Accepted Manuscript

Randomized, placebo-controlled, double-blind study of oral tranexamic acid in the

treatment of moderate to severe melasma

Eunice Del Rosario, MD, MS, Stephanie Florez- Pollack, BS, Lucio Zapata, Jr., BS,
Katia Hernandez, Andrea Tovar-Garza, MD, Michelle Rodrigues, MBBS (Hons)
FACD, Consultant Dermatologist, Linda S. Hynan, PhD, Professor, Amit G. Pandya,
MD, FAAD, Professor

PII: S0190-9622(17)32458-1
DOI: 10.1016/j.jaad.2017.09.053
Reference: YMJD 12026

To appear in: Journal of American Dermatology

Received Date: 21 May 2017

Revised Date: 17 September 2017
Accepted Date: 20 September 2017

Please cite this article as: Del Rosario E, Florez- Pollack S, Zapata Jr. L, Hernandez K, Tovar-Garza
A, Rodrigues M, Hynan LS, Pandya AG, Randomized, placebo-controlled, double-blind study of oral
tranexamic acid in the treatment of moderate to severe melasma, Journal of American Dermatology
(2017), doi: 10.1016/j.jaad.2017.09.053.

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
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1 Randomized, placebo-controlled, double-blind study of oral tranexamic acid in

2 the treatment of moderate to severe melasma

3 Eunice Del Rosario, MD, MS, Department of Dermatology, University of Texas

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4 Southwestern Medical Center, Dallas, Texas

5 Stephanie Florez- Pollack, BS, Department of Dermatology, University of Texas

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6 Southwestern Medical Center, Dallas, Texas

Lucio Zapata, Jr., BS, Department of Dermatology, University of Texas Southwestern

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7

8 Medical Center, Dallas, Texas

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9 Katia Hernandez, Department of Dermatology, University of Texas Southwestern
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10 Medical Center, Dallas, Texas

11 Andrea Tovar-Garza, MD, Department of Dermatology, University of Texas

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12 Southwestern Medical Center, Dallas, Texas

13 Michelle Rodrigues, MBBS (Hons) FACD, Consultant Dermatologist, Department of

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14 Dermatology, St. Vincent’s Hospital, The Skin and Cancer Foundation Inc. and The
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15 Royal Children’s Hospital, Victoria, Australia

16 Linda S. Hynan, PhD, Professor, Departments of Clinical Sciences – Biostatistics and

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17 Psychiatry, University of Texas Southwestern Medical Center, Dallas, Texas

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18 Amit G. Pandya, MD, FAAD, Professor, Department of Dermatology, University of

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19 Texas Southwestern Medical Center, Dallas, Texas

20 Corresponding Author:

21 Amit G. Pandya, M.D.

22 Department of Dermatology
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23 The University of Texas Southwestern Medical Center

24 5323 Harry Hines Blvd.

25 Dallas, Texas 75390-9069

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26 Phone: 214-648-2879

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27 Fax: 214-648-5559

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28 E-mail: amit.pandya@utsouthwestern.edu

29 Funding Sources: This study has no funding source

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30 The authors are responsible for the accuracy of the information presented

31 Conflict of Interest Disclosure: The authors have no conflicts of interest to declare

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32 Reprints not available

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33 The information in this manuscript has not been previously published

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34 Word count: 2585

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35 Tables and appendices: 3

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36 Figures: 6
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37 References: 26

38 No ghostwriters were involved in the preparation of this manuscript

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40 ABSTRACT

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42 Background: Melasma is a common pigmentary disorder that is often difficult to treat.

43 Tranexamic acid (TA) has emerged as a promising treatment for melasma; however,

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44 few controlled studies exist.

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45 Objective: To determine the efficacy of oral TA in patients with moderate to severe

46 melasma

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47 Methods: Patients with moderate to severe melasma were treated with 250 mg of TA or

48 placebo capsules twice daily for 3 months and sunscreen followed by 3 months of

49
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treatment with sunscreen only. The primary outcome measure was the modified
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50 Melasma Area and Severity Index (mMASI) score.

