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

Primary Purpose

Non-alcoholic Steatohepatitis

Status
Recruiting
Phase
Phase 4
Locations
Egypt
Study Type
Interventional
Intervention
Dapagliflozin 10Mg Tab
Pioglitazone 30 mg
Sponsored by
Cairo University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Non-alcoholic Steatohepatitis focused on measuring Dapagliflozin, SGLT2 inhibitors, NASH, Efficacy, Safety, Liver biopsy, Pioglitazone, Fatty Liver, NAFLD activity score

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • National Hepatology and Tropical Medicine Research InstituteRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Active Comparator

Experimental

Active Comparator

Arm Label

Diabetic Group 1

Diabetic Group 2

Non-diabetic Group 1

Non-diabetic Group 2

Arm Description

25 diabetic patients will be prescribed on dapagliflozin 10 mg - once daily (OD) - to be taken orally (PO) for 24 weeks

25 diabetic patients will be prescribed on Pioglitazone 30 mg - once daily (OD) - to be taken orally (PO) for 24 weeks

25 non-diabetic patients will be prescribed on dapagliflozin 10 mg - once daily (OD) - to be taken orally (PO) for 24 weeks.

25 non-diabetic patients will be prescribed on Pioglitazone 30 mg - once daily (OD) - to be taken orally (PO) for 24 weeks

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.
NAFLD fibrosis score (NFS)
Change in NAFLD fibrosis score (NFS) (lower score means better outcome).
Fibro-controlled attenuated parameter (fibro CAP)
Improvement of fibro-controlled attenuated parameter (fibro CAP)
Serum Alanine Transaminase level (ALT)
Change in ALT serum level as inflammatory markers of NASH
Serum Aspartate Aminotransferase level (AST)
Change in AST serum level as inflammatory markers of NASH
Serum Alkaline Phosphatase level (ALP)
Change in ALP serum level as inflammatory markers of NASH
Serum Gamma-glutamyl Transferase level (GGT)
Change in GGT serum level as inflammatory markers of NASH
Serum total and direct bilirubin.
Change in levels of serum total and direct bilirubin.
Waist circumference
Change in waist circumference
Body weight
Change in body weight
Visceral and subcutaneous abdominal fat
Change in visceral and subcutaneous abdominal fat using abdominal ultrasound (US)
Lipid profile
Change in serum lipids
Glycated hemoglobin (HbA1C)
Change in HbA1C level for patients with T2DM
Fasting blood glucose level
Change in fasting blood glucose for patients with T2DM
Insulin resistance (HOMA-IR)
Quality of life Questionnaire (quality of life assessment)
Change in health-related quality of life scores using chronic liver disease questionnaire (CLDQ)
Drugs adverse events
Assessment of safety by reporting any adverse events

Full Information

First Posted
December 1, 2021
Last Updated
May 6, 2023
Sponsor
Cairo University
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1. Study Identification

Unique Protocol Identification Number
NCT05254626
Brief Title
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

2. Study Status

Record Verification Date
May 2023
Overall Recruitment Status
Recruiting
Study Start Date
August 1, 2022 (Actual)
Primary Completion Date
January 2024 (Anticipated)
Study Completion Date
August 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Cairo University

4. Oversight

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

5. 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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Non-alcoholic Steatohepatitis
Keywords
Dapagliflozin, SGLT2 inhibitors, NASH, Efficacy, Safety, Liver biopsy, Pioglitazone, Fatty Liver, NAFLD activity score

