Low-Dose Pioglitazone for NASH

Overseen By Kenneth Cusi, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

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 This treatment has passed at least one previous human trial

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 12

Duration: 72 weeks

166 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines the safety and effectiveness of a low dose of pioglitazone for treating nonalcoholic steatohepatitis (NASH) in individuals with type 2 diabetes. Participants will receive either pioglitazone or a placebo (a pill with no active ingredients) for 72 weeks. The trial targets those diagnosed with both NASH and type 2 diabetes who manage their diabetes with certain stable medications. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group, providing participants an opportunity to contribute to significant medical advancements.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that pioglitazone is generally safe for people. It improves liver function in individuals with nonalcoholic steatohepatitis (NASH) and type 2 diabetes, and most people tolerate it well. While pioglitazone is already used safely for diabetes, it also appears to benefit those with NASH. Some studies report improved liver health and fewer liver issues in those taking it compared to those who are not. Although side effects like weight gain and swelling can occur, they are uncommon. Overall, pioglitazone maintains a good safety record for its current uses. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Pioglitazone is unique because it's being explored as a low-dose option for treating non-alcoholic steatohepatitis (NASH), a liver condition with limited effective treatments. Most current treatments focus on lifestyle changes and managing symptoms, but pioglitazone works by improving insulin sensitivity and reducing liver fat through its action as a PPAR-gamma agonist. Researchers are excited because this approach could offer a new, targeted way to tackle the underlying causes of NASH, potentially slowing or reversing liver damage with fewer side effects due to the lower dosage.

What evidence suggests that low-dose pioglitazone might be an effective treatment for NASH?

Research has shown that pioglitazone can help treat nonalcoholic steatohepatitis (NASH), a liver condition. Studies indicate it can improve liver issues such as scarring, swelling of liver cells, and inflammation. Pioglitazone, already used for diabetes, has proven effective for NASH patients. While most benefits have been observed with doses of 30 to 45 mg per day, this trial will test a lower dose of 15 mg daily in one arm. The goal is to achieve similar benefits with fewer side effects. Participants in the other arm will receive a placebo for comparison. ^{1 6 7 8 9}

Who Is on the Research Team?

Kenneth Cusi, MD

Principal Investigator

University of Florida

Are You a Good Fit for This Trial?

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.

Timeline for a Trial Participant

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)

What Are the Treatments Tested in This Trial?

Interventions

• Pioglitazone
• Placebo

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.

How Is the Trial Designed?

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.

Pioglitazone is already approved in United States for the following indications:

Approved in United States as Actos for:

• Type 2 diabetes mellitus

Who Is Running the Clinical Trial?

University of Florida

Lead Sponsor

Trials

1,428

Recruited

987,000+

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

Collaborator

Trials

2,513

Recruited

4,366,000+

Published Research Related to This Trial

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]

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 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 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]

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]

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]

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]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10091905/

Response to pioglitazone in non-alcoholic fatty liver disease ... We demonstrated the outcomes of pioglitazone in NAFLD patients on improvements in fibrosis, hepatocellular ballooning, lobular inflammation, and ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9678615/

Pioglitazone on nonalcoholic steatohepatitis - PubMed Central Conclusion: Pioglitazone intake is effective in nonalcoholic steatohepatitis management. Keywords: meta-analysis, nonalcoholic steatohepatitis, ...

3. journal-of-hepatology.eu journal-of-hepatology.eu/article/S0168-8278(23)00091-0/fulltext

pioglitazone in patients with NASH: A phase II randomized ... Pioglitazone (Pio) is an approved diabetes medicine with proven efficacy in non-alcoholic steatohepatitis (NASH); PXL065 is a novel related oral ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT04501406?cond=NASH%20-%20Nonalcoholic%20Steatohepatitis&intr=pioglitazone&rank=2

Low-Dose Pioglitazone in Patients With NASH (AIM 2) Rationale: Several studies have shown that pioglitazone, at either 30 to 45 mg per day, is safe and effective in randomized, controlled trials (RCTs) of 6- ...

5. diabetesjournals.org diabetesjournals.org/spectrum/article/37/1/48/154182/Pharmacological-Approaches-to-Nonalcoholic-Fatty

Pharmacological Approaches to Nonalcoholic Fatty Liver ... Of note, the improvement in steatohepatitis with pioglitazone has been reported with doses of 30–45 mg/day (29–34). Because lower pioglitazone ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/29223443/

Response to Pioglitazone in Patients With Nonalcoholic ... Results: The primary outcome was met by 48% of patients with type 2 diabetes vs 46% without diabetes. Resolution of NASH was achieved in 44% of patients ...

7. nejm.org nejm.org/doi/full/10.1056/NEJMoa060326

A Placebo-Controlled Trial of Pioglitazone in Subjects with ... In this proof-of-concept study, the administration of pioglitazone led to metabolic and histologic improvement in subjects with nonalcoholic steatohepatitis.

8. clinicaltrials.gov clinicaltrials.gov/study/NCT00227110

Role of Pioglitazone in the Treatment of Non-alcoholic ... Pioglitazone, a new thiazolidinedione (TZD), has proven to be safe and effective for the treatment of type 2 diabetes mellitus (T2DM) (4). NASH affects ~10-20% ...

9. sciencedirect.com sciencedirect.com/science/article/abs/pii/S1542356517314246

Response to Pioglitazone in Patients With Nonalcoholic ... The primary outcome was met by 48% of patients with type 2 diabetes vs 46% without diabetes. Resolution of NASH was achieved in 44% of patients with type 2 ...