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Efficacy and Safety of Tacrolimus 0.1% for the Treatment of Facial Vitiligo: A Multicenter Randomized, Double-Blinded, Vehicle-Controlled Study

Open ArchivePublished:February 04, 2021DOI:https://doi.org/10.1016/j.jid.2020.12.028

      Background

      Topical calcineurin inhibitors are used off label in the treatment of vitiligo, and there is a lack of placebo-controlled, blinded studies to support their use.

      Objective

      This study aimed to compare the efficacy of tacrolimus 0.1% ointment with that of the vehicle for repigmentation in adult patients with facial vitiligo.

      Design

      This study was a 24-week multicenter randomized parallel double-blind study with a 24-week post-treatment follow-up extension.

      Population

      Participants included were adult patients with recent facial vitiligo target lesions (<2 years) without changes in pigmentation or size over the previous 3 months.

      Intervention

      Patients received either tacrolimus 0.1% ointment or vehicle twice daily.

      Main Outcomes and Measures

      The primary outcome was a therapeutic success, defined as a change ≥75% in the repigmentation of the target lesion between baseline and week 24, measured by ImageJ software. Secondary outcome measures were a variation of the physicians’ global assessment scores and patients’ satisfaction scores, safety data, and the rate of relapse at week 48.

      Results

      A total of 42 patients were included. Therapeutic success was achieved in 65% of tacrolimus-treated patients versus 0% of vehicle-treated patients at week 24 (P < 0.0001). Only 40% of relapse was observed at 48 weeks.

      Conclusions and Relevance

      Twice-daily tacrolimus 0.1% ointment showed superior efficacy to that of the vehicle through the 24 weeks of intervention and 24 weeks of follow-up in adult patients with facial vitiligo.

      Trial Registration

      This study was registered at ClinicalTrials.gov (identifier: NCT02466997).

      Abbreviations:

      DLQI (Dermatology Quality of Life Index), TCI (topical calcineurin inhibitor), VIPs (Vitiligo Impact Patient scale)

      Introduction

      Vitiligo is a chronic autoimmune depigmenting skin disease characterized by the loss of epidermal melanocytes, which affects 0.5‒1% of the general population (
      • Ezzedine K.
      • Eleftheriadou V.
      • Whitton M.
      • Geel N van
      Vitiligo.
      ). Vitiligo heavily impacts the QOL, especially when visible areas are involved (
      • Elbuluk N.
      • Ezzedine K.
      Quality of life, burden of disease, co-morbidities, and systemic effects in vitiligo patients.
      ). Its pathogenesis involves genetic and environmental factors that lead to skin infiltration by CD8+ T cells, which produce elevated levels of IFN-γ and TNF-α (
      • Boniface K.
      • Seneschal J.
      • Picardo M.
      • Taïeb A.
      Vitiligo: focus on clinical aspects, immunopathogenesis, and therapy.
      ). Thus far, no drug has been approved for the treatment of vitiligo. Treatment options remain limited, lack sustained efficacy, and are mainly based on immunosuppressive agents associated with the use of UV light.
      Among the various topical therapies used for vitiligo, topical calcineurin inhibitors (TCIs), such as tacrolimus, are widely used off label, especially for the treatment of patients with facial vitiligo (
      • Taieb A.
      • Alomar A.
      • Böhm M.
      • Dell’anna M.L.
      • De Pase A.
      • Eleftheriadou V.
      • et al.
      Guidelines for the management of vitiligo: the European Dermatology Forum consensus.
      ). Indeed, immunopharmacological data suggest that TCIs have multiple roles in the treatment of vitiligo. First, as immunosuppressive agents, TCIs inhibit the activation, proliferation, and cytokine production of CD8+ T cells (
      • Grimes P.E.
      • Morris R.
      • Avaniss-Aghajani E.
      • Soriano T.
      • Meraz M.
      • Metzger A.
      Topical tacrolimus therapy for vitiligo: therapeutic responses and skin messenger RNA expression of proinflammatory cytokines.
      ;
      • Tsuda K.
      • Yamanaka K.
      • Kitagawa H.
      • Akeda T.
      • Naka M.
      • Niwa K.
      • et al.
      Calcineurin inhibitors suppress cytokine production from memory T cells and differentiation of naïve T cells into cytokine-producing mature T cells.
      ). In addition, TCIs act directly on melanocytes by stimulating their proliferation, migration, and function (
      • Jung H.
      • Chung H.
      • Chang S.E.
      • Kang D.H.
      • Oh E.S.
      FK506 regulates pigmentation by maturing the melanosome and facilitating their transfer to keratinocytes.
      ;
      • Lan C.C.
      • Chen G.S.
      • Chiou M.H.
      • Wu C.S.
      • Chang C.H.
      • Yu H.S.
      FK506 promotes melanocyte and melanoblast growth and creates a favourable milieu for cell migration via keratinocytes: possible mechanisms of how tacrolimus ointment induces repigmentation in patients with vitiligo.
      ). A recent systematic review concerning the efficacy of TCIs alone or in combination with UV light therapy showed that better responses are obtained in facial treatment among patients with vitiligo (
      • Lee J.H.
      • Kwon H.S.
      • Jung H.M.
      • Lee H.
      • Kim G.M.
      • Yim H.W.
      • et al.
      Treatment outcomes of topical calcineurin inhibitor therapy for patients with vitiligo: a systematic review and meta-analysis.
      ). However, it is difficult to draw definitive conclusions regarding TCI efficacy because the available data were obtained from studies with considerable heterogeneity in design and drug administration. Besides, there is a lack of placebo-controlled, blinded studies to support their use. In this study, we aimed to investigate the efficacy of tacrolimus ointment at the atopic dermatitis label dosage of 0.1% compared with that of the vehicle for repigmentation of facial vitiligo in adult patients.

