumference
10. Body weight [ Time Frame: Baseline, 6th, 12th, 18th and 24th week ]
    Change in body weight
11. Visceral and subcutaneous abdominal fat [ Time Frame: Baseline and 24th week ]
    Change in visceral and subcutaneous abdominal fat using abdominal ultrasound (US)
12. Lipid profile [ Time Frame: Baseline, 12th and 24th week ]
    Change in serum lipids
13. Glycated hemoglobin (HbA1C) [ Time Frame: Baseline, 12th and 24th week ]
    Change in HbA1C level for patients with T2DM
14. Fasting blood glucose level [ Time Frame: Baseline, 12th and 24th week ]
    Change in fasting blood glucose for patients with T2DM
15. Insulin resistance (HOMA-IR) [ Time Frame: Baseline, 12th and 24th week ]
16. Quality of life Questionnaire (quality of life assessment) [ Time Frame: Baseline and 24th week ]
    Change in health-related quality of life scores using chronic liver disease questionnaire (CLDQ)
17. Drugs adverse events [ Time Frame: Baseline, 3rd, 6th, 12th, 18th and 24th week. ]
    Assessment of safety by reporting any adverse events

Other Outcome Measures:

1. Serum creatinine [ Time Frame: Baseline, 3rd, 6th, 12th, 18th and 24th week. ]
2. Estimated glomerular filtration rate (eGFR) [ Time Frame: Baseline, 3rd, 6th, 12th, 18th and 24th week. ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 65 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Contacts

Contact: Nirmeen A. Sabry; (00202) 23639307 - 23624917; nirmeen.sabry@pharma.cu.edu.eg

Locations

Egypt

National Hepatology and Tropical Medicine Research Institute; Recruiting

Cairo, Egypt

Contact: Mona Gaber (00202)23639307-23624917 mona.sobhy@pharma.cu.edu.eg

Sponsors and Collaborators

Cairo University

Investigators

• Principal Investigator: Nirmeen A. Sabry; Clinical Pharmacy Department - Faculty of Pharmacy - Cairo university

More Information

• Responsible Party: Nirmeen Ahmed Sabry, Professor Dr., Cairo University
• ClinicalTrials.gov Identifier: NCT05254626
• Other Study ID Numbers: CL (3148)
• First Posted: February 24, 2022
• Last Update Posted: May 9, 2023
• Last Verified: May 2023

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Keywords provided by Nirmeen Ahmed Sabry, Cairo University:

Dapagliflozin; SGLT2 inhibitors; NASH; Efficacy; Safety; Liver biopsy; Pioglitazone; Fatty Liver; NAFLD activity score

Additional relevant MeSH terms:

Fatty Liver; Non-alcoholic Fatty Liver Disease; Liver Diseases; Digestive System Diseases; Dapagliflozin; Pioglitazone; Sodium-Glucose Transporter 2 Inhibitors; Molecular Mechanisms of Pharmacological Action; Hypoglycemic Agents; Physiological Effects of Drugs