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| ID | Type | Description | Link |
|---|---|---|---|
| Ethical Review Committee | Other Identifier | Ziauddin Univeristy |
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| Name | Class |
|---|---|
| University of Karachi | OTHER |
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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.
Oral submucous fibrosis stands as a persistent inflammatory and potentially malignant condition affecting the oral cavity, marked by progressive fibrosis of the oral mucosa. Existing therapies, such as corticosteroids, are costly and merely treat the symptoms without addressing the molecular pathways that cause fibrosis, which results in limited efficacy, relapse, and side effects. Given the financial constraints of affected communities, there is a desperate need for affordable and accessible treatments. This research project aims to investigate the effects of metformin and antifibrotic drugs on the secretion and biological activity of exosomes in oral submucous fibrosis (OSF) cell lines. The study will explore how these treatments impact morphological changes, exosomal gene expression, and protein profiles in OSF cell lines compared to control and vehicle-controlled groups. Additionally, the project will identify molecular pathways influenced by metformin and antifibrotic drugs, with a focus on their modulation of exosomal protein content and functional profiles. The clinical relevance of exosomal protein profiles in OSF treatment, particularly through the repurposing of metformin, will also be evaluated. Methodologically, the study involves in vitro experiments on OSF cell lines, employing techniques such as qPCR, Western Blot, and Liquid Chromatography-Mass Spectrometry (LCMS) for protein profiling, alongside a clinical trial to assess therapeutic efficacy.
The project is structured around several key objectives:
This research has the potential to uncover new therapeutic strategies for OSF, particularly through the repurposing of metformin, which could lead to better clinical outcomes for patients suffering from this precancerous condition.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Beclomaethasone and Vitamin E | Active Comparator | Group 1 Control (Supportive Care): Beclomethasone mouthwash three times + Capsule vitamin E 400mg daily. |
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| Metformin + Supportive Care | Experimental | Group 2 (Metformin + Supportive Care): Metformin: 500 mg twice daily + Beclomethasone mouthwash three times + Capsule vitamin E 400mg daily. |
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| Pirfenidone + Supportive Care | Experimental | Group 3 (Pirfenidone + Supportive Care): Pirfenidone: 200 mg twice daily + Beclomethasone mouthwash three times + Capsule vitamin E 400mg daily. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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 |
| Measure | Description | Time Frame |
|---|---|---|
| Morphological Changes in OSF Cell Lines Post-Treatment | This outcome evaluates the morphological alterations in OSF cell lines following treatment with Metformin and Pirfenidone. Changes in cell shape, size, and fibrosis-associated structural modifications will be assessed using Scanning Electron Microscopy (SEM). | 24, 48, and 72 hours post-treatment |
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Inclusion Criteria:
Exclusion Criteria:
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Ziauddin University | Karachi | Sindh | 74700 | Pakistan |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 38003450 | Background | 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. | |
| 38192410 | 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. |
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IPD will not be shared because this study involves in vitro experiments on OSF cell lines and does not include individual patient data. Additionally, for the clinical trial component, data privacy regulations and ethical considerations prevent the sharing of participant-specific data
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| ID | Term |
|---|---|
| D009914 | Oral Submucous Fibrosis |
| ID | Term |
|---|---|
| D009059 | Mouth Diseases |
| D009057 | Stomatognathic Diseases |
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| ID | Term |
|---|---|
| D008687 | Metformin |
| D013607 | Tablets |
| C093844 | pirfenidone |
| D014810 | Vitamin E |
| ID | Term |
|---|---|
| D001645 | Biguanides |
| D006146 | Guanidines |
| D000578 | Amidines |
| D009930 | Organic Chemicals |
| D004304 |
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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
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double-blind intervention
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| 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 |
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| 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. |
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| Size and Distribution of Exosomes in OSF Cell Lines | This outcome measures changes in exosome size, distribution, and concentration after treatment with Metformin and Pirfenidone. Characterization will be performed using Dynamic Light Scattering (DLS) and Scanning Electron Microscopy (SEM). | 24, 48, and 72 hours post-treatment |
| Functional Impact of Treated OSF cells | This outcome evaluates whether Metformin- and Pirfenidone-treated OSF cell lines, as compared to control untreated OSF cells, influence fibroblast migration and proliferation. Cell behavior will be assessed through Scratch migration and proliferation assays to determine functional effects. | 24, 48, 72 and 96 hours post- treatment |
| Safety and Viability of OSF Cell Lines Post-Treatment | This outcome measures the cytotoxicity and cell viability of OSF cell lines following treatment with Metformin and Pirfenidone. MTT assay will be used to assess potential toxic effects of the drugs at different concentrations. | 24, 48, and 72 hours post-treatment |
| 37828490 | 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. |
| 36828692 | 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. |
| 38360641 | 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. |
| 38627767 | 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. |
| Dosage Forms |
| D004364 | Pharmaceutical Preparations |
| D001578 | Benzopyrans |
| D011714 | Pyrans |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |