Effect of Oral Anti-diabetic Medication on Liver Fat in Subjects With Type II Diabetes and Non-alcoholic Fatty Liver

Sponsor

Getz Pharma (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04976283

Collaborator

(none)

123

Enrollment

Location

Arms

Anticipated Duration (Months)

4.7

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This randomized clinical trial aims to compare the effect of the pioglitazone and SGLT2 inhibitor combination on liver fat mass, as compared to either drug used alone, with or without background medical therapy of metformin and/or DDP4 inhibitors.

Condition or Disease	Intervention/Treatment	Phase
Diabetes Mellitus, Type 2 NASH - Nonalcoholic Steatohepatitis NAFLD	Drug: Pioglitazone Drug: Empagliflozin Drug: Pioglitazone + Empagliflozin	Phase 4

Detailed Description

To compare the effect of pioglitazone with or without Metformin and/or DPP4 inhibitor (no SGLT2 inhibitor) on improvement of NAFLD parameters, versus

The effect of SGLT inhibitor with or without metformin and/or DPP4 inhibitor (no pioglitazone) on NAFLD parameters and versus

Pioglitazone with or without metformin and/or DPP4 inhibitor, plus empagliflozin on improvement of NAFLD parameters.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

123 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Which Oral Combination of Anti-diabetes Medication May Work Better in Subjects With Type 2 Diabetes and Nonalcoholic Fatty Liver Disease: a Randomized Control Trial

Actual Study Start Date :

Sep 15, 2021

Anticipated Primary Completion Date :

May 15, 2023

Anticipated Study Completion Date :

Nov 15, 2023

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Pioglitazone The starting dose would be 15mg/day for pioglitazone and 500 to 1500mg per day for metformin (depending on blood glucose levels). Starting dose for DPP4 inhibitors would be 50 to 100mg daily.	Drug: Pioglitazone Pioglitazone with (or without) metformin and/or DPP4 inhibitor (no SGLT2 inhibitor). The maximum dose for metformin would be 2.5 g/day, while for pioglitazone would be 45mg/day. The maximum dose for DPP4 inhibitor would be 100mg/day. Other Names: Zolid
Active Comparator: Empagliflozin The starting dose would be 500-1500mg/day of metformin, plus 5/10/12.5mg empagliflozin (depending on blood glucose levels). Starting dose for DPP4 inhibitors would be 50 to 100mg daily.	Drug: Empagliflozin Empagliflozin with (or without) metformin and/or DPP4 inhibitor (no pioglitazone). The maximum dose for metformin would be 2.5g/day, while for empagliflozin would be 25mg/day depending on follow up blood sugar levels and tolerability. The maximum dose 100mg daily. Other Names: Diampa
Active Comparator: Pioglitazone + Empagliflozin The starting dose would be 15mg/day for pioglitazone and 500 to1500mg per day for metformin and 5/10/12.5mg/25mg/day empagliflozin and 50 to 100mg daily for DPP4 inhibitors depending on blood sugar levels.	Drug: Pioglitazone + Empagliflozin Pioglitazone with (or without) metformin and/or DPP4 inhibitor, plus empagliflozin. The maximum dose for metformin would be 2.5g/day; for pioglitazone would be 45mg/day and 25mg/day for empagliflozin, and 100mg daily for DPP4 inhibitors (depending on follow up blood sugar levels and tolerability). Other Names: Zolid + Diampa

Arm

Intervention/Treatment

Active Comparator: Pioglitazone

The starting dose would be 15mg/day for pioglitazone and 500 to 1500mg per day for metformin (depending on blood glucose levels). Starting dose for DPP4 inhibitors would be 50 to 100mg daily.

Drug: Pioglitazone

Pioglitazone with (or without) metformin and/or DPP4 inhibitor (no SGLT2 inhibitor). The maximum dose for metformin would be 2.5 g/day, while for pioglitazone would be 45mg/day. The maximum dose for DPP4 inhibitor would be 100mg/day.

Other Names:

Zolid

Active Comparator: Empagliflozin

The starting dose would be 500-1500mg/day of metformin, plus 5/10/12.5mg empagliflozin (depending on blood glucose levels). Starting dose for DPP4 inhibitors would be 50 to 100mg daily.

Drug: Empagliflozin

Empagliflozin with (or without) metformin and/or DPP4 inhibitor (no pioglitazone). The maximum dose for metformin would be 2.5g/day, while for empagliflozin would be 25mg/day depending on follow up blood sugar levels and tolerability. The maximum dose 100mg daily.

Other Names:

Diampa

Active Comparator: Pioglitazone + Empagliflozin

The starting dose would be 15mg/day for pioglitazone and 500 to1500mg per day for metformin and 5/10/12.5mg/25mg/day empagliflozin and 50 to 100mg daily for DPP4 inhibitors depending on blood sugar levels.

