ORIGINAL ARTICLE

Effective Tyrosinase Inhibition by Thiamidol

Results in Significant Improvement of Mild
to Moderate Melasma
Craig Arrowitz1, Andrea M. Schoelermann2, Tobias Mann2, Lily I. Jiang3, Teresa Weber1 and
Ludger Kolbe2

Melasma is a pigmentary disorder characterized by hyperpigmented patchy skin in sun-exposed areas,

especially the face. Treatment of melasma can be challenging because long-term therapy is required, reoc-
currence is common, and existing therapies are insufficient and unsatisfactory. To investigate new treatment
options, we performed an exploratory double-blinded, randomized split-face study to assess the efficacy of the
tyrosinase inhibitor Thiamidol compared to hydroquinone in women with mild to moderate melasma. After 12
weeks, modified Melasma Area and Severity Index scores significantly improved on both the Thiamidol-treated
and the hydroquinone-treated sides of the face. Additionally, Thiamidol treatment improved modified Melasma
Area and Severity Index scores significantly better than hydroquinone, and more subjects improved following
treatment with Thiamidol (79%) compared with hydroquinone (61%). During treatment, no subjects displayed
worsening of modified Melasma Area and Severity Index scores on the Thiamidol-treated side, while
approximately 10% of the subjects showed a worsening of modified Melasma Area and Severity Index scores on
the hydroquinone-treated side. All subjects routinely used sunscreens and consistent results were obtained in
low and in high UV ambient conditions. Subjects rated the efficacy of the Thiamidol formulation significantly
better with regard to overall decreased intensity of dark spots and their overall appearance throughout
the study. Thiamidol was well-tolerated and well-perceived and represents an effective agent to reduce
hyperpigmentation.
Journal of Investigative Dermatology (2019) 139, 1691e1698; doi:10.1016/j.jid.2019.02.013

INTRODUCTION
Melasma is a common pigmentary disorder characterized by
asymmetrical, hyperpigmented macules and dark patchy skin
that develops in sun-exposed areas, especially the face and
neck (Guinot et al., 2010; Tamega Ade et al., 2013). In the
United States alone, melasma affects more than 5 million
people (Grimes, 1995). While the pathogenesis of melasma
remains unclear, certain risk factors are known, such as
exposure to UV light, female gender, a genetic predisposi-
tion, hormonal changes like pregnancy, use of oral contra-
ceptives, and hormone replacement therapy (Achar and
Rathi, 2011; Goh and Dlova, 1999; Hexsel et al., 2013;
Pichardo et al., 2009). The significance of those triggering
factors is underscored by the fact that melasma mainly
affects adult women with darker complexions (Fitzpatrick
skin types IIIeV) who live in areas with intense sun exposure
1
Beiersdorf Inc, Wilton, Connecticut, USA; 2Beiersdorf AG, Hamburg,
Germany; and 3Thomas J. Stephens & Associates, Inc, Richardson, Texas,
USA
Correspondence: Ludger Kolbe, Front End Innovation, Beiersdorf AG,
Unnastrasse 48, BF519, 20245 Hamburg, Germany. E-mail: Ludger.Kolbe@
Beiersdorf.com
Abbreviation: mMASI, modified Melasma Area and Severity Index
Received 23 September 2018; revised 5 February 2019; accepted 11 February
2019; accepted manuscript published online 27 February 2019; corrected
proof published online 10 May 2019
(Handel et al., 2014; Sheth and Pandya, 2011). The emotional
and psychological effects of this disorder can severely impact
a patient’s quality of life (Maymone et al., 2017). This dis-
tressing situation is exacerbated by the fact that treatment of
melasma can be challenging because long-term therapy is
often required and reoccurrence is common.
For decades, the benchmark in the treatment of hyperpig-
mentation of the skin has been hydroquinone, which alters
melanosome formation and increases melanosome destruc-
tion (Jimbow et al., 1974). However, concerns regarding the
systemic absorption of the drug and drug-induced carcino-
genesis have been expressed (Mishra et al., 2013; Westerhof
and Koovers, 2005). Due to safety issues, the European Union
banned hydroquinone from use as a cosmetic ingredient in
2001. In the United States, formulations containing up to 2%
hydroquinone are still sold over-the-counter. However, the
Food and Drug Administration is re-evaluating this current
situation and a final decision is pending (Food and Drug
Administration, 2006).
Thus, it is evident that an effective and safe topical inhib-
itor of human skin hyperpigmentation is lacking. Recently,
more than 50,000 compounds were screened for their ability
to inhibit a recombinant human tyrosinase (Cordes et al.,
2013) and Thiamidol (isobutylamido-thiazolyl-resorcinol)
was identified as an especially potent inhibitor of human
tyrosinase (Mann et al., 2018a, 2018b). In vitro, Thiamidol
was superior to frequently used inhibitors of

ª 2019 The Authors. Published by Elsevier, Inc. on behalf of the Society for Investigative Dermatology. This is an open access
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 C Arrowitz et al.
Efficacy/Safety of Thiamidol to Treat Melasma

