Fibrosis-Modulating Effects of Metformin and Pirfenidone in Oral Submucous Fibrosis

NCT06871904 | Completed Phase 1 DMC

• 2 other identifiers: 9840125ARMMEthical Review Committee
• Study Type: interventional
• Target: 45
• Locations: 1 country
• Sites: 1

Brief Summary

The goal of this clinical trial is to learn if metformin and antifibrotic drugs (pirfenidone) can modulate fibrosis and improve treatment outcomes in patients with oral submucous fibrosis (OSF). The study also aims to investigate the molecular mechanisms underlying their effects on exosome secretion and protein expression. The main questions it aims to answer are: Do metformin and antifibrotic drugs alter exosome secretion and biological activity in OSF cell lines? What molecular pathways are influenced by these drugs in modulating fibrosis? Does treatment with metformin and antifibrotic drugs improve clinical outcomes in OSF patients? Researchers will compare metformin and antifibrotic drug treatment groups to a control group to see if these drugs lead to significant changes in fibrosis-related exosomal protein expression and clinical improvement in OSF patients. Participants will : Undergo in vitro experiments on OSF cell lines to analyze drug effects using qPCR, Western Blot, and LCMS for protein profiling. Participate in a randomized, double-blind clinical trial where they receive metformin, antifibrotic drugs, or a placebo. Undergo clinical evaluations and laboratory tests to assess treatment efficacy. This study aims to develop an affordable and effective fibrosis-targeted therapy for OSF by repurposing metformin, potentially improving patient outcomes and reducing the risk of malignant transformation.

Conditions

Oral Submucous Fibrosis

Keywords

Oral submucous fibrosis; Fibrosis Modulation; Metformin; Pirfenidone; Exosome secretion; Molecular Pathway; LCMS; Clinical Trial; Exosome Protein Profiling

Outcome Measures

Primary Outcomes (4)

• Change in Exosome Secretion and Characterization in OSF Cell Lines

  This outcome evaluates the effect of Metformin and Pirfenidone on exosome secretion and size distribution in OSF cell lines. Exosomes will be isolated and characterized using Scanning Electron Microscopy (SEM) and Dynamic Light Scattering (DLS) to assess morphological changes, size, and concentration differences across treatment groups.

  24, 48, and 72 hours post-treatment

• Changes in Fibrosis-Related Gene Expression in OSF Cell Lines

  This outcome assesses the effect of Metformin and Pirfenidone on fibrosis-related gene expression (TGF-β, Collagen 1A1, α-SMA) in OSF cell lines. Changes will be analyzed using quantitative PCR (qPCR).

  24 and 48 hours post-treatment

• Reduction in Fibrosis Severity in OSF Patients

  This outcome measures clinical improvement in Oral Submucous Fibrosis (OSF) patients treated with Metformin, Pirfenidone, or Supportive Care (Beclomethasone + Vitamin E). Severity will be assessed using the Burning Mouth Index by verbal numeric rating scale (0-10) at baseline and every 4 weeks during the trial and Interincisal Mouth Opening (IMO).

  Baseline, 4 weeks, 8 weeks, and 12 weeks, 16 weeks, 20 weeks and 24 weeks

• Change in TGF-β and Collagen Levels in Exosomes from OSF Cell Lines

  This outcome assesses whether Metformin and Pirfenidone reduce fibrosis-related molecular markers (TGF-β and Collagen) in exosomes isolated from OSF cell lines. Exosomal protein levels will be analyzed using Western Blot and Liquid Chromatography-Mass Spectrometry (LCMS) to determine drug-induced changes in fibrosis-related pathways.

  24, 48, and 72 hours post-treatment

Secondary Outcomes (4)

• Morphological Changes in OSF Cell Lines Post-Treatment

  24, 48, and 72 hours post-treatment

• Size and Distribution of Exosomes in OSF Cell Lines

  24, 48, and 72 hours post-treatment

• Functional Impact of Treated OSF cells

  24, 48, 72 and 96 hours post- treatment

• Safety and Viability of OSF Cell Lines Post-Treatment

  24, 48, and 72 hours post-treatment

Study Arms (3)

Beclomaethasone and Vitamin E

ACTIVE COMPARATOR

Group 1 Control (Supportive Care): Beclomethasone mouthwash three times + Capsule vitamin E 400mg daily.

