http://informahealthcare.com/jdt ISSN: 0954-6634 (print), 1471-1753 (electronic) J Dermatolog Treat, Early Online: 1–11 ! 2015 Informa UK Ltd. DOI: 10.3109/09546634.2014.998609

REVIEW ARTICLE

Pitfalls in clinical trials reveal need for well tolerated, more effective depigmenting agents S. Saxena, R. M. Andersen, and H. I. Maibach

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Department of Dermatology, UCSF, San Francisco, CA, USA

Abstract

Keywords

Objective: Examine clinical trials performed for depigmenting agents in order to determine the most effective and well-tolerated depigmenting agent. Methods: We searched clinical trials, published and unpublished, performed for hydroquinone, ascorbic acid, azelaic acid, retinol and niacinamide in the period 2009 till present. Studies were examined based on participant information, design, duration, intervention, outcome measurements and statistical significance. Results: Sixty-one studies were examined, 40 published and 21 unpublished. Design, outcome measures and intervention showed sources of bias were not avoided. Only 30% of published trials were double-blind, 27% used a placebo and 80% used subjective measurements for their results. Unpublished trials follow similar outcomes, however, did not provide any significant results. Conclusion: Based on these results, we are unable to recommend a safer, more effective depigmenting agent. Lack of thorough trials limits us from accepting depigmenting agent full evaluation. To accept a depigmenting agent, its duration must test for long-term safety, clinical trial must be double-blind and comparative, use participants of the correct skin type and measure outcomes objectively. In addition, lack of results for parallel unpublished studies leaves room for discussion. Efforts toward creating more effective formulations are welcomed.

Clinical trial, efficacy, hyperpigmentation, hydroquinone, safety

Introduction Hyperpigmentation is a disorder resulting from an overproduction of melanin in skin. Common disorders of hyperpigmentation include, but not limited to, postinflammatory hyperpigmentation (PIH) and melasma (1). PIH typically results from inflammation, e.g. caused by acne or skin injury, and has been shown to be a larger issue for Fitzpatrick skin types IV–VI (2). Because darker skin has a tendency to become much more pigmented than lighter phototypes, which tend to inflame but leave no tan, hyperpigmentation is an issue of higher Fitzpatrick skin types (3). Melasma is characterized by patches of discoloration, typically on the face, as a result of hormonal changes such as pregnancy, oral contraceptives or sun exposure (4). While laser treatment, chemical peels and systemic therapy are treatments for hyperpigmentation, topical depigmenting agents remain a popular option. Hydroquinone is the most used, and so far, effective depigmenting agent available. Use of hydroquinone as a depigmenting agent began in the late 1930s as its monobenzyl ether was discovered to depigment worker’s skin in a rubber factory (5). Over time, hydroquinone was combined with other drugs to improve efficacy. Kligman et al. created Kligman’s formula, consisting of 0.1% tretinoin, 5% hydroquinone and 0.1% dexamethasone as a more effect agent for depigmenting skin (6). An issue, however, is hydroquinone’s safety. In 2001, the European Union banned hydroquinone due to harmful side effects such as exogenous ochronosis, luekoderma en confetti and the

History Received 5 September 2014 Accepted 3 November 2014 Published online 11 February 2015

possibility of carcinogenity (7). In response to hydroquinone’s toxicity, companies are creating natural depigmenting agents such as kojic acid, licorice extract, niacinamide, azelaic acid, etc. Here we review clinical studies of depigmenting agents to ascertain whether a safer, more effective depigmenting agent than hydroquinone exists. Assessing the quality of studies is a tool to approach efficacy of newer agents. Along with outcome, we compare study setup regarding study design, cohort size, skin type, duration, intervention, result measurements and statistical significance to examine unnecessary forms of bias. Case-control designs open themselves up to biases more than comparative studies (8). We document if comparative studies are doubleblinded and placebo controlled. This design provides more accurate results because double-blinded trials and placebo solutions mitigate against false positive results (9). To further investigate bias, we reviewed if studies measured results subjectively or objectively. Subjective measurements include investigator and participant evaluations. Objective measurements include those which quantified melanin content such as Melasma Area and Severity Index (MASI) score. KimbroughGreen et al. introduced MASI scoring, a calculation similar to the scoring system for psoriasis, which assigned a number to the severity of melasma by evaluating content of melasma, darkness and homogeneity of skin (10). By analyzing the design of recent studies on depigmenting agents, we assessed if an alternative to hydroquinone exists.

Methods Correspondence: Dr. R. M. Andersen, 90 Medical Center Way, Surge Bldg., Room 110, San Francisco, CA 94143-0989, USA. Tel: +1 415 696 9578. Fax: +1 415 673 3533. E-mail: [email protected]

Topical depigmentation agents studied are hydroquinone, ascorbic acid, niacinamide, kojic acid, licorice extract,

S. Saxena et al.

All products p50.001 compared to baseline

Group 1: Received peel and combination hydroquinone cream Group 2: Hydroquinone cream alone Each patient randomly received 2 products:

Investigator evaluation, standard digital

Yes, MASI scoring p50.05

Statistically significant hyperpigmentation scores (p  0.008) Group 1: Hydroquinonebased system Group 2: Hydroquinonebased

Melanin, erythema levels by spectrophotometer + Lentigines count, colour homogeneity and global improvement Investigator evaluation, participant self-evaluation, digital photography MASI scoring every six weeks Group 1: Received OD active intervention + sunscreen Group 2: Only sunscreen

Intervention

Measurement of results

Statistical significance of results

N-acetylglucosamine, azelaic acid and retinol and its derivatives (tretinoin, tazotarene, adapalene). For published studies we conducted a systematic literature search on MEDLINE using search strings of the depigmentation agents, e.g. ‘‘hydroquinone’’ and the term ‘‘clinical trial’’. Further studies were found by going through references. Unpublished trials were found via US National Institute of Health service on unpublished clinical trials: www.clinicaltrials.gov using similar search strings as used for the published studies, e.g. ‘‘hydroquinone’’ and ‘‘hyperpigmentation’’. Included clinical studies were limited to January 2009 till present (primo July 2014), writing in English, performed on humans with more than 10 participants. For the published trials, we documented following outcomes: number of participants, Fitzpatrick skin type, duration, design, if sunscreen was used, outcome measurements and significant results. Agents compared to hydroquinone or were included with hydroquinone in a combination treatment are included in the hydroquinone data table. For unpublished trials of depigmenting agents, we documented: status, number of participants, Fitzpatrick skin type, design, intervention and significant results.

