This randomised controlled trial aims to compare the efficacy of topical metformin (30%) and topical tranexamic acid (3%) in the treatment of melasma using reduction in the Melasma Area and Severity Index (MASI) score over 12 weeks. Melasma is a common hyperpigmentation disorder with significant cosmetic and psychological impact, and current treatments often have limitations. Both metformin and tranexamic acid have shown promising depigmenting effects through different mechanisms. A total of 70 patients will be enrolled and randomly divided into two groups. Participants will apply the assigned treatment once daily along with sunscreen and will be assessed at baseline and at 4, 8, and 12 weeks. The primary outcome is MASI score reduction, while secondary outcomes include patient-reported improvement and safety. This study seeks to provide comparative evidence for safer and more effective treatment options for melasma management.

Introduction / Background Melasma is a common acquired disorder of hyperpigmentation characterized by symmetrical light-to-dark brown macules and patches predominantly affecting sun-exposed areas of the face, particularly the cheeks, forehead, upper lip, and chin (1). It occurs more frequently in women of reproductive age and individuals with darker skin type (Fitzpatrick III to VI) (1). The precise cause of melasma is unknown but factors such as UV light exposure, pregnancy, exogenous hormones, and genetics have been shown to have an important role in the pathogenesis of melasma (1). The condition often causes significant cosmetic concern and psychological distress due to its chronic and recurrent nature (3,4).

Various treatment modalities have been used for melasma, including topical depigmenting agents, chemical peels, laser therapies, and systemic medications (8). Consequently, there is a continuous search for newer, safer, and more effective therapeutic options for the management of melasma (4).

Tranexamic acid (TXA), a synthetic antifibrinolytic agent, has recently gained attention as a promising treatment for melasma. Its depigmenting effect is believed to occur through inhibition of the plasminogen-plasmin system in keratinocytes, leading to decreased release of arachidonic acid and prostaglandins that stimulate melanocyte activity.. Clinical studies evaluating topical TXA have demonstrated significant reductions in Melasma Area and Severity Index (MASI) scores with good tolerability and minimal adverse effects (4,5,6) Metformin, a widely used oral antidiabetic drug, has recently emerged as a potential therapeutic agent for hyperpigmentary disorders. Experimental studies have demonstrated that metformin inhibits melanogenesis through activation of AMP-activated protein kinase (AMPK) resulting in down-regulating MITF and melanogenic enzymes. Topical formulations of metformin have shown promising depigmenting effects in preliminary clinical studies, with reductions in MASI scores comparable to standard triple combination therapy and fewer adverse effects (3,5).

Recent clinical trials and systematic reviews suggest that topical metformin may represent a novel and safe treatment option for melasma, demonstrating significant improvement in MASI scores and good patient tolerability. However, direct comparative evidence between topical tranexamic acid and topical metformin remains limited. (5). Therefore, this study aims to perform a comparative evaluation of topical tranexamic acid and topical metformin in melasma using MASI score reduction after 12 weeks of treatment.

Rationale of the Study Melasma remains a therapeutic challenge due to its chronicity, high recurrence rate, and limitations associated with existing treatments such as hydroquinone-based therapies. Emerging agents like tranexamic acid and metformin have shown promising depigmenting effects through different mechanisms of action. However, limited comparative data exist regarding their relative effectiveness in reducing melasma severity.

This study aims to compare the efficacy of topical tranexamic acid and topical metformin using changes in MASI score over a 12-week period. The findings may provide evidence for the use of topical metformin as a potential alternative depigmenting agent in melasma management.

Objectives

Primary Objective To compare the efficacy of topical metformin and topical tranexamic acid in reducing melasma severity based on change in MASI score after 12 weeks of treatment.

Secondary Objectives

• To assess patient-reported improvement using a visual analog scale (VAS).
• To evaluate photographic improvement through standardized digital imaging.
• To compare the safety and tolerability of both topical agents. Hypothesis

Null Hypothesis (H0):

There is no significant difference between 3% topical tranexamic acid and 30% topical metformin in reducing melasma severity as measured by the change in MASI score after 12 weeks of treatment.

Alternative Hypothesis (H1):

Topical 30% metforminis more effective than topical 3% tranexamic acid in reducing MASI score after 12 weeks of treatment.

Operational Definitions

Melasma Acquired symmetrical hyperpigmented macules and patches on sun-exposed facial areas (forehead, malar regions, upper lip, and chin) diagnosed clinically by a dermatologist and confirmed by characteristic clinical appearance.