Drug: Beclomaethasone and Vitamin E

Metformin + Supportive Care

EXPERIMENTAL

Group 2 (Metformin + Supportive Care): Metformin: 500 mg twice daily + Beclomethasone mouthwash three times + Capsule vitamin E 400mg daily.

Drug: Metformin Hydrochloride 500Mg Tablet; Drug: Beclomaethasone and Vitamin E

Pirfenidone + Supportive Care

EXPERIMENTAL

Group 3 (Pirfenidone + Supportive Care): Pirfenidone: 200 mg twice daily + Beclomethasone mouthwash three times + Capsule vitamin E 400mg daily.

Drug: Pirfenidone (PFD); Drug: Beclomaethasone and Vitamin E

Interventions

Beclomaethasone and Vitamin E DRUG

The Supportive Care Group will receive Beclomethasone mouthwash (three times daily) and Vitamin E 400 mg (once daily) as part of supportive care for oral submucous fibrosis . This intervention serves as a comparison group to evaluate the efficacy of Metformin and Pirfenidone. Beclomethasone is a topical corticosteroid that reduces inflammation and provides symptomatic relief in OSF. Vitamin E is an antioxidant that may help reduce oxidative stress and improve tissue healing. Distinction from Other Arms: Unlike Pirfenidone and Metformin, which target fibrosis at the molecular level, Beclomethasone + Vitamin E primarily focus on symptom relief. This arm will serve as an active comparator to determine whether the antifibrotic effects of Metformin and Pirfenidone provide superior therapeutic benefits.

Also known as: Beclamethasone, Vitamin E

Beclomaethasone and Vitamin E; Metformin + Supportive Care; Pirfenidone + Supportive Care

Metformin Hydrochloride 500Mg Tablet DRUG

Metformin 500 mg is being tested for its potential role in treating oral submucous fibrosis (OSF) due to its antifibrotic and anti-inflammatory effects. This intervention will be administered orally at a dose of 500 mg twice daily (OD) for a specified 6 months treatment period for Group 2 . Metformin activates AMPK (AMP-activated protein kinase), which inhibits TGF-β signaling and collagen deposition, reducing fibrosis and inflammation. Distinction from Other Arms: Unlike Pirfenidone, which directly targets profibrotic cytokines, Metformin modulates metabolic pathways to exert antifibrotic effects. The Control Group will receive supportive care for OSF.

Also known as: Glucophage

Metformin + Supportive Care

Pirfenidone (PFD) DRUG

Pirfenidone 200 mg (Pirfibet by Mactor Pharma, Pakistan) is an antifibrotic drug being tested for its potential role in treating oral submucous fibrosis (OSF). This intervention will be administered orally at a dose of 200 mg, twice daily for a specified treatment period which will be 6 months for Group 3 . Pirfenidone modulates fibrotic pathways by inhibiting TGF-β and collagen synthesis, reducing fibrosis progression. Distinction from Other Arms: Unlike Metformin, which has antifibrotic effects via AMPK activation, Pirfenidone specifically targets profibrotic cytokines. The Control Group will receive either a supportive care for OSF

Also known as: Pirfibet

Pirfenidone + Supportive Care

Eligibility Criteria

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

You may qualify if:

• Patients with OSF having fibrous bands
• Patients with limited mouth opening due to OSF in Stage 2 and Stage 3
• Patients who have not received any treatment for OSF in the previous three months
• Patients with habits of pan, Chalia, Gutkha
• The age group between 18 and 45 years

You may not qualify if:

• Patients presenting with OSCC
• Patients with limited mouth opening due to impaction of the third molar
• Patients with limited mouth opening due to temporomandibular joint disorder
• Any history of Metformin intolerance or contraindications to its use.
• Medical conditions (e.g., cardiovascular disease, renal/hepatic impairment) or drug therapy (\>6 months) with immunosuppressants, corticosteroids, or antifibrotics.
• Pregnancy or lactation.
• Participation in other clinical trials concurrently.
• Inability / unwilling to provide informed written consent.