p50.001 for less melanin count at the end point for intervention group

J Dermatolog Treat, Early Online: 1–11

Yes Double-blind, randomized, half-face 12 weeks Caucasian Safety and efficacy of three new brightening

Chaudary et al. (21)

Makino et al. (22)

68

Yes Non-randomized 24 Weeks, peel sessions every 3 weeks III–V 40

Yes Randomized, investigator-blinded 12 weeks I–IV

Efficacy study comparing Hydroquinone-based and hydroquinone-free in treating hyperpigmentation Treatment of melasma with regimen of triple combination cream and glycolic acid peel Fabi et al. (12)

36

Yes Prospective, randomized, controlled, investigatorblinded, singlecenter 2 weeks intervention, followed by cryotherapy 3 weeks pause and 2 weeks intervention II–IV 45

Study type Duration Phototype of patients Patients completed Study objective

Safety and efficacy of a triple combination cream (fluccinolone, hydroquinone, tretinoin) as adjuvant to cryotherapy of solar lentigines

Hydroquinone has been the longest, most used depigmenting agent to date. However, issues of safety arise with hydroquinone, making it a less viable option for treating hyperpigmentation.

Hexsel et al. (20)

Discussion

Study

Sixty-one studies were included, 40 published and 21 unpublished. Hydroquinone had 22 published (Table 1) and 12 unpublished studies (Table 2); asorbic acid had five published (Table 3) and two unpublished studies (Table 4); azelaic acid had one published (Table 5) and two unpublished studies (Table 6); retinol had seven published (Table 7) and two unpublished studies (Table 8); niacinamide had five published (Table 9) and two unpublished studies (Table 10). No studies without hydroquinone were performed for kojic acid, licorice extract and N-acetylglucosamine. Number of participants ranged from 10 to 207, with most studies containing fewer than 100 participants. All phototypes were tested. This is similar for unpublished trials. Duration of these trials ranged from 2 to 52 weeks, the most common length being 24 weeks. For unpublished trials, since many do not provide results or update frequently, duration is difficult to calculate. Three published trials for hydroquinone were double-blinded. Number of double-blinded trials for ascorbic acid, azelaic acid, retinol and its derivatives, and niacinamide were 2, 0, 2 and 5, respectively. For published trials on hydroquinone, ascorbic acid, azelaic acid, retinol and niacinamide there were 3, 3, 0, 1 and 4 placebo-controlled trials, respectively. With the exception of nine trials, all published trials used sunscreen in conjunction with treatment. Number of double-blinded unpublished trials for hydroquinone, ascorbic acid, azelaic acid, retinol and niacinamide were 7, 0, 0, 1 and 1, respectively. Sunscreen usage was not specified for the unpublished trials. In published trials, number outcome measurements that were investigator and/or patient evaluation for hydroquinone, ascorbic acid, azelaic acid, retinol and niacinamide were 18, 3, 1, 6 and 4, respectively. Based on outcome measurements hydroquinone, ascorbic acid, azelaic acid, retinol and niacinamide documented 19, 3, 1, 3 and 4 statistically significant results, respectively. No statistical significance was posted for unpublished trials, much less than any results.

Sunscreen Used?

Results

Table 1. Published clinical trials for hydroquinone.

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2

Efficacy of hydroquinone regimen for users of botulinum toxin type A

Evaluate the clinical efficacy and safety of belides, emblica, and licorice 7% compared to 2% hydroquinone in the treatment of melasma

Evaluate the efficacy of kojic acid, emblica extract, and glycolic acid compared with hydroquinone

Evaluate the efficacy of continuous therapy combined with a triple combination cream regimen for melasma

Evaluate the efficacy of topical niacinamide 4% compared to hydroquinone for melasma

Evaluate the efficacy of 4% Hydroquinone plus 0.05% tretinoin to treat melasma Evaluate the efficacy of kojic acid with hydroquinone compared to kojic acid

Schlessinger et al. (24)

Costa et al. (25)

Draelos et al. (26)

Grimes et al. (27)

Navarete-Solis et al. (28)

Gold et al. (29)

Deo et al. (30)

Treatment of photodamage with 4% hydroquinone/ 10% ascorbic acid

Bruce et al. (23)

formulations in comparison to 4% hydroquinone

80

37

27

Asian Indian patients

III–VI

IV–V

IV–V

Multiethnic

79

52

I–IV

Not provided

61

50

II–IV

30

12 weeks

24 weeks

8 weeks

24 weeks

12 weeks

60 days

120 days

12 weeks

Randomized, singleblinded

Multicenter, openlabel study

Double-blind, leftright randomized clinical trial

Non-randomized, open-label trial

Randomized, doubleblind

Non-randomized, single-blinded

Multicenter, randomized, investigator-masked

Non-randomized

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Participants received hydroquinone and tretinoin treatment Group 1: Kojic acid with 2% hydroquinone Group 2: Kojic acid with

Group 1: Triple combination cream with 4% HQ Group 2: Topical treatment, followed by 12 weeks continuous therapy Group 3: 12 week treatment, relapse, begin dosing again Put both treatments on either side of the face

Group 1: Kojic Acid, emblica extract, and glycolic acid Group 2: 4% Hydroquinone

Group 1: Cream of emblica, licorice, and belides Group 2: 2% HQ

Group 1: Active formulation (4% hydroquinone/0.05% tretinoin) Group 2: sunscreen use

Patients given hydroquinone and ascorbic acid regimen

4% HQ, BR1, BR2, BR3

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Participant evaluation, MASI scoring MASI scoring, digital photographs,

Investigator global assessment, photography, infrared thermography

Narrowband reflectance spectrophotometer, investigator global assessment, participant evaluation

Investigator and patient evaluation, dermospectrophotometer reading

Investigator and patient evaluation, standard digital photography

Investigator and participant evaluation

photography, Cromameter measurements every four weeks Investigator and participant evaluation every four weeks

(continued )

Statistically significant (HQ: p ¼ 0.003 and Niacinamide p ¼ 0.005) with no statistical difference between treatments Statistically significant depigmentation p  0.001 Statistical significance not mentioned

  0.05 considered statistically significant, but no p-value given Statistically significant p  0.05 for hyperpigmentation scores Statistically significant for lesion depigmentation for both groups (p50.001) with no difference between groups (p50.05) Statistically significant reduction of hyperpigmentation (p50.001) no statistical difference between groups Statistically significant results (p50.001) for Group 1 and Group 3