      Results

      Patient characteristics

      In the context of recruitment difficulty related to the widespread off-label use of tacrolimus for the treatment of patients with facial vitiligo, the Data Safety and Monitoring Board, which met for an interim analysis after 40 inclusions, advised for an interruption of recruitment and dissemination of the study results with the scientific community. The Scientific Advisory Board endorsed this proposition, and the trial was therefore closed. In total, 44 adult patients with facial nonsegmental vitiligo were assessed for eligibility. Of these, 42 were randomized (20 in the tacrolimus group and 22 in the vehicle group). During the 24-week treatment period, six patients were lost to follow-up (three in each group), one patient in the vehicle group withdrew consent, and one patient in the tacrolimus group discontinued tacrolimus treatment because of pregnancy. Finally, two patients had missing data in the vehicle group. The flow diagram of the study is summarized in Figure 1. Patient characteristics and clinical data were comparable at baseline, as shown in Table 1.
      Table 1Patient Demographics and Clinical Characteristics at Baseline
      CharacteristicsTacrolimus (n = 20)Vehicle (n = 22)
      Sex, n (%)
       Male9 (45.0)12 (54.5)
       Female11 (55.0)10 (45.5)
      Age (years), mean (SD)47.0 (10.7)48.4 (14.4)
      Associated Autoimmune diseases, n (%)
       No11 (55.0)9 (40.9)
       Yes9 (45.0)13 (59.1)
      Disease duration (years), mean (SD)10.1 (8.7)10.3 (11.1)
      Previous episodes of spontaneous repigmentation, n (%)
       No19 (95.0)21 (95.5)
      Depigmented area surface (cm2), mean (SD)21.9 (27.4)19.0 (17.4)
      Depigmentation score of the target lesion, n (%)
       500 (0.0)2 (9.1)
       755 (25.0)6 (27.3)
       903 (15.0)3 (13.6)
       10012 (60.0)11 (50.0)

