A randomized controlled trial of the efficacy and safety of a fixed triple combination (fluocinolone acetonide 001, hydroquinone 4, tretinoin 005) compared with hydroquinone 4 cream in Asian patients with moderate to severe melasma
Open accessAbstract
BACKGROUND: Melasma is an acquired, chronic hypermelanosis for which therapy remains a challenge. OBJECTIVES: To compare the efficacy and safety of a triple combination [TC: fluocinolone acetonide 0.01%, hydroquinone (HQ) 4%, tretinoin 0.05%] vs. HQ 4% after 8 weeks of treatment of moderate to severe facial melasma in Asian patients. METHODS: This was a multicentre, randomized, controlled, investigator-blinded, parallel comparison study. East and South-East Asian patients aged 18 years or older, with a clinical diagnosis of moderate to severe melasma, were enrolled in this study. Patients were enrolled at baseline and treated daily for 8 weeks with TC cream (one application at bedtime) or HQ cream (twice daily). There were four study visits: at baseline and weeks 2, 4 and 8. The primary efficacy variable was the melasma global severity score (GSS). Other outcome measures included Melasma Area and Severity Index, global improvement and patient satisfaction. Safety was assessed through the reporting of adverse events. RESULTS: TC had superior efficacy to HQ for the primary variable: 77/120 patients (64.2%) on TC had GSS 'none' or 'mild' at week 8 vs. 48/122 patients (39.4%) on HQ (P < 0.001). The secondary efficacy variables confirmed these results. Patient satisfaction was in favour of TC (90/127, 70.8%, vs. 64/129, 49.6%; P = 0.005). More patients had related adverse events on TC (63/129, 48.8%) than on HQ (18/131, 13.7%) but most were mild and none was severe. CONCLUSIONS: Efficacy in Asians and patient satisfaction were superior with the fixed TC than with HQ 4%.
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Chan et al.'s study is graded as Level 2b according to Oxford CEBM.
“The level of evidence for this study is graded as Level 2b according to the Oxford Centre for Evidence‐Based Medicine.”
From Cosmeceuticals in photoaging: A review. (2024) · cites this paper as [69]
Chan et al.'s randomized controlled trial found triple combination (fluocinolone acetonide 0.01%, hydroquinone 4%, tretinoin 0.05%) significantly more effective in reducing pigmentation and improving melasma compared with hydroquinone 4% alone in Asian patients.
“The study found that the triple combination treatment was significantly more effective in reducing pigmentation and improving melasma compared to hydroquinone alone.”
From Cosmeceuticals in photoaging: A review. (2024) · cites this paper as [69]
Chan et al.'s study had limitations including small sample size, short follow-up of 12 weeks, and no reported adverse events or long-term outcomes.
“However, the study had some limitations including a small sample size and a relatively short follow‐up period of 12 weeks. Additionally, the study did not report any adverse events or long‐term outcomes of the triple combination treatment.”
From Cosmeceuticals in photoaging: A review. (2024) · cites this paper as [69]
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“[4,10] In the present study, the low potency TC group showed a significant reduction in mean MASI score after 6 and 12 weeks of therapy with only 4 patients experiencing mild adverse effects.”
Cosmeceuticals in photoaging: A review.
Chan, L. K. W., Lee, K. W. A., Lee, C. H., Lam, K. W. P., Lee, K. F. V., Wu, R., Wan, J., Shivananjappa, S., Sky, W. T. H., Choi, H., et al. (2024) · Skin Research and Technology · doi:10.1111/srt.13730 · Cited by 23 · see citing works
Goldman, A., Goldust, M., & Wollina, U. (2021) · Cosmetics · doi:10.3390/cosmetics8020026 · Cited by 21 · see citing works
Redox active donor-substituted punicin derivatives
Albrecht, M., Schneider, O., & Schmidt, A. J. (2009) · Organic & Biomolecular Chemistry · doi:10.1039/b822353j · Cited by 21 · see citing works
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Photoaging and Topical Rejuvenation
Berry, K. A., Hallock, K. K., & Lam, C. (2023) · Clinics in Plastic Surgery · doi:10.1016/j.cps.2022.12.003 · Cited by 18 · see citing works
Updates in the understanding and treatments of skin & hair disorders in women of color
Lawson, C. N., Hollinger, J. C., Sethi, S., Rodney, I. J., Sarkar, R., Dlova, N. C., & Callender, V. D. (2015) · International Journal of Women’s Dermatology · doi:10.1016/j.ijwd.2015.04.002 · Cited by 18 · see citing works
Topical and Systemic Therapies in Melasma: A Systematic Review
Sarkar, R., Handog, E. B., Das, A., Bansal, A., Macarayo, M. J., Keshavmurthy, V., Narayan, V., Jagadeesan, S., Pipo, E., Ibaviosa, G. M., et al. (2023) · Indian Dermatology Online Journal · doi:10.4103/idoj.idoj_490_22 · Cited by 17 · see citing works
Comparison between Intralesional Triamcinolone and Kligman's Formula in Treatment of Melasma.