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
100 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Diabetic Group 1
Arm Type
Experimental
Arm Description
25 diabetic patients will be prescribed on dapagliflozin 10 mg - once daily (OD) - to be taken orally (PO) for 24 weeks
Arm Title
Diabetic Group 2
Arm Type
Active Comparator
Arm Description
25 diabetic patients will be prescribed on Pioglitazone 30 mg - once daily (OD) - to be taken orally (PO) for 24 weeks
Arm Title
Non-diabetic Group 1
Arm Type
Experimental
Arm Description
25 non-diabetic patients will be prescribed on dapagliflozin 10 mg - once daily (OD) - to be taken orally (PO) for 24 weeks.
Arm Title
Non-diabetic Group 2
Arm Type
Active Comparator
Arm Description
25 non-diabetic patients will be prescribed on Pioglitazone 30 mg - once daily (OD) - to be taken orally (PO) for 24 weeks
Intervention Type
Drug
Intervention Name(s)
Dapagliflozin 10Mg Tab
Intervention Description
Dapagliflozin 10 mg, administered orally and to be prescribed for diabetic and non-diabetic patients with NASH for 24 weeks; in comparison to pioglitazone.
Intervention Type
Drug
Intervention Name(s)
Pioglitazone 30 mg
Intervention Description
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.
Primary Outcome Measure Information:
Title
NAFLD activity score (NAS)
Description
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.
Time Frame
Baseline and 24th week
Secondary Outcome Measure Information:
Title
NAFLD activity score (NAS)
Description
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.
Time Frame
Baseline and 24th week
Title
NAFLD fibrosis score (NFS)
Description
Change in NAFLD fibrosis score (NFS) (lower score means better outcome).
Time Frame
Baseline and 24th week
Title
Fibro-controlled attenuated parameter (fibro CAP)
Description
Improvement of fibro-controlled attenuated parameter (fibro CAP)
Time Frame
Baseline and 24th week
Title
Serum Alanine Transaminase level (ALT)
Description
Change in ALT serum level as inflammatory markers of NASH
Time Frame
Baseline, 12th and 24th week
Title
Serum Aspartate Aminotransferase level (AST)
Description
Change in AST serum level as inflammatory markers of NASH
Time Frame
Baseline, 12th and 24th week
Title
Serum Alkaline Phosphatase level (ALP)
Description
Change in ALP serum level as inflammatory markers of NASH
Time Frame
Baseline, 12th and 24th week
Title
Serum Gamma-glutamyl Transferase level (GGT)
Description
Change in GGT serum level as inflammatory markers of NASH
Time Frame
Baseline, 12th and 24th week
Title
Serum total and direct bilirubin.
Description
Change in levels of serum total and direct bilirubin.
Time Frame
Baseline, 12th and 24th week
Title
Waist circumference
Description
Change in waist circumference
Time Frame
Baseline, 6th, 12th, 18th and 24th week
Title
Body weight
Description
Change in body weight
Time Frame
Baseline, 6th, 12th, 18th and 24th week
Title
Visceral and subcutaneous abdominal fat
Description
Change in visceral and subcutaneous abdominal fat using abdominal ultrasound (US)
Time Frame
Baseline and 24th week
Title
Lipid profile
Description
Change in serum lipids
Time Frame
Baseline, 12th and 24th week
Title
Glycated hemoglobin (HbA1C)
Description
Change in HbA1C level for patients with T2DM
Time Frame
Baseline, 12th and 24th week
Title
Fasting blood glucose level
Description
Change in fasting blood glucose for patients with T2DM
Time Frame
Baseline, 12th and 24th week
Title
Insulin resistance (HOMA-IR)
Time Frame
Baseline, 12th and 24th week
Title
Quality of life Questionnaire (quality of life assessment)
Description
Change in health-related quality of life scores using chronic liver disease questionnaire (CLDQ)
Time Frame
Baseline and 24th week
Title
Drugs adverse events
Description
Assessment of safety by reporting any adverse events
Time Frame
Baseline, 3rd, 6th, 12th, 18th and 24th week.
Other Pre-specified Outcome Measures:
Title
Serum creatinine
Time Frame
Baseline, 3rd, 6th, 12th, 18th and 24th week.
Title
Estimated glomerular filtration rate (eGFR)
Time Frame
Baseline, 3rd, 6th, 12th, 18th and 24th week.

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Nirmeen A. Sabry
Phone
(00202) 23639307 - 23624917
Email
nirmeen.sabry@pharma.cu.edu.eg
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Nirmeen A. Sabry
Organizational Affiliation
Clinical Pharmacy Department - Faculty of Pharmacy - Cairo university
Official's Role
Principal Investigator
Facility Information:
Facility Name
National Hepatology and Tropical Medicine Research Institute
City
Cairo
Country
Egypt
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Mona Gaber
Phone
(00202)23639307-23624917
Email
mona.sobhy@pharma.cu.edu.eg

12. IPD Sharing Statement

Learn more about this trial

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

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