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Comparison of the therapeutic efficacy of combined glycolic acid 50% peeling and topical silymarin cream vs. combined intradermal injection of tranexamic acid and topical silymarin cream in the treatment of epidermal melasma among Filipino women: prospective, randomized, single-blind split-face trial Janelle G. Go, M.D.1 Zharlah Gulmatico-Flores, M.D., F.P.D.S.2 Department of Dermatology Jose R. Reyes Memorial Medical Center Manila, Philippines 1 Resident, Department of Dermatology, Jose R. Reyes Memorial Medical Center 2 Consultant, Department of Dermatology, Jose R. Reyes Memorial Medical Center TABLE OF CONTENTS Page Number Introduction ------------------------------------------------------------------------------------- 3 Review of Related Literature --------------------------------------------------------------- 4 Statement of the Problem ------------------------------------------------------------------- 7 Significance of the Study -------------------------------------------------------------------- 8 Objectives of the Study ---------------------------------------------------------------------- 8 Methodology ------------------------------------------------------------------------------------9 Dummy Tables ------------------------------------------------------------------------------- 11 Budget Proposal ----------------------------------------------------------------------------- 12 Gantt Chart ----------------------------------------------------------------------------------- 12 References ----------------------------------------------------------------------------------- 13 Page 2 of 15 INTRODUCTION Melasma is a relatively common acquired hyperpigmentation of the skin usually affecting the sun-exposed areas of the face, mostly around the cheeks, forehead, upper lip, nose and chin. 1 Pathogenesis lies in the dysfunction of the pigmentary system resulting to irregularly shaped macules or patches, with color ranging from light to dark brown or ash/blue. It can occur in both sexes and any skin type, however, it is more frequently observed in women and those with Fitzpatrick skin types IV to IV, especially to those residing in areas with intense ultraviolet (UV) radiation, such as Asians, African American and Hispanic/Latinos.2 Although a benign condition, it causes significant cosmetic disfigurement bringing psychosocial burden, and creating a negative impact on the quality of life, social and emotional well-being.3 Moreover, variable outcomes of the current therapeutic options along with its refractory and recurrent nature augment the psychological stress of the patient. Treatment for melasma includes topical bleaching agents, chemical peels, oral medications, lasers, lights, intradermal injections and other therapies. While no single therapy has proven to be of benefit to all patients, combination of modalities can be used to optimize management in difficult cases. 4 Silymarin, a natural flavonoid derived from milk thistle plant, offers photoprotective mechanisms for the skin making it a promising agent for melasma. The investigator aims to compare the efficacy of topical silymarin cream with intradermal injection of tranexamic acid versus topical silymarin cream with glycolic acid 50% peeling in the treatment of melasma. REVIEW OF RELATED LITERATURE Page 3 of 15 Melasma is an acquired disorder of symmetrical hyperpigmentation appearing as light brown to dark muddy brown macules and patches, affecting most commonly the sun-exposed areas of the face.1,5 The reported prevalence of melasma ranges from 8.8% among Latino females in the Southern United States to as high as 40% in Southeast Asia.5 It predominantly affects female of reproductive age with Fitzpatrick skin type III-VI, and those living in areas with intense ultraviolet light exposure.1 The etiopathogenesis of melasma is still poorly understood. Several well-known risk factors exist, which include UV exposure, hormonal changes (pregnancy, use of oral contraceptives), genetic predisposition, cosmetic use, thyroid dysfunction, and phototoxic medications.1, 5 Sun exposure plays a key role in the development of melasma being supported by the centrofacial pattern of distribution and UV-induced upregulation of melanocyte-stimulating cytokines resulting to melanocyte proliferation, migration and melanogenesis. 