DOI: 10.3109/09546634.2014.998609

Pitfalls in clinical trials 3

Evaluate efficacy of zinc sulfate compared to hydroquinone for melasma

Evaluate efficacy of 20% azelaic acid compared to 4% hydroquinone Efficacy of copper zinc malonate complex plus hydroquinone and tretinoin in treating photodamage Efficacy of hydroquinone, tretinoin, and mometasome furoate with glycolic acid peels in treatment of melasma Efficacy of hydroquinone and tretinoin with intense pulsed light for treating hyperpigmentation

Iraji et al. (34)

Farshi (35)

Tirado-Sanchez et al. (39)

Woodhall et al. (38)

Godse (37)

Asian Indian patients

I–IV

10

35

III

III–IV

42

92

Middle Eastern

Middle Eastern

I–VI

III–IV

Asian Indian patients

Phototype of patients

29

55

52

20

60

Patients completed

12 weeks

90 days

6 weeks

24 weeks

8 weeks

24 weeks

12 weeks

24 weeks

12 weeks

Duration

Non-randomized

Observer masked, randomized, placebo-controlled

Non-randomized

Non-randomized

Non-randomized

Investigator-blinded, randomized

Randomized, singleblind

Non-randomized

Non-randomized

Study type

Not specified

Yes

Yes

Not specified

Yes

Yes

Yes

Yes

Yes

Sunscreen Used?

Group 1: 4% hydroquinone Group 2: 20% azelaic acid Participants received treatment of copper zinc malonate complex and 4% hydroquinone and tretinoin Participants received treatment of 4% hydroquinone, 0.05% tretinoin, and 0.1% mometasome furoate Group 1: 4% hydroquinone and 0.05% tretinoin with intense pulsed light Group 2: Placebo products Group 1: 1% dioic acid Group 2: 2% hydroquinone

Group 1: 10% zinc sulfate Group 2: 4% hydroquinone

Participants received treatment of 4% hydroquinone and 0.025% tretinoin Group 1: Ellagic acid and salicylic acid Group 2: 4% hydroquinone

0.1% betamethasone valerate Group 1: 4% hydroquinone Group 2: 0.75% kojic acid

Intervention

MASI scoring

Investigator and participant evaluation

Investigator evaluation

Investigator and participant evaluation

MASI scoring, investigator evaluation

MASI scoring, investigator and participant evaluations

Cromameter baseline measurements, global investigator evaluation

MASI scoring, participant evaluation

investigator and patient evaluation MASI scoring, color photography

Measurement of results

Statistically significant hyperpigmetation reduction p value for both

Statistically significant reduction in hyperpigmentation for both groups, p  0.05

No statistical significance reported

No statistically significant cromameter results for Group 1, but 4% hydroquinone had statistically significant results (p ¼ 0.006) No statistical difference between groups p ¼ 0.434. p values of individual solutions not provided Statistically significant MASI scores (p50.001) Statistically significant scores p  0.05

Statistically significant results (HQ: p50.001 and Kojic Acid p50.001) Statistically significant MASI score (p  0.001)

Statistical significance of results

S. Saxena et al.

Efficacy of dioic acid compared with hydroquinone in melasma treatment

Evaluate efficacy of product containing ellagic acid and salicylic acid compared to hydroquinone

Dahl et al. (33)

Leyden et al. (36)

Evaluate efficacy of hydroquinone and tretinoin to treat melasma

with betamethasone valerate Evaluate the efficacy of hydroquinone versus kojic acid in treatment of melasma

Study objective

Grimes et al. (32)

Monteiro et al. (31)

Study

Table 1. Continued

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4 J Dermatolog Treat, Early Online: 1–11

Evaluate clinical efficacy of hydroquinone compared versus chemical peeling with 30% tricholoroacetic acid versus laser therapy

March 2012

December 2013

June 2009

March 2014

January 2014

Terminated

Recruiting participants Unknown status

Recruiting participants Complete

Compare efficacy of a triple combination cream with laser and without

Evaluate efficacy of hydroquinone compared to miconazole

Evaluate efficacy of azelaic acid versus hydroquinone

Evaluate efficacy of hydroquinone for melasma

Evaluate efficacy salicylic acid peels and hydroquinone for melasma

Centre Hospitalier Universitare de Nice (43)

Castanedo-Cazares (44)

Callender Center for Clinical Research (45)

Mesoestetic Pharma Group S.L (46)

Pandya (47)

Hexsel (42)

January 2014

Evaluation of a herbalbased de-pigmenting system compared to hydroquinone

Sadick Research Group (41)

Completed

Last updated

Average 6 months

Evaluate efficacy of Triluma for solar lentigine treatment

Status

IV–V

May 2014

Objective

39

Recruiting participants

Study reviewer

Table 2. Unpublished clinical trials for hydroquinone.

Salem et al. (40)

20

20

30

30

20

50

28

Participants

Not provided

I-IV

All

III or more

V–VI

II–IV

Phototype not provided

Participant phototype

Non-randomized

Design

Randomized, safety/efficacy, single group, investigator blind, treatment

Randomized, efficacy study, parallel assignment, open label, prevention Randomized, efficacy study, parallel assignment, single-blind, treatment Randomized, efficacy study, parallel assignment, double-blind, treatment Randomized, safety/efficacy study, single group assignment, double blind, treatment Randomized, safety/efficacy, parallel, doubleblind, treatment

Intervention

Investigator evaluations, MASI scoring

One-side pulsed dye treatment, full face triple combination cream Group 1: 2% Miconazole Group 2: 4% Hydroquinone Group 1: 15% Azelaic acid Group 2: 4% Hydroquinone Group 1: 4% Hydroquinone Group 2: Placebo products Salicylic acid peel, followed by 4% hydroquinone cream

Group 1: Herbal depigmenting agent Group 2: 4% Hydroquinone Triluma cream

Group 1: 4% hydroquinone for 6 months Group 2: Chemical peeling 12 times, 2 weeks between every study Group 3: YAG-laser, does not say how many treatments

Non-randomized, efficacy study, single group assignment, double blind, treatment

Yes

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No statistical significance of results posted

No results posted

No results posted

No results posted

No results posted

No results posted

No results posted

Statistical significance

dioic acid and hydroquinone is 0.001 Hydroquinonegroup significant improvement (p50.001) than the two other groups

DOI: 10.3109/09546634.2014.998609

Pitfalls in clinical trials 5

IV–V

III–V

Japanese

III–V

Asian

35

14

60

80

Phototype

14

Number of patients

Englewood Hospital and Medical Center (53)