      Efficacy

      The blinded-physician analysis of therapeutic success supported the results of the interim analysis. Specifically, the main outcome measure, defined as a change ≥75% in repigmentation of the target lesion between baseline and week 24, was achieved in 65% of tacrolimus-treated patients, whereas it was achieved in 0% of vehicle-treated patients (P < 0.0001) (Table 2). In the intention-to-treat analysis (n = 42), the mean depigmented area of the target lesion (cm2) significantly decreased from 21.9 cm2 to 5.5 cm2 at week 24 in the tacrolimus-treated group (P = 0.0003), whereas its size remained stable (P = 0.65) in the vehicle-treated group (Figures 2 and 3). Measurement of the change in repigmentation of the target lesions as a continuous variable between baseline and week 24 revealed repigmentation in 82.9% of tacrolimus-treated patients, compared with 0.7% of vehicle-treated patients (Figure 4). Moreover, assessment of the changes in target lesion depigmentation score between baseline and week 24 revealed a depigmentation score improvement in 79.8% of tacrolimus-treated patients, compared with 19.3% of vehicle-treated patients (P = 0.0002).
      Table 2Efficacy Endpoints through Weeks 12 and 24
      Clinical Characteristics of the Target LesionsWeek 12Week 24
      Tacrolimus (n = 20)Vehicle (n = 22)P-ValueTacrolimus (n = 20)Vehicle (n = 22)P-Value
      Depigmentation score improvement from baseline (%), mean (SD)56.7 (38.5)7.0 (17.6)0.0004
      Assessed by Wilcoxon test.
      79.8 (32.6)19.3 (26.2)0.0002
      Assessed by Wilcoxon test.
      Target lesion repigmentation rate from baseline, n (%)
       Not specified2 (10.0)3 (13.6)4 (20.0)6 (27.3)
       No repigmentation3 (15.0)10 (45.5)1 (5.0)7 (31.8)
      1‒24%2 (10.0)7 (31.8)1 (5.0)3 (13.6)
      25‒49%1 (5.0)1 (4.5)0 (0.0)4 (18.2)
      50‒74%2 (10.0)1 (4.5)1 (5.0)2 (9.1)
      75‒100%10 (50.0)0 (0.0)13 (65.0)0 (0.0)
      Therapeutic success, n (%)0.0001
      Assessed by Fisher’s exact test.
      <0.0001
      Assessed by chi-square test.
       No10 (50.0)22 (86.4)7 (35.0)22 (100)
       Yes10 (50.0)0 (0.0)13 (65.0)0 (0.0)
      1 Assessed by Wilcoxon test.
      2 Assessed by Fisher’s exact test.
      3 Assessed by chi-square test.
      Figure thumbnail gr2
      Figure 2Patient responses at baseline, week 12, and week 24, assessed by UV light photographs. All patients have given their written consent for the publication of their images.
      Figure thumbnail gr3
      Figure 3Mean depigmented surface areas of the target lesion (cm2) at baseline, W12, W24, and W48 in the placebo- and tacrolimus-treated groups. W, week.
      Figure thumbnail gr4
      Figure 4Mean repigmentation rates (%) of target lesion at W12, W24, and W48 in the placebo- and tacrolimus-treated groups. W, week.
      After 24 weeks of treatment, the patients’ satisfaction scores and the physicians’ global assessment scores also significantly improved in the tacrolimus-treated group compared with that in the vehicle-treated group. The differences between the two groups were statistically significant (P = 0.03 and P < 0.0001, respectively). No significant differences in Dermatology Quality of Life Index (DLQI) or Vitiligo Impact Patient scale (VIPs) scores were found between the tacrolimus- and vehicle-treated groups at week 24.
      During the 24-week follow-up phase of the study, 32 patients were eligible (16 patients in each group). Notably, three patients from the tacrolimus-treated group and one patient from the vehicle-treated group were excluded because they did not want to stop their assigned treatment. Two patients withdrew their consent because of poor efficacy (one in each group). In the vehicle-treated group, one patient was excluded on the basis of the physician’s recommendation, and one patient was lost to follow-up. Finally, three patients had incomplete data (two in the tacrolimus-treated group and one in the vehicle-treated group). Only 4 of the 10 patients in the tacrolimus-treated group exhibited >25% depigmentation of the repigmented area at week 48.