Table 1. Subject demographic characteristics face showed a significant decrease compared to the baseline,
6.44  4.42 (P  0.001), while there was no significant
Cell A: Thiamidol Cell B: Thiamidol Versus change on the control side of the face after 12 weeks (8.44 
Measure Versus Control Hydroquinone 4.95). The improvement on the Thiamidol-treated side of the
Female subjects, n 31 28 face was also significant compared to the control side of the
Age, y, mean  52.0  8.6 (29e63) 50.6  7.7 (31e65) face at 12 weeks (P  0.001).
SD (range) After 4 weeks of treatment, 35.5% of the Thiamidol-treated
Asian, n (%) 15 (48.4) 10 (35.7) side of the face showed an improvement in mMASI scores,
African American, 3 (9.7) 0 (0) which increased further to 83.9% after 8 and 12 weeks of
n (%)
treatment (Figure 1b). No subject displayed a worsening of
Caucasian, n (%) 12 (38.7) 17 (60.7)
Multiracial, n (%) 1 (3.2) 1 (3.6)
melasma. On the control side of the face, after 4 weeks, only
6.5% of subjects exhibited improvement and 3.2% had a
Abbreviation: SD, standard deviation.
worsening of melasma. After 12 weeks, a slight improvement
was observed on the control side of the face for 25.9% of
subjects, while 12.9% showed worsening. However,
considering that all subjects used suncreens prior to any sun
hyperpigmentation, such as arbutin, kojic acid, and hydro-
exposure and because none of the changes on the control
quinone. In vivo, Thiamidol reduced the visibility of solar
side of the face were significant, a confounding effect of sun
lentigines at concentrations as low as 0.1% within 4 weeks of
exposure can be excluded. In contrast, even as early as after 4
treatment (Mann et al., 2018a). Therefore, an exploratory
weeks, significant improvements in mMASI scores were
clinical study was conducted to assess the efficacy and
observed on the Thiamidol-treated side of the face (P 
tolerance of a formulation containing 0.2% Thiamidol, and to
0.001) (Figure 1c).
compare it to a formula comprising 2.0% hydroquinone,
when used by women with mild to moderate melasma. All
Thiamidol versus hydroquinone (cell B)
subjects used sunscreens prior to any UV exposure and the
Of the 41 subjects enrolled in cell B, 28 completed
study assessed the effects of Thiamidol with hydroquinone in
the treatment. At baseline, the Thiamidol-treated side of the
low and in high UV conditions.
face displayed a mean mMASI score  standard deviation of
7.84  3.56 and the side of the face treated with the
RESULTS
hydroquinone formulation showed a score of 7.98  2.92
The study was performed from November 2015 to September
(Figure 2a). At week 12, statistically significant improvements
2016 at the Texas Research Center (Thomas J. Stephens &
in mMASI scores relative to pretreatment for both the
Associates, Inc) in Richardson, Texas. Of the 150 females
Thiamidol-treated side of the face (P  0.001) and the side of
screened (Supplementary Figure S1 online), 80 were selected
the face treated with hydroquinone (P ¼ 0.002) were evident.
and randomized to two treatment groups and 59 of them
However, the Thiamidol-treated sides demonstrated signifi-
completed the study. The demographics of the subjects are
cantly lower mMASI scores than the hydroquinone-treated
summarized in Table 1. From November 2015 until mid-
sides (P  0.001).
April 2016, a time of relatively low ambient UV exposure,
A detailed analysis of the number of subjects with mMASI
30 subjects completed the study (cell A, n ¼ 16; cell B,
score improvements revealed increasing improvements with
n ¼ 14), while 29 subjects completed the study by the end of
the duration of Thiamidol treatment: 21.4% after 4 weeks,
September (cell A, n ¼ 15; cell B, n ¼ 14) and, therefore,
67.9% after 8 weeks and 78.6% after 12 weeks (Figure 2b).
their treatment period comprised the time of relatively high
No subject displayed a worsening of their melasma. On the
UV exposure. All subjects in both groups routinely used
hydroquinone-treated side of the face, after 4 weeks, 21.4%
sunscreens with an SPF 30 prior to any UV exposure. The
of subjects displayed improvement. After 8 weeks of treat-
side of the faces of subjects in cell A where they used a
ment with hydroquinone, 46.4% of subjects showed
sunscreen only (control side) did not show any significant
improvement, while 3.6% exhibited worsening. After 12
change in modified Melasma Area and Severity Index
weeks of treatment with hydroquinone, improvement could
(mMASI) score during the treatment period (Figure 1a),
be observed for 60.7% of subjects, but 10.7% showed
excluding a confounding effect of sun exposure.
worsening. After 4 weeks, the Thiamidol-treated side of the
Results from tolerability evaluations indicated that both the
face displayed a significant decrease in mMASI scores of
Thiamidol-containing formulation and the hydroquinone-
e0.38  0.75 (P ¼ 0.031) compared with the baseline
containing formulation were well tolerated, with no statisti-
(Figure 2c). For the hydroquinone-treated side of the face, a
cally significant changes from baseline in tolerability scores at
significant reduction in mMASI scores of e0.50  1.15 was
any time point (Supplementary Tables S1, S2 online). No serious
documented (P ¼ 0.031). After 8 weeks, the mMASI scores
adverse events were observed in either treatment group.
on the Thiamidol-treated side of the face were significantly
Thiamidol versus untreated control (cell A) reduced by e1.91  1.86 (P  0.001). For the hydroquinone-
In cell A, 39 subjects were enrolled and 31 completed the treated side of the face, a significant decline of e1.25  1.87
study. At baseline, mMASI scores were 9.73  4.45 for was found at 8 weeks (P ¼ 0.003). At the end of the treatment
the Thiamidol-treated side of the face and 8.71  4.59 for the period, the mMASI scores on the Thiamidol-treated side of
control side of the face (Figure 1a). After 12 weeks of treat- the face were significantly diminished by e2.84  2.25 (P 
ment, the mMASI scores for the Thiamidol-treated side of the 0.001), while the hydroquinone-treated side of the face

1692 Journal of Investigative Dermatology (2019), Volume 139


showed a significant decrease of e1.52  2.15 (P ¼ 0.002)
relative to the baseline. A statistical comparison of the two
treatments revealed that the Thiamidol treatment produced
superior effects after 12 weeks compared with the hydro-
quinone treatment (P < 0.001).
Measurements of pigmentary changes by image analysis of
photographs
Figure 3 shows representative images of the sides of faces of 2
subjects treated with Thiamidol. In the photographs, irregularly
shaped areas of interest were selected to target a dark spot on
the left and right cheek for the analysis of L*-value. Results from
image analysis indicated a statistically significant improve-
ment in L*-values for Thiamidol-treated sides at weeks 4, 8, and
12 for cell A and at weeks 4 and 8 for cell B compared with
baseline. No statistically significant differences from baseline
were observed for the control side of the face in cell A and for
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Efficacy/Safety of Thiamidol to Treat Melasma
Figure 1. Mean mMASI scores before
and after treatment with Thiamidol
versus the control in cell A. (a) Pre-
and post-treatment mMASI scores. (b)
Percentage of subjects displaying
improved or worsened mMASI scores
during treatment. (c) Change of
mMASI scores relative to baseline
measurements. Scores were assessed
after 4, 8, and 12 weeks of treatment.
Data are reported as mean  SD.
Significant differences as marked in
comparison to baseline and control
(*P  0.05, **P  0.01, ***P  0.001).
mMASI, modified Melasma Area and
Severity Index; SD, standard
deviation.
hydroquinone in cell B (Supplementary Table S3 online).
Treatment comparisons showed that Thiamidol outperformed
the control side at weeks 4 and 12 (cell A).
Self-assessment of pigmentary changes
Each subject was asked to rate her melasma according to a
10-point Griffiths scale (Griffiths et al., 1992). During Thia-
midol treatment, the values for overall intensity of dark spots
dropped from 5.25 at baseline to 3.70 after 12 weeks, and
from 5.05 to 3.98 for overall appearance. The improvement
was statistically significant for all study time points compared
to the baseline. On the hydroquinone-treated side of the face,
the values for overall intensity of dark spots decreased from
5.11 to 4.21 and from 5.18 to 4.46 for overall appearance.
Compared with the baseline scores, with the exception
of overall appearance at week 4, improvements were signif-
icant for all study time points. The overall intensity of dark
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Efficacy/Safety of Thiamidol to Treat Melasma