National University Hospital, Singapore (52)

Evaluate the efficacy of a glycolic acid peel and vitamin C for PIH Evaluate efficacy for vitamin C peel for PIH

Objective

10

15

June 2014

Not open for participant recruitment

Participants

N/A

Last updated

III–VI

I–IV

Design

Group 1: 10% ascorbic acid glucoside Group 2: 10% sodium ascorbate (placebo) Group 1: Oral procyanidin with vitamins A, C, and E Group 2: Placebo products Group 1: Silicon gel and vitamin C Group 2: Placebo products

Participants received 70% glycolic acid peel on one side and vitamin C iontophoresis on other side of face Participants received full face iontophoresis mask and a mandelic/malic acid skin care regimen

Intervention

Efficacy study, single group assignment, open-label, treatment

Safety and efficacy study, single-group assignment, open-label, treatment

Not specified

Yes

Not specified

Yes

Yes

Participant phototype

Randomized, not disclosed whether single- or doubleblind

Ranomized, double-blind, placebo-controlled

Split-face, double-blind

Non-randomized

Not open for participant recruitment

Status

24 weeks

8 weeks

24 weeks

1–2 months

Single-blind, left-right comparison

Design

Sunscreen used?

Statistical significance not reported

Results not statistically significant

Statistically significant results (p50.0001)

Investigator evaluation, standard digital photography, MASI score

Digital photography and brightness analysis

Mexameter, MASI scoring, patient and investigator evaluation Vancouver scar scale, spectrophotometer

No results posted

No results posted Chemical peel, microneedling, and retinol/vitamin C cream

Statistical significance 70% glycolic acid peel and vitamin C cream

Intervention

Significant MASI scores (p50.001) for both groups

MASI scores, digital photography, investigator evaluation

Statistically significant (p ¼ 0.045)

Statistical significance of results

Measurement of results

S. Saxena et al.

Study

Duration Only says six sessions

Table 4. Unpublished clinical trials for ascorbic acid as a depigmenting agent.

Yun et al. (14)

Handog et al. (51)

Evaluate efficacy of oral procyanidin with vitamins A, C, and E for melasma treatment Evaluate scar treatment with use of silicon gel and vitamin C

Efficacy of vitamin C iontophoresis mask and a mandelic/malic acid skin care regimen to treat melasma and postinflammatory hyperpigmentation Evaluate the efficacy of vitamin C on dark circles of lower eyelids

Taylor et al. (49)

Ohshima et al. (50)

Efficacy and safety of vitamin C iontophoresis versus glycolic acid peel

Objective

Sobhi et al. (48)

Study

Table 3. Published clinical trials of asorbic acid.

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Pitfalls in clinical trials

Group 1: Iontophoresis, 15% azelaic acid Group 2: 20% Azelaic acid

Significance not posted No results posted 15% Azelaic acid

July 2012 Unknown

70

III–V

Safety and efficacy study, single group, open label, treatment Randomized, safety and efficacy study, parallel assignment, single blind, treatment IV–VI 20 August 2012 Completed

Medical University of Vienna (56)

Evaluate efficacy of Finacea for PIH Evaluate efficacy of azelaic acid iontophoresis versus topical azelaic acid for melasma Kircik (55)

Design Participant phototype Participants Last updated Study status Objective Study

Table 6. Unpublished clinical trials for azelaic acid as a depigmenting agent.

Statistical significance

Statistical significance Intervention

Investigator evaluation Participants received 15% azelaic acid gel Not specified Non-randomized IV–VI Kircik (54)

Evaluation of efficacy and safety of azelaic acid in treatment of PIH and acne

20

16 weeks

Measurement of results Intervention Participant phototype Participants completed Objective Study

Table 5. Published clinical trials azelaic acid.

Duration

Design

Sunscreen used?

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Statistically significant (p ¼ 0.0039)

DOI: 10.3109/09546634.2014.998609

7

Although we recognize difficulty in constructing a perfect clinical trial, studies should avoid sources of unnecessary bias. Much bias comes from individual self-assessment or investigator evaluation (11). Eighteen of the 22 published trials for hydroquinone used subjective evaluation to document results. Since this method of result retrieval is inherently subjective (and should be avoided), investigators should rely on objective assessments such as a MASI score, chromameter measurements and spectroscopy. Even if reported in conjunction with objective measurements, subjective results still affect the statistical significance of the results and general report. For example, Fabi et al. showed that a hydroquinone-free system was as effective as a hydroquinonebased system (12). However, results were evaluations rather than objective measurements. Statistical significance is influenced only by biased measurements. Double-blinded trials mitigate bias because neither investigators nor participants know treatments they are receiving. Overall only 30% of trials were double-blinded. Within published doubleblinded trials, however, other areas were lacking. CastanedoCazares et al. conducted a double-blinded experiment to test efficacy of niacinamide and desonide for hyperpigmentation, however, only measured results through colorimetric and clinical evaluation (13). While the results were statistically significant, the results were also subjective in nature, making clinicians unable to determine the true efficacy of the drug. Another means to assess efficacy is through using a placebo. In addition to facilitating a double-blind trial, this design could highlight another aspect of the disorder: whether hyperpigmentation sometimes can cure itself. This is indispensable information to a patient, who may not have to risk treatment for curing this disease. Twenty-seven percent of the trials contained a placebo, however, other flaws were present. For example, even though Yun et al. did use placebo products, the trial was not doubleblinded, making the statistically significant results less valid (14). While use of sunscreen does not necessarily attribute to bias, sunscreen has been shown to improve hyperpigmentation on its own (15). Woodhall et al. showed through a placebo-controlled trial, sunscreen provides a statistically significant reduction of hyperpigmentation (16). Using sunscreen in conjunction with treatment is beneficial to participants suffering from hyperpigmentation, but this practice does not improve investigator’s understanding of a depigmenting agent’s or even sunscreen’s potency. Investigators can mitigate discrepancies of results with the use of sunscreen by comparing just sunscreen use to active formulations. Hyperpigmentation treatment might benefit from greater than 24 week studies given the nature of disorder is that conditions such as melasma or post-inflammatory inflammation are recurring. Since the majority of trials were 24 weeks, we cannot say if it is enough time to make a medical or safety claim. Longer trials would provide more information on an agent’s safety. Since toxicity of hydroquinone has been shown, we do not know if other agents that inhibit melanogenesis such as ascorbic acid, azelaic acid, retinol and niacinamide are toxic (17). In addition to impacting a physician’s treatment, patients can decide whether the cost of a treatment is worth its reward. Hyperpigmentation is known to be of greater cosmetic concern to people of higher Fitzpatrick skin types because melanocytes in black skin are more active and more able to produce melanin by a factor of 10 in comparison to white skin (18). Overall, the published trials did test on skin of color, but did not end up testing on phototypes greater than V, which struggle the most with hyperpigmentation. Makino et al. performed a double-blinded, randomized trial for brightening formulations, but used Caucasian skin, which does not tend to have a large issue with hyperpigmentation (19). Even though the trial had objective measurements

