Randomised, Placebo-Controlled, Double-Blind Study of Oral Tranexamic Acid in the Treatment of Moderate-to-Severe Melasma in an Australian Cohort

Sir,

Melasma is a complex and therapeutically challenging condition for dermatologists globally. Oral tranexamic acid (TA), first described in the treatment of melasma in 1979 is a plasmin inhibitor that can inhibit epidermal melanocyte tyrosinase activity, decrease mast cell activity and inhibit of fibroblast growth factor.[1,2] To date, there have been two randomised controlled trials (RCT) showing significant improvement in melasma after 12 weeks treatment with 250 mg oral TA twice daily compared to placebo.[3,4] There are no trials involving a heterogenous ethnic group. We present a RCT investigating the use of low-dose oral tranexamic acid in the treatment of moderate-to-severe melasma in a diverse ethnic Australian population.

Eligibility criteria included females over 18 years of age with moderate-to-severe melasma based on mMASI. Exclusion criteria included contraindications to TA from the United States Food and Drug Administration and Monthly Index of Medical Specialities, Australia.[3] Eligible participants were randomised to the treatment or control group in a 1:1 ratio and stratified based on moderate or severe melasma. Both participants and investigators were blinded to the treatment.

Participants were advised to take 250 mg TA or placebo twice daily for 12 weeks. Both groups were advised to apply regular sunscreen (Neutrogena Ultra Sheer sun protection factor 50+) until their final visit at week 24. mMASI, mexameter readings and QoL questionnaire were performed at weeks 0, 12 and 24. Participants were also assessed in person at weeks 4, 8, 12 and 24 for clinical photography.

From June 2016 to March 2018, 61 females were pre-screened via telephone, of which 17 patients were recruited after satisfying the inclusion/exclusion criteria. At 12 weeks, 1 participant in the placebo group discontinued the medication due to worsening premorbid anxiety. At 24 weeks, 2 participants in the treatment group were lost to follow up. Both intention-to-treat (TA n = 9, placebo n = 8) and per-protocol (TA n = 7, placebo n = 7) were used to analyse the results.

Baseline participant demographics and results are summarised in Table 1. There were no significant differences between the TA group and the placebo group at baseline except for body weight index with a mean of 26 kg/m² in the TA group and 22 kg/m² in the placebo group (P = 0.03). Using intention-to-treat analysis, the mean mMASI for the TA and placebo group reduced by 7.92 ± 1.93 (60.7%) and 4.46 ± 3.26 (36.5%), respectively (P = 0.016) at 12 weeks. At 24 weeks, mMASI remained stable with reduction from baseline of 8.26 ± 2.68 (63.2%) and 4.44 ± 3.61 (36.3%), respectively (P = 0.025) [Figure 1]. There was no statistical difference for MI and QoL score. Per-protocol analysis showed similar results for mMASI, MI and QoL. Oral TA was well tolerated without any significant side effects.

Table 1.

