MASLD in Primary Hypothyroidism and Efficacy of Dapaglifozin

NCT06373523 | Not Yet Recruiting Early Phase 1 DMC

• 1 other identifier: SHIELD
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 1

Brief Summary

Non-alcoholic fatty liver disease (NAFLD) is a global epidemic with a prevalence of 25-40%.Primary Hypothyroidism is one of Endocrinopathies who are at risk of developing NAFLD/NASH and estimated prevalence of Primary Hypothyroidism in NAFLD patients is 10-15 %.Though First line Management is Dietary changes and lifestyle modifications(LSM),unfortunately Adherence to Lifestyle has been poor,rise of Lean NAFLD is on rise, faster progression of NAFLD,evolving risk factors for NAFLD like endocrinopathies,these push need for Pharmacotherapy.Currently therapies for NAFLD patients without diabetes mellitus (DM) are limited, and are associated with various adverse side effects. Sodium-glucose cotransporter type-2 (SGLT2) inhibitors can reduce hepatic fat content in patients with DM which is independent of glycemic control. However, the role of SGLT2 inhibitors in NAFLD patients without DM has not been investigated.Magnetic resonance imaging-derived proton density fat fraction (MRI-PDFF) is an emerging non-invasive imaging technique, and is more sensitive than liver biopsy/histology in quantifying liver fat change. Liver stiffness measurement (LSM) by Transient Elastography is a non-invasive method to diagnose fibrosis/cirrhosis with high accuracy.The novelty of utilizing the concept of "drug repositioning" by changing the role of SGLT2 inhibitors in treating DM to treating NAFLD in patients without DM deserves exploration.The investigators propose a double-blind, randomized, placebo-controlled trial to compare the effects of Dapagliflozin (a type of SLGT2 inhibitors) versus placebo (in a 1:1 ratio) in reducing hepatic fat content as measured by MRI-PDFF in NAFLD patients with Primary Hypothyroidism.The study results will determine whether SGLT2 inhibitors can reduce hepatic steatosis/hepatic fibrosis in NAFLD patients with Primary Hypothyroidism.

Conditions

Hepatic Steato-Fibrosis; Non-Alcoholic Fatty Liver Disease

Keywords

Dapaglifozin; MRI-PDFF; Primary hypothyroidism

Outcome Measures

Primary Outcomes (1)

• Change in liver fat content

  Difference in the change in liver fat content between the two groups at week 28 from the baseline as measured by MRI-PDFF

  28 weeks

Secondary Outcomes (3)

• Proportion of participants achieving 1 Stage decrease in steatosis at 6 months asassessed by Transient Elastography

  28 weeks

• Changes in Improvement in hepatic fibrosis measured by non invasive parameters like Fib4 score at 3 and 6 months

  28 weeks

• Changes in Lipid Profile at 3 and 6 months

  28 weeks

Study Arms (2)

Dapagliflozin Plus levothyroxine Group

EXPERIMENTAL

Dapagliflozin 10mg daily will be given to the treatment arm in addition to Levothyroxine replacement therapy. Eligible subjects will be followed up until week 28, and will undergo clinical, anthropometric and laboratory assessments (including liver function test and lipid profile) at baseline, week 14 and week 28. They will undergo LSM and CAP By Transient Elastography at baseline, week 14 and week 28, and MRI-PDFF at baseline and week 28. The primary outcome will be a difference in change of liver fat content (measured by MRI-PDFF) at week 28 from baseline between the two groups. The secondary outcomes will be proportion of participants achieving remission of steatosis (MRIPDFF \<5%) at week 28, reduction of liver fibrosis (LSM) and decrease in hepatic steatosis by 1 stage at week 14 and 28 and other secondary outcomes as mentioned above.