Evaluate efficacy of tri-retinol versus tretinoin for photodamage

Evaluate efficacy of adapalene compared to ketoconazole cream in pityriasis versicolor Evaluate efficacy of tretinoin for reduction of photodamage

Evaluate efficacy of tricholoacetic acid versus glycolic acid chemical peels for melasma

Evaluate efficacy of tretinoin chemical peel in melasma treatment

Evaluate efficacy and safety of clindamycin phosphate and tretinoin for treatment of acne and PIH

Ho et al. (58)

Shi et al. (59)

Kumari (61)

Ghersetich et al. (62)

Callender et al. (63)

Wanner (65)

Callender Center for Clinical Research (64)

Study

Evaluate efficacy of tretinoin and clindamycin for PIH Evaluate efficacy of Nu Skin product for hyperpigmentation

Objective

May 2012

12 weeks

Completed

IV–VI

33

12 weeks

May 2010

II–VI

20

2 weeks

80

30

Participants

Design

Intervention

No results posted

No results posted

Statistical significance of results

Statistically significant results from baseline (p ¼ 0.05)

Not reported

Statistically insignificant results

MASI scoring, color photography

Standard digital photograpy, MASI scoring, investigator evaluation Lesion count, PIH severity scale, participant and investigator evaluation

Statistically significant (p50.0005)

Not statistically significant

p value not provided

Statistically significant (p50.001)

Statistical significance of results

Investigator and participation evaluation

Standard digital photography, participant and investigator evaluation Investigator and participant evaluation, digital photography Investigator and participant evaluation

Measurement of results

1.2% Clindamycin phosphate and 0.025% tretinoin Nu Skin product (0.05% tretinoin)

Group 1: 1.2% clindamycin phosphate and 0.025% tretinoin Group 2: Placebo products

Group 1: (20-35%) glycolic acid chemical peel Group 2: (10-20%) tricholoroacetic acid All received 10% tretinoin mask

Received 0.02% tretinoin

Group 1: 1.1% triretinol Group 2: 0.025% tretinoin Group 1: Adapalene Group 2: 2% ketoconazole cream

Participants received treatment of tretinoin product

Intervention

Randomized, safety and efficacy study, double blind, treatment Randomized, efficacy study, parallel, singleblind, treatment

SPF 30

Not specified

SPF 15

SPF 15 +

Not specified

SPF 30

Not provided

IV–VI

Sunscreen used? Yes

Participant photoype

Randomized, double-blind, placebo-controlled

Non-randomized

Non-randomized

Single-center, open-label

52 weeks

Unknown

Not specified, although majority Caucasian Asian Indian

12

Randomized, controlled

Single-center, double-blind

Open-label, singlecenter clinical study

Design

2 weeks

Last updated

Han people

67

12 weeks

12 weeks

Duration

Study status

Not provided

34

40

II–IV

Participant phototype

21

Participants completed

S. Saxena et al.

Table 8. Unpublished clinical trials for retinol and its derivatives.

Kircik (60)

Evaluate tolerability and efficacy of hydroquinone-free skin lightening system

Objective

Herndon et al. (57)

Study

Table 7. Published clinical trials for retinol and its derivatives.

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8 J Dermatolog Treat, Early Online: 1–11

Evaluate efficacy of N-undecyl-10-enoylL-phenylalainan and niacinamide in hyperpigmentation

III–V

Asian Indians 10 week

24

207

Evaluate efficacy of niacinamide and desonide for hyperpigmentation

Evaluate efficacy of imiquiod cream and tazarotene cream for lentigo maligna

University of Utah (71)

Objective

Castanedo-Cazares (70)

Study

Last updated November 2012

July 2013

Study status Completed

Completed

(i) Japanese 10 weeks (ii) Caucasian (2 weeks washout + 8 week treatment)

9 weeks

8 weeks

Korean

42

(i) 79 (ii) 147

Design

90

23

Participant information

Not provided

Randomized, efficacy, parallel assignment, open label, treatment

Randomized, efficacy, parallel assignment, doubleblind, treatment

Design

No results posted

No significance provided

Group 1: Imiquiod cream Group 2: 0.1% tazarotene

Statistical significance Group 1: 4% Niacinamide Group 2: 0.05% desonide Group 3: Placebo products

Intervention

(i) Statistically significant Group 1: p ¼ 0.02 Group 2: p50.003 (ii) Statistically significant Group 1: p ¼ 0.05 Group 2: p ¼ 0.003

Statistical significance not disclosed

Statistically significant for Group 1 (p ¼ 0.002)

Statistically significant for Group 1 (p50.05)

Statistically significant niacinamide and NAG (p ¼ 0.041)

Group 1: 4% niacinamide, 2% NAG Group 2: Placebo products

Standard digital photography, investigator evaluations, melanin-specific imaging and analysis Investigator evaluYes Group 1: 2% niacinaations, mexamide, 2% tranexamic meter, acid chromameter Group 2: Placebo products Colorimetric and Not Group 1: 4% niacinaclinical specified mide, 0.05% desoevaluation nide Group 2: Placebo products Yes Group 1: Facial lotion Investigator evaluation with 4% niacinamide, 0.5% panthenol, 0.5% tocophenyl acetate Group 2: Placebo products Not Group 1: 5% niacinaParticipant evaluspecified mide ation, standard Group 2: 5% niacinadigital photogmide and 1% Nraphy, color undecyl-10-enoyl-Lcalibration phenylalainan Yes

Statistical significance of results

Intervention

Measurement of results

Sunscreen used?

Not provided

Participant phototypes

Double-blind, randomized, left-right, split-face clinical studies

Randomized, doubleblind

Randomized, doubleblind, left-right axilla, placebo controlled

Randomized, doubleblind, vehicle controlled trial

Randomized, double10 weeks (2 week blind, vehicle-conconditioning period trolled, full-face, plus 8 week parallel-group clintreatment) ical study

Duration

Caucasian

Participant phototype

188

Participants completed

Table 10. Unpublished clinical trials for niacinamide.