51 Results: 44 patients were enrolled and 39 completed the study. At 3 months, there was
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52 a 49% reduction in mMASI score in the TA group vs. 18% in the control group. Patients
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53 with severe melasma improved more than those with moderate melasma. Three months
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54 after stopping treatment, there was a 26% reduction in mMASI in the TA group

55 compared to the baseline visit versus a 19% reduction in the placebo arm. No serious
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56 adverse events were noted in either group.

57 Limitations: Single center study enrolling predominantly Hispanic women

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58 Conclusions: Oral TA appears to be an effective treatment for moderate to severe

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59 melasma with minimal side effects.

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61 Key Words: melasma, pigmentation, melanin, tranexamic acid, randomized controlled

62 trial, evidence based medicine, Hispanic

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63 CAPSULE SUMMARY

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65 • Melasma is often recalcitrant to therapy.

66 • Oral tranexamic acid was found to be effective and superior to placebo in

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67 patients with moderate to severe melasma.

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68 • Tranexamic acid should be considered in the treatment of patients with moderate

69 to severe melasma who do not respond to standard therapy.

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70

71

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72 INTRODUCTION

73 Melasma is a common cause of facial hyperpigmentation affecting millions of individuals

74 worldwide.1 It is particularly common in Latino females, affecting 8.8% of this population

75 in one study.2 Exposure to sunlight, oral contraceptives and pregnancy may exacerbate

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76 melasma but the cause in many individuals is unknown.3, 4, 5 Treatment includes topical

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77 depigmenting agents, chemical peels, laser and energy devices. Recently, an

78 antifibrinolytic agent, tranexamic acid (TA), has been reported to be effective for

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79 melasma in several studies. These trials have been performed in Asian individuals and

80 most are uncontrolled.6, 7 The purpose of this study was to determine the efficacy of TA

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in North American women with melasma using a randomized, controlled study design.
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82 METHODS

83 This study was approved by the University of Texas Southwestern (UTSW)

84 Medical Center Institutional Review Board and all patients gave written, informed

85 consent. Subjects were recruited through interviews on local English and Spanish

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86 language television stations as well as flyers posted on the UTSW campus. Eligibility

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87 criteria were: female subjects, age 18 or older with moderate or severe melasma.

88 Moderate melasma was defined as those with a modified Melasma Area and Severity

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89 Index (mMASI) score of 5.8 to 7.9 and severe melasma were those with a mMASI > 8

90 based on previously defined ranges for melasma severity.8 Exclusion criteria are

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provided in Table 1, and include items listed by the FDA as contraindications to the use
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92 of TA.

93 Patients were screened by telephone and, if eligible, underwent a screening

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94 examination by investigators in the dermatology clinic at UTSW. Eligible patients who

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95 agreed to be in the study were enrolled by investigators and randomized into TA or

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96 placebo groups stratified by severity (moderate or severe melasma). SAS V9.4 was

97 used to generate the two randomization lists using a block factor of 4. All patients were
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98 randomized to receive 250 mg of TA or placebo twice daily and all received sunscreen

99 (Neutrogena Ultra Sheer, SPF 30) with instructions to apply every morning, with
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100 reapplication every 2 hours during daylight hours. The dose of TA was decided upon
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101 based on a review of published studies using TA for melasma, including a large open

102 study of 561 patients treated in Singapore.7 Both patients and raters were blinded to

103 treatment arms. The randomization code was held by the study pharmacist and
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104 biostatistician, neither of whom saw the patients. A 30-day treatment supply was given

105 at the baseline, 1 month, and 2 month visits.

106 Demographic information, photography, mMASI measurement and determination

107 of pigmentation of involved and uninvolved skin with a narrow band reflectance

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108 spectrophotometer (Mexameter, Courage-Khazaka Electronic, Köln, Germany) were

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109 obtained at the baseline visit. The degree of pigmentation measured by this instrument

110 is displayed as a number ranging from 0-1000, with 0 representing white and 1000

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111 representing black. By measuring the degree of pigmentation of involved and adjacent

112 uninvolved skin, the difference in pigmentation, also called the melanin index, can be

113
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obtained. Effective reduction in melasma pigment causes a reduction in melanin index
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114 and complete resolution of melasma should result in a melanin index of 0.