      Safety

      Most reported side effects were mild and included transient erythema as well as stinging and burning sensations that did not require treatment suspension (Table 3). A total of 4 of 20 patients from the treatment group experienced flushes after alcohol consumption. In addition, many patients reported the greasy texture of topical tacrolimus to be unpleasant for daily skin care. One patient from the vehicle-treated group was diagnosed with severe pancreatitis, considered not related to treatment, which led to withdrawal from the study.
      Table 3Treatment-Emergent Adverse Events up to 24 Weeks
      Adverse EventsTacrolimus (n = 20)Vehicle (n = 22)
      Patients with treatment-emergent adverse effects, n (%)11 (55)12 (54.5)
      Most common treatment-emergent adverse effects, n (%)
       Flushes after alcohol consumption4 (20)0 (0)
       Application site burning sensation3 (15)3 (13.6)
       Herpes zoster cutaneous infection01 (4.5)
       Hyperpigmentation1 (5)0
       Severe pancreatitis01 (4.5)
      Patients with treatment-related adverse effects, n (%)8 (40)4 (18.2)
      Most common treatment-related adverse effects, n (%)
       Flushes after alcohol consumption4 (20)0 (0)
       Application site burning sensation3 (15)3 (13.6)
      Patients with treatment-emergent adverse events leading to treatment discontinuation, n (%)01 (4.5)
      Patients with serious treatment-emergent adverse effects, n (%)01 (4.5)