MASI Score (Melasma Area and Severity Index) A validated scoring system used to assess melasma severity based on area of involvement, darkness of pigmentation, and homogeneity of lesions across four facial regions (forehead, right malar, left malar, and chin). Scores range from 0 to 48, with higher scores indicating greater severity.

Study Design: Randomized controlled trial. Study Setting Department of Dermatology, Fauji Foundation Hospital, Rawalpindi,Pakistan. Duration of Study 6 months after approval of synopsis Sample Size Sample size was calculated using WHO Sample Size Calculator (OpenEpi) for comparison of two means using data derived from previous studies (references mentioned)

Previous studies have reported:

• Mean MASI reduction with topical tranexamic acid ≈ 3.8 ± 2.1
• Mean MASI reduction with topical metformin ≈ 2.2 ± 1.9

Parameters used:

• Confidence level: 95%
• Power: 80%
• Ratio of groups: 1:1 The calculated sample size is approximately 31 patients per group.

Adding 10% possible dropouts, the final sample size becomes:

• 35 patients per group Final Sample Size Total sample size = 70 patients
• Group A: 35 patients (Topical Tranexamic Acid)
• Group B: 35 patients (Topical Metformin)

Sampling Technique:

Eligible patients will be recruited using non-probability consecutive sampling and then randomly allocated into two groups using the sealed opaque envelope method. consecutive sampling.

Sample Selection:

Inclusion Criteria

• Patients aged 18-50 years
• Clinically diagnosed facial melasma
• Both genders
• Patients willing to give informed consent

Exclusion Criteria

• Pregnant or lactating women
• Patients using systemic or topical melasma treatments in the previous 4 weeks
• Known hypersensitivity to study medications
• Presence of other facial dermatoses
• History of photosensitivity disorders

Data Collection Procedure:

Patients fulfilling the inclusion criteria will be enrolled after informed consent. Baseline demographic data including age, gender, duration of melasma, and skin phototype will be recorded.

Baseline MASI score will be calculated for each patient. Participants will then be randomly divided into two groups:

Group A: Topical Tranexamic Acid 3% solution Group B: Topical Metformin 30 % cream The 30% metformin cream will be prepared in the hospital pharmacy by dissolving 30 g of metformin powder in a mixture of 70% ethyl alcohol and propylene glycol to make 100 g of the final formulation, stored in airtight containers under aseptic conditions, While the tranexamic acid 3 % solution will be prepared by dissolving 3g of tranexamic powder in 10ml of 96% ethanol plus 10ml of 1'3-butanediol with distilled water added upto 100ml to make a 3% concentration.

Patients will be instructed to apply the assigned topical treatment once daily for 12 weeks along with sunscreen (SPF >50) use during daytime. Follow-up visits will be conducted at 4 weeks, 8 weeks, and 12 weeks. MASI score will be reassessed at each visit.

Baseline Assessment

• Demographic data
• Disease duration
• Baseline MASI score
• Fitzpatrick skin type
• Type of melasma - epidermal' dermal' mixed.
• Baseline Visual Analog Scale (VAS) 0-10 for pigmentation severity from patient's perspective Follow-Up Visits
• Week 4
• Week 8
• Week 12

At each visit:

• MASI score reassessment
• Change in VAS score from baseline
• Recording of adverse effects - erythema ' irritation' burning'scaling. Data Analysis Plan: Data will be entered and analyzed using SPSS version 26.
• Quantitative variables such as age and MASI score will be presented as mean ± standard deviation.
• Categorical variables such as gender will be presented as frequency and percentage.
• Paired t-test will be used to assess within-group MASI score reduction.
• Independent t-test will be used to compare mean MASI score reduction between the two groups.
• P-value ≤ 0.05 will be considered statistically significant. Limitations of the Study: This study may have certain limitations. It will be conducted at a single center with a relatively small sample size, which may limit the generalizability of the findings. Additionally, different topical formulations (tranexamic acid solution and metformin cream) will be used, which may influence drug penetration and treatment response. Furthermore, the follow-up duration of 12 weeks may be insufficient to evaluate long-term outcomes or recurrence of melasma.

Inclusion Criteria:

• Patients aged 18-50 years

  • Clinically diagnosed facial melasma
  • Both genders
  • Patients willing to give informed consent

Exclusion Criteria:

• • Pregnant or lactating women

  • Patients using systemic or topical melasma treatments in the previous 4 weeks
  • Known hypersensitivity to study medications
  • Presence of other facial dermatoses
  • History of photosensitivity disorders

The evaluating dermatologist, assessing MASI scores and photographs, will remain blinded to group allocation.