Will individual participant data (IPD) be shared publicly (including data dictionaries)?  

Response - YES

Melasma is a chronic, relapsing pigmentary disorder involving mainly face. It is not only a cosmetic concern but have psychosocial impact. It is more common in Asian population with Fitzpatrick skin type IV-V. Females during their reproductive age are at higher risk. Ultraviolet rays, sex hormones and genetic factors are important precipitating factors. Melasma can be described as abnormal brown to gray brown patches on the face. Most common areas affected are cheeks, chin, nose bridge, forehead and above the upper lip. Most commonly found in females in comparison to males. Possible reasons are pregnancy, oral contraceptive pills and various hormonal treatment. Other possible causes are anti seizure drugs, cosmetic treatment, genetic influences and prolonged exposure to UV radiations. In 50% cases, family history of condition is positive. Prolonged sun exposure i.e UV radiation can cause lipid peroxidation in membranes leading to free radical production which further stimulate melanocytes to produce excessive melanin producing melasma.

Treatment modalities available for the melasma are as follows: Topical treatment -Sun screens, Hydroquinone, Retinoid, Modified Kligman-willis formula (triple combination)-containing 2%Hydroquinone w/w, 0.01% flucinoloneacetonide w/w and 0.05% tretinoin w/w., Mequinol ,Topical Metformin, Methimazole, Melatonin, Malassezin and Nonphenolic compounds like Corticosteroids, Azelaic acid, Kojic acid, Arbutin , Vitamin C, Niacinamide. Systemic agents like Tranexamic acid, Procyanidin, Oral polypodiumleucotomos extract, Pycnogenol ,Glutathione. Procedures like Chemical peeling agents:The most commonly used agents for chemical peeling are 15% or 20% trichloroacetic acid (TCA) in aqueous solution, 30%, 50%, or 70% glycolic acid (GA) in gel, 20% or 30% salicylic acid (SA) in ethanol, Jessner’s solution (JS), which is composed of 14 g resorcinol, 14 g salicylic acid, and 14 mL lactic acid (85%) in ethyl alcohol 95%.Other procedural methods are Micro needling , Intradermotherapy with Tranexamic acid, Platelet rich plasma(PRP), Laser and light technology .

Modified Kligman formula or triple combination i.e flucinolone acetonide 0.01% , hydroquinone 2 % and tretinoin 0.05%: Hydroquinone is a hydroxyphenolic compound that is structurally similar to precursors of melanin. It is most frequently prescribed depigmenting agent worldwide and its gold standard for the treatment of melasma. Flucinolone acetonide is a reversible hypopigmentation of normal skin is a well-known untoward effect of prolonged potent steroid application. The mechanism of the skin-lightening effect of topical corticosteroids is illunderstood. Melanocytes respond to a wide variety of chemical mediators. The inhibitory effects of corticosteroids on the synthesis of mediators like prostaglandin and leukotriene may partly explain their effects on melanogenesis. Topical steroids are used in combination products for their synergistic effects and for the reduction of irritation from other products like tretinoin. Tretinoin is a retinoid, were first used in combination with HQ as penetration enhancers, but were later recognized to have their own effect on melanogenesis. Retinoids affect multiple steps in the melanization pathway. Tretinoin promotes the rapid loss of pigment through epidermopoiesis and increased epidermal turnover decreases the contact time between keratinocytes and melanocytes. Tretinoin monotherapy has produced a good therapeutic response in clinical trials but better results are obtained in combination with other agents like HQ and corticosteroids. As a combination i.e triple combination which contains fluocinolone acetonide 0.01% , hydroquinone 2 % and tretinoin 0.05% , considered as most effective first-line treatment for melasma as combination therapies. It shorten the duration of treatment, increase the efficacy of therapy and reduced side effects . Tretinoin helps in preventing oxidation of HQ thus improving epidermal penetration. Steroid reduces irritation from the other two ingredients and suppresses biosynthetic and secretory functions of melanocytes, leading to an early response in melasma. Consequently, it is hypothesized that the benefit of faster response can be obtained with this combination, while avoiding adverse effects of the individual drugs

Topical metformin : It decrease melanin content in melanoma cells and normal human melanocytes via a cyclic adenosine monophosphate (cAMP)-dependent pathway, which correlates with the decreased expression of melanogenesis master genes. So has anti melanogenic action. 

Melasma is one of common acquired condition of hyperpigmentation which is burdensome for both patient and clinician. It affects quality of life of patient to great extent cosmetically, making some of patient landing up in psychiatric clinics for treatment of depression and anxiety related to it. Management of this condition is often challenging. As per various studies, estimated prevalence of melasma in the general population at 1% and in higher-risk populations at 9–50%. These wide ranges are secondary to variations in prevalence among darker skin types, different ethnic heritages, and different levels of UV exposure within various geographic locations. As such, the true prevalence across the entire population is unknown. The age of onset is also unknown, with average age ranging being between 20 and 30 years. It can be treated in many ways with varying success since long. In spite of the presence of such an array of treatment modalities, none of these can be claimed to be an ideal treatment option as most of them have limited efficacy, significant side effects or increased chances of recurrence with monotherapy.

Hence, in this study our aim is to compare various existing and newer treatment options in combination and search for an ideal treatment for melasma which is safe, effective and with low rate of recurrence.