Bissett et al. (69)

Jerajani et al. (68) Evaluate efficacy of facial lotion containing vitamins B3 and E

Evaluate efficacy of niacinamide and tranexamic acid in reducing hyperpigmentation Castanedo-Cazares Evaluate efficacy of et al. (13) niacinamide and desonide for hyperpigmentation

Evaluate the efficacy of niacinamide and Nacetylglucosamine (NAG) in treating hyperpigmentation

Kimball et al. (66)

Lee et al. (67)

Objective

Study name

Table 9. Published clinical trials for niacinamide.

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DOI: 10.3109/09546634.2014.998609

Pitfalls in clinical trials 9

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10

S. Saxena et al.

and avoided bias through randomization, the skin type tested is known to not suffer severely from hyperpigmentation disorders. Even though targeted phototypes were tested, other aspects of a conclusive clinical study were not included. Unpublished trials followed similar methods concerning design, phototypes and intervention. However, no statistically significant results were published, or any results at all. Even though there is not enough information to make a conclusion on efficacy of those products, room for discussion exists. Overall, we see trial methods support tangible results rather than efficacy and tolerance. Lack of a well-done trial invariably yields inaccurate results. Despite numerous trials, we know little about newer depigmenting agent’s safety and efficacy. Until a trial is double-blind, long-term, performed on proper phototypes, placebo-controlled and objectively measured, we cannot recommend these agents for hyperpigmentation treatment. Intensified action for a safer, more effective formulation than hydroquinone is welcomed. Such a formulation is non-irritating, safe to use over time and effectively clears hyperpigmentation in comparison to hydroquinone and placebo products.

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18. 19.

20.

21. 22. 23. 24.

Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.

25.

References

26.

1. Baumann L, Rodriguez D, Taylor SC, Wu J. Natural considerations for skin of color. Cutis. 2006;78:2–19. 2. Davis EC, Callender VD. Postinflammatory hyperpigmentation: a review of the epidemiology, clinical features, and treatment options in skin of color. J Clin Aesthet Dermatol. 2010;3:20–31. 3. Fitzpatrick TB. The validity and practicality of sun-reactive skin types I through VI. Arch Dermatol. 1988;124:869–71. 4. Pathak MA, Fitzpatrick TB, Kraus EW. Usefulness of retinoic acid in the treatment of melasma. J Am Acad Dermatol. 1986;15:894–9. 5. Engasser PG, Maibach HI. Cosmetics and dermatology: bleaching creams. J Am Acad Dermatol. 1981;5:143–7. 6. Kligman AM. A new formula for depigmenting human skin. Arch Dermatol. 1975;111:40–8. 7. Kooyers T, Westerhof W. Toxicology and health risks of hydroquinone in skin lightening formulations. J Eur Acad Dermatol Venereol. 2005;20:777–80. 8. Schulz KF, Grimes DA. Case-control studies: research in reverse. Lancet. 2002;359:431–4. 9. Noseworthy JH, Ebers GC, Vandervoort MK, et al. The impact of blinding on the results of a randomized, placebo-controlled multiple sclerosis clinical trial. Neurology. 1994;44:16–16. 10. Kimbrough-Green CK. Topical retinoic acid (tretinoin) for melasma in black patients. Arch Dermatol. 1994;130:727. 11. Pronin E, Lin DY, Ross L. The bias blind spot: perceptions of bias in self versus others. Personal Soc Psychol Bull. 2002;28:369–81. 12. Fabi SG, Goldman MP. Comparative study of hydroquinone-free and hydroquinone-based hyperpigmentation regimens in treating facial hyperpigmentation and photoaging. J Drugs Dermatol. 2013;12: S32–7. 13. Castanedo-Cazares JP, La´rraga-Pin˜ones G, Ehnis-Pe´rez A, et al. Topical niacinamide 4% and desonide 0.05% for treatment of axillary hyperpigmentation: a randomized, double-blind, placebocontrolled study. Clin Cosmet Investig Dermatol. 2013;6:29–36. 14. Yun IS, Yoo H-S, Kim YO, Rah DK. Improved scar appearance with combined use of silicone gel and vitamin C for Asian patients: a comparative case series. Aesthetic Plast Surg. 2013;37:1176–81. 15. Va´zquez M, Sa´nchez JL. The efficacy of a broad-spectrum sunscreen in the treatment of melasma. Cutis. 1983;32:92, 95–6. 16. Woodhall KE, Goldman MP, Gold MH, Biron J. Benefits of using a hydroquinone/tretinoin skin care system in patients undergoing intense pulsed light therapy for photorejuvenation: a placebocontrolled study. J Drugs Dermatol. 2009;8:862–7. 17. Zhai H, Maibach HI. Skin-whitening agents. In Paye M, Barel AO, Maibach HI eds. Handbook of Cosmetic Science and Technology, 3rd ed. Chapter 57. London, UK: Informa Healthcare, 2009.

27. 28.

29.

30.

31. 32. 33.

34. 35. 36. 37. 38.

39.