Figure 2. Changes in mMASI scores

during treatment with Thiamidol
compared to hydroquinone in cell B.
(a) Mean of mMASI scores pre- and
post-treatment. (b) Percentage of
subjects with improved or worsened
mMASI scores in comparison to the
baseline. (c) Time course of mMASI
score changes compared to the
baseline. Scores were assessed after 4,
8, and 12 weeks of treatment. Data
are reported as means  SD.
Significant differences as marked in
comparison to baseline and
hydroquinone (*P  0.05, **P  0.01,
***P  0.001). mMASI, modified
Melasma Area and Severity Index; SD,
standard deviation.

spots at week 4 was improved in 60.7% of subjects on the
Thiamidol-treated side of the face and in 32.1% on the
hydroquinone-treated side of the face (Figure 4a). After 8
weeks, the overall intensity of dark spots on the Thiamidol-
treated side of the face had improved in 89.3% of subjects
and in 50.0% of subjects on the hydroquinone-treated side of
the face. After completion of the treatment, improvement was
perceived on the Thiamidol-treated side of the face by 96.4%
of the subjects, and by 57.1% of subjects on the
hydroquinone-treated side of the face. Statistical analysis
revealed that the differences in dark spot intensity between
treatments were significant at all study time points. Compa-
rable results were obtained for subject ratings of their overall
appearance (Figure 4b).
DISCUSSION
The treatment of melasma presents a major challenge and no
definitive standard therapy has yet been established. Ac-
cording to a Cochrane review (Rajaratnam et al., 2010),
which assessed 20 studies with a total of 2,125 participants
covering 23 different melasma treatments, current available
therapies are insufficient and unsatisfactory. Because sun

1694 Journal of Investigative Dermatology (2019), Volume 139


Figure 3. Representative images of subjects showing improvement on the Thiamidol-treated side of the face at baseline and after 4, 8, and 12 weeks of
treatment. All subjects signed a photo release consent form authorizing the reproduction and distribution of any images collected during the study.
exposure is an aggravating factor in melasma, sunscreen use
is mandatory to prevent worsening of the melasma. However,
when new treatment options are to be evaluated for efficacy
in melasma, the study needs to be controlled carefully to
avoid confounding sunscreen effects. Therefore, only subjects
using a broad-spectrum sunscreen with at least SPF 30 on a
regular basis qualified for enrollment in this study, and sub-
jects were not allowed to change their sunscreen products or
application regimens during the study period.
The best-studied and most widely used topical active
ingredient to treat hyperpigmentation of the skin is hydro-
quinone. Hydroquinone is considered the most effective
pigment lightening agent (Draelos, 2007, 2015) and in
the United States, hydroquinone is used at concentrations of
2% in over-the-counter drugs and at 4% and higher in pre-
scription products. Treatment with 2% hydroquinone has
been demonstrated to be effective for treating melasma
(Makhecha et al., 2016; Tirado-Sánchez et al., 2009). While
hydroquinone quite potently reduces skin hyperpigmenta-
tion, it also can cause irritant dermatitis, ochronosis, and
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Efficacy/Safety of Thiamidol to Treat Melasma
post-inflammatory hyperpigmentation (Mishra et al., 2013;
Ogbechie-Godec and Elbuluk, 2017). Treatment with
higher hydroquinone concentrations should not exceed 3
months to avoid severe side effects. Thus, an effective long-
term treatment option is needed.
Inhibiting the activity of the enzyme tyrosinase is the safest
and most effective approach to reduce hyperpigmentation.
However, the clinical efficacy of current tyrosinase inhibitors
is limited due to the fact that they were typically selected
based on their ability to inhibit mushroom tyrosinase
(Chang, 2009; Lee et al., 2016). In recent studies, Thiamidol
was characterized as an especially potent inhibitor of human
tyrosinase (Mann et al., 2018a, 2018b). In vitro, Thiamidol
was superior to frequently used inhibitors of hyperpigmen-
tation such as arbutin, kojic acid, and hydroquinone. This
superiority of Thiamidol compared to hydroquinone was
confirmed in this in vivo study. After 12 weeks, the
Thiamidol-treated sides of the face demonstrated significantly
lower mMASI scores than the hydroquinone-treated sides of
the face. Noteworthy is the fact that the concentration of
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Efficacy/Safety of Thiamidol to Treat Melasma
Figure 4. Subjective assessment of
melasma improvement. Each subject
rated the (a) intensity of spots and (b)
overall appearance separately on the
right and left side of the face using a
modified Griffiths 10-point scale.
Values were assessed after 4, 8, and
12 weeks of treatment. Data are
reported as percent of subjects with
improvement. Asterisks mark
significant differences versus the
baseline (*P  0.05, **P  0.01, ***P 
0.001). Numbers show P-values
between treatments.
Thiamidol (0.2%) used in the formulation was 10 times lower
than the concentration of hydroquinone (2.0%) used. During
treatment, no subject displayed a worsening of melasma on
the Thiamidol-treated side of the face. However, on the
hydroquinone-treated side of the face, approximately 10% of
subjects showed a worsening of the mMASI score at the end
of the treatment period.
Due to psychosocial implications, hyperpigmentary disor-
ders, such as melasma, have a profound impact on a patient’s
quality of life (Maymone et al., 2017). Also, due to frequent
relapses, the treatment of melasma is frustrating for patients
and challenging for physicians. For this reason, a subjective
assessment of efficacy is crucial to support compliance. In
both arms of the study, subjects reported a statistically sig-
nificant improvement after Thiamidol treatment for the
overall intensity of dark spots at all study time points. Simi-
larly, the hydroquinone-treated sides of the face showed
significant improvements, however, to a lesser extent. When
asked to evaluate Thiamidol with regard to its efficacy in
comparison to hydroquinone, subjects rated the use of the
Thiamidol-containing formulation significantly better for both
the improvement of overall intensity of dark spots and the
improvement of overall appearance at all study time points.
Tolerability evaluations demonstrated that both the Thia-
midol formulation and the 2% hydroquinone formulation
were well tolerated throughout the study.
Limitations of this study include the focus on female sub-
jects only. In addition, there was no post-study follow-up on
the subjects after the treatment ended, which may have
yielded valuable information. The treatment period of 12
weeks was chosen based on experience from preceding
studies (Mann et al., 2018a). Our previous studies with other
tyrosinase inhibitors showed that it takes several weeks for
hyperpigmentation to return to baseline after treatment and
no rebound effect was observed (Kolbe et al., 2013). Never-
theless, more extensive randomized clinical trials comprising
longer treatment durations and a follow-up should be carried
out in the near future.
In summary, after 12 weeks of treatment, Thiamidol
significantly improved facial hyperpigmentation in women
with mild to moderate melasma. Thiamidol was
1696 Journal of Investigative Dermatology (2019), Volume 139
well-tolerated, well-perceived, and presents an effective, safe
agent to reduce pigmentation irregularities.
MATERIALS AND METHODS
Test materials
For this study, Thiamidol was formulated at 0.2% in an oil-in-water
emulsion. For hydroquinone treatment, a commercially available
over-the-counter drug product with 2.0% hydroquinone (Esotérica
Fade Cream Nighttime with Moisturizers; Medicis, Scottsdale, AZ)
was purchased. In order to study the effect of the active ingredients
only, both test products were night care face products with no
additional SPF. Subjects were instructed to also apply their own
sunscreen (must be broad spectrum and at least SPF 30) as they had
been doing prior to the study.
Study design
The study was approved by the IntegReview Institutional Review
Board (Austin, TX, approval #IORG0000689) and was performed at
the Texas Research Center of Thomas J. Stephens & Associates, Inc,
Richardson, TX. Each subject provided written Institutional Review
Boardeapproved informed consent. The study was performed from
November 2015 to September 2016. Of the enrolled 80 females, a
total of 59 completed the study (Supplementary Figure S1 online).
Subject demographics and characteristics are presented in Table 1.
Eligible subjects with clinically determined mild to moderate hy-
perpigmentation due to melasma on both sides of the face partic-
ipated in the following procedures: Subjects were assessed for
mMASI parameters separately on the global right and left sides of
the face. Also, subjects performed a subjective assessment with
respect to the overall intensity of dark spots and the overall
appearance separately on the right and left side of the face. Local
cutaneous tolerability was evaluated by assessing the signs and
symptoms of objective (erythema and edema) and subjective
(burning, stinging, itching, and tingling) irritation separately on the
right and left sides of the face. Additionally, full-face digital images
were taken of each subject (right side and left side views) for image
analysis of pigmentary changes (see Supplementary Material online
for details).
Eligible subjects were enrolled and assigned to cell A or cell B
according to a computerized randomization scheme. Treatment was
done by patient self-application; products and instructions were