115 All patients filled out a melasma quality of life (QOL) survey in English or
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116 Spanish.9, 10 At the 1 month and 2 month visits, patients were photographed, screened
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117 for side effects, and a pill count was done to determine compliance. At the 3 month visit,
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118 photography, pill count, mMASI and melanin index measurements were performed and

119 all patients completed the melasma QOL survey again. Patients were then instructed to
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120 use sunscreen alone for 3 months. Procedures at the final 6 month visit included

121 photography, mMASI, melanin index measurements and melasma QOL questionnaire.
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122 Statistical plan

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123 The primary objective was to evaluate whether TA plus sunscreen improved

124 melasma in comparison to placebo plus sunscreen using the mMASI score. Secondary

125 end points were improvement in melanin index and QOL. Adverse effects were also

126 documented.
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127 The statistical design for the primary measure, mMASI, was a repeated

128 measures analysis of variance (ANOVA) with 2 between factors (melasma severity:

129 moderate and severe; treatment: placebo and TA) and 1 within factor (time: baseline, 12

130 weeks and 24 weeks) analyses. Effect sizes for the placebo group were estimated

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131 using our current database in which the mean mMASI scores of participants with

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132 moderate and severe melasma are 6.5 and 11.5, respectively. For a group of non-

133 treated subjects in this database who used sunscreen alone and returned for a visit at

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134 approximately 24 weeks, the average mMASI was 5.7 in the moderate group and 9.0 in

135 the severe group. In the current study, we assumed the treatment group will have a

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similar mean mMASI score to the placebo group at baseline, whereas at 12 weeks, the
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137 score will be 3 or more points below those in the placebo group and 2 or more points

138 below the placebo group at 24 weeks.

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139 PASS 12 was used to perform the sample size estimates.11 A minimum of 10
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140 participants randomized to each treatment arm by melasma severity group (moderate
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141 and severe, 40 cases total) achieves 93% power to test the treatment effect (effect size

142 .56) and greater than 99% power for both the melasma effect (effect size of 1.34) and
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143 the time effect (effect size of 1.23) using a F Test and a 5% significance level. The

144 estimated power for the interaction of time by treatment (effect size of .58) was 90% and
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145 time by melasma (effect size of .44) was 68% using an F Test and a 5% significance
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146 level. The estimated power for both the three-way interaction (time by treatment by

147 melasma; effect size .21) and the interaction of melasma severity by treatment group

148 (effect size of .16) was less than 20% using an F Test and a 5% significance level. A

149 conservative Geisser-Greenhouse corrected F Test was used for any effects or
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150 interactions involving the repeated factor of time. Assuming a 16% attrition rate, a total

151 of 44 randomized subjects were needed (11 cases into each treatment arm by melasma

152 severity group). A modified intention-to-treat analysis was used for all randomized

153 patients with more than baseline measures (5 patients dropped out after baseline). P-

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154 value for significance was set at <0.05 and SPSS V24 was used to analyze the data.

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155

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157 RESULTS

158 The study was performed from July 2015 to October 2016 at UTSW in Dallas,

159 Texas. Of the 205 females screened by telephone, 129 met the inclusion/exclusion

160 criteria and were invited for screening examination. 78 subjects were screened, of which

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161 44 satisfied the inclusion/exclusion criteria and were randomized into the two treatment

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162 groups (Figure 1). Demographics and background characteristics are summarized in

163 Table 2. Twenty-one (95%) in the TA group and 18 (82%) in the placebo group were

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164 Hispanic Caucasian women, 6 with skin phototype (SPT) 3, 15 with SPT 4 and 14 with

165 SPT 5. The mean age was 43.9 years in the TA group and 44.2 years in the placebo

166
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group. Average duration of melasma was 13.4 years in the TA group and 12.3 years in
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167 the placebo group. The mean body mass index was 29.2 in the TA group and 28.1 in

168 the placebo group. Of the 39 patients who completed the study, 18 (46%) reported no
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169 previous treatment for melasma. Of the remaining 21 patients, previous treatments
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170 included: 19 with depigmenting creams, 3 with chemical peels, 2 with laser therapy and
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171 2 with microdermabrasion.

172 Of the 39 patients who completed visits at 12 and 24 weeks, 18 were in the TA
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173 arm and 21 were in the placebo arm. The interactions of Time*Treatment (TA vs.

