Low-Dose Pioglitazone for NASH

Recruiting in Palo Alto (17 mi)

Overseen by Kenneth Cusi, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: University of Florida

Must be taking: Metformin, Insulin

Must not be taking: Estrogen, Glucocorticoids

Disqualifiers: Alcohol use, Chronic liver disease, Heart disease, others

Prior Safety Data

Approved in 1 Jurisdiction

Trial Summary

What is the purpose of this trial?

This trial is testing a small daily dose of pioglitazone in patients with type 2 diabetes and a specific liver condition called NASH. The goal is to see if this medication can improve their liver health by helping their bodies manage blood sugar and fat levels better.

Will I have to stop taking my current medications?

The trial allows participants to continue their current diabetes medications at stable doses, such as metformin, sulfonylurea, acarbose, DPP-IV inhibitors, SGLT2 inhibitors, or insulin. However, you cannot take pioglitazone, vitamin E at high doses, or any FDA-approved drug for NASH during the study.

What data supports the effectiveness of the drug Pioglitazone for treating NASH?

Research shows that Pioglitazone is effective in treating non-alcoholic steatohepatitis (NASH), especially in patients with prediabetes or type 2 diabetes. It has been shown to improve liver histology, which means it can help reduce liver damage in these patients. ^{1 2 3 4 5}

Is low-dose pioglitazone safe for humans?

Pioglitazone, used for type 2 diabetes, is generally well tolerated but can cause side effects like weight gain, edema (swelling), and liver dysfunction. It has not been reported to cause liver toxicity like some other drugs in its class, but it can affect liver and kidney function, as well as cause anemia. ^{1 2 6 7 8}

How does the drug Pioglitazone differ from other treatments for NASH?

Pioglitazone is unique for NASH treatment because it targets insulin resistance and lipotoxicity, which are key factors in the disease, and it can improve liver health over time. A new version, PXL065, is being studied to offer similar benefits with fewer side effects by focusing on non-genomic activity without activating PPARγ, which is linked to side effects. ^{1 7 8 9 10}

Research Team

Kenneth Cusi, MD

Principal Investigator

University of Florida

Eligibility Criteria

This trial is for adults aged 21-75 with Type 2 Diabetes and biopsy-proven nonalcoholic steatohepatitis (NASH). Participants must have certain blood cell counts, liver function tests within specific limits, controlled diabetes (HbA1c ≤ 9.5%), and not be on medications affecting glucose tolerance or have other liver diseases. Pregnant women, heavy alcohol users, those with recent malignancies or heart disease are excluded.

Inclusion Criteria

I am between 21 and 75 years old.

Your blood tests need to show a certain level of hemoglobin, white blood cells, neutrophils, and platelets. Your albumin, creatinine, INR, bilirubin, AST, and ALT levels also need to be within specific ranges.

My HbA1c level is 9.5% or lower, and I manage it with diet or stable diabetes medication.

Exclusion Criteria

I have a form of diabetes that is not type 2.

I have had cancer in the last 5 years, except for non-dangerous skin cancer which is cured.

I do not have uncontrolled high blood pressure, recent strokes, severe lung or kidney disease.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive either pioglitazone 15 mg/day or placebo for 72 weeks

72 weeks

10 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

1 visit (in-person)

Treatment Details

Interventions

• Pioglitazone (Thiazolidinedione)
• Placebo (Other)

Trial Overview The study aims to test the safety and effectiveness of a low-dose pioglitazone treatment (15 mg daily) compared to a placebo in improving liver health for patients with NASH who also have Type 2 Diabetes. The participants will either receive the actual medication or a placebo without knowing which one they are taking.

Participant Groups

Group I: Pioglitazone Active Control 1 Intervention

Two arm, randomized, double-blind, placebo-controlled, 72 week treatment study receiving pioglitazone 15mg/day.

Group II: Placebo Placebo Group 1 Intervention

Two arm, randomized, double-blind, placebo-controlled, 72 week treatment study receiving placebo.

Who Is Running the Clinical Trial?

