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

NCT06332612 | Completed Phase 1 DMC

• 1 other identifier: 8420224AROM
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

Brief Summary

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

Conditions

Oral Submucous Fibrosis

Keywords

Oral Submucous Fibrosis; Metformin; Randomized Controlled Clinial Trial; TGF Beta; Smad2/ 3 Signaling; Wnt Signaling

Outcome Measures

Primary Outcomes (9)

• 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 Outcomes (3)

• Clinical Oral Mucosal Characteristics

  9 months

• Patient Burning sensation pain

  9 months

• Patient Mouth Opening

  9 months

Study Arms (3)

Standard

ACTIVE COMPARATOR

Group 1: Standard treatment with topical cream betamethasone and Pentoxifylline tablet.

Drug: betamethasone dipropionate; Drug: Pentoxifylline

MetforminO

EXPERIMENTAL

Metformin 500 mg thrice daily.

Drug: Metformin Hydrochloride

MetforminT

EXPERIMENTAL

Topical cream metformin thrice daily

Drug: Metformin Hydrochloride

Interventions

Metformin Hydrochloride DRUG

Group B will receive Metformin 500 mg thrice daily. Group C will receive topical cream metformin thrice daily.

Also known as: Glucophage

MetforminO; MetforminT

betamethasone dipropionate DRUG

Group 1will recieve topical cream betamethasone thrice daily

Also known as: Betnovate

Standard

Pentoxifylline DRUG

Group 1 will receive Pentoxifylline tablet 400 mg twice daily

Also known as: Trental

Standard

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

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

You may not qualify if:

• Patients presenting with both OSCC and OSF
• 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).
• 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)
• Any history of Metformin intolerance or contraindications.
• Presence of other severe medical conditions along with drug therapy.
• Pregnancy or lactation.
• Participation in other clinical trials concurrently.
• Inability to provide informed consent.

Sponsors & Collaborators

• Ziauddin University: lead

Study Sites (1)

Ziauddin University

Karachi, Sindh, 74700, Pakistan

Location

Related Publications (6)

• 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.

  PMID: 28390753 RESULT

• 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.

  PMID: 33008091 RESULT

• 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.

  PMID: 36552855 RESULT

• 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.

  PMID: 34007848 RESULT

• 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.

  PMID: 35410255 RESULT

• 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.

  PMID: 31472446 RESULT

MeSH Terms

Conditions

Oral Submucous Fibrosis; Camurati-Engelmann Syndrome

Interventions

Metformin; betamethasone-17,21-dipropionate; Betamethasone Valerate; Pentoxifylline

Condition Hierarchy (Ancestors)

Mouth Diseases; Stomatognathic Diseases; Osteochondrodysplasias; Bone Diseases, Developmental; Bone Diseases; Musculoskeletal Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Biguanides; Guanidines; Amidines; Organic Chemicals; Betamethasone; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated; Theobromine; Xanthines; Purinones; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Masking Details: It would be a single-blind, placebo-controlled design
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Model Details: 1\. In Vitro (Cell Line) Study Design: Experimental in vitro study using OSF cell lines. Groups: * Metformin-treated * Control (untreated) * Vehicle control Clinical Trial Study Design: A pilot Randomized Controlled Trial (RCT) translating the in vitro findings into a clinical setting. It would be a single-blind, placebo-controlled designAll groups will undergo a 24-week intervention phase. Group 1 will receive standard treatment including topical cream betamethasone thrice daily and Pentoxifylline tablet 400 mg twice daily. Group 2 will receive Metformin 500 mg thrice daily. Group 3 will receive topical cream metformin thrice daily. All groups will be instructed to perform a stick mouth opening exercise twice daily, alternating sides, holding the stick for 10 minutes on each side, with a 10-minute rest in between. All groups will be single blinded to the intervention.

Study Record Dates

• First Submitted: February 22, 2024
• First Posted: March 27, 2024
• Study Start: August 12, 2024
• Primary Completion: December 30, 2024
• Study Completion: January 6, 2025
• Last Updated: May 2, 2025

Record last verified: 2025-04

Data Sharing

• IPD Sharing: Will not share

Locations

PA (1)