provided by staff who were not involved in any evaluations.
Personnel involved in evaluation did not know which side of the face
was treated (cell A) or the identity of the products (cell A and cell B).
Subjects in both cells were supplied with a formulation containing
0.2% Thiamidol and subjects in cell B were additionally given an on
the market over-the-counter 2.0% hydroquinone-containing formu-
lation. Subjects were randomized to treat one side of the face (right
or left) twice daily with the Thiamidol-containing formulation and
the opposite side of the face was used as the control (cell A) or was
treated with the hydroquinone-containing formulation (cell B).
Therefore, cell A was single-blinded (evaluator) and cell B was
double-blinded (subjects and evaluator).
Subjects were instructed to apply their own sunscreen (must be
broad-spectrum and at least SPF 30) prior to any sun exposure and as
needed but at least 10 minutes after application of the Thiamidol-
containing formulation or the 2% hydroquinone-containing formu-
lation (if applicable) or until those formulations had been completely
absorbed.
Subjects were also instructed to avoid extended periods of sun
exposure and all use of tanning beds for the duration of the study. Extra
care was taken to wear protective clothing, including sunglasses, and
to avoid sun exposure from 10 a.m. to 2 p.m. Subjects were allowed to
continue the use of all regular brands of color cosmetics and makeup
remover for the duration of the study. Subjects were to refrain from
using any anti-aging, anti-melasma, or anti-pigmentation products,
and the use of any new facial products other than the assigned test
material. Subjects returned to the clinic after 4 weeks, 8 weeks, and 12
weeks of treatment. At each clinical visit, after acclimatization,
mMASI assessments, subjective assessments, tolerability evaluations,
and imaging procedures were performed. All subjects signed a photo
release consent form authorizing the reproduction and distribution of
any images collected during the study.
Determination of melasma area and severity (MASI)
parameters
The following parameters were graded for the determination of the
MASI parameters: pigment intensity (darkness) (0 ¼ absent, 1 ¼ slight,
2 ¼ mild, 3 ¼ marked, 4 ¼ severe), lesion size (area) (0 ¼ no
involvement, 1 ¼ >10%, 2 ¼ 10e29%, 3 ¼ 30e49%, 4 ¼ 50e 69%,
5 ¼ 70e89%, 6 ¼ 90e100%), homogeneity (0 ¼ absent, 1 ¼ slight,
2 ¼ mild, 3 ¼ marked, 4 ¼ maximum). A modified Hemi-MASI
(mMASI) was calculated for the global half-face using the following
equation: mMASI ¼ 0.5  (PI þ H)  A, where PI is pigment intensity,
H is homogeneity, and A is area.
Subjective assessment
Each subject performed a subjective assessment with respect to the
overall intensity of dark spots (0 ¼ absent, 9 ¼ severe) and overall
appearance (0 ¼ excellent, 9 ¼ poor) separately on the right and left
side of the face using a modified Griffiths 10-point scale (Griffiths
et al., 1992).
Outcome measures and statistical analysis
The primary objective was to evaluate whether 0.2% Thiamidol in
comparison to 2.0% hydroquinone improved melasma with
respect to the clinical grading of overall hyperpigmentation and
discrete hyperpigmentation (mMASI assessment). Secondary
outcome measures were an evaluation of local cutaneous tolera-
bility by assessing the signs and symptoms of objective and sub-
jective irritation.
C Arrowitz et al.
Efficacy/Safety of Thiamidol to Treat Melasma
At least 60 subjects meeting the eligibility requirements were
expected to complete the study, with 30 subjects in each treatment
cell. The sample size for this study was estimated based on the
results of previous efficacy studies on solar lentigines (Mann et al.,
2018a).
For clinical grading of efficacy parameters, tolerability evalua-
tions, mMASI assessments, and subjective assessments, the mean
change from baseline (defined as the post-baseline value minus the
baseline value) was estimated at each applicable post-baseline
time point. The null hypothesis that the mean change from
baseline equals zero was tested using a Wilcoxon signed-rank test
with Bonferroni-Holm P-value adjustment for efficacy parameters,
tolerability evaluations, mMASI assessment, and subjective
assessment.
The mean percent change from baseline and percentage of sub-
jects showing improvement or worsening was calculated using the
following formula:
Percent of subjects improved =worsened ¼
ðnumber of subjects improved =worsened Þ x 100
total number of subjects
Comparisons between the left and right sides of the face were
made within each cell. The null hypothesis that the mean change
from baseline is equal between treatments on each side of the face at
post-baseline time points was tested at each applicable post-baseline
time point using a Wilcoxon signed-rank test with Bonferroni-Holm
P-value adjustment.
Statistical analyses were performed using the SAS software,
version 9.4 series (SAS Institute, Cary, NC). All statistical tests
were two-sided at significance level a ¼ 0.05.
Data availability statement
Data sets related to this article can be found at https://doi.org/1
0.17632/npxdprzf7f.1, an open-source online data repository hos-
ted at Mendeley Data.
ORCIDs
Craig Arrowitz: https://orcid.org/0000-0003-0498-8792
Andrea M. Schoelermann: https://orcid.org/0000-0002-2463-3940
Tobias Mann: https://orcid.org/0000-0002-6339-9683
Lily I. Jiang: https://orcid.org/0000-0002-6915-7386
Teresa Weber: https://orcid.org/0000-0002-1007-2513
Ludger Kolbe: https://orcid.org/0000-0001-8608-8901
CONFLICTS OF INTEREST
CA, AMS, TM, TW, and LK are employees of Beiersdorf AG. Thiamidol is
patented by Beiersdorf AG. The remaining author states no conflict of interest.
ACKNOWLEDGMENTS
The study was sponsored by Beiersdorf AG, Hamburg, Germany. The
authors would like to thank Silke Gallinat for providing medical writing
support for this manuscript.
SUPPLEMENTARY MATERIAL
Supplementary material is linked to the online version of the paper at
www.jidonline.org, and at https://doi.org/10.1016/j.jid.2019.02.013.
REFERENCES
Achar A, Rathi SK. Melasma: a clinico-epidemiological study of 312 cases.
Indian J Dermatol 2011;56:380e2.
Chang TS. An updated review of tyrosinase inhibitors. Int J Mol Sci
2009;26(10):2440e75.
Cordes P, Sun W, Wolber R, Kolbe L, Klebe G, Röhm KH. Expression in
nonmelanogenic systems and purification of soluble variants of human
tyrosinase. Biol Chem 2013;394:685e93.
www.jidonline.org 1697
 C Arrowitz et al.