      Discussion

      Our results in this prospective multicenter randomized trial showed that twice-daily tacrolimus 0.1% ointment was effective for the treatment of facial vitiligo in adult patients. This study was specifically designed for patients with facial vitiligo because the head and neck are known to respond better to TCIs. Besides, these body locations are easily exposed to natural UV light. The importance of combined natural UV light therapy with TCIs has been highlighted by previous studies (
      • Ezzedine K.
      • Whitton M.
      • Pinart M.
      Interventions for vitiligo.
      ;
      • Lee J.H.
      • Kwon H.S.
      • Jung H.M.
      • Lee H.
      • Kim G.M.
      • Yim H.W.
      • et al.
      Treatment outcomes of topical calcineurin inhibitor therapy for patients with vitiligo: a systematic review and meta-analysis.
      ). Indeed, this combined therapy, through melanocyte regeneration and immunomodulatory effects, seems critical in achieving successful repigmentation in facial vitiligo. In addition, natural sunlight exposure is a cost- and time-effective concomitant therapeutic option for patients with facial vitiligo. Experts have reported agreement with the low-risk nature of this combined treatment (
      • Taieb A.
      • Alomar A.
      • Böhm M.
      • Dell’anna M.L.
      • De Pase A.
      • Eleftheriadou V.
      • et al.
      Guidelines for the management of vitiligo: the European Dermatology Forum consensus.
      ).
      Another study showed a greater efficacy for combination treatment with potent topical steroids and narrowband UVB than for topical steroids alone or narrowband UVB alone, highlighting the importance of combined light-based and topical treatment (
      • Thomas K.S.
      • Batchelor J.M.
      • Akram P.
      • Chalmers J.R.
      • Haines R.H.
      • Meakin G.D.
      • et al.
      Randomised controlled trial of topical corticosteroid and home-based narrowband UVB for active and limited vitiligo - results of the HI-Light Vitiligo Trial [e-pub ahead of print].
      ). Notably, tacrolimus has fewer side effects than potent topical steroids when used for facial treatment, and its efficacy was more robust in our randomized controlled trial.
      A recent investigational study led by the International Initiative for Outcome indicated that a target outcome of more than 80% repigmentation is appropriate for patients with facial vitiligo (
      • Eleftheriadou V.
      • Hamzavi I.
      • Pandya A.G.
      • Grimes P.
      • Harris J.E.
      • Huggins R.H.
      • et al.
      International Initiative for Outcomes (INFO) for vitiligo: workshops with patients with vitiligo on repigmentation.
      ). Although our primary outcome (repigmentation rate ≥75%) was designed before those recommendations, we presume that our results are similar to patient expectations for facial locations. In total, 65% of tacrolimus-treated patients achieved the predefined primary outcome, compared with 0% of vehicle-treated patients (P < 0.0001) at week 24. Rapid and statistically significant repigmentation rates were achieved during the first 12 weeks of the trial, such that 50% of tacrolimus-treated patients achieved ≥75% repigmentation (P = 0.0001). Surprisingly, a recent meta-analysis showed a much lower rate of therapeutic success during tacrolimus treatment: only 35.4% of patients with facial vitiligo achieved a 75% repigmentation (
      • Lee J.H.
      • Kwon H.S.
      • Jung H.M.
      • Lee H.
      • Kim G.M.
      • Yim H.W.
      • et al.
      Treatment outcomes of topical calcineurin inhibitor therapy for patients with vitiligo: a systematic review and meta-analysis.
      ). However, the analysis included highly heterogeneous studies with respect to design and baseline patient population. Indeed, most of those studies were unblinded and uncontrolled, whereas some included segmental vitiligo, which is refractory to medical treatments after a few months of progression. Furthermore, our study focused on recent vitiligo lesions, which are known to have a better response to any treatment.
      Notably, a good repigmentation response rate was achieved in a phase II study regarding the efficacy of ruxolitinib cream, a Jak 1/2 inhibitor, in patients with facial vitiligo (
      • Rosmarin D.
      • Pandya A.G.
      • Lebwohl M.
      • Grimes P.
      • Hamzavi I.
      • Gottlieb A.B.
      • et al.
      Ruxolitinib cream for treatment of vitiligo: a randomised, controlled, phase 2 trial.
      ). Examination of the repigmentation response (assessed by facial Vitiligo Area Scoring Index score) under twice-daily ruxolitinib 1.5% treatment showed that 45% of patients achieved a 50% reduction in facial Vitiligo Area Scoring Index score between baseline and week 24, compared with 3% of patients in the vehicle-treated group. However, because of differences in primary outcome measurements, a cross-study comparison with TCI treatment is difficult. Caution is needed when comparing these two topical agents until head-to-head data are available.
      Although vitiligo treatment should aim to treat both the skin condition and the related psychological symptoms, the effect of tacrolimus treatment on psychosocial consequences in patients with facial vitiligo has not been previously reported. Our results showed significant improvements in patients’ satisfaction scores and physicians’ global assessment scores in tacrolimus-treated patients compared with that in the vehicle-treated patients. Surprisingly, no statistically significant variation was observed in the DLQI or VIPs scores when compared between the patient groups. This is presumably because those scales do not specifically examine facial vitiligo. Indeed, although patients achieved successful repigmentation of facial lesions, most still exhibited other visible vitiligo lesions that continued to impact their QOL.
      The main limitation of this study was that difficulties in recruitment were encountered mainly because TCIs are widely used off label in daily practice. Moreover, patients were often reluctant to receive, potentially, a placebo treatment. Despite this difficulty, the overall rate of repigmentation with tacrolimus after 12 weeks of treatment was significantly greater than expected. Another potential bias could have resulted from the differences between groups in terms of the season of inclusion (e.g., greater natural sun exposure during the summer season), although natural sunlight‒exposure modalities were standardized throughout the trial. Finally, our cohort may not have represented a wide array of ethnicities because this study was performed in a single country and no ethnicity data are available for the overall French population.
      During tacrolimus treatment withdrawal in the 24-week follow-up study, the relapse rate of 40% was similar to previously reported findings (
      • Nicolaidou E.
      • Antoniou C.
      • Stratigos A.J.
      • Stefanaki C.
      • Katsambas A.D.
      Efficacy, predictors of response, and long-term follow-up in patients with vitiligo treated with narrowband UVB phototherapy.
      ). Achievement of disease remission is a considerably challenging goal for patients with vitiligo. This is often prevented by the presence of tissue-resident memory T cells in perilesional vitiligo skin (
      • Boniface K.
      • Seneschal J.
      Vitiligo as a skin memory disease: the need for early intervention with immunomodulating agents and a maintenance therapy to target resident memory T cells.
      ;
      • Boniface K.
      • Jacquemin C.
      • Darrigade A.S.
      • Dessarthe B.
      • Martins C.
      • Boukhedouni N.
      • et al.
      Vitiligo skin is imprinted with resident memory CD8 T cells expressing CXCR3.
      ;
      • Cheuk S.
      • Schlums H.
      • Gallais Sérézal I.
      • Martini E.
      • Chiang S.C.
      • Marquardt N.
      • et al.
      CD49a expression defines tissue-resident CD8+ T cells poised for cytotoxic function in human skin.
      ;
      • Richmond J.M.
      • Strassner J.P.
      • Rashighi M.
      • Agarwal P.
      • Garg M.
      • Essien K.I.
      • et al.
      Resident memory and recirculating memory T cells cooperate to maintain disease in a mouse model of vitiligo.
      ). These tissue-resident memory T cells are capable of maintaining IFN-γ and TNF-α production and may be the main factors involved in disease recurrence. One study showed that maintenance therapy with twice-weekly tacrolimus ointment allowed sustained repigmentation (
      • Cavalié M.
      • Ezzedine K.
      • Fontas E.
      • Montaudié H.
      • Castela E.
      • Bahadoran P.
      • et al.
      Maintenance therapy of adult vitiligo with 0.1% tacrolimus ointment: a randomized, double blind, placebo–controlled study.
      ). We presume that tacrolimus may limit tissue-resident memory T-cell activation, thus preventing vitiligo relapses. The markers linked to long-term response to tacrolimus topical treatment have not yet been assessed, but we propose that they include short disease duration, a lower tissue-resident memory T-cell perilesional skin infiltration, and a higher repigmentation rate at week 24.
      A 6-month course of tacrolimus 0.1% ointment provided high efficacy for the treatment of adult patients with <2-year history of facial vitiligo. Maintenance intermittent treatment was justified because relapses occurred over 6 months in 40% of the included patients. Side effects were negligible, consistent with >20 years of data regarding overall tacrolimus treatment.

