Topical Metformin Versus Triple Regimen for Epidermal Melasma

Melasma is an acquired hyperpigmentation disorder characterized by symmetrical brown or dark-brown patches, most commonly affecting the centrofacial, malar, or mandibular regions of the face. Epidermal melasma is identified by enhanced contrast and sharply defined pigmentation under Wood's lamp examination, indicating superficial epidermal melanin deposition. The condition is particularly common among women of reproductive age and is associated with ultraviolet exposure, heat exposure, pregnancy, hormonal factors, oral contraceptive use, and genetic susceptibility.

Topical triple-combination therapy has been widely used as a standard treatment for melasma. However, prolonged treatment may be limited by adverse effects, including erythema, desquamation, burning, telangiectasia, and steroid-related complications. Topical metformin has emerged as a possible alternative because experimental studies suggest that it may reduce melanogenesis by downregulating melanogenic proteins and decreasing expression of microphthalmia-associated transcription factor. Previous clinical studies have reported improvement in melasma severity with topical metformin, but comparative evidence remains limited.

This study is a randomized clinical trial that will be conducted in the Dermatology Department of Combined Military Hospital Malir Cantt, Karachi. The study aims to compare the efficacy of topical 30% metformin with a topical triple regimen in patients with epidermal melasma. The planned sample consists of 104 participants, with 52 participants in each treatment group. Participants will be recruited through non-probability consecutive sampling and then randomly allocated to either group using the lottery method.

Eligible participants will include men and women aged 18-50 years with epidermal melasma confirmed according to the study's operational definition. Participants must not have used treatment for epidermal melasma during the previous month and must not have undergone dermabrasion, laser ablation, or chemical peeling during the previous three months. Patients with acne vulgaris, rosacea, pregnancy, or comorbid conditions will be excluded.

After written informed consent, demographic and clinical information will be recorded, including age, sex, marital status, education, residence, employment status, duration of melasma, estimated daily sun exposure, treatment history, and site of facial involvement. Each participant will undergo clinical examination using a Wood's lamp, and a baseline modified Melasma Area and Severity Index score will be calculated.

Participants assigned to Group A will receive topical 30% metformin cream. Participants assigned to Group B will receive a topical triple regimen containing 2% hydroquinone, 0.05% tretinoin, and 0.01% fluocinolone acetonide. Both treatments will be applied once daily at night for eight consecutive weeks. All participants will be advised to apply SPF 50 or higher sunscreen in the morning. Digital photographs will be taken before treatment and after completion of therapy.

The primary outcome is treatment efficacy at eight weeks. Efficacy will be measured using the percentage reduction in modified MASI score from baseline:

Percentage reduction = \[(baseline score - post-treatment score) ÷ baseline score\] × 100

Treatment will be classified as effective when the participant achieves a reduction of at least 25% from the baseline modified MASI score. The modified MASI score will be recorded at the first visit and at the final assessment after eight weeks.

Quantitative variables, including age, disease duration, and modified MASI scores, will be summarized using mean and standard deviation. Qualitative variables, including sex, marital status, education, residence, sun exposure, melasma site, and efficacy, will be summarized using frequencies and percentages. The efficacy proportions of the two groups will be compared using the chi-square test, with a p-value of 0.05 or less considered statistically significant. Stratification will be used to control for potential confounders such as age, sex, disease duration, marital status, education, residence, sun exposure, and site of melasma.

• Topical 30% metformin cream (Drug): Topical metformin cream at a concentration of 30% will be applied once daily at night to affected facial areas for eight consecutive weeks. Participants will use SPF 50 or higher sunscreen in the morning.
• Topical Triple Regimen (Drug): A topical triple-combination regimen containing 2% hydroquinone, 0.05% tretinoin, and 0.01% fluocinolone acetonide will be applied once daily at night to affected facial areas for eight consecutive weeks. Participants will use SPF 50 or higher sunscreen in the morning.

Primary outcomes

• Proportion of Participants Achieving at Least 25% Reduction in Modified Melasma Area and Severity Index (mMASI) Score [Baseline to 8 weeks]: The modified Melasma Area and Severity Index (mMASI) score will be assessed at baseline and Week 8. Percentage reduction in mMASI score will be calculated as: \[(baseline mMASI score - Week 8 mMASI score) / baseline mMASI score\] × 100. A participant will be classified as a responder if the mMASI score decreases by at least 25% from baseline to Week 8. The outcome will be reported as the proportion of participants meeting this response criterion in each treatment group.

Sex: All, ages: 18 Years to 50 Years

Inclusion Criteria:

* Male or female participants aged 18 to 50 years.
* Confirmed diagnosis of epidermal melasma according to the study's operational definition.
* Epidermal melasma confirmed by Wood's lamp examination, showing accentuated hyperpigmentation with enhanced contrast and sharp borders.
* No treatment for epidermal melasma during the previous one month.
* No dermabrasion, laser ablation, or chemical peel during the previous three months.
* Willing to provide written informed consent.

Exclusion Criteria:

* Acne vulgaris.
* Rosacea.
* Pregnancy.
* Presence of comorbid conditions.