University of Florida

Lead Sponsor

Trials

1,428

Recruited

987,000+

Dr. Stephen J. Motew

University of Florida

Chief Executive Officer since 2024

MD cum laude from the University of Illinois at Chicago School of Medicine, Master's in Healthcare Administration from the University of North Carolina at Chapel Hill

Dr. Timothy E. Morey

University of Florida

Chief Medical Officer since 2023

MD and Bachelor's from the University of Florida

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Collaborator

Trials

2,513

Recruited

4,366,000+

Dr. Griffin P. Rodgers

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Chief Executive Officer since 2007

MD, M.A.C.P.

Dr. Griffin P. Rodgers

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Chief Medical Officer since 2007

MD, M.A.C.P.

Findings from Research

In a study of 117 patients with non-alcoholic steatohepatitis (NASH), PXL065 demonstrated a significant reduction in liver fat content (21-25%) compared to placebo, indicating its efficacy in treating NASH.

PXL065 showed a favorable safety profile, lacking the PPARγ-driven side effects associated with pioglitazone, and improved metabolic markers such as HbA1c and insulin sensitivity, suggesting it could be a safer alternative for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of PXL065 - deuterium-stabilized (R)-pioglitazone in patients with NASH: A phase II randomized placebo-controlled trial (DESTINY-1). Harrison, SA., Thang, C., Bolze, S., et al.[2023]

Non-alcoholic steatohepatitis (NASH) is a leading cause of liver failure and transplantation in the U.S., linked to conditions like obesity and type 2 diabetes, highlighting the urgent need for effective treatments.

Current first-line treatments focus on weight loss and lifestyle changes, but these may not work for patients with advanced liver disease, emphasizing the importance of ongoing drug development targeting NASH's underlying mechanisms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New drugs for NASH. Albhaisi, SAM., Sanyal, AJ.[2021]

In a study of 55 patients with non-alcoholic steatohepatitis (NASH), genetic variations were found to significantly influence the effectiveness of pioglitazone treatment, with a genetic response score linked to better treatment outcomes.

Specific genetic markers, such as ADORA1 and LPL SNPs, were associated with improvements in liver health indicators, suggesting that genetic testing could help predict which patients will respond best to pioglitazone therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Genetic Score Associates With Pioglitazone Response in Patients With Non-alcoholic Steatohepatitis. Kawaguchi-Suzuki, M., Cusi, K., Bril, F., et al.[2022]

In a study of 101 adults with biopsy-proven nonalcoholic steatohepatitis (NASH), pioglitazone was found to be effective in reducing liver disease activity in both patients with type 2 diabetes and those with prediabetes, with 48% of diabetic patients meeting the primary outcome compared to 46% of non-diabetic patients.

Patients with type 2 diabetes experienced a significant reduction in liver fibrosis and greater improvements in insulin sensitivity in adipose tissue compared to those with prediabetes, suggesting that pioglitazone may have enhanced benefits for individuals with type 2 diabetes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Response to Pioglitazone in Patients With Nonalcoholic Steatohepatitis With vs Without Type 2 Diabetes. Bril, F., Kalavalapalli, S., Clark, VC., et al.[2019]

Nonalcoholic fatty liver disease (NAFLD) is a widespread condition affecting at least one-third of the global population, with nonalcoholic steatohepatitis (NASH) being a more severe form that can lead to cirrhosis and liver cancer, particularly in patients with type 2 diabetes mellitus (T2DM).

Currently, the only FDA-approved treatments that have shown significant improvement in liver histology for patients with diabetes are pioglitazone and liraglutide, highlighting the need for more research focused on effective therapies for NASH in this high-risk population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of Nonalcoholic Fatty Liver Disease (NAFLD) in patients with Type 2 Diabetes Mellitus. Portillo-Sanchez, P., Cusi, K.[2020]

A study on 120 mice showed that prolonged use of pioglitazone, an oral antidiabetic drug, resulted in significant toxicity affecting liver, kidney, heart, and bladder functions, with effects worsening at higher doses.