Efficacy/Safety of Thiamidol to Treat Melasma
Draelos ZD. Skin lightening preparations and the hydroquinone controversy.
Dermatol Ther 2007;20:308e13.
Draelos ZD. A split-face evaluation of a novel pigment-lightening agent
compared with no treatment and hydroquinone. J Am Acad Dermatol
2015;72:105e7.
Food and Drug Administration. Skin Bleaching Drug Products for Over-the-
Counter Human Use; Proposed Rule. 71 Federal Register 51146-
5115521. 2006 (codified at 21 CFR Part 310).
Goh CL, Dlova CN. A retrospective study on the clinical presentation and
treatment outcome of melasma in a tertiary dermatological referral centre
in Singapore. Singapore Med J 1999;40:455e8.
Griffiths CE, Wang TS, Hamilton TA, Voorhees JJ, Ellis CN. A photonumeric
scale for the assessment of cutaneous photodamage. Arch Dermatol
1992;128:347e51.
Grimes PE. Melasma: etiologic and therapeutic considerations. Arch Der-
matol 1995;131:1453e7.
Guinot C, Cheffai S, Latreille J, Dhaoui MA, Youssef S, Jaber K, et al.
Aggravating factors for melasma: a prospective study in 197 Tunisian pa-
tients. J Eur Acad Dermatol Venereol 2010;24:1060e9.
Handel AC, Miot LD, Miot HA. Melasma: a clinical and epidemiological
review. Ann Bras Dermatol 2014;89:771e82.
Hexsel D, Lacerda DA, Cavalcante AS, Machado Filho CA, Kalil CL, Ayres EL,
et al. Epidemiology of melasma in Brazilian patients: a multicenter study.
Int J Dermatol 2013;53:440e4.
Jimbow K, Obata H, Pathak M, Fitzpatrick TB. Mechanism of depigmentation
by hydroquinone. J Invest Dermatol 1974;62:436e49.
Kolbe L, Mann T, Gerwat W, Batzer J, Ahlheit S, Scherner C, et al. 4-n-
butylresorcinol, a highly effective tyrosinase inhibitor for the topical
treatment of hyperpigmentation. J Eur Acad Dermatol Venereol
2013;27(Suppl. 1):19e23.
Lee SY, Baek N, Nam TG. Natural, semisynthetic and synthetic tyrosinase
inhibitors. J Enzyme Inhib Med Chem 2016;31:1e13.
Makhecha M, Nagzarkar R, Khatib Y, Khade A. A comparative study of the
efficacy of 2% hydroquinone, 2% kojic acid and 30% glycolic peel in the
treatment of facial melasma and evaluation of melanin content using
SIAscopy—a novel objective method of assessment. Sch J App Med Sci
2016;4:3948e53.
1698 Journal of Investigative Dermatology (2019), Volume 139
Mann T, Gerwat W, Batzer J, Eggers K, Scherner C, Wenck H, et al. Inhibition of
human tyrosinase requires molecular motifs distinctively different from
mushroom tyrosinase. J Invest Dermatol 2018a;138:1601e8.
Mann T, Scherner C, Röhm KH, Kolbe L. Structure-activity relationships of
Thiazolyl resorcinols, potent and selective inhibitors of human tyrosinase.
Int J Mol Sci 2018b;19(3).
Maymone MBC, Neamah HH, Wirya SA, Patzelt NM, Secemsky EA,
Zancanaro PQ, et al. The impact of skin hyperpigmentation and hyper-
chromia on quality of life: a cross-sectional study. J Am Acad Dermatol
2017;77:775e8.
Mishra SN, Dhurat RS, Deshpande DJ, Nayak CS. Diagnostic utility of der-
matoscopy in hydroquinone- induced exogenous ochronosis. Int J Der-
matol 2013;52:413e7.
Ogbechie-Godec OA, Elbuluk N. Melasma: an up-to-date comprehensive
review. Dermatol Ther (Heidelberg) 2017;7:305e18.
Pichardo R, Vallejos Q, Feldman SR, Schulz MR, Verma A, Quandt SA,
et al. The prevalence of melasma and its association with quality of
life in adult male Latino migrant workers. Int J Dermatol 2009;48:
22e6.
Rajaratnam R, Halpern J, Salim A, Emmett C. Interventions for melasma.
Cochrane Database Syst Rev 2010;7:CD003583.
Sheth VM, Pandya AG. Melasma: a comprehensive update: part I. J Am Acad
Dermatol 2011;65:689e97.
Tamega Ade A, Miot LD, Bonfietti C, Gige TC, Marques ME, Miot HA. Clinical
patterns and epidemiological characteristics of facial melasma in Brazilian
women. J Eur Acad Dermatol Venereol 2013;27:151e6.
Tirado-Sánchez A, Santamarı́a-Román A, Ponce-Olivera RM. Efficacy of dioic
acid compared with hydroquinone in the treatment of melasma. Int J
Dermatol 2009;48:893e5.
Westerhof W, Kooyers TJ. Hydroquinone and its analogues in dermatology—a
potential health risk. J Cosmet Dermatol 2005;4:55e9.
This work is licensed under a Creative Commons
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International License. To view a copy of this license, visit
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SUPPLEMENTARY MATERIAL
Digital images
A total of two full-face digital images were taken of each
subject (right side and left side views) under standard lighting
1 and 2, and cross-polarized lighting conditions using a VISIA
CR photostation (Canfield Imaging Systems, Fairfield, NJ) with
a Canon Mark II 5D digital SLR camera (Canon, Tokyo, Japan).
Image analysis of photographs for skin brightness (L*)
Prior to image analysis for skin brightness, RGB digital
images were first converted to CIELAB color space using
Macro version ConvertToLab_20140315, then analyzed us-
ing Macro version SkinBright_20140619 developed by
Thomas J. Stephens & Associates, Inc using Image Pro Plus
software, version 7 (Media Cybernetics, Rockville, MD).
Irregularly shaped areas of interest were selected to target a
dark spot on the left and right cheek areas for the analysis of
L* value. Higher L* value indicates brighter skin.
Results for cell A
Results from the image analysis of skin brightness (L*) indi-
cated a statistically significant improvement in values for the
Thiamidol-treated side at weeks 4, 8, and 12 compared with
baseline. No statistically significant differences from baseline
were observed for the control side of the face. Treatment
comparisons showed that the Thiamidol outperformed the
control side at weeks 4 and 12 (see Supplementary Table S3).
Results for cell B
Thiamidol induced a statistically significant improvement in
scores for skin brightness (L*) at weeks 4 and 8 compared
with baseline scores. Use of the 2% hydroquinone product
produced no statistically significant differences from baseline
(see Supplementary Table S3).
Eligibility criteria
Individuals were admitted to the study at the discretion of
the Investigator, based on medical history and findings of
the pre-study interview and examination. Individuals were
screened for the eligibility criteria listed below prior to study
enrollment.
Inclusion criteria
Subject were eligible to participate if they met all of the
following inclusion criteria:
1. Women 18e65 years of age having general good health.
2. Fitzpatrick skin type IIeIV.
3. Individuals with mild to moderate hyperpigmentation due
to melasma on both sides of the face (score of 3e6 on
according to the modified Griffiths scale 1, where 0 ¼ none
