Clinical trial NCT06373523: MASLD in Primary Hypothyroidism and Efficacy of Dapaglifozin
Official title: MASLD in Primary Hypothyroidism and Efficacy of Dapaglifozin
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: EARLY_PHASE1
Conditions: Hepatic Steato-Fibrosis
Non-Alcoholic Fatty Liver Disease
Keywords: Dapaglifozin
MRI-PDFF
Primary hypothyroidism
Lead sponsor: Post Graduate Institute of Medical Education and Research, Chandigarh
Sponsor class: OTHER
First posted: 2024-04-18
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Eligible subjects will be randomly allocated to either the Dapagliflozin group or placebo group (i.e. control group)
Primary purpose: TREATMENT

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.

Detailed description: Non-alcoholic fatty liver disease (NAFLD) is a global epidemic with a prevalence of 25-40%.Cirrhosis can occur without intervening NASH .Time line of progression is variable - modified by risk factors.Over all average progression from one disease Stage to another can take up 7 years for NASH while 14 years for NAFLD.In general ,10-30% of patient NAFLD progress to NASH ; Of which 15-25 % progress to advanced fibrosis.Amongst advanced fibrosis,20 % Progress to Cirrhosis over 2 years and 20 % of cirrhotics will have decompensation over 2 years.Overall in NAFLD MCC of mortality - CVD\>Extrahepatic cancer \> Liver specific mortality ( HCC and Hepatic decompensation).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.The Dixon proton density fat fraction sequence is frequently used to determine the liver's fat composition.To estimate PDFF across the entire liver, 9 regions of interest (ROIs) of 200 mm2 to 300 mm2 in the area will be placed in the nine liver segments on the PDFF parametric maps.This fat percentage called PDFF is calculated by the following formula; PDFF

= F / (F +W) x 100% The radiological findings will be examined by the radiology investigator who will be blinded to prior liver fat fraction maps.

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.

A total of 60 adult patients will be randomly sampled from the Endocrinology/liver/Internal Medicine clinics from our institute. Dapagliflozin 10mg daily will be given to the treatment arm. The placebo pill will be manufactured to be identical in appearance to the study drug. 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 4, 12 and 28 weeks. They will undergo LSM/CAP at baseline, week 14 and 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 steatosis by 1 stage at week 14 and 28, improvement of laboratory results (including liver transaminases and ductal enzymes, fasting glucose, HbA1c, lipid profile), improvement of anthropometric measurements, and cardiovascular events.

The study results will determine whether SGLT2 inhibitors can reduce hepatic steatosis and regress fibrosis in NAFLD patients with Primary Hypothyroidism.

Eligibility criteria: Inclusion Criteria:

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

Exclusion Criteria:

1. Patients with Diabetes Mellitus(T1DM AND T2DM)
2. Patient with Secondary Hypothyroidism
3. Patients with other Endocrinopathies who are at risk of MASLD (T1DM and T2DM, Growth Hormone Insufficiency,Cushing Syndrome)
4. 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)
5. Patient with Drug Induced Liver Injury(DILI)
6. Patients with Decompensated Cirrhosis or Portal hypertensionPatients with Cirrhosis or Portal hypertension
7. Patients with HCC or any other malignancy
8. Drugs like OCPS
9. Patients \<18 years of age
10. Patients already on Vitamin E or pioglitazone
11. Pregnancy/Lactation
12. Patients who are too sick to carry out the protocol
13. Those who do not consent to participate in the study

Primary outcomes:
measure: Change in liver fat content
timeFrame: 28 weeks
Secondary outcomes:
measure: Proportion of participants achieving 1 Stage decrease in steatosis at 6 months asassessed by Transient Elastography
timeFrame: 28 weeks
measure: Changes in Improvement in hepatic fibrosis measured by non invasive parameters like Fib4 score at 3 and 6 months
timeFrame: 28 weeks
measure: Changes in Lipid Profile at 3 and 6 months
timeFrame: 28 weeks
Other outcomes:
Locations:
city: Chandigarh
country: India
facility: PGIMER
state: Punjab
Study officials:
affiliation: PGIMER, Chandigarh
name: Ashu Rastogi, MD,DM
role: PRINCIPAL_INVESTIGATOR
References: