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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if combining pioglitazone and metformin can reduce oral leukoplakia, a condition with white patches in the mouth that may become cancerous. Researchers seek to find out if these medications can shrink the patches by at least half and produce positive changes in tissue samples. Suitable candidates for the trial have measurable oral leukoplakia lesions that can be biopsied. As a Phase 2 trial, the research focuses on assessing 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 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.

Is there any evidence suggesting that the pioglitazone-metformin combination treatment is likely to be safe for humans?

Research has shown that taking pioglitazone and metformin together is generally safe. Most individuals do not experience serious side effects, and the side effects resemble those from each drug individually. This is reassuring, as both pioglitazone and metformin are commonly used to treat diabetes.

In other studies, participants reported mild side effects, such as an upset stomach or slight swelling, while serious side effects remained rare. Although some risks accompany any treatment, the safety profile of pioglitazone and metformin is reassuring. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for leukoplakia?

Most treatments for oral leukoplakia, like surgical removal or laser therapy, focus on eliminating visible lesions. But the pioglitazone-metformin combination works differently by targeting the underlying cellular changes. Pioglitazone, a type of drug known as a thiazolidinedione, helps regulate cell growth and reduce inflammation, while metformin, commonly used for diabetes, is known for its potential anti-cancer properties. Researchers are excited because this combo not only addresses the symptoms but might also prevent the progression of these lesions into cancer, offering a more comprehensive approach to treatment.

What evidence suggests that the pioglitazone-metformin combination might be an effective treatment for oral leukoplakia?

Research has shown that using pioglitazone and metformin together may help treat oral leukoplakia, a condition characterized by white patches in the mouth. In this trial, participants will receive the Pioglitazone-Metformin Combination Treatment. Pioglitazone can improve the body's use of insulin, while metformin helps control blood sugar levels. Together, they may enhance how the body manages sugar and fats. Early studies suggest that this combination could reduce leukoplakia patches in more than half of the patients. Researchers are also investigating whether this treatment can lower the risk of oral cancer in people with these mouth changes. Initial results appear promising, making this combination a hopeful option for those with oral leukoplakia. ^{1 2 3 4 5}

Who Is on the Research Team?

Frank Ondrey

Principal Investigator

University of Minnesota

Are You a Good Fit for This Trial?

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.

I have measurable white patches in my mouth.

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

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]

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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05727761

Study Details | NCT05727761 | 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 ...

2. trialx.com trialx.com/clinical-trials/listings/306001/pioglitazone-metformin-combination-treatment-for-high-risk-oral-preneoplasia/

Pioglitazone-Metformin Combination Treatment for High ... Outcomes are defined as are a reduction of the leukoplakia grade in > 50% of treated participants and a partial or complete clinical response ...

3. withpower.com withpower.com/trial/phase-2-leukoplakia-7-2023-0858a?condition=&query=Pioglitazone&overallStatus=Recruiting&hasNoPlacebo=false

Pioglitazone-Metformin for Oral Leukoplakia Pioglitazone reduces insulin resistance, while metformin improves blood sugar control, and their combined effects on glucose and lipid metabolism might offer ...

4. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2023-06521

Testing Pioglitazone and Metformin to Prevent Oral ... This phase II trial studies how well the combination of pioglitazone and metformin works in preventing oral cancer in patients with abnormal looking tissue.

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11466946/

Efficacy and Safety of Pioglitazone/Metformin Fixed-Dose ... The combination of pioglitazone and metformin improves glycemic control by reducing insulin resistance and improving insulin sensitivity, ...