Drug: Pioglitazone + Empagliflozin

Pioglitazone with (or without) metformin and/or DPP4 inhibitor, plus empagliflozin. The maximum dose for metformin would be 2.5g/day; for pioglitazone would be 45mg/day and 25mg/day for empagliflozin, and 100mg daily for DPP4 inhibitors (depending on follow up blood sugar levels and tolerability).

Other Names:

Zolid + Diampa

Outcome Measures

Primary Outcome Measures

Change in radiologic liver parameters [12 months]
Number of participants reported change in liver fat content from baseline, as quantified by fibroscan

Secondary Outcome Measures

Change in liver enzymes [12 months]
Number of participants reported change in liver enzymes levels including ALT, AST and GGT
Change in Fibrosis-4 (FIB-4) Score and NAFLD Fibrosis Score [12 months]
Number of participants reported change in FIB-4 Score and NAFLD Fibrosis Score. Fibrosis-4 scores range from 0 to 4, where <1.45 indicates absence of cirrhosis; score between 1.45 - 3.25 are deemed inconclusive and score >3.25 indicates cirrhosis.
Change in body weight [12 months]
Number of participants reported change in body weight from baseline (treat to target response of at least 5% of baseline at 6 months, 10% baseline over 12 months).
Change in waist circumference (WC) [12 months]
Number of participants reported change in waist circumference (WC)
Change in liver fat mass with total body fat (TBF) [12 months]
Comparison of baseline and end of treatment liver fat mass with total body fat (TBF) using a Body Composition Monitor
Change in HbA1C levels (< 7.0%) [12 months]
Number of participants reported change in HbA1C levels from baseline to end of treatment
Change in Fasting Blood Sugar (FBS) [12 months]
Number of participants reported change in Fasting Blood Sugar (FBS) from baseline to end of treatment
Change in Lipid profile [12 months]
Number of participants reported change in Fasting triglycerides (TG), Low-Density Lipoprotein (LDL), High-Density Lipoprotein (HDL) from baseline to end of treatment

Other Outcome Measures

Change in Urine Albumin to Creatinine Ratio (UACR) [12 months]
Number of participants reported change in Urine Albumin to Creatinine Ratio (UACR) from baseline to end of treatment
Change in Systolic and Diastolic blood pressure [12 months]
Number of participants reported change in Systolic and Diastolic blood pressure from baseline to end of treatment

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 60 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

Inclusion Criteria:

Patient who give informed consent voluntarily
Type 2 diabetic patient having age from 18 years to 60 years
HbA1C ≥ 7.0 %
Diabetes diagnosis of ≤ 5 years (longer duration more likely to be associated with use of multiple drug regimens for glycemic control which may affect liver fat mass)
Either treatment naïve or on metformin alone or metformin/DPP4i combination
Absolute weight < 100kg; BMI < 45 (fibro scan machine cannot accommodate heavier individuals)
Documented hepatosteatosis (If the fibroscan reveals S1 (mild fatty liver: 11-33% fatty liver) to S3 (severe fatty liver: > 67% fatty liver) liver fat

Exclusion Criteria:

Hba1c ≥ 9% and/or blood sugar > 250mg/dl
History of uncontrolled Endocrine disorder (for example uncontrolled hypothyroidism, or that requiring frequent dose adjustment, or Cushings syndrome)
History of anti-obesity medication use within 3 months of consent for study enrollment or weight loss procedure(bariatric surgery) within same duration
History of use of SGLT 2 inhibitors, glitazones, Glucagon-like peptide (GLP) 1 agonists 3 months prior to study enrollment as they influence liver fat
History of use of insulin/sulphonylurea 3 months prior to study enrollment owing to weight gain and potential increase in liver fat conferred by these agents
History of vitamin E use (400mg twice daily) within 3 months of study enrollment
Drug induced liver disease or active substance abuse (cannabonnoid-derived substances like heroin, cocaine, amphetamines) based on history and/or laboratory tests
Drugs known to be associated with hepatic steatosis like steroids, traditional homeopathic medication (likely to contain steroids), methotrexate, valproate, tamoxifen, amiodarone.
Alcohol use (History of alcoholism or a greater than recommended alcohol intake (> 21 standard drinks on average per week in men and > 14 standard drinks on average per week in women)
Severe hepatic impairment (ALT levels > 3 times upper limit normal)
Hepatitis B/C hepatitis (based on positive Hepatitis B surface antigen, Anti Hepatitis C antibodies positive
Autoimmune hepatitis (in case of females), based on positive Anti-nuclear Antibody (ANA) (homogenous, high titre)
Positive Human Immunodeficiency Virus ( HIV) test as this could influence liver functions
Pregnant or lactating women/ plans for pregnancy over proceeding 13 months
Obstructive liver disease on the basis of laboratory and imaging studies
Chronic renal failure, or Glomerular Filtration Rate (GFR) < 30 mls/minute (as estimated by the MDRD equation)
Chronic heart failure, history of acute coronary artery disease or cerebrovascular accident within 3 months of consent for study enrollment, based on history and/or cardiac imaging
History of recurrent Urinary Tract Infections (UTI's) or mycotic infections
Presence of ketones on Urine Analysis