5 The treatment of melasma can be challenging because of its chronic and relapsing nature. Combination of modalities is often used, especially in recalcitrant cases. The goals of treatment include reduction of recurrence, improvement in the cosmetic defect, and shorter time for clearance, with the least possible side effects.6 Principle of therapy includes protection from UV light, inhibition of melanocyte activity, and removal of melanin granules. In an abridged Cochrane review, a large number of different treatments evaluated showed that there is no standard therapy for melasma.7 Management includes utilization of skin-lightening agents, chemical peels, laser and light therapies, and measures to avoid UV exposure. Page 4 of 15 Among the first-line therapies currently employed are phenolic compounds (hydroquinone, mequinol), azelaic acid, kojic acid, topical retinoid, and combination formulations (hydroquinone/retinoid/steroid).1,4 Several peeling agents are also being widely used with glycolic acid being the most popular. Dermabrasion, intense pulse light therapy and laser treatments are useful adjunct in the treatment of melasma minimizing the risk of more serious side effects of prolong application of topical medications.6 Silymarin Cream Silymarin is a natural polyphenolic flavonoid derived from the milk thistle plant. It has potent antioxidant properties reducing the harmful effects of solar UV radiation, which involves UV-induced oxidative stress, inflammation, immunosuppression, and DNA damage leading to apoptosis.8 Moreover, it prevents melanin production in a dose-dependent manner with no significant toxic or harmful effects.9 In a study made by Tagreed Altaei, twice daily application of silymarin cream over the course of 4 weeks among patients with melasma showed significant excellent pigment improvement and lesion size reduction. All patients were fully satisfied with no reported side effects.10 The main mechanism of action in the treatments of melasma lies on its ability to inhibit L-DOPA oxidation activity of tyrosinase, which is the rate-limiting enzyme in melanin production. Western blot assay also showed its ability to decrease expression of tyrosinase protein.11 Because of its radical-scavenging activity and inhibition of melanin production; it has gained much interest in the treatment of melasma. In a comparative study made by Efar NN and El-Maghraby GM, there was no statistically significant difference among topical Page 5 of 15 silymarin, and glycolic acid 50% peeling, and has shown better outcome compared with intradermal tranexamic acid injection.12 Intradermal Tranexamic Acid Injection Tranexamic acid, also known as trans–4-aminomethylcyclohexanecarboxylic acid, is a plasmin inhibitor and lysine analog, which prevents the binding of plasminogen to keratinocytes, leading to less free arachidonic acid and subsequent prostaglandin production. This ultimately leads to a decrease in tyrosinase activity of melanocytes.4 Due to irritating and allergic side effects brought about by topical tranexamic acid in the treatment of melasma, newer liposomal delivery systems have been created to improve tolerability. Lee et al have investigated intradermal tranexamic acid injection among 85 patients with melasma showing significant decrease in the MASI scores from baseline to 8 and 12 weeks.13 Furthermore, only minimal burning and mild wheal at the injection site were reported. No other significant side effects were noted. Glycolic Acid Peel Glycolic acid, an alpha hydroxyl acids, is often used as an ingredient of skin-lightening agent for the treatment of pigment disorders.4 It has shown modest benefits in clinical studies of melasma. A doe-response trial showed that 52.5% glycolic acid applied for 3 minutes led to clinical improvement. 14 Another study made among Indian females revealed a decrease in the MASI scores after nightly application of glycolic acid 10% lotion for 2 weeks followed by monthly facial peels with 50% glycolic acid for 3 months.15 Among the reported side effects include erythema, superficial desquamation and post Page 6 of 15 inflammatory hyperpigmentation. Based on the current evidence, glycolic acid peel is a useful adjunct treatment for melasma especially in refractory cases. Melasma Area and Severity Index (MASI) Kimbrough-Green et al created The Melasma Area and Severity Index (MASI) to standardize the subjective evaluation of melasma. It is calculated by dividing the face into four areas: the forehead, right malar area, left malar area, and the chin. Each area is weighted such that forehead, right malar and left malar area accounts for 30% each, and the chin is 10%. . The area (A) of melasma involvement is graded from 0 to 6: 0 = no involvement, 1 = less than 10% involvement, 2 = 10% to 29% involvement, 3 = 30% to 49% involvement, 4 = 50% to 69% involvement, 5 = 70% to 89% involvement and 6 = 90% to 100% involvement. The degree of pigmentation (P) and homogeneity (H) graded from 0 to 4: 0 = absent, 1 = slight, 2 = mild, 3= marked, 4 = maximum The total score is calculated as follows: MASI = 0.3A (P+H) [forehead] + 0.3A (P+H) [R malar] + 0.3A (P+H) [L malar] + 0.1A (P+H) [chin]. The range of score is 0 to 48. It is the most commonly used measurement technique for the study of melasma.5 STATEMENT OF THE PROBLEM 1. Is silymarin cream combined with glycolic acid peel effective in the treatment of melasma? 