Sponsors & Collaborators

• Ziauddin University: lead
• University of Karachi: collaborator

Study Sites (1)

Ziauddin University

Karachi, Sindh, 74700, Pakistan

Location

Related Publications (6)

• Wang L, Zhong NN, Wang X, Peng B, Chen Z, Wei L, Li B, Li Y, Cheng Y. Metformin Attenuates TGF-beta1-Induced Fibrosis in Salivary Gland: A Preliminary Study. Int J Mol Sci. 2023 Nov 13;24(22):16260. doi: 10.3390/ijms242216260.

  PMID: 38003450 BACKGROUND

• Huh JY, Lee JH, Song JW. Efficacy and safety of combination therapy with pirfenidone and nintedanib in patients with idiopathic pulmonary fibrosis. Front Pharmacol. 2023 Dec 12;14:1301923. doi: 10.3389/fphar.2023.1301923. eCollection 2023.

  PMID: 38192410 BACKGROUND

• Chen X, Xie H, Guo J. Drug treatment for oral submucous fibrosis: an update. BMC Oral Health. 2023 Oct 12;23(1):748. doi: 10.1186/s12903-023-03488-9.

  PMID: 37828490 BACKGROUND

• Ahmadpour F, Rasouli HR, Talebi S, Golchin D, Esmailinejad MR, Razie A. Effects of exosomes derived from fibroblast cells on skin wound healing in Wistar rats. Burns. 2023 Sep;49(6):1372-1381. doi: 10.1016/j.burns.2023.02.003. Epub 2023 Feb 14.

  PMID: 36828692 BACKGROUND

• Abbasi-Malati Z, Azizi SG, Milani SZ, Serej ZA, Mardi N, Amiri Z, Sanaat Z, Rahbarghazi R. Tumorigenic and tumoricidal properties of exosomes in cancers; a forward look. Cell Commun Signal. 2024 Feb 15;22(1):130. doi: 10.1186/s12964-024-01510-3.

  PMID: 38360641 BACKGROUND

• Abbasi R, Nejati V, Rezaie J. Exosomes biogenesis was increased in metformin-treated human ovary cancer cells; possibly to mediate resistance. Cancer Cell Int. 2024 Apr 16;24(1):137. doi: 10.1186/s12935-024-03312-6.

  PMID: 38627767 BACKGROUND

MeSH Terms

Conditions

Oral Submucous Fibrosis

Interventions

Metformin; Tablets; pirfenidone; Vitamin E

Condition Hierarchy (Ancestors)

Mouth Diseases; Stomatognathic Diseases

Intervention Hierarchy (Ancestors)

Biguanides; Guanidines; Amidines; Organic Chemicals; Dosage Forms; Pharmaceutical Preparations; Benzopyrans; Pyrans; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Masking Details: double-blind intervention
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Model Details: Clinical Trial :All groups will undergo a 24-week intervention phase. The groups will be divided according to the treatment regime. Group 1 Control (Supportive Care): Beclomethasone mouthwash three times + Capsule vitamin E 400mg daily. Group 2 (Metformin + Supportive Care): Metformin: 500 mg twice daily + Beclomethasone mouthwash three times + Capsule vitamin E 400mg daily. Group 3 (Pirfenidone + Supportive Care): Pirfenidone: twice 200 mg daily + Beclomethasone mouthwash three times + Capsule vitamin E 400mg daily. Each group will be advised to refrain from spicy ingredients and cease eating pan, chalia or gutkha. All groups will be instructed to perform a mouth-opening stick exercise twice daily, alternating sides, holding the stick for 10 minutes on each side, with a 10-minute rest in between.Clinical evaluations will be conducted every 4 weeks

Study Record Dates

• First Submitted: March 5, 2025
• First Posted: March 12, 2025
• Study Start: April 7, 2025
• Primary Completion: December 30, 2025
• Study Completion: December 30, 2025
• Last Updated: February 3, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will not share

Locations

PA (1)