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

Primary Purpose

Diabetes Mellitus, Type 2, NASH - Nonalcoholic Steatohepatitis, NAFLD

Status

Recruiting

Phase

Phase 4

Locations

Pakistan

Study Type

Interventional

Intervention

Pioglitazone

Empagliflozin

Pioglitazone + Empagliflozin

About this trial

This is an interventional treatment trial for Diabetes Mellitus, Type 2

Eligibility Criteria

18 Years - 60 Years (Adult)All SexesAccepts Healthy Volunteers

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

Sites / Locations

Aga Khan University HospitalRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Active Comparator

Arm Label

Pioglitazone

Empagliflozin

Pioglitazone + Empagliflozin

Arm Description

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.

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.

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.

Outcomes

Primary Outcome Measures

Change in radiologic liver parameters

Number of participants reported change in liver fat content from baseline, as quantified by fibroscan

Secondary Outcome Measures

Change in liver enzymes

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

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

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)

Number of participants reported change in waist circumference (WC)

Change in liver fat mass with total body fat (TBF)

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%)

Number of participants reported change in HbA1C levels from baseline to end of treatment

Change in Fasting Blood Sugar (FBS)

Number of participants reported change in Fasting Blood Sugar (FBS) from baseline to end of treatment

Change in Lipid profile

Number of participants reported change in Fasting triglycerides (TG), Low-Density Lipoprotein (LDL), High-Density Lipoprotein (HDL) from baseline to end of treatment

Full Information

NCT ID

NCT04976283

First Posted

July 19, 2021

Last Updated

March 17, 2022

Sponsor

Getz Pharma

1. Study Identification

Unique Protocol Identification Number

NCT04976283

Brief Title

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

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

Study Type

Interventional

2. Study Status

Record Verification Date

March 2022

Overall Recruitment Status

Recruiting

Study Start Date

September 15, 2021 (Actual)

Primary Completion Date

May 15, 2023 (Anticipated)

Study Completion Date

November 15, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Getz Pharma

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. 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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Diabetes Mellitus, Type 2, NASH - Nonalcoholic Steatohepatitis, NAFLD

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 4

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

123 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Pioglitazone

Arm Type

Active Comparator

Arm Description

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.

Arm Title

Empagliflozin

Arm Type

Active Comparator

Arm Description

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.

Arm Title

Pioglitazone + Empagliflozin

Arm Type

Active Comparator

Arm Description

Intervention Type

Drug

Intervention Name(s)

Pioglitazone

Other Intervention Name(s)

Zolid

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

Empagliflozin

Other Intervention Name(s)

Diampa

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

Pioglitazone + Empagliflozin

Other Intervention Name(s)

Zolid + Diampa

Intervention Description

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).

Primary Outcome Measure Information:

Title

Change in radiologic liver parameters

Description

Number of participants reported change in liver fat content from baseline, as quantified by fibroscan

Time Frame

12 months

Secondary Outcome Measure Information:

Title

Change in liver enzymes

Description

Number of participants reported change in liver enzymes levels including ALT, AST and GGT

Time Frame

12 months

Title

Change in Fibrosis-4 (FIB-4) Score and NAFLD Fibrosis Score

Description

Time Frame

12 months

Title

Change in body weight

Description

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).

Time Frame

12 months

Title

Change in waist circumference (WC)

Description

Number of participants reported change in waist circumference (WC)

Time Frame

12 months

Title

Change in liver fat mass with total body fat (TBF)

Description

Comparison of baseline and end of treatment liver fat mass with total body fat (TBF) using a Body Composition Monitor

Time Frame

12 months

Title

Change in HbA1C levels (< 7.0%)

Description

Number of participants reported change in HbA1C levels from baseline to end of treatment

Time Frame

12 months

Title

Change in Fasting Blood Sugar (FBS)

Description

Number of participants reported change in Fasting Blood Sugar (FBS) from baseline to end of treatment

Time Frame

12 months

Title

Change in Lipid profile

Description

Number of participants reported change in Fasting triglycerides (TG), Low-Density Lipoprotein (LDL), High-Density Lipoprotein (HDL) from baseline to end of treatment

Time Frame

12 months

Other Pre-specified Outcome Measures:

Title

Change in Urine Albumin to Creatinine Ratio (UACR)

Description

Number of participants reported change in Urine Albumin to Creatinine Ratio (UACR) from baseline to end of treatment

Time Frame

12 months

Title

Change in Systolic and Diastolic blood pressure

Description

Number of participants reported change in Systolic and Diastolic blood pressure from baseline to end of treatment

Time Frame

12 months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

60 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Azra Rizwan, FCPS

Phone

+923212655271

azra.rizwan@aku.edu

Facility Information:

Facility Name

Aga Khan University Hospital

City

Karachi

State/Province

Sindh

ZIP/Postal Code

74800

Country

Pakistan

Individual Site Status

Recruiting

12. IPD Sharing Statement

Learn more about this trial

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

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