Pioglitazone-Metformin for Oral Leukoplakia

Overseen By Beverly Wuertz

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Minnesota

Must be taking: Pioglitazone, Metformin

Must not be taking: Insulin, Antidiabetics

Disqualifiers: Pregnancy, Diabetes, Bladder cancer, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 12 weeks

36 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a Phase IIa oral cavity leukoplakia study of pioglitazone 15mg and metformin 500mg BID for 12 weeks. The primary objective is to determine the clinical and histologic changes of leukoplakia from baseline following a 12 week course of twice daily pioglitazone-metformin. Outcomes are defined as are a reduction of the leukoplakia grade in \> 50% of treated participants and a partial or complete clinical response defined as 50% or greater reduction in the sum of measured targeted lesions. In addition, participants who show clinical and histologic improvement should correlate with a significant reduction of Ki-67 proliferative indices in lesions of these participants as compared to baseline.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot participate if you are taking insulin or an antidiabetic agent for diabetes, or another investigational drug not approved by the FDA.

What data supports the effectiveness of the drug Pioglitazone-Metformin for treating oral leukoplakia?

Pioglitazone activates a protein called PPARγ, which helps regulate cell growth and is being tested for cancer prevention, including in conditions like oral leukoplakia. ^{1 2 3 4 5}

Is the combination of pioglitazone and metformin safe for humans?

The combination of pioglitazone and metformin is generally considered safe for humans, as it is well tolerated with side effects similar to those seen with each drug alone. Common side effects include weight gain and edema (swelling), but serious liver or heart issues have not been associated with pioglitazone, unlike some other drugs in its class. ^{6 7 8 9 10}

How is the Pioglitazone-Metformin drug unique for treating oral leukoplakia?

The Pioglitazone-Metformin combination is unique because it combines two drugs typically used for type 2 diabetes to potentially treat oral leukoplakia, a condition with no standard treatment. Pioglitazone reduces insulin resistance, while metformin improves blood sugar control, and their combined effects on glucose and lipid metabolism might offer novel benefits for oral leukoplakia. ^{6 7 8 9 11}

Research Team

Frank Ondrey

Principal Investigator

University of Minnesota

Eligibility Criteria

This trial is for adults with biopsy-proven high-risk oral leukoplakia, specifically in areas like the floor of the mouth or tongue. Participants must have lesions measurable in two dimensions and be able to swallow tablets whole. They should not have active invasive cancer within the last 18 months, no diabetes treated with insulin or antidiabetic agents, and not be pregnant or breastfeeding.

Inclusion Criteria

My mouth sore has abnormal cell growth.

I have a biopsy showing abnormal cell growth in specific areas of my mouth or throat.

Body mass index (BMI) is ≥ 18.5

Exclusion Criteria

I have no medical reasons preventing me from undergoing a skin biopsy.

Pregnant or breastfeeding or planning to become pregnant

I have had bladder cancer in the past.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive pioglitazone 15mg and metformin 500mg BID for 12 weeks

12 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Pioglitazone-Metformin Combination Treatment

Trial Overview The study tests a combination of pioglitazone (15mg) and metformin (500mg) taken twice daily for 12 weeks on patients with oral leukoplakia. It aims to see if this treatment reduces the grade of leukoplakia and decreases cell proliferation in lesions compared to before treatment.

Participant Groups

Group I: oral leukoplakia patients Experimental Treatment 1 Intervention

36 total high risk oral leukoplakia patients.

Pioglitazone-Metformin Combination Treatment is already approved in United States, European Union for the following indications:

Approved in United States as Actos (pioglitazone) for:

• Type 2 diabetes mellitus

Approved in United States as Glucophage (metformin) for:

• Type 2 diabetes mellitus

Approved in European Union as Actos (pioglitazone) for:

• Type 2 diabetes mellitus

Approved in European Union as Glucophage (metformin) for:

• Type 2 diabetes mellitus

Who Is Running the Clinical Trial?

University of Minnesota

Lead Sponsor

Trials

1,459

Recruited

1,623,000+

Findings from Research

Leukoplakia is the most common premalignant oral lesion, and its risk of becoming cancerous can be assessed based on its appearance, location in the mouth, and biopsy results.

Erythroplakia, while less common, poses a much higher risk of malignant transformation and should always be surgically removed and closely monitored afterward.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The diagnosis and treatment of precancerous lesions. van der Waal, I.[2005]

Leukoplakia is the most common potentially malignant lesion in the mouth, often linked to tobacco and areca nut use, but some cases are idiopathic and can arise from precancerized tissue.

