Comparative Evaluation of Topical 30% Metformin and Kligman's Regimen in Women With Melasma

Title: A Novel Approach to Melasma Management: Comparative Evaluation of Topical 30% Metformin and Kligman's Regimen in Middle-Aged Women Introduction: Melasma is a common acquired pigmentary disorder that primarily affects middle-aged women and leads to symmetrical brown patches on the face, causing cosmetic and psychological distress. Multiple factors contribute, including ultraviolet radiation, hormonal influences, and genetic predisposition. (1,2) Various treatment options are available for melasma, including topical depigmenting agents, chemical peels, laser therapy, and photoprotection. (2) Kligman's regimen - a combination of hydroquinone, tretinoin, and fluocinolone acetonide - remains the gold standard for treatment but has side effects like irritation, rebound pigmentation, and steroid-induced dermatoses. (3) Topical metformin, an antidiabetic agent with antioxidant and anti-melanogenic properties, (4) has recently shown potential as a safe and effective alternative. A Randomized Control Trial in 2022 compared 30% topical metformin with Kligman's regimen and found comparable efficacy with fewer adverse effects. (5) Similarly, an RCT in 2023 reported that topical metformin demonstrated equivalent improvement to hydroquinone with a favorable safety profile. (6) These findings highlight the potential of metformin as an effective topical alternative for melasma management. The present study aims to compare the efficacy and tolerability of 30% topical metformin cream with Kligman's regimen in middle-aged women with epidermal melasma.

Objectives Primary Objective To compare the efficacy, in terms of mean reduction in modified MASI (mMASI) score from baseline to 8 weeks, between patients treated with 30% topical metformin and Kligman's regimen.

Secondary Objectives To compare the proportion of patients developing adverse effects (erythema, burning, peeling, or PIH) in both treatment groups.

Operational Definitions Melasma: Symmetrical hyperpigmented macules and patches on the face diagnosed clinically by a postgraduate trainee and then confirmed by a senior consultant and further verified as epidermal or dermal type using Wood's lamp examination.

Modified MASI (mMASI): A scoring system that evaluates the area (A: 0-6) and darkness (D: 0-4) of pigmentation in four facial regions - forehead (30%), right malar (30%), left malar (30%), and chin (10%).

Efficacy: Measured as the mean reduction in mMASI score from baseline to 8 weeks.

Adverse Effects: Any redness, burning, irritation, peeling, or dyspigmentation during treatment.

Hypothesis H₀ (Null Hypothesis): There is no significant difference in reduction of mMASI score between 30% topical metformin and Kligman's regimen.

H₁ (Alternate Hypothesis): Topical 30% metformin is more effective than Kligman's regimen in reducing mMASI score after 8 weeks.

Material and Methods Study Design: Prospective, randomized controlled, assessor-blinded comparative clinical study.

Setting: Dermatology Outpatient Department, Fauji Foundation Hospital, Rawalpindi.

Duration of Study: One Year, including recruitment, follow-up (8 weeks), and data analysis after approval from CPSP.

Sample Size: The sample size was calculated using G\*Power software (version 3.1.9.7) for comparison of means between two independent groups using a two-tailed independent samples t-test. The study was powered to detect a clinically significant treatment effect corresponding to a standardized effect size (Cohen's d) of 0.65. This effect size reflects an estimated difference of approximately 5.8 units in MASI score, based on a pooled standard deviation of 9.035 derived from previous literature (Ahmed et al., 2022). Assuming a significance level of 5% (α = 0.05) and a power of 80% (1-β = 0.80), the required sample size was 39 participants in each group. After allowing for a 5% dropout rate, the final sample size was increased to 41 participants per group, giving a total sample size of 82 participants.

Sampling Technique: Convenient sampling. Sample Selection

Inclusion Criteria:

Female patients aged 35-55 years

* Clinically diagnosed epidermal or dermal melasma (confirmed by Wood's lamp examination) * Fitzpatrick skin types III-V * Duration of melasma ≥6 months * No topical or systemic treatment for melasma in the past month

Exclusion Criteria:

* Pregnancy or lactation * Known allergy to study medications * Active facial dermatitis, acne, or recent cosmetic procedures Data Collection Procedure

After approval from CPSP, data collection will be started. Patients fulfilling inclusion criteria will be selected from OPD using convenient sampling. Melasma will be diagnosed clinically by a postgraduate trainee and then confirmed by senior consultant and further verified using Wood's lamp examination. After obtaining written informed consent, baseline mMASI scores and standardized facial photographs will be recorded. Participants will then be randomly assigned via lottery method to:

* Group A: Topical 30% metformin cream, once nightly * Group B: Kligman's regimen (hydroquinone 2%, tretinoin 0.025%, fluocinolone acetonide 0.01%), once nightly The 30% topical metformin will be prepared in the hospital pharmacy by compounding 30 g metformin powder with 70% ethyl alcohol and propylene glycol to make 100 g of final formulation, dispensed in airtight light-protected containers. Kligman's regimen will be provided as a standard commercially available formulation. All participants will be instructed to apply a thin layer of the assigned cream nightly on affected areas and use a mineral sunscreen (zinc oxide paste) available in the hospital pharmacy. Compliance will be ensured through patient counseling and demonstration of the correct application technique at each follow-up. Follow-ups at week 4 and week 8 will include mMASI reassessment, photographic documentation, and side-effect recording. The evaluating dermatologist will remain blinded to group allocation.

Data Collection Instrument: A structured proforma will record patient details, mMASI scores, and side effects.

Data Analysis Plan: Data will be analyzed using SPSS version 26. Quantitative variables (mMASI) will be expressed as mean ± standard deviation. Within-group comparisons (baseline vs. 8 weeks) will be analyzed using paired t-test, and between-group comparisons by independent t-test. Qualitative variables (side effects) will be presented as proportions (frequencies and percentages). The proportion of patients developing side effects in both groups will be compared using the Chi-square test. A p-value \< 0.05 will be considered statistically significant.

Ethical Considerations: Ethical approval will be obtained from the Institutional Review Board of Fauji Foundation Hospital, Rawalpindi. Written informed consent will be taken from all participants. Confidentiality and the right to withdraw at any time will be ensured.

• Patients with adverse effects [Срок оценки: Baseline to 8 weeks]