Demographics and results

Baseline demographics of participants
Variable	TA (n=9)	Placebo (n=8)	P
Age (year), median (IQR)	45 [42-51]	41 [39-48]	0.27
BMI, median (IQR)	26 [24-36]	22 [22-24]	0.03
Ethnicity			0.53
Aboriginal	0 (0%)	1 (12.5%)
African	1 (11.1%)	1 (12.5%)
Asian	3 (33.3%)	2 (25%)
Caucasian	5 (55.6%)	2 (25%)
Mixed	0 (0%)	2 (25%)
Skin type			0.57
II	3 (33.3%)	2 (25%)
III	3 (33.3%)	5 (62.5%)
IV	3 (33.3%)	1 (12.5%)
Duration of melasma (years), median (IQR)	7 [5-10]	8 [4-16]	0.96
Melasma severity
Results
	Baseline	12 weeks	24 weeks
mMASI: Intention-to-treat analysisa
TA (n=9)	13.06±5.19	5.13±5.32	4.80±3.42
Placebo (n=8)	12.21±4.32	7.75±5.64	7.78±6.05
Difference from baseline TA		7.92±1.93 (-60.7%)	8.26±2.68 (-63.2%)
Difference from baseline placebo		4.46±3.26 (-36.5%)	4.44±3.61 (-36.3%)
Between group difference, P value	0.72	0.016	0.025
mMASI: Per-protocol analysisb
TA (n=7)	12.81±5.53	5.27±5.74	4.84±3.30
Placebo (n=7)	11.37±3.89	6.27±4.09	6.30±4.73
Difference from baseline TA		7.54±2.05 (-58.9%)	7.97±3.02 (-62.2%)
Difference from baseline placebo		5.10±2.93 (-44.9%)	5.07±3.39 (-44.6%)
Between group difference, P value	0.58	0.096	0.12
Melanin Index: Intention-to-treat analysis
TA (n=9)	106.63±103.12	74.26±71.58	80.19±103.45
Placebo (n=8)	90.25±70.16	63.42±80.38	96.75±76.24
Difference from baseline TA		32.37±54.02 (-30.4%)	26.44±37.72 (-24.8%)
Difference from baseline placebo		26.83±33.59 (-29.7%)	-6.50±34.52 (+7.2%)
Between group difference, P value	0.71	0.81	0.081
Melanin Index: Per-protocol analysis
TA (n=7)	107.43±109.03	75.67±60.34	83.29±105.07
Placebo (n=7)	86.33±74.83	55.67±83.53	93.76±81.85
Difference from baseline TA		31.76±61.77 (-29.6%)	24.14±42.38 (-22.5%)
Difference from baseline placebo		30.67±34.34 (-35.5%)	-7.43±37.18 (+8.6%)
Between group difference, P value	0.68	0.97	0.16
Quality of life: Intention-to-treat analysis
TA (n=9)	43.89±11.61	25.89±15.45	39.11±17.80
Placebo (n=8)	44.38±18.08	33.13±21.98	38.13±21.81
Difference from baseline TA		18.00±18.36 (-41.0%)	4.78±14.91 (-10.9%)
Difference from baseline placebo		11.25±16.29 (-25.3%)	6.25±9.13 (-14.1%)
Between group difference, P value	0.95	0.44	0.81
Quality of life: Per-protocol analysis
TA (n=7)	43.71±12.68	24.14±15.39	41.14±18.32
Placebo (n=7)	40.71±16.01	27.86±17.45	33.57±19.02
Difference from baseline TA		19.57±20.55 (-44.8%)	2.57±16.03 (-5.9%)
Difference from baseline placebo		12.86±16.90 (-31.6%)	7.14±9.48 (-17.5%)
Between group difference, P value	0.70	0.52	0.53

TA=Tranexamic, IQR=Inter-quartile range *All results reported as mean and standard deviation unless specified. ^aIntention-to-treat analysis: all participants who were randomised were included. ^bPer-protocol analysis: participants did not adhere to the study protocol were excluded

Figure 1.

Clinical photos of a participant with severe melasma showing overall improvement from baseline after 12 weeks of oral TA treatment: (a) Week 0, (b) Week 12, (c) Week 2

There have been two other RCTs comparing oral TA with placebo in the treatment of melasma.[3,4] Colferai et al.[4] conducted a 12-week RCT in Brazil involving 36 female and 1 male participants with melasma. Del Rosario et al.[3] conducted a 24-week RCT with 12 weeks of treatment with oral TX or placebo in 44 mostly Hispanic participants in Texas, USA with moderate-to-severe melasma. Compared to these two studies, our study showed similar improvement in mMASI or MASI score following 12 weeks of treatment with oral TA compared to placebo group. Similar to the American RCT, the mMASI remained stable for a further 12 weeks following the cessation of TA, suggesting a sustained therapeutic benefit for oral TA. Like the prior RCTs, our study demonstrated reduction in the mMASI in the placebo group demonstrating the importance of strict photoprotection for melasma. Our study is limited by the small sample size.

In summary, oral TA at 250 mg twice daily used over 12 weeks appears effective in treating moderate-to-severe melasma with minimal side effects in a diverse ethnic Australian population. The effects were sustained 12 weeks after stopping TA. This trial also highlighted the importance of regular photoprotection in melasma treatment, especially in Australia which has significantly higher ultraviolet radiation indices. Larger Australian multi-centre studies with longer treatment durations, longer follow up periods and with adjuvant therapy should be further investigated.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

This study was partially funded by Rationale Skin Care, Richmond, Victoria, Australia.

Conflicts of interest

There are no conflicts of interest.