and 9 ¼ severe, half points are acceptable to qualify).
4. Individuals who use sunscreen daily with at least SPF 30.
5. Individuals that are willing to provide written informed
consent and are able to read, speak, write, and understand
English.
6. Individuals of child-bearing potential who are willing to take
a urine pregnancy test prior to study enrollment and when
deemed appropriate by the investigator and/or sponsor.
7. Individuals of child-bearing potential who use an
acceptable method of contraception throughout the study.
Acceptable methods of birth control include: oral and
other system contraceptives (individuals must be on a
C Arrowitz et al.
Efficacy/Safety of Thiamidol to Treat Melasma
stable use for 3 months prior to study enrollment and must
not alter their use, including dose or regimen for the
duration of the study), double barrier, bilateral tubal liga-
tion, partner vasectomy, and abstinence.
8. Willing to withhold all facial treatments during the
course of the study, including botulinum toxin, injectable
fillers, microdermabrasion, intense pulse light, peels,
facials, laser treatments, and tightening treatments.
Waxing, sugaring, and threading are allowed, but not
laser facial hair removal.
9. Willingness to cooperate and participate by following
study requirements for the duration of the study and to
report any changes in health status or medications,
adverse event symptoms, or reactions immediately.
Exclusion criteria
A subject would not be eligible to participate if they met any
of the following exclusion criteria:
1. History of laser resurfacing procedures, deep skin peel,
botulinum toxin, or injection with a dermal filler, or
cosmetic procedures on the face within 6 months prior to
enrollment.
2. Use of depigmenting products within 2 months prior to
enrollment.
3. Use of any topical medications on the face for the
treatment of hyperpigmented lesions or other conditions,
or use of photosensitizing medication or procedures,
bleaching products on the face, UV light therapy, topical
prescription treatments, or topical tretinoin on the face
fewer than 30 days prior to the study entry.
4. Use of acitretin, isotretinoin, systemic retinoids, metho-
trexate, or photoallergic, phototoxic, or photo-sensitizing
drugs within 6 months prior to enrollment.
5. Facial microdermabrasion treatment within 6 weeks
prior to study entry.
6. Known allergies to facial skin care products.
7. Pregnancy or nursing or planning to become pregnant
during the study according to subject self-report,
including those who are not using an acceptable
method of contraception throughout the study.
8. History of skin cancer.
9. A health condition and/or pre-existing or dormant
dermatologic disease on the face (e.g., psoriasis, rosacea,
acne, eczema, seborrheic dermatitis, severe excoriations)
that the investigator deems inappropriate for participation
or could interfere with the outcome of the study.
10. History of immunosuppression/immune deficiency dis-
orders, including HIV infection or acquired immune
deficiency syndrome, or currently using immunosup-
pressive medications (e.g., azathioprine, belimumab,
cyclophosphamide, Enbrel, Imuran, Humira, myco-
phenolate mofetil, methotrexate, prednisone, Remi-
cade, Stelara) and/or radiation as determined by study
documentation.
11. Uncontrolled disease such as asthma, diabetes, hyper-
tension, hyperthyroidism, or hypothyroidism. Individuals
having multiple health conditions may be excluded from
participation even if the conditions are controlled by diet
or medication.
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 C Arrowitz et al.
Efficacy/Safety of Thiamidol to Treat Melasma
12. Start of hormone replacement therapies or hormones for
birth control fewer than 3 months prior to study entry.
13. Individuals with observable suntan, scars, nevi, excessive
hair, or other dermal conditions on the face that might
influence the test results in the opinion of the investigator.
Determination of local cutaneous tolerability
Tolerability evaluations were performed at baseline, week 4,
week 8, and week 12. Local cutaneous tolerability was
evaluated by assessing the signs and symptoms of erythema
and edema, and by subject reporting of the degree of
burning, stinging, itching, and tingling separately on the right
and left side of the face (treatment area).
The following static (without reference to any prior visits)
scales and definitions were used for tolerability evaluations
(with half-point scores used as necessary to better describe
the clinical condition):
Erythema
0 ¼ None: No erythema of the treatment area
1 ¼ Mild: Slight, but definite redness of the treatment area
2 ¼ Moderate: Definite redness of the treatment area
3 ¼ Severe: Marked redness of the treatment area
Edema
0 ¼ None: No edema/swelling of the treatment area
1 ¼ Mild: Slight, but definite edema of the treatment area
2 ¼ Moderate: Definite edema of the treatment area
3 ¼ Severe: Marked edema of the treatment area
Burning
0 ¼ None: No burning of the treatment area
1 ¼ Mild: Slight burning sensation of the treatment area;
not really bothersome
1698.e2 Journal of Investigative Dermatology (2019), Volume 139
2 ¼ Moderate: Definite warm, burning of the treatment
area that is somewhat bothersome
3 ¼ Severe: Hot burning sensation of the treatment area
that causes definite discomfort and may interrupt daily ac-
tivities and/or sleep
Stinging
0 ¼ None: No stinging of the treatment area
1 ¼ Mild: Slight stinging sensation of the treatment area;
not really bothersome
2 ¼ Moderate: Definite stinging of the treatment area that
is somewhat bothersome
3 ¼ Severe: Marked stinging sensation of the treatment
area that causes definite discomfort and may interrupt daily
activities and/or sleep
Itching
0 ¼ None: No itching of the treatment area
1 ¼ Mild: Slight itching sensation of the treatment area; not
really bothersome
2 ¼ Moderate: Definite itching of the treatment area that is
somewhat bothersome
3 ¼ Severe: Marked itching sensation of the treatment area
that causes definite discomfort and may interrupt daily ac-
tivities and/or sleep
Tingling
0 ¼ None: No skin tingling sensation of the treatment area
1 ¼ Mild: Slight, but definite tingling sensation of the
treatment area
2 ¼ Moderate: Definite tingling sensation of the treatment
area that is somewhat bothersome
3 ¼ Severe: Marked tingling sensation of the treatment area
that causes definite discomfort
 C Arrowitz et al.
Efficacy/Safety of Thiamidol to Treat Melasma

