Clinical trial NCT06332612: Metformin Repurposing in Oral Submucous Fibrosis: Unveiling In Vitro Signaling Pathways, Progressing to Clinical Trial
Official title: Repurposing Metformin for the Treatment of Oral Submucous Fibrosis: Unraveling Novel Signaling Pathways In Vitro and Advancing to Clinical Trial"
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Oral Submucous Fibrosis
Keywords: Oral Submucous Fibrosis
Metformin
Randomized Controlled Clinial Trial
TGF Beta
Smad2/ 3 Signaling
Wnt Signaling
Lead sponsor: Ziauddin University
Sponsor class: OTHER
First posted: 2024-03-27
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: 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.
Primary purpose: TREATMENT

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

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Cell Viability
timeFrame: 8 months
measure: Cytotoxicity
timeFrame: 8 Months
measure: Morphological Changes Cell Shape
timeFrame: 8months
measure: Morphological Change Cell Density
timeFrame: 8 months
measure: Morphological Change Extracellular Matrix (ECM) Structure
timeFrame: 8 months
measure: Cell Migration Assays
timeFrame: 8months
measure: Cell Invasion Assays
timeFrame: 8 months
measure: Apoptosis Analysis
timeFrame: 8months
measure: Assess Signaling pathway with optimal metformin concentration
timeFrame: 9 months
Secondary outcomes:
measure: Clinical Oral Mucosal Characteristics
timeFrame: 9 months
measure: Patient Burning sensation pain
timeFrame: 9 months
measure: Patient Mouth Opening
timeFrame: 9 months
Other outcomes:
Locations:
city: Karachi
country: Pakistan
facility: Ziauddin University
state: Sindh
Study officials:
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.