p 587–96. Available from http://informahealthcare.com/doi/abs/ 10.3109/9781420069686.057. Accessed July 17, 2014. Valverde P. The Asp84Glu variant of the melanocortin 1 receptor (MC1R) is associated with melanoma. Hum Mol Genet. 1996;5: 1663–6. Makino ETT, Mehta RCC, Banga A, et al. Evaluation of a hydroquinone-free skin brightening product using in vitro inhibition of melanogenesis and clinical reduction of ultraviolet-induced hyperpigmentation. J Drugs Dermatol. 2013;12:s16–20. Hexsel D, Hexsel C, Porto MD, Siega C. Triple combination as adjuvant to cryotherapy in the treatment of solar lentigines: investigator-blinded, randomized clinical trial. J Eur Acad Dermatol Venereol. 2014. [Epub ahead of print]. doi:10.1111/jdv.12484. Chaudhary S, Dayal S. Efficacy of combination of glycolic acid peeling with topical regimen in treatment of melasma. J Drugs Dermatol. 2013;12:1149–53. Makino ET, Mehta RC, Garruto J, et al. Clinical efficacy and safety of a multimodality skin brightener composition compared with 4% hydroquinone. J Drugs Dermatol. 2013;12:s21–6. Bruce S, Watson J. Evaluation of a prescription strength 4% hydroquinone/10% L-ascorbic acid treatment system for normal to oily skin. J Drugs Dermatol. 2011;10:1455–61. Schlessinger J, Kenkel J, Werschler P. Further enhancement of facial appearance with a hydroquinone skin care system plus tretinoin in patients previously treated with botulinum toxin Type A. Aesthet Surg J. 2011;31:529–39. Costa A, Moise´s TA, Cordero T, et al. Association of emblica, licorice and belides as an alternative to hydroquinone in the clinical treatment of melasma. An Bras Dermatol. 2010;85:613–20. Draelos ZD, Yatskayer M, Bhushan P, et al. Evaluation of a kojic acid, emblica extract, and glycolic acid formulation compared with hydroquinone 4% for skin lightening. Cutis. 2010;86:153–8. Grimes PE, Bhawan J, Guevara IL, et al. Continuous therapy followed by a maintenance therapy regimen with a triple combination cream for melasma. J Am Acad Dermatol. 2010;62:962–7. ´ lvarez B, et al. Navarrete-Solı´s J, Castanedo-Ca´zares JP, Torres-A A double-blind, randomized clinical trial of niacinamide 4% versus hydroquinone 4% in the treatment of melasma. Dermatol Res Pract. 2011;2011:1–5. Gold M, Rendon M, Dibernardo B, et al. Open-label treatment of moderate or marked melasma with a 4% hydroquinone skin care system plus 0.05% tretinoin cream. J Clin Aesthet Dermatol. 2013;6: 32–8. Deo KS, Dash KN, Sharma YK, et al. Kojic acid vis-a-vis its combinations with hydroquinone and betamethasone valerate in melasma: a randomized, single blind, comparative study of efficacy and safety. Indian J Dermatol. 2013;58:281–5. Monteiro RC, Kishore BN, Bhat RM, et al. A comparative study of the efficacy of 4% hydroquinone vs 0.75% kojic acid cream in the treatment of facial melasma. Indian J Dermatol. 2013;58:157. Grimes P, Watson J. Treating epidermal melasma with a 4% hydroquinone skin care system plus tretinoin cream 0.025%. Cutis. 2013;91:47–54. Dahl A, Yatskayer M, Raab S, Oresajo C. Tolerance and efficacy of a product containing ellagic and salicylic acids in reducing hyperpigmentation and dark spots in comparison with 4% hydroquinone. J Drugs Dermatol. 2013;12:52–8. Iraji F, Tagmirriahi N, Gavidnia K. Comparison between the efficacy of 10% zinc sulfate solution with 4% hydroquinone cream on improvement of melasma. Adv Biomed Res. 2012;1:39. Farshi S. Comparative study of therapeutic effects of 20% azelaic acid and hydroquinone 4% cream in the treatment of melasma. J Cosmet Dermatol. 2011;10:282–7. Leyden JJ, Parr L. Treating photodamage of the de´colletage area with a novel copper zinc malonate complex plus hydroquinone and tretinoin. J Drugs Dermatol. 2010;9:220–6. Godse KV. Triple combination of hydroquinone, tretinoin and mometasone furoate with glycolic acid peels in melasma. Indian J Dermatol. 2009;54:92–3. Woodhall KE, Goldman MP, Gold MH, Biron J. Benefits of using a hydroquinone/tretinoin skin care system in patients undergoing intense pulsed light therapy for photorejuvenation: a placebocontrolled study. J Drugs Dermatol. 2009;8:862–7. Tirado-Sa´nchez A, Santamarı´a-Roma´n A, Ponce-Olivera RM. Efficacy of dioic acid compared with hydroquinone in the treatment of melasma. Int J Dermatol. 2009;48:893–5.

J Dermatolog Treat Downloaded from informahealthcare.com by UMEA University Library on 04/04/15 For personal use only.

DOI: 10.3109/09546634.2014.998609

40. Salem A, Gamil H, Ramadan A, et al. Melasma: treatment evaluation. J Cosmet Laser Ther. 2009;11:146–50. 41. Sadick Research Group; Sadick Research Group. Evaluation of an herbal-based depigmenting system. In ClinicalTrials.gov [Internet]. Betheseda (MD): National Library of Medicine (US), 2000. Available from http://clinicaltrials.gov/ct2/s. Accessed July 29, 2014. 42. Brazilan Center for Studies in Dermatology. A fixed triple combination cream for solar lentigines associated to cryotherapy. In ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000. Available from https://clinicaltrials.gov/ct2/ show/NCT01778179?term=A+fixed+triple+combination+cream+ for+solar+lentigines+associated+to+cryotherapy&rank=1. Accessed July 29, 2014. 43. Centre Hospitalier Universitaire de Nice; Centre Hospitalier Universitaire de Nice. Treatment of melasma with stabilized kligman preparation associated or not with pulsed dye laser. In ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). Available from https://clinicaltrials.gov/ct2/show/ NCT00863278?term=treatment+of+melasma+with+stabilized+kligman+preparation+associated+or+not+with+pulsed+dye+laser& rank=1. Accessed December 30, 2014. 44. Castanedo-Cazares, Juan Pablo; Universidad Autonoma de San Luis Potosi. Clinical trial of hydroquinone versus miconazol in melasma. In ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000. Available from https://clinicaltrials.gov/ct2/ show/NCT00927771?term=azelaic+acid+versus+hydroquinone+ in+melasma&rank=1. Accessed July 29, 2014. 45. Callender Center for Clinical Research; Callender Center for Clinical Research. Azelaic acid versus hydroquinone in melasma. In ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000. Available from: ht. Accessed July 29, 2014. 46. Mesoestetic Pharma Group S.L.; Mesoestetic Pharma Group S.L. Efficacy and safety of a 4% hydroquinone cream (melanoderm 4%) for the treatment of melasma: a randomized controlled split-face study. In ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). Available from https://clinicaltrials.gov/ ct2/show/NCT02095990?term=efficacy+and+safety+of+a+4%25+ hydroquinone+cream+for+the+treatment+of+melasma&rank=1. Accessed December 30, 2014. 47. Pandya A. University of Texas Southwestern Medical Center. Salicylic acid peels combined with 4% hydroquinone in the treatment of moderate to severe melasma in hispanic women. In ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine. Available from https://clinicaltrials.gov/ct2/show/ results/NCT00616239?term=Salicylic+acid+peels+combined+with+ 4%25+hydroquinone+in+the+treatment+of+moderate+to+severe+ melasma+in+hispanic+women&rank=1§=X70156#outcome1. Accessed December 30, 2014. 48. Sobhi RM, Sobhi AM. A single-blinded comparative study between the use of glycolic acid 70% peel and the use of topical nanosome vitamin C iontophoresis in the treatment of melasma. J Cosmet Dermatol. 2012;11:65–71. 49. Taylor MB, Yanaki JS, Draper DO, et al. Successful short-term and long-term treatment of melasma and postinflammatory hyperpigmentation using vitamin C with a full-face iontophoresis mask and a mandelic/malic acid skin care regimen. J Drugs Dermatol. 2013;12: 45–50. 50. Ohshima H, Mizukoshi K, Oyobikawa M, et al. Effects of vitamin C on dark circles of the lower eyelids: quantitative evaluation using image analysis and echogram. Skin Res Technol. 2009;15:214–17. 51. Handog EB, Galang DAVF, de Leon-Godinez MA, Chan GP. A randomized, double-blind, placebo-controlled trial of oral procyanidin with vitamins A, C, E for melasma among Filipino women. Int J Dermatol. 2009;48:896–901. 52. National University Hospital, Singapore. The efficacy and safety of a single 70% glycolic acid peel with vitamin c for the treatment of acne scars. In ClinicalTrials.gov [Internet]. Bethesda (MD): Nationa Library of Medicine (US). 2000. Accessed July 29, 2014. 53. Englewood Hospital and Medical Center. Microneedling plus the universal peel for acne scarring. In ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000. Available from: NCT02174393 NLM Identifier: NCT. Accessed July 29, 2014. 54. Kircik LH. Efficacy and safety of azelaic acid (AzA) gel 15% in the treatment of post-inflammatory hyperpigmentation and acne: a 16-week, baseline-controlled study. J Drugs Dermatol. 2011;10: 586–90.

