Metformin Repurposing in Oral Submucous Fibrosis: Unveiling In Vitro Signaling Pathways, Progressing to Clinical Trial (MROSF)

Repurposing Metformin for the Treatment of Oral Submucous Fibrosis: Unraveling Novel Signaling Pathways In Vitro and Advancing to Clinical Trial"

OSF is a widespread health issue in Asian countries, notably Pakistan, linked to the consumption of pan, chalia, and gutka, affecting a rising number of young individuals as an epidemic. This condition significantly impairs oral function, resulting in ulcers and chronic lesions, often progressing to oral cancer. Current treatments focus on symptom relief and halting disease progression. This study explores the repurposing of metformin, an FDA-approved drug with antifibrotic properties, for OSF treatment. Our objective is to unveil its therapeutic potential and comprehend its impact on the dysregulated signaling pathways associated with OSF. This research offers promising insights for an enhanced management approach, providing hope for those grappling with this debilitating condition

Study Overview

• Status: Not yet recruiting
• Conditions: Oral Submucous Fibrosis
• Intervention / Treatment: Drug: betamethasone dipropionate; Drug: Pentoxifylline; Drug: Metformin Hydrochloride

Detailed Description

OSF stands as a persistent inflammatory and potentially malignant condition affecting the oral cavity, marked by progressive fibrosis of the oral mucosa. The spectrum of its manifestations spans from initial inflammation to the gradual emergence of fibrous bands, leading to restricted mouth opening and mucosal rigidity. Common symptoms encompass burning sensations, difficulty in swallowing, and alterations in taste perception. This health concern has gained prominence in Pakistan, experiencing a worrisome surge in prevalence from 8.3/105 to 16.2/105 in recent years. Formerly confined to Southeast Asia, OSF has now transcended borders, manifesting in Asian immigrant communities in Britain and America, evolving into a global oral potential malignant disorder (OPMD) with a malignant rate of 9.13% .

Presently, the corticosteroid-based approach effectively reduces inflammation in OSF but falls short in addressing the underlying molecular mechanisms contributing to fibrosis. Furthermore, the prolonged use of corticosteroids raises concerns about adverse effects, including mucosal atrophy and compromised tissue integrity. This study aims to investigate the potential of metformin, a recognized emerging drug for treating fibrosis, and its anti-fibrotic properties in various organs. The established safety profile of metformin adds an advantageous aspect to its potential applications.

Numerous studies indicate that metformin exhibits anti-fibrotic effects by inhibiting TGF-β1 production, reducing phosphorylation and nuclear translocation of Smad2/3. Additionally, metformin inhibits Smad2/3 phosphorylation independently and activates AMPK, hindering Smad3 phosphorylation. The impact on reactive oxygen species (ROS) generation moderates TGF-β1-induced Smad2/3 phosphorylation and myofibroblast differentiation.Metformin has shown promise in hindering collagen production and promoting trans differentiation in various organ, including the lung, kidney, heart and adipose tissue. A clinical trial reported metformin therapy's impact on postmenopausal ovaries, patients with type 2 diabetes mellitus (T2DM) exhibited isotropic collagen organization and reduced fibrosis during oophorectomy.The observed risk reduction for ovarian cancer in T2DM women using metformin suggests its potential as an ovarian cancer prophylaxis. Despite conflicting clinical trial results in liver fibrosis, metformin consistently improves hepatocyte damage and inflammation. Clinical trials have explored the role of metformin antitumor activity when combined with conventional chemotherapeutic drugs and in idiopathic pulmonary fibrosis it inhibits TGFβ1, suppressing collagen formation, activating PPARγ signaling and inducing lipogenic differentiation.

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Afifa Razi, FCPS; Phone Number: +92 300 2247389; Email: afifa.razi@zu.edu.pk
• Study Contact Backup: Name: Shumaila Usman, PhD; Phone Number: +92 336 1882779; Email: shumaila.usman@zu.edu.pk

Study Locations

• Pakistan
  • Sindh
    • Karachi, Sindh, Pakistan, 74700
      • Ziauddin University
      • Contact: Shumaila Usman, PhD; Phone Number: +92 336 1882779; Email: shumaila.usman@zu.edu.pk
      • Contact: Afifa Razi, FCPS OMFS; Phone Number: +92 300 2247389; Email: afifa.razi@zu.edu.pk
      • Principal Investigator: Afifa Razi, FCPS
      • Sub-Investigator: Shumaila Usman, PhD
      • Sub-Investigator: Yamna Khurshid, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Patients with OSF- palpable bands on oral examination
2. Patients with limited mouth opening due to OSF
3. Patients who have not received any treatment for OSF in the previous three months
4. Patients with habits of pan, Chalia, Ghutka
5. Age group between 18 and 45 years

Exclusion Criteria:

1. Patients presenting with both OSCC and OSF
2. Patients with limited mouth opening due to impaction of the third molar (impaction of third molar results in limited mouth opening hence such patients are excluded since limited mouth opening due to third molar impaction can be mistaken for OSF).
3. Patients with limited mouth opening due to temporomandibular joint disorder (temporomandibular joint disorders can limit the ability of patient to open their mouth and hence can be mistaken for OSF)
4. Any history of Metformin intolerance or contraindications.
5. Presence of other severe medical conditions along with drug therapy.
6. Pregnancy or lactation.
7. Participation in other clinical trials concurrently.
8. Inability to provide informed consent.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Standard; Group 1: Standard treatment with topical cream betamethasone and Pentoxifylline tablet.	Drug: betamethasone dipropionate; Group 1will recieve topical cream betamethasone thrice daily; Other Names: Betnovate; Drug: Pentoxifylline; Group 1 will receive Pentoxifylline tablet 400 mg twice daily; Other Names: Trental
Experimental: MetforminO; Metformin 500 mg thrice daily.	Drug: Metformin Hydrochloride; Group B will receive Metformin 500 mg thrice daily. Group C will receive topical cream metformin thrice daily.; Other Names: Glucophage
Experimental: MetforminT; Topical cream metformin thrice daily	Drug: Metformin Hydrochloride; Group B will receive Metformin 500 mg thrice daily. Group C will receive topical cream metformin thrice daily.; Other Names: Glucophage

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cell Viability	Cell Viability by MTT Assay Unit: Percentage Assessment of cell viability will be reported as a percentage of untreated control cells.	8 months
Cytotoxicity	Cytotoxicity Unit: Percentage Measurement of cytotoxicity will be presented as a percentage relative to untreated control cells.	8 Months
Morphological Changes Cell Shape	Unit: Qualitative description Cell shape alterations will be described qualitatively based on microscopic observations.	8months
Morphological Change Cell Density	Unit: Cells per unit area Changes in cell density will be quantified and reported as cells per unit area. Sub-Measure 3: Extracellular Matrix (ECM) Structure Unit: Qualitative description Alterations in ECM structure will be qualitatively assessed.	8 months
Morphological Change Extracellular Matrix (ECM) Structure	Extracellular Matrix (ECM) Structure Unit: Qualitative description Alterations in ECM structure will be qualitatively assessed.	8 months
Cell Migration Assays	Unit: Distance migrated (micrometers) The extent of cell migration will be quantified as the distance migrated from the original point.	8months
Cell Invasion Assays	Unit: Invaded area (e.g., square millimeters) Assessment of cell invasion will be presented as the invaded area relative to untreated control cells.	8 months
Apoptosis Analysis	Unit: Percentage Apoptotic cells will be quantified and reported as a percentage of the total cell population.	8months
Assess Signaling pathway with optimal metformin concentration	To evaluate the effect of TGF-beta Smad 2/3 and wnt/b-catenin signaling pathways in vitro	9 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical Oral Mucosal Characteristics	Unit: Descriptive score (based on a scale ranging from 0 to 3 (normal to severe).0=No changes 1=Soreness 2=Soreness and ulceration 3=Soreness, ulceration and ability to use a liquid diet only	9 months
Patient Burning sensation pain	Unit: Units on a scale (Verbal numeric rating scale graded on a 10-point scale from 0 to 10, where 0 indicated no burning sensation while 10 represented the worst burning sensation)	9 months
Patient Mouth Opening	Unit: Millimeters on a scale of Grade 0 = > 35 mm, Grade1= 26-35mm, Grade 2= 15-25mm, Grade 3: < 10mm	9 months