The research highlights the potential risks associated with sub-chronic use of pioglitazone, indicating that it can lead to serious health issues, including abnormalities in liver and kidney function and changes in cardiac and hematological indices.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Toxicological evaluation of subchronic use of pioglitazone in mice. Elshama, SS., El-Kenawy, Ael-M., Osman, HE.[2020]

Pioglitazone (Actos) effectively reduces insulin resistance and improves blood sugar levels in type 2 diabetes patients, leading to a decrease in HbA1c levels.

Unlike another thiazolidinedione, troglitazone, which was banned due to liver toxicity, pioglitazone has not been linked to hepatotoxicity, making it a safer option for managing type 2 diabetes, although it may cause side effects like edema and anemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Evaluation of a thiazolidinedione compound as a new antidiabetic drug]. Toyota, T.[2018]

Pioglitazone effectively increases insulin sensitivity and improves glycemic control in patients with type 2 diabetes, whether used alone or in combination with other medications, based on clinical trials.

The medication is generally well tolerated, with weight gain and edema being the most common side effects, and it also shows potential benefits in reducing cardiovascular risk and arteriosclerosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Spotlight on pioglitazone in type 2 diabetes mellitus. Waugh, J., Keating, GM., Plosker, GL., et al.[2019]

In a study of 222 patients with poorly controlled type 2 diabetes, pioglitazone significantly reduced insulin dosage requirements by an average of 12.0 units (21.5% reduction) after 20 weeks, indicating its efficacy in improving glycaemic control.

Pioglitazone also positively affected lipid profiles by increasing HDL cholesterol and decreasing triglycerides, although it was associated with a higher incidence of side effects like edema and weight gain compared to placebo.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of pioglitazone in combination with insulin therapy on glycaemic control, insulin dose requirement and lipid profile in patients with type 2 diabetes previously poorly controlled with combination therapy. Berhanu, P., Perez, A., Yu, S.[2022]

Pioglitazone has shown significant histological improvement in patients with non-alcoholic steatohepatitis (NASH) associated with type 2 diabetes, with benefits observed within 6 months and lasting for at least 3 years, suggesting it may become the standard treatment for this condition.

Emerging treatments, such as glucagon-like peptide 1 receptor agonists, along with ongoing development of various agents targeting different pathways, indicate a promising future for combination therapies in managing NASH and improving patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of patients with type 2 diabetes and non-alcoholic fatty liver disease: current approaches and future directions. Cusi, K.[2022]

References

1. Netherlands pubmed.ncbi.nlm.nih.gov

Evaluation of PXL065 - deuterium-stabilized (R)-pioglitazone in patients with NASH: A phase II randomized placebo-controlled trial (DESTINY-1). [2023]

2. United States pubmed.ncbi.nlm.nih.gov

New drugs for NASH. [2021]

3. Switzerland pubmed.ncbi.nlm.nih.gov

A Genetic Score Associates With Pioglitazone Response in Patients With Non-alcoholic Steatohepatitis. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

Response to Pioglitazone in Patients With Nonalcoholic Steatohepatitis With vs Without Type 2 Diabetes. [2019]

5. England pubmed.ncbi.nlm.nih.gov

Treatment of Nonalcoholic Fatty Liver Disease (NAFLD) in patients with Type 2 Diabetes Mellitus. [2020]

6. Iran pubmed.ncbi.nlm.nih.gov

Toxicological evaluation of subchronic use of pioglitazone in mice. [2020]

7. Japan pubmed.ncbi.nlm.nih.gov

[Evaluation of a thiazolidinedione compound as a new antidiabetic drug]. [2018]

8. New Zealand pubmed.ncbi.nlm.nih.gov

Spotlight on pioglitazone in type 2 diabetes mellitus. [2019]

9. England pubmed.ncbi.nlm.nih.gov

Effect of pioglitazone in combination with insulin therapy on glycaemic control, insulin dose requirement and lipid profile in patients with type 2 diabetes previously poorly controlled with combination therapy. [2022]

10. Germany pubmed.ncbi.nlm.nih.gov

Treatment of patients with type 2 diabetes and non-alcoholic fatty liver disease: current approaches and future directions. [2022]