Assessed for eligibility

(n = 150)

Excluded (n = 70)
• Not meeƟng inclusion
criteria (n = 66)
• Other reasons (n = 4)

Randomized (n = 80)

Allocated to Cell A Allocated to Cell B

0.2% Thiamidol vs. control 0.2% Thiamidol vs. 2% hydroquinone
(split face design) (split face design)
(n = 38) (n = 42)

DisconƟnued (n =7): DisconƟnued (n =14):

• Requested a withdrawal (n = 1) • Requested a withdrawal (n = 5)
• Non-compliant (n = 0) • Non-compliant (n = 1)
• Lost to follow-up (n = 6) • Lost to follow-up (n = 8)

Completed (n= 31) Completed (n= 28)

Supplementary Figure S1. Consolidated Standards of Reporting Trials (CONSORT) flow diagram.

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 C Arrowitz et al.
Efficacy/Safety of Thiamidol to Treat Melasma

Supplementary Table S1. Tolerability results for cell A (Thiamidol versus untreated)
Parameter Treatment Time Point n Mean SD Minimum Median Maximum

Erythema Thiamidol Baseline 31 0.03 0.12 0.00 0.00 0.50

wk 4 31 0.03 0.12 0.00 0.00 0.50
wk 8 31 0.08 0.26 0.00 0.00 1.00
wk 12 31 0.02 0.09 0.00 0.00 0.50
Untreated Baseline 31 0.06 0.21 0.00 0.00 1.00
wk 4 31 0.05 0.15 0.00 0.00 0.50
wk 8 31 0.08 0.26 0.00 0.00 1.00
wk 12 31 0.02 0.09 0.00 0.00 0.50
Edema Thiamidol Baseline 31 0.00 0.00 0.00 0.00 0.00
wk 4 31 0.00 0.00 0.00 0.00 0.00
wk 8 31 0.00 0.00 0.00 0.00 0.00
wk 12 31 0.00 0.00 0.00 0.00 0.00
Untreated Baseline 31 0.00 0.00 0.00 0.00 0.00
wk 4 31 0.00 0.00 0.00 0.00 0.00
wk 8 31 0.00 0.00 0.00 0.00 0.00
wk 12 31 0.00 0.00 0.00 0.00 0.00
Burning Thiamidol Baseline 31 0.00 0.00 0.00 0.00 0.00
wk 4 31 0.00 0.00 0.00 0.00 0.00
wk 8 31 0.00 0.00 0.00 0.00 0.00
wk 12 31 0.00 0.00 0.00 0.00 0.00
Untreated Baseline 31 0.00 0.00 0.00 0.00 0.00
wk 4 31 0.00 0.00 0.00 0.00 0.00
wk 8 31 0.00 0.00 0.00 0.00 0.00
wk 12 31 0.00 0.00 0.00 0.00 0.00
Stinging Thiamidol Baseline 31 0.00 0.00 0.00 0.00 0.00
wk 4 31 0.00 0.00 0.00 0.00 0.00
wk 8 31 0.00 0.00 0.00 0.00 0.00
wk 12 31 0.00 0.00 0.00 0.00 0.00
Untreated Baseline 31 0.00 0.00 0.00 0.00 0.00
wk 4 31 0.00 0.00 0.00 0.00 0.00
wk 8 31 0.00 0.00 0.00 0.00 0.00
wk 12 31 0.00 0.00 0.00 0.00 0.00
Itching Thiamidol Baseline 31 0.00 0.00 0.00 0.00 0.00
wk 4 31 0.00 0.00 0.00 0.00 0.00
wk 8 31 0.00 0.00 0.00 0.00 0.00
wk 12 31 0.00 0.00 0.00 0.00 0.00
Untreated Baseline 31 0.00 0.00 0.00 0.00 0.00
wk 4 31 0.00 0.00 0.00 0.00 0.00
wk 8 31 0.00 0.00 0.00 0.00 0.00
wk 12 31 0.00 0.00 0.00 0.00 0.00
Tingling Thiamidol Baseline 31 0.00 0.00 0.00 0.00 0.00
wk 4 31 0.00 0.00 0.00 0.00 0.00
wk 8 31 0.00 0.00 0.00 0.00 0.00
wk 12 31 0.00 0.00 0.00 0.00 0.00
Untreated Baseline 31 0.00 0.00 0.00 0.00 0.00
wk 4 31 0.00 0.00 0.00 0.00 0.00
wk 8 31 0.00 0.00 0.00 0.00 0.00
wk 12 31 0.00 0.00 0.00 0.00 0.00
Abbreviation: SD, standard deviation.