Eshghi, G., Khezrian, L., & Ashari, F. E. (2016) · PubMed · Cited by 17 · see citing works
Photoaging and Topical Rejuvenation
Berry, K. A., Hallock, K. K., & Lam, C. (2022) · Facial Plastic Surgery Clinics of North America · doi:10.1016/j.fsc.2022.03.003 · Cited by 16 · see citing works
Pratchyapruit, W., Vashrangsi, N., Sindhavananda, J., & Tagami, H. (2011) · Skin Research and Technology · doi:10.1111/j.1600-0846.2010.00489.x · Cited by 16 · see citing works
“(20) reported that vascular alterations frequently occurred in the skin of patients with melasma even before treatment but that the erythema remained concealed by the pigment until effective treatment of the hyperpigmentation increases their visibility.”
BackgroundSerum Albumin and C3 Complement Levels in Endometriosis
Hasan, A., Rahim, A., Afzal, M., Naveed, A. K., Ayub, S., & Jahan, S. (2019) · Journal of College of Physicians And Surgeons Pakistan · doi:10.29271/jcpsp.2019.08.702 · Cited by 15 · see citing works
Fermented Fish Collagen Attenuates Melanogenesis via Decreasing UV-Induced Oxidative Stress
Byun, K.-A., Lee, S. Y., Oh, S., Batsukh, S., Jong-Won, J. A. N. G., Lee, B.-J., Rheu, K.-M., Li, S., Jeong, M.-S., Son, K. H., et al. (2024) · Marine Drugs · doi:10.3390/md22090421 · Cited by 15 · see citing works
“Side effects of HQ such as erythema, burning sensation, pruritus, and desquamation have been reported [58–61].”
BackgroundMelasma and Common Pigmentary Dermatoses in Asian Individuals and an Overview of their Treatment
Chan, P. K. (2014) · Journal of Clinical and Investigative Dermatology · doi:10.13188/2373-1044.1000006 · Cited by 15 · see citing works
“7%), most of them were mild and none were severe [20].”
BackgroundPerspectives of topical formulations for melasma
de Freitas, A. C. P., Rigon, R. B., Bagatin, E., & Leonardi, G. R. (2022) · International Journal of Dermatology · doi:10.1111/ijd.16421 · Cited by 14 · see citing works
“…0.01% and reduced concentrations of T.31,32 This combination has been considered effective and safe for the treatment of melasma,33 as evidenced by Chan et al. (2008), by reducing the MASI after a daily application of cream containing HQ (4%), FA (0.01%), and T 0.05%, for 8 weeks.31 The same was…”
MethodInfluentialAdvances in the Treatment of Melasma
Sadeghpour, M., Dover, J. S., & Rohrer, T. E. (2018) · Advances in Cosmetic Surgery · doi:10.1016/j.yacs.2018.02.008 · Cited by 11 · see citing works
Topical treatment of hyperpigmentation disorders
Rendon, M. I., & Horwitz, S. (2012) · Annales de Dermatologie et de Vénéréologie · doi:10.1016/s0151-9638(12)70128-x · Cited by 11 · see citing works
Alikhan, A., Daly, M., Wu, J., Balkrishnan, R., & Feldman, S. R. (2010) · Journal of Dermatological Treatment · doi:10.3109/09546630903200612 · Cited by 10 · see citing works
“Other studies have shown a much greater efficacy of tCt when it is based on ‘good’ or ‘excellent’ results inclusively, and the efficacy increases as the medication is used for longer than 8 weeks (13,14,26).”
BackgroundUnmasking Melasma: Confronting the Treatment Challenges
Parać, E., & Mokoš, Z. B. (2024) · Cosmetics · doi:10.3390/cosmetics11040143 · Cited by 9 · see citing works
Scar Management in Pediatric Patients
Barone, S., Bao, E., Rothberg, S. E., Palacios, J. F., Smith, I. T., Tanna, N., & Bastidas, N. (2025) · Medicina · doi:10.3390/medicina61040553 · Cited by 9 · see citing works
Periorbital Discolouration Diagnosis and Treatment: Evidence-Based Review
Pissaridou, M. K., Ghanem, A. M., & Lowe, N. J. (2020) · Journal of Cosmetic and Laser Therapy · doi:10.1080/14764172.2021.1899238 · Cited by 9 · see citing works
Melasma management: Unveiling recent breakthroughs through literature analysis
Kumar, D. R., Sood, R., & Tiwari, P. K. (2025) · Health Sciences Review · doi:10.1016/j.hsr.2025.100213 · Cited by 10 · see citing works
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Exploring drug combinations in a drug-cocktail network
Xu, K., Hu, F., Song, J., & Zhao, X.-M. (2011) · IEEE International Conference on Systems Biology · doi:10.1109/isb.2011.6033183 · Cited by 8 · see citing works
“[6] identified a combination drug, namely Tri-Luma, for combating melasma (dark skin patches) of the face based on efficacy and safety experiments.”
BackgroundPasseron, T., & Toubel, G. (2009) · Annales de Dermatologie et de Vénéréologie · doi:10.1016/s0151-9638(09)72541-4 · Cited by 7 · see citing works
“Le traitement de référence reste les agents dépigmentants topiques et notamment le Trio de Kligman [21].”
Dermatologic conditions in patients of color who are pregnant
Jeon, C., Agbai, O. N., Butler, D., & Murase, J. E. (2017) · International Journal of Women’s Dermatology · doi:10.1016/j.ijwd.2017.02.019 · Cited by 8 · see citing works
“…erythema, stinging, and desquamation, postinflammatory hyper- and hypopigmentation a Balina and Graupe 1991; Intendis 2005; Lynde et al. 2006. b Chan et al. 2008; Nussbaum and Benedetto 2006; Taylor et al. 2003. c Bandyopadhyay 2009; Plewig and Kligman 1973. d Shapiro et al. 1997. patients…”
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Prathyoosha, S., Ananditha, K., Rao, T. N., Gopal, K. V. T., & Raju, P. V. K. (2024) · Indian Dermatology Online Journal · doi:10.4103/idoj.idoj_797_23 · Cited by 6 · see citing works
Hyperpigmentation in a middle aged woman: a common yet underdiagnosed condition
Melnick, S., Lohani, S., & Alweis, R. L. (2016) · Journal of Community Hospital Internal Medicine Perspectives · doi:10.3402/jchimp.v6.31544 · Cited by 6 · see citing works
“The Melasma Area and Severity Index has been used in clinical trials to standardize subjective evaluation; however, this has yet to be validated (5).”
MethodMelasma hyperpigmentation: An overview of current topical therapeutics
AlSalem, S. B., & Alexis, A. F. (2022) · Dermatological Reviews · doi:10.1002/der2.152 · Cited by 8 · see citing works
“The therapeutic efficacy of TCC has been well studied and documented.(21,48,49) In a large systematic review of 20”
BackgroundSkin Pigmentation and Cosmetic Considerations for Even Skin Tone
Damodaran, A., & Nair, N. (2022) · IntechOpen eBooks · doi:10.5772/intechopen.108693 · Cited by 5 · see citing works
Bhardwaj, V., Handler, M. Z., Mao, J., Azadegan, C., Panda, P. K., Breunig, H. G., Wenskus, I., Diaz, I., & König, K. (2024) · Experimental Dermatology · doi:10.1111/exd.15069 · Cited by 5 · see citing works
“2,20 One successful example is Tri-Luma®, a combination of three drugs (HQ, tretinoin and fluocinolone ace-tonide), which has emerged as more effective treatment than HQ monotherapy for melasma and PIH.”
BackgroundTreatment Strategies for Hyperpigmentation
Cheng, J., & Vashi, N. A. (2017) · Springer eBooks · doi:10.1007/978-3-319-53961-4_23 · Cited by 5 · see citing works
Passeron, T. (2012) · Annales de Dermatologie et de Vénéréologie · doi:10.1016/s0151-9638(12)70129-1 · Cited by 5 · see citing works
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Rahrovan, S., Hasanzadeh, H., & Khodakarim, S. (2015) · Journal of Pigmentary Disorders · doi:10.4172/2376-0427.1000222 · Cited by 4 · see citing works
“Although the reduction in pigmentation is expected, the increase in erythema index is an interesting finding [17].”