174 placebo, p=0.0003) and Time*Melasma (moderate vs. severe p=0.0312) as well as the
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175 main effects of time (p<0.0001) and melasma group (p<0.0001) were significant. For
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176 both melasma groups, mMASI decreased over time, with those on TA decreasing more

177 than the placebo group at 12 weeks. Both groups increased from 12 to 24 weeks, but

178 were found to have lower mMASI scores than at baseline. Those with severe melasma
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179 had higher average mMASI scores than those with moderate melasma at all time points

180 (Figure 2).

181 After 3 months of treatment with TA, there was a 49% reduction in mMASI in all

182 patients in the TA arm versus an 18% reduction in the placebo arm (mean decrease in

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183 mMASI of 4.2 vs 1.4). Compared to placebo, TA patients with moderate melasma had

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184 a 45% vs 16% reduction in mMASI (decrease in mMASI of 2.9 vs 1.0), while patients

185 with severe melasma had a 51% vs 19% reduction in mMASI (decrease in mMASI of

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186 5.9 vs 1.9). Figures 3-6 are examples of patients treated with TA. Pill counts revealed

187 excellent compliance, with 38 of the 39 patients taking over 85% of the doses. The

188
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single patient who missed 17.7% of the doses was on placebo.
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189 At the 6 month visit, there was a 26% reduction in mMASI in all patients in the TA

190 arm compared to the baseline visit versus a 19%reduction in the placebo arm (mean
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191 decrease in mMASI of 2.2 vs 1.6). Compared to placebo, TA patients with moderate
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192 melasma had 32% vs 13% reduction in mMASI (decrease in mMASI of 2.0 vs 0.8),
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193 while patients with severe melasma had 21% vs 24% reduction in mMASI (decrease in

194 mMASI of 2.4 vs 2.4).

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195 Melanin index results were similar to those for the mMASI. The interaction of

196 Time*Treatment (p=0.0315) and the main effects of Time (p<0.0001) and melasma
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197 Group (p=0.0329) were significant. For both melasma groups, the melanin index
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198 decreased from baseline to 12 weeks, with those on TA decreasing more than the

199 placebo group. Melanin index increased in both groups from 12 to 24 weeks except the

200 moderate placebo group; however, both groups had lower melanin index scores at 24

201 weeks compared to baseline. Those with severe melasma had higher average melanin
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202 index scores than those with moderate melasma. There was no significant difference in

203 QOL scores between patients taking TA versus placebo.

204 Side effects occurred in 63.6% of patients on TA vs. 36.3% on placebo (Table 3).

205 Fisher’s exact p values were greater than .488 for all side effects, indicating no

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206 significant differences between the TA and placebo groups. Side effects were

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207 predominantly mild, and resolved within one month despite continued treatment. Only

208 one patient discontinued the medication due to moderate myalgias. No thromboembolic

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209 events or other serious adverse events were observed in either group.

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211 DISCUSSION

212 Melasma is a common, chronic, pigmentation disorder seen in all skin types but

213 more frequent in higher skin phototypes, especially in women of reproductive age.

214 Melasma can be psychologically debilitating and has a significant effect on QOL.10

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215 Although there are several treatment options for melasma, including topical

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216 depigmenting agents, chemical peels, laser and energy devices, many patients are

217 recalcitrant to these therapies and more effective treatments are needed .12,13

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218 The exact pathogenesis of melasma remains unknown. Studies have implicated

219 several factors that cause melanocytes to become activated and produce excessive

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melanin in patients with melasma. These factors include sun exposure, hormones,
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221 genetic influences, and vascular influences.3,4,5,14 Histologically, lesional skin has

222 increased melanocytes, melanosomes, solar elastosis,15 mast cells,16,17 blood vessels,
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223 vascular endothelial growth factor (VEGF),3 c-kit, and kit ligand.17,18 A disrupted and
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224 thinner basement has also been reported.17

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225 Tranexamic acid, an antifibrinolytic agent, has emerged as a promising treatment

226 for melasma.6, 19, 20 TA was originally developed for the treatment of menorrhagia and
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227 bleeding diathesis. It was found that patients on TA for these indications in Asia had