2. Is silymarin cream combined with intradermal tranexamic acid injection effective in the treatment of melasma? 3. Is silymarin cream combined with glycolic acid peel more effective than Page 7 of 15 silymarin cream combined with intradermal tranexamic acid injection? SIGNIFICANCE OF THE STUDY Melasma is a chronic relapsing pigmentary disorder, which brings about psychosocial stress to most patients. Multiple clinical trials have been conducted to determine the optimum treatment for melasma, however evidence supporting any intervention is weak. Currently, there has been no standard therapy for melasma. Monotherapy and combination formulations have shown variable outcomes; nevertheless a systematic review of clinical trial supports the efficacy of multiple interventions. Randomized controlled trial on well-defined participants with long-term follow-up is advised. In this light, the investigator aims to compare the efficacy of topical silymarin cream in combination with glycolic acid 50% peel versus topical silymarin cream with intradermal tranexamic acid injection in the treatment of melasma. Silymarin, with its anti-melanogenic, anti-oxidant properties and good safety profile, offers a promising outcome in the treatment of melasma much more if combined with other treatment modalities. OBJECTIVES OF THE STUDY The general objective is to compare the efficacy of topical silymarin cream in combination with glycolic acid 50% peel versus topical silymarin cream with intradermal tranexamic acid injection in the treatment of melasma among Filipino women. The specific objectives are: 1) to determine the efficacy of topical silymarin cream in combination with glycolic acid 50% peel in the treatment of melasma using MASI score within a period of 12 weeks; 2) to determine the efficacy of Page 8 of 15 topical silymarin cream with intradermal tranexamic acid injection in the treatment of melasma using MASI score within a period of 12 weeks; 3) to compare the efficacy of topical silymarin cream in combination with glycolic acid 50% peel versus topical silymarin cream with intradermal tranexamic acid injection in the treatment of melasma among Filipino women using MASI scores during a period of 12 weeks. METHODOLOGY Study Design and Study Population This is a prospective, randomize, single blind, split-face trial study to compare the efficacy of combined glycolic acid 50% peeling and topical silymarin cream vs. combined intradermal injection of tranexamic acid and topical silymarin cream in the treatment of Melasma among Filipino women. The target study population are Filipino women aged 18 and above with bilateral epidermal melasma, Fitzpatrick skin types III-IV who will consult at Jose R Reyes Memorial Medical Center, Manila, Philippines starting January 2017 to May 2017. Exclusion criteria include pregnant or nursing women, those on contraceptive pills at the time of the study or during the past 12 months, those anti-inflammatory taking drug, any photosensitizing tetracycline, drugs spiranolactone, like non-steroidal phenytoin, and carbamazepine at the time of the study, those with bleeding disorders or taking any kind of anticoagulants, active herpes simplex, facial warts, active dermatoses, hypersensitivity reaction, and administration of any concurrent therapy for melasma. Moreover, a washout period of 1 month is necessary for subjects with previously applied topical hypopigmenting agents. Sample Size Determination Page 9 of 15 The researcher set the maximum permissible error at 5%, α at 5% and confidence level at 5%. Open Epi results indicated that a minimum of 31 patients in each group will be needed to achieve a 95% level of confidence. An adjusted minimum of 62 patients, 31 in each arm, are needed to achieve a 95% level of confidence, precision of 5% to accommodate the expected 20% drop outs. Data Collection Approval from the Institutional Review Board and the Chair of the Department of Dermatology will be obtained before conducting the study. Wood's lamp examination will be performed at the study entry to determine the type of melasma (epidermal, mixed or dermal). Patients with bilateral epidermal facial melasma will be chosen. After screening of eligible participants, the study will be explained to the participants and informed consent will be obtained. The researchers will interview and do a physical examination on the participants who will voluntarily sign the Informed Consent Form. Topical silymarin cream (14mg/mL) will be applied on both side of the face with the amont of about one finger tip of cream, twice daily for 12 weeks. The left side of