Collaborators and Investigators

• Sponsor: Ziauddin University

Publications and helpful links

General Publications

• Yang SF, Wang YH, Su NY, Yu HC, Wei CY, Yu CH, Chang YC. Changes in prevalence of precancerous oral submucous fibrosis from 1996 to 2013 in Taiwan: A nationwide population-based retrospective study. J Formos Med Assoc. 2018 Feb;117(2):147-152. doi: 10.1016/j.jfma.2017.01.012. Epub 2017 Apr 5.
• Shen YW, Shih YH, Fuh LJ, Shieh TM. Oral Submucous Fibrosis: A Review on Biomarkers, Pathogenic Mechanisms, and Treatments. Int J Mol Sci. 2020 Sep 30;21(19):7231. doi: 10.3390/ijms21197231.
• Septembre-Malaterre A, Boina C, Douanier A, Gasque P. Deciphering the Antifibrotic Property of Metformin. Cells. 2022 Dec 16;11(24):4090. doi: 10.3390/cells11244090.
• Wu M, Xu H, Liu J, Tan X, Wan S, Guo M, Long Y, Xu Y. Metformin and Fibrosis: A Review of Existing Evidence and Mechanisms. J Diabetes Res. 2021 Apr 29;2021:6673525. doi: 10.1155/2021/6673525. eCollection 2021.
• Teague TT, Payne SR, Kelly BT, Dempsey TM, McCoy RG, Sangaralingham LR, Limper AH. Evaluation for clinical benefit of metformin in patients with idiopathic pulmonary fibrosis and type 2 diabetes mellitus: a national claims-based cohort analysis. Respir Res. 2022 Apr 11;23(1):91. doi: 10.1186/s12931-022-02001-0.
• Pimentel I, Lohmann AE, Ennis M, Dowling RJO, Cescon D, Elser C, Potvin KR, Haq R, Hamm C, Chang MC, Stambolic V, Goodwin PJ. A phase II randomized clinical trial of the effect of metformin versus placebo on progression-free survival in women with metastatic breast cancer receiving standard chemotherapy. Breast. 2019 Dec;48:17-23. doi: 10.1016/j.breast.2019.08.003. Epub 2019 Aug 22.

Study record dates

Study Major Dates

• Study Start (Estimated): March 1, 2024
• Primary Completion (Estimated): September 1, 2024
• Study Completion (Estimated): December 1, 2024

Study Registration Dates

• First Submitted: February 22, 2024
• First Submitted That Met QC Criteria: March 20, 2024
• First Posted (Actual): March 27, 2024

Study Record Updates

• Last Update Posted (Actual): March 27, 2024
• Last Update Submitted That Met QC Criteria: March 20, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: Metformin; TGF Beta; Oral Submucous Fibrosis; Randomized Controlled Clinial Trial; Smad2/ 3 Signaling; Wnt Signaling
• Additional Relevant MeSH Terms: Pathologic Processes; Stomatognathic Diseases; Mouth Diseases; Fibrosis; Oral Submucous Fibrosis; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Enzyme Inhibitors; Anti-Inflammatory Agents; Platelet Aggregation Inhibitors; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Protective Agents; Anti-Asthmatic Agents; Respiratory System Agents; Antioxidants; Phosphodiesterase Inhibitors; Free Radical Scavengers; Radiation-Protective Agents; Betamethasone; Betamethasone Valerate; Betamethasone-17,21-dipropionate; Betamethasone benzoate; Betamethasone sodium phosphate; Metformin; Pentoxifylline
• Other Study ID Numbers: 8420224AROM

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: The decision not to share Individual Participant Data (IPD) may be based on several considerations and could be influenced by institutional policies, ethical guidelines, and practical constraints.Sharing individual-level data may risk the identification of study participants, even with anonymization efforts, especially in smaller studies or specific populations

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No