228 improvement of melasma. Subsequently, it was found that TA causes decreased

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229 tyrosinase activity in melanocytes, possibly due to decreased production of fibroblast

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230 growth factor (FGF) and prostaglandins by blocking the conversion of plasminogen to

231 plasmin.6, 19, 20, 21 Both FGF and prostaglandins are potent stimulants of melanocyte

232 activity.21
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233 Although TA has been administered in topical and intradermal forms, 22, 23 the

234 majority of published studies have used oral TA. The most commonly reported side

235 effects are headaches, menstrual irregularity, nausea, and back pain.7, 24 Even women

236 taking high doses of TA for menorrhagia, usually 3.9-4g/day for 5 days per month, have

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237 few adverse effects. There is no evidence to support an increased risk of

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238 thromboembolic events at these doses.25

239 The largest study to date using TA for melasma was a retrospective review of

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240 561 patients treated in Singapore.7 Median duration of treatment was 4 months and

241 90% of the patients improved. Importantly, adverse events occurred in 40 (7.1%) of

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patients. Most were transient and mild, but 1 patient developed deep vein thrombosis
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243 requiring discontinuation. It was later found that this patient had familial protein S

244 deficiency, a personal history of spontaneous miscarriage, and a positive family history
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245 of thromboembolic phenomenon in 2 siblings.

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246 Another recent report studied 100 patients with melasma in Iran.26 Half of the
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247 patients were assigned to receive 250 mg of oral TA thrice daily plus hydroquinone

248 (HQ) 4% cream nightly vs. HQ 4% cream only for 3 months in the other half. There was
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249 a 51% reduction in MASI after 3 months in the TA + HQ group vs. a 33% reduction in

250 the control group. When the patients were examined 3 months later off TA, the relapse
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251 rate was not significantly different between the two groups (30% vs. 26% in the
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252 treatment vs. control group, respectively). Side effects were similar in both groups but

253 treatment satisfaction was higher in the intervention group. Most of the patients in this

254 study had SPT 3 and mild to moderate melasma.

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255 Our study enrolled patients with moderate to severe melasma, the type of

256 patients that often seek the help of dermatologists for recalcitrant disease. We found a

257 significant overall decrease in melasma severity (mMASI) of 49% in moderate and

258 severe melasma at 3 months in patients taking TA capsules in comparison to an 18%

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259 decrease in melasma severity in patients taking placebo. There was a concomitant

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260 reduction in melanin index as well.

261 Three months after stopping TA, the beneficial effects of this medication were

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262 sustained in those with moderate melasma. However, most of the improvement in those

263 with severe melasma was lost after three months of using sunscreen alone. A longer

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course of therapy may be needed in patients with severe melasma and further
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265 investigation into this possibility is warranted.

266 Interestingly, we found no significant difference in quality of life between patients

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267 taking TA and placebo, despite significant reduction in both mMASI and melanin index.
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268 This could be due to high expectations by our patients for treatments for melasma, in
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269 which complete clearance is the preferred goal. Since our patients did not use a topical

270 depigmenting cream, it’s possible that the addition of a topical tyrosinase inhibitor, such
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271 as HQ or triple combination cream could improve results. Future studies investigating

272 this hypothesis are warranted.

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273 Oral TA was well tolerated in the vast majority of patients. Importantly, no
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274 thromboembolic events occurred, similar to the vast majority of studies using TA for

275 melasma. Limitations of our study include lack of male subjects and enrollment of

276 predominantly Hispanic patients. In addition, the follow up period after treatment was

277 only 3 months.

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278 In summary, oral TA at a dose of 250 mg twice daily for 3 months significantly

279 improved moderate to severe melasma. Severe melasma responded better than

280 moderate melasma, however, those with severe melasma did not sustain their

281 improvement compared to those with moderate melasma after TA was discontinued.

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282 The use of sunscreen alone improves melasma, but its effects are modest. Larger

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283 studies with longer treatment durations and follow up periods as well as combining TA

284 with depigmenting creams should be performed. Side effects were mild; however, it is

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285 important to screen patients for risk of thromboembolism prior to treatment.