The risk of progression to cancer is higher in non-homogenous leukoplakia and those located in high-risk areas of the mouth, especially if they show high-grade dysplasia or cytogenetic changes associated with cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral Leukoplakia as It Relates to HPV Infection: A Review. Feller, L., Lemmer, J.[2023]

Pioglitazone effectively inhibits the proliferation of human leukoplakia cells and transformed bronchial epithelial cells in a dose-dependent manner, suggesting its potential as a chemopreventive therapy for oral and aerodigestive cancers.

The treatment with pioglitazone leads to the induction of the p21 protein, which is linked to decreased cell proliferation, indicating that p21 could serve as a biomarker for evaluating the effectiveness of pioglitazone in future cancer prevention studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PPARγ-Mediated p21 Induction in Aerodigestive Preneoplastic Cell Lines. Miller, WA., Wuertz, BR., Ondrey, FG.[2022]

The use of a complex phytoadaptogen in treating oral leukoplakia led to normalization of important proteins involved in cell differentiation and immune response, indicating a potential mechanism of action.

Patients treated with this phytopreparation experienced significant clinical improvements, including shrinkage of lesions and complete healing of erosive areas, suggesting its efficacy in managing leukoplakia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Leukoplakia of oral mucosa: pathogenesis and possible correction with phytoadaptogen. Bocharova, OA., Pozharitskaya, MM., Chekalina, TL., et al.[2019]

A systematic review of 12 studies involving 397 patients with proliferative verrucous leukoplakia (PVL) found a high recurrence rate of 67.2% after treatment, indicating that current treatment strategies may not effectively prevent recurrences.

The most common treatment was surgical removal, yet the analysis showed no significant evidence that any specific treatment could reduce the likelihood of PVL recurrence, highlighting a need for further research in this area.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recurrences following treatment of proliferative verrucous leukoplakia: A systematic review and meta-analysis. Proaño-Haro, A., Bagan, L., Bagan, JV.[2021]

The fixed-dose combination of pioglitazone and metformin is effective for improving glycaemic and lipid control in adults with type 2 diabetes, showing significant benefits over metformin plus placebo in a 16-week trial.

This combination therapy is well tolerated and demonstrates similar antihyperglycaemic efficacy to rosiglitazone plus metformin, while providing superior lipid control, particularly in lowering triglycerides and increasing HDL cholesterol.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pioglitazone/metformin. Deeks, ED., Scott, LJ.[2018]

The combination of pioglitazone and metformin in a single tablet for treating type 2 diabetes is supported by evidence showing it is both therapeutically effective and clinically safe.

The side effects of the combination therapy do not increase beyond those expected from taking each medication separately, indicating a manageable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pioglitazone and metformin. Hill, NR., Matthews, DR.[2018]

Pioglitazone effectively reduces insulin resistance in over 4500 patients with type 2 diabetes, showing significant decreases in HbA1c levels and improvements in lipid profiles, whether used alone or in combination with other diabetes medications.

It is well tolerated with a low incidence of side effects and does not carry the risk of hepatotoxicity associated with a similar drug, troglitazone, making it a safer option for managing type 2 diabetes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pioglitazone. Lawrence, JM., Reckless, JP.[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]

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 effectively lowers blood glucose levels in patients with type 2 diabetes, achieving reductions of up to 95 mg/dL and glycosylated hemoglobin by up to 2.6%, based on a review of 11 studies.

While pioglitazone can improve lipid profiles by reducing triglycerides and increasing HDL cholesterol, it is also associated with significant weight gain and mild edema, suggesting it may be best used in combination with other medications like metformin or sulfonylureas for better overall management of diabetes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A systematic review of the clinical effectiveness of pioglitazone in the treatment of type 2 diabetes mellitus. Chilcott, J., Tappenden, P., Jones, ML., et al.[2019]

References

1. England pubmed.ncbi.nlm.nih.gov

The diagnosis and treatment of precancerous lesions. [2005]

2. Egypt pubmed.ncbi.nlm.nih.gov

Oral Leukoplakia as It Relates to HPV Infection: A Review. [2023]

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

PPARγ-Mediated p21 Induction in Aerodigestive Preneoplastic Cell Lines. [2022]

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

Leukoplakia of oral mucosa: pathogenesis and possible correction with phytoadaptogen. [2019]

5. Denmark pubmed.ncbi.nlm.nih.gov

Recurrences following treatment of proliferative verrucous leukoplakia: A systematic review and meta-analysis. [2021]

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

Pioglitazone/metformin. [2018]

7. Spain pubmed.ncbi.nlm.nih.gov

Pioglitazone and metformin. [2018]

8. India pubmed.ncbi.nlm.nih.gov

Pioglitazone. [2018]

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

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

10. Iran pubmed.ncbi.nlm.nih.gov

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

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

A systematic review of the clinical effectiveness of pioglitazone in the treatment of type 2 diabetes mellitus. [2019]