the face (side A) will undergo intradermal injection of 0.05 mL of tranexamic acid solution in normal saline (4mg/mL) at 1 cm interval by using sterile insulin syringe, weekly for 12 weeks. The right side of the face (side B) will be treated with glycolic acid 50% peeling within a period of 20-30 seconds, every 2 weeks for 12 weeks. Participants will be advised to avoid excessive sun exposure and will be instructed to apply a broad spectrum sunscreen with a sun protection factor of 30 in the morning and every 2 hours .Clinical evaluation of melasma severity using MASI score will be performed at baseline and at weeks 4, 8 and12 by two dermatologists. Page 10 of 15 Photographs will be taken with a standard camera, in a well-lit room, in a standardized position at baseline and week 12. Melasma improvement will be graded by the patient and 2 independent investigator along four scales: 1 = >75% lightening (excellent), 2 = 51-75% (good), 3 = 26-50% (fair), and 4 = 0-25% (poor). Safety parameter will be evaluated using a 4-point grading system (0=none; not noticed by the physician or patient; 1=mild; noticed by the physician and/or patient but not disturbing to the patient; 2=moderate; definitely present and disturbing to the patient and interferes with some activity or sleep; 3=severe; very marked, very disturbing, interfering with most activities and sleep). The scores of each parameter will be added. A clinical scoring of mild (total score of 1-6), moderate (total score of 7-12) and severe (total score of 13-18) will be used. Stopping Guidelines The trial will be stopped on a patient who will experience moderate or severe reaction on 2 consecutive visits as determined by the safety parameter of the study. Any patient who fails to comply with the treatment, and those who use other topical medications other than the one provided will be withdrawn. DUMMY TABLES Time Tranexamic Acid Hydroquinone group P- value MASI score MASI score group MASI score Baseline Week 4 Week 8 Week 12 BUDGET PROPOSAL Page 11 of 15 Price (Php) Intradermal tranexamic acid PHP 19,200 injection Silymarin cream PHP 33,600 Glycolic acid 50% peel PHP 2000 Printing materials PHP 500 Tuberculin syringes PHP 500 Statistician PHP 5000 TOTAL PHP 60,8000 GANTT CHART November December January to May June-August 2017 September 2017 2017 2016 IRB application Preparation of materials, compound medications Recruitment of patients Completion of treatment of all enrolled subjects Data analysis, Drafting and finalizing of paper Page 12 of 15 REFERENCES 1Goldstein BG, Goldstein AO, Callender VD, et.al Melasma.UpToDate Website. http://www.uptodate.com/contents/melasma. Updated Mar 01, 2016 Accessed November 25, 2016 2 Balkrishnan R, McMichael AJ, Camacho FT, et al. Development and validation of a health-related quality of life instrument for women with melasma. Br J Dermarol 2003; 149:572 3 Dominguez AR, Balkrishnan R, Ellzey AR, Pandya AG. Melasma in Latina patients:cross-cultural adaptation and validation of a quality-of-life questionnaire in Spanish language. J Am Acad Dermatol Treat 2007; 18:5 4 Sheth VM, Pandya A. Melasma: a comprehensive update part II. J Am Acad Dermatol 2011; 65:700-714 5Sheth VM, Pandya A. Melasma: a comprehensive update part II. J Am Acad Dermatol 2011; 65:689-697 6Gupta AK, Gover MD, Nouri K, Taylor S. The treatment of melasma: a review of clinical trials. 2006; 55:1049-1065 7Jutley GS, Rajaratnam R, Halpern J et al. Systematic review if randomized controlled trials on interventions for melasma: An abridged Cochrane review. 2014; 70:370-373 8 Vladimir K, Daniela W. Silybin and silymarin-new effects and applications. Biomed papers 2005; 149: 29-41 9Mereish KA, Brunner DL, et al. Protection against microcystin-LR-induced hepatoxicity by Silymarin: biochemistry, histopathology, and lethality. Pharm Res 1991; 8:273-277 10Altaei Tagreed. The treatment of melasma by silymarin cream. BMC Page 13 of 15 Dermatology 2012; 12:2-6 11Choo SJ, Ryoo et al. Silymarin inhibits melanin synthesis in melanocyte cells. J Pharm Pharmacol 2009; 61: 663-667 12 Elfar NN, El-Maghraby GM. Efficacy of intradermal injection of tranexamic acid, topical silymarin, and glycolic acid peelingin the treatment of melasma: a comparative studt. J Clin Exp Dermatol Res. 2015; 6: 2-7 13 Lee JH, Park JG, Lim SH et al. Localized intradermal microinjection of tranexamic acid for treatment of melasma in Asian patients: a preliminary clinical trial. Dermatol Surg 2006; 32-626-631 14Gupta RR, Mahajan BB, Garg G. Chemical peeling-evaluation of glycolic acid in varying concentrations and time intervals. Cosmetology 2001; 67:28-29 15Javaheri SM, Handa S, Kaur I, Kumar B. Safety and efficacy of glycolic acid facial peel in Indian women with melasma. Int J Dermatol 2001; 40:354-357 Page 14 of 15 Page 15 of 15