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290 Abbreviations and acronyms

291 ANOVA Analysis of variance

292 HQ Hydroquinone

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293 MASI Melasma Area and Severity Index

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294 mMASI Modified Melasma Area and Severity Index

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295 QOL Quality of life

296 TA Tranexamic acid

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297 UTSW University of Texas Southwestern Medical Center

298 SPT Skin phototype

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300 Acknowledgements

301 The authors would like to thank Manisha Kaur, Bpharm(Hons) MPS ABAAHP FRAAM,

302 Nova Pharmacy, Forrest Hill, Victoria, Australia, for preparing placebo and active

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303 medication for this study

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385 26. Lajevardi V, Ghayoumi A, Abedini R, et al. Comparison of the therapeutic efficacy and

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386 safety of combined oral tranexamic acid and topical hydroquinone 4% treatment vs. topical

387 hydroquinone 4% alone in melasma: a parallel-group, assessor and analyst-blinded,

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388 randomized controlled trial with a short-term follow-up. J Cosmet Dermatol. 2016; 0:1-18.

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389

390

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391 Legends

392 Table 1: Exclusion criteria

393 Table 2: Patient demographics

394 Table 3: Adverse events

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395 Figure 1: CONSORT flow diagram

396 Figure 2: Improvement in modified MASI scores in patients with moderate and severe

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397 melasma treated with tranexamic acid vs. placebo

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398 Figure 3: Moderate melasma: baseline

399 Figure 4: Moderate melasma: after 3 months of tranexamic acid

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400 Figure 5: Severe melasma: baseline

401 Figure 6: Severe melasma: after 3 months of tranexamic acid

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402

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404 Table 1: Exclusion Criteria

405
406
407 • Pregnant or nursing women
408 • Current use of hormonal birth control medication or any hormonal therapy
409 • Use of topical hydroquinone within 3 months of study enrollment
410 • Use of topical steroids within 1 month of study enrollment

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411 • History of laser or dermabrasion to the face within 9 months of study enrollment
412 • Regular use of tanning parlors
413 • Occupation involving primarily outdoor activities

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414 • Current treatment with blood thinning medications
415 • History of thrombosis or thrombophilia
416 • History of thromboembolic disease such as deep vein thrombosis (DVT),

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417 pulmonary embolism or and cerebral thrombosis
418 • Family history of thromboembolic disease
419 • History of stroke,

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420 • History of >2 spontaneous abortions
421 • History of kidney dysfunction
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422 • History of cancer
423 • Smoking
424 • Significant cardiovascular or respiratory disease (end stage congestive heart
425 failure or chronic obstructive pulmonary disease)
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426 • History of subarachnoid hemorrhage

427 • History of acquired disturbances of color vision
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429 Table 2: Patient demographics

430
Independent samples
Placebo TA
t-test
Measure Std. Std.
N Mean Deviatio N Mean Deviatio t df p-value

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n n
Age (years) 22 44.18 6.68 22 43.86 5.48 0.17 42 0.8637

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Height (in) 20 62.13 3.54 20 61.48 2.14 0.70 31.3 0.4874

154.6 156.7

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Weight (lbs.) 20 26.38 20 23.19 -0.28 38 0.7843
0 6
Body mass index
20 28.11 3.91 20 29.19 4.48 -0.82 38 0.4196
(BMI)
Duration of
22 12.30
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6.14 22 13.36 6.37 -0.57 42 0.5742
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melasma (years)
Melanin index 22 47.15 16.90 22 55.44 20.96 -1.44 42 0.1563
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Total mMASI score 22 8.24 2.44 22 8.80 2.93 -0.69 42 0.4919

Quality of life score 22 40.23 17.60 22 43.09 17.16 -.55 42 .5877

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431 df- degrees of freedom

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435 Table 3: Adverse events

Tranexamic
Placebo
Adverse Event Acid
n (%) n (%)
Gastrointestinal
5 (22.7%) 3 (13.6%)
discomfort

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Change in menstrual
4 (18.2%) 3 (13.6%)
period
Headache 3 (13.6%) 5 (22.7%)
Myalgias 2 (9.1%) 1 (4.5%)

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Somnolence 2 (9.1%) 0
Arthralgias 1 (4.5%) 0

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Blurry vision 1 (4.5%) 0
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