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Efficacy/Safety of Thiamidol to Treat Melasma

Supplementary Table S2. Tolerability results for cell B (Thiamidol versus hydroquinone)
Parameter Treatment Time Point n Mean SD Minimum Median Maximum

Erythema Thiamidol Baseline 28 0.07 0.18 0.00 0.00 0.50

wk 4 28 0.07 0.18 0.00 0.00 0.50
wk 8 28 0.13 0.29 0.00 0.00 1.00
wk 12 28 0.09 0.20 0.00 0.00 0.50
Hydroquinone Baseline 28 0.07 0.18 0.00 0.00 0.50
wk 4 28 0.13 0.29 0.00 0.00 1.00
wk 8 28 0.11 0.25 0.00 0.00 1.00
wk 12 28 0.09 0.24 0.00 0.00 1.00
Edema Thiamidol Baseline 28 0.00 0.00 0.00 0.00 0.00
wk 4 28 0.00 0.00 0.00 0.00 0.00
wk 8 28 0.00 0.00 0.00 0.00 0.00
wk 12 28 0.00 0.00 0.00 0.00 0.00
Hydroquinone Baseline 28 0.00 0.00 0.00 0.00 0.00
wk 4 28 0.00 0.00 0.00 0.00 0.00
wk 8 28 0.00 0.00 0.00 0.00 0.00
wk 12 28 0.00 0.00 0.00 0.00 0.00
Burning Thiamidol Baseline 28 0.00 0.00 0.00 0.00 0.00
wk 4 28 0.00 0.00 0.00 0.00 0.00
wk 8 28 0.00 0.00 0.00 0.00 0.00
wk 12 28 0.00 0.00 0.00 0.00 0.00
Hydroquinone Baseline 28 0.00 0.00 0.00 0.00 0.00
wk 4 28 0.00 0.00 0.00 0.00 0.00
wk 8 28 0.00 0.00 0.00 0.00 0.00
wk 12 28 0.00 0.00 0.00 0.00 0.00
Stinging Thiamidol Baseline 28 0.00 0.00 0.00 0.00 0.00
wk 4 28 0.00 0.00 0.00 0.00 0.00
wk 8 28 0.00 0.00 0.00 0.00 0.00
wk 12 28 0.00 0.00 0.00 0.00 0.00
Hydroquinone Baseline 28 0.00 0.00 0.00 0.00 0.00
wk 4 28 0.00 0.00 0.00 0.00 0.00
wk 8 28 0.00 0.00 0.00 0.00 0.00
wk 12 28 0.00 0.00 0.00 0.00 0.00
Itching Thiamidol Baseline 28 0.00 0.00 0.00 0.00 0.00
wk 4 28 0.02 0.09 0.00 0.00 0.50
wk 8 28 0.04 0.19 0.00 0.00 1.00
wk 12 28 0.00 0.00 0.00 0.00 0.00
Hydroquinone Baseline 28 0.00 0.00 0.00 0.00 0.00
wk 4 28 0.00 0.00 0.00 0.00 0.00
wk 8 28 0.04 0.19 0.00 0.00 1.00
wk 12 28 0.00 0.00 0.00 0.00 0.00
Tingling Thiamidol Baseline 28 0.00 0.00 0.00 0.00 0.00
wk 4 28 0.00 0.00 0.00 0.00 0.00
wk 8 28 0.00 0.00 0.00 0.00 0.00
wk 12 28 0.00 0.00 0.00 0.00 0.00
Hydroquinone Baseline 28 0.00 0.00 0.00 0.00 0.00
wk 4 28 0.00 0.00 0.00 0.00 0.00
wk 8 28 0.00 0.00 0.00 0.00 0.00
wk 12 28 0.00 0.00 0.00 0.00 0.00
Abbreviation: SD, standard deviation.

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 C Arrowitz et al.
Efficacy/Safety of Thiamidol to Treat Melasma

Supplementary Table S3. Image analysis of photographs for skin brightness (L*)
t Test (P-Values)

Treatment Time Point n Mean L* DL*, Mean – SD Comparison to Baseline Comparison to Control

Cell A
Thiamidol Baseline 31 60.95 — — —
4 wk 31 61.96 1.01  1.62 0.0051 0.0112
8 wk 31 61.80 0.85  2.31 0.0491 0.118
12 wk 31 61.91 0.96  2.26 0.0491 0.0112
Control Baseline 31 61.69 — — —
4 wk 31 62.02 0.33  1.48 0.687 —
8 wk 31 61.96 0.26  2.23 0.824 —
12 wk 31 61.47 e0.23  1.52 0.824 —
t test (P-values)

Treatment Time Point n Mean L* DL*, mean – SD Comparison to baseline Comparison to Hydroquinone

Cell B
Thiamidol Baseline 28 62.09 — — —
4 wk 28 62.95 0.87  1.66 0.0311 0.161
8 wk 28 63.31 1.22  2.48 0.0311 0.064
12 wk 28 62.66 0.57  2.56 0.251 0.161
Hydroquinone Baseline 28 62.83 — — —
4 wk 28 63.26 0.43  1.65 0.543 —
8 wk 28 63.32 0.48  2.24 0.543 —
12 wk 28 62.94 0.10  1.87 0.770 —
1
Significant P-values calculated from paired t test with Bonferroni-Holm P-value adjustment for multiple testing. Testing hypothesis is that the mean change
from baseline is equal to zero.
2
Significant P-values calculated from paired t test with Bonferroni-Holm P-value adjustment for multiple testing. Testing hypothesis is that the mean change
from baseline is equal between treatments.

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