Drug: Dapagliflozin 10mg Tab; Drug: Levothyroxine Replacement daily

Levothyroxine daily and Placebo pill identical to Dapaglifozin for 28 weeks

PLACEBO COMPARATOR

The placebo pill will be manufactured to identical in appearance to the Dapaglifozin will be given to the Placebo arm in addition to Levothyroxine replacement therapy. Eligible subjects will be followed up until week 28, and will undergo clinical, anthropometric and laboratory assessments (including liver function test and lipid profile) at baseline, week 14 and week 28. They will undergo LSM and CAP By Transient Elastography at baseline, week 14 and week 28, and MRI-PDFF at baseline and week 28. The primary outcome will be a difference in change of liver fat content (measured by MRI-PDFF) at week 28 from baseline between the two groups. The secondary outcomes will be proportion of participants achieving remission of steatosis (MRI PDFF \<5%) at week 28, reduction of liver fibrosis (LSM) and decrease in hepatic steatosis by 1 stage at week 14 and 28 and other secondary outcomes as mentioned above.

Drug: Placebo; Drug: Levothyroxine Replacement daily

Interventions

Dapagliflozin 10mg Tab DRUG

Dapagliflozin 10mg daily will be given to the treatment arm.Eligible subjects will be followed up until week 28, and will undergo clinical, anthropometric and laboratory assessments (including liver function test and lipid profile) at baseline, week 14 and week 28. They will undergo LSM and CAP By Transient Elastography at baseline, week 14 and week 28, and MRI-PDFF at baseline and week 28. The primary outcome will be a difference in change of liver fat content (measured by MRI-PDFF) at week 28 from baseline between the two groups.

Also known as: Dartdapa

Dapagliflozin Plus levothyroxine Group

Placebo DRUG

The placebo pills will be manufactured to be identical in appearance to the study drug(Dapaglifozin 10 mg tablet).

Also known as: Placib

Levothyroxine daily and Placebo pill identical to Dapaglifozin for 28 weeks

Levothyroxine Replacement daily DRUG

Levothyroxine Replacement daily for 28 weeka

Also known as: LT4

Dapagliflozin Plus levothyroxine Group; Levothyroxine daily and Placebo pill identical to Dapaglifozin for 28 weeks

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age 18-75 years
• Patients with Primary Overt hypothyroidism (Low FT3/Low FT4 and TSH\>ULN)

You may not qualify if:

• Patients with Diabetes Mellitus(T1DM AND T2DM)
• Patient with Secondary Hypothyroidism
• Patients with other Endocrinopathies who are at risk of MASLD (T1DM and T2DM, Growth Hormone Insufficiency,Cushing Syndrome)
• Patients with concomitant other etiologies for hepatic steatosis or elevated transaminases (chronic viral hepatitis infection, autoimmune hepatitis, Wilson's disease, hemochromatosis, congestive hepatopathy, primary biliary cholangitis, primary sclerosing cholangitis, biliary tract obstruction)
• Patient with Drug Induced Liver Injury(DILI)
• Patients with Decompensated Cirrhosis or Portal hypertensionPatients with Cirrhosis or Portal hypertension
• Patients with HCC or any other malignancy
• Drugs like OCPS
• Patients \<18 years of age
• Patients already on Vitamin E or pioglitazone
• Pregnancy/Lactation
• Patients who are too sick to carry out the protocol
• Those who do not consent to participate in the study

Sponsors & Collaborators

• Post Graduate Institute of Medical Education and Research, Chandigarh: lead

Study Sites (1)

PGIMER

Chandigarh, Punjab, 160012, India

Location

MeSH Terms

Conditions

Non-alcoholic Fatty Liver Disease; Hypothyroidism

Interventions

dapagliflozin

Condition Hierarchy (Ancestors)

Fatty Liver; Liver Diseases; Digestive System Diseases; Thyroid Diseases; Endocrine System Diseases

Study Officials

• Ashu Rastogi, MD,DM

  PGIMER, Chandigarh

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Ashu Rastogi, MD,DM

CONTACT

9781001046; rastogi.ashu@pgi.ac.in

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: The placebo pills will be manufactured in identical appearance to the study drug (Dapagliflozin)
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor

Model Details: Eligible subjects will be randomly allocated to either the Dapagliflozin group or placebo group (i.e. control group)

Study Record Dates

• First Submitted: December 17, 2023
• First Posted: April 18, 2024
• Study Start: September 1, 2024
• Primary Completion: June 30, 2025
• Study Completion: July 30, 2025
• Last Updated: August 9, 2024

Record last verified: 2024-08

Data Sharing

• IPD Sharing: Will not share

Locations

IN (1)