BackgroundStörungen der Melaninpigmentierung
Böhm, M. (2018) · Springer eBooks · doi:10.1007/978-3-662-49544-5_69 · Cited by 4 · see citing works
Takekawa, C., Fukumoto, T., Haraoka, G., & Terashi, H. (2020) · Journal of Plastic Reconstructive & Aesthetic Surgery · doi:10.1016/j.bjps.2020.08.131 · Cited by 4 · see citing works
Li, H. O., Pastukhova, E., & Dover, J. S. (2023) · Advances in Cosmetic Surgery · doi:10.1016/j.yacs.2022.10.003 · Cited by 4 · see citing works
Etiology and Treatments of Melasma
Lee, J. D., Lee, J. K., & Oh, M. J. M. (2020) · Springer eBooks · doi:10.1007/978-981-15-6556-4_12 · Cited by 4 · see citing works
MELASMA: TRATAMENTO E SUAS IMPLICAÇÕES ESTÉTICAS
Barbosa, K. L., & Guedes, M. R. M. (2018) · Infarma - Ciências Farmacêuticas · doi:10.14450/2318-9312.v30.e2.a2018.pp85-94 · Cited by 3 · see citing works
Review of Topical Lightening Agents
Dharmana, S. (2014) · Journal of Pigmentary Disorders · doi:10.4172/2376-0427.1000145 · Cited by 3 · see citing works
Treatment of Hyperpigmentation in Darker Skins
(2015) · Journal of Pigmentary Disorders · doi:10.4172/2376-0427.1000158 · Cited by 3 · see citing works
“TC was associated with more but mostly mild adverse effects [9].”
Background
- Authors
- Chan, R., Park, K. C., Lee, M. H., Lee, E.-S., Chang, S. E., Leow, Y. H., Tay, Y.-K., Legarda-Montinola, F., Tsai, R.-Y., Tsai, T.-H., Shek, S., Kerrouche, N., Thomas, G., & Verallo-Rowell, V.
- Affiliations
- National Skin Centre (SG)
- Seoul National University Bundang Hospital (KR)
- Kyung Hee University (KR)
- Ajou University Hospital (KR)
- Asan Medical Center (KR)
- Changi General Hospital (SG)
- Makati Medical Center (PH)
- Wan Fang Hospital (TW)
- Queen Mary Hospital (CN)
- Galderma (France) (FR)
- Corresponding author
- Chan, R.
- Venue
- British Journal of Dermatology
- Publisher
- Oxford University Press (OUP)
- Published
- 2008-06
- Volume
- 159
- Issue
- 3
- Pages
- ???-???
- ISSN
- 0007-0963 (ISSN-L)
- 1365-2133
- OpenAlex
- W1980482640
- Cited by
- 132
- References
- 28
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 13 · 2023: 4 · 2022: 15 · 2021: 3 · 2020: 7 · 2019: 7 · 2018: 8 · 2017: 14 · 2016: 6 · 2015: 7 · 2014: 12 · 2013: 3 · 2012: 8
- FWCI
- 7.15
- Type
- journal article
- Language
- en
- Open access
- Locations
- British Journal of Dermatology (publishedVersion)
- PubMed (publishedVersion)
- AJOU Open Repository (Ajou University) (submittedVersion)
- Seoul National University Open Repository (Seoul National University) (submittedVersion)
- Funders
- Galderma
- Topics
- Health Sciences › Medicine › Dermatology › Dermatologic Treatments and Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › melanin and skin pigmentation
- Health Sciences › Medicine › Oncology › Cutaneous Melanoma Detection and Management
- Keywords
- melasma, triple combination therapy, fluocinolone acetonide, hydroquinone, all-trans retinoic acid, Asian patients, facial hyperpigmentation, Melasma Area and Severity Index, patient satisfaction, adverse events, topical treatment efficacy
- MeSH terms
- Administration, Cutaneous, Adult, Analysis of Variance, Double-Blind Method, Drug Combinations, Facial Dermatoses, Female, Fluocinolone Acetonide, Humans, Hydroquinones, Male, Melanosis, Middle Aged, Ointments, Tretinoin, Treatment Outcome, Patient Satisfaction, Asian People
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