Pitfalls in clinical trials

11

55. Derm Research, PLLC. Efficacy and safety study of finacea to treat acne vulgaris and post-inflammatory hyperpigmentation. In ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000. Available from https://clinicaltrials.gov/ ct2/show/NCT01038869?term=efficacy+and+safety+study+of+ finacea+to+treat+acne+vulgaris+and+post-inflammatory+hyperpigmentation&rank=1. Accessed July 29, 2014. 56. Medical University of Vienna. Azelaic acid iontophoresis versus topical azelaic acid cream in the treatment of melasma. In ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000. Available from https://clinicaltrials.gov/ct2/ show/NCT00848458?term=azelaic+acid+iontophoresis+versus+ topical+azelaic+acid+cream+in+the+treatment+of+melasma& rank=1. Accessed July 29, 2014. 57. Herndon JH, Makino ET, Stephens TJ, Mehta RC. Hydroquinonefree skin brightener system for the treatment of moderate-to-severe facial hyperpigmentation. J Clin Aesthet Dermatol. 2014;7:27–31. 58. Ho ET, Trookman NS, Sperber BR, et al. A randomized, doubleblind, controlled comparative trial of the anti-aging properties of non-prescription tri-retinol 1.1% vs. prescription tretinoin 0.025%. J Drugs Dermatol. 2012;11:64–9. 59. Shi T-W, Ren X-K, Yu H-X, Tang Y-B. Roles of adapalene in the treatment of pityriasis versicolor. Dermatology. 2012;224:184–8. 60. Kircik LH. Safety and efficacy evaluation of tretinoin cream 0.02% for the reduction of photodamage: a pilot study. J Drugs Dermatol. 2012;11:83–90. 61. Kumari R, Thappa DM. Comparative study of trichloroacetic acid versus glycolic acid chemical peels in the treatment of melasma. Indian J Dermatol Venereol Leprol. 2010;76:447. 62. Ghersetich I, Troiano M, Brazzini B, et al. Melasma: treatment with 10% tretinoin peeling mask. J Cosmet Dermatol. 2010;9:117–21. 63. Callender VD, Young CM, Kindred C, Taylor SC. Efficacy and safety of clindamycin phosphate 1.2% and tretinoin 0.025% gel for the treatment of acne and acne-induced post-inflammatory hyperpigmentation in patients with skin of color. J Clin Aesthet Dermatol. 2012;5:25–32. 64. Callender Center for Clinical Research. Efficacy & safety of clindamycin and tretinoin in acne. In ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000. Available from: http://clinicaltrials.gov/show/. Accessed July 29, 2014. 65. Massachusetts General Hospital. Study to evaluate the effect of a nu skin product and device for brown spots. In ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000. Available from: http://clinicaltr. Accessed July 29, 2014. 66. Kimball AB, Kaczvinsky JR, Li J, et al. Reduction in the appearance of facial hyperpigmentation after use of moisturizers with a combination of topical niacinamide and N-acetyl glucosamine: results of a randomized, double-blind, vehicle-controlled trial. Br J Dermatol. 2010;162:435–41. 67. Lee DH, Oh IY, Koo KT, et al. Reduction in facial hyperpigmentation after treatment with a combination of topical niacinamide and tranexamic acid: a randomized, double-blind, vehicle-controlled trial. Skin Res Technol. 2014;20:208–12. 68. Jerajani HR, Mizoguchi H, Li J, et al. The effects of a daily facial lotion containing vitamins B3 and E and provitamin B5 on the facial skin of Indian women: a randomized, double-blind trial. Indian J Dermatol Venereol Leprol. 2010;76:20–6. 69. Bissett DL, Robinson LR, Raleigh PS, et al. Reduction in the appearance of facial hyperpigmentation by topical N-undecyl-10enoyl-L-phenylalanine and its combination with niacinamide. J Cosmet Dermatol. 2009;8:260–6. 70. Universidad Autonoma de San Luis Potosi. Clinical trial of 4% niacinamide versus 0.05% desonide for the treatment of axillar hyperpigmentation. In ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000. Available from https:// clinicaltrials.gov/ct2/show/NCT01542138?term=clinical+trial+of+ 4%25+niacinamide+versus+0.05%25+desonide+for+the+treatment+ of+axillar+hyperpigmentation&rank=1. Accessed July 29, 2014. 71. University of Utah; University of Utah. Combination therapy with imiquimod cream 5% and tazarotene cream 0.1% for the treatment of lentigo maligna. In ClinicalTrails.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000–2013. Available from https:// clinicaltrials.gov/ct2/show/NCT00707174?term=Combination+ therapy+with+imiquimod+cream+5%25+and+tazarotene+cream+ 0.1%25+for+the+treatment+of+lentigo+maligna&rank=1.