      Methods

      Protocol

      This 24-week multicenter randomized parallel double-blind study with a 24-week post-treatment follow-up extension was performed in seven French dermatology hospital departments between July 2015 and June 2017. The study was approved by the Ethics Committee (Comité de Protection des Personnes Sud-Ouest et Outre-Mer III) and registered on Clinicaltrials.gov under the number NCT02466997 on 9 June 2015 (https://clinicaltrials.gov/ct2/show/NCT02466997). Declaration of Helsinki protocols was followed. All patients provided written informed consent before enrollment.
      Datasets related to this article are available on request and are hosted by the University Hospital Center of Bordeaux, France.

      Participants

      Included patients were aged ≥18 years with facial nonsegmental vitiligo. All the patients had at least one vitiligo target lesion in the last 2 years, which had no change in pigmentation or size over the last 3 months, had a surface area >3 cm2, and had a local depigmentation score ≥50% on the basis of the Vitiligo Area Scoring Index score atlas (
      • Hamzavi I.
      • Jain H.
      • McLean D.
      • Shapiro J.
      • Zeng H.
      • Lui H.
      Parametric modeling of narrowband UV-B phototherapy for vitiligo using a novel quantitative tool: the vitiligo area scoring index.
      ). Patients with active lesions were excluded because there was a concern about spreading for patients allocated to the vehicle group. Other exclusion criteria were as follows: spontaneous ongoing repigmentation in the last 3 months; other topical tacrolimus treatment in the last 3 months; any specific vitiligo treatment within the 4 weeks preceding randomization, including any topical treatment, phototherapy, systemic steroids, or immunosuppressive drugs; other underlying dermatological diseases (i.e., history of atopic dermatitis, eczema, and/or psoriasis); contraindications concerning the use of topical tacrolimus; past history of skin cancer or lymphoma; congenital or acquired immunodeficiency; ongoing pregnancy or lactation; and/or absence of contraceptive use among female patients.

      Assignment

      Patients were randomly assigned at a 1:1 ratio to receive either tacrolimus 0.1% ointment or vehicle ointment. A centralized randomization block list was generated using SAS software, version 9.4 (SAS Institute, Cary, NC). An online randomization module assigned each patient a random number. The pharmacist assigned each random number to a treatment group.

      Masking

      Investigators were blinded to the treatment assignments of the participants. The blinded randomization list was provided in a web browser available to all coinvestigators.

      Intervention

      One group received tacrolimus 0.1% ointment twice daily, whereas the other received vehicle ointment twice daily. Patients from both groups were advised to expose themselves progressively to natural light throughout the trial, beginning with 5‒10 minutes of sun exposure without sunscreen. If a light pink color was not observed, patients were advised to increase the time of exposure by 10% the next day. The maximum recommended sun exposure was 45 minutes per day.

      Participant flow and follow-up

      Study visits were scheduled at weeks 12, 24, and 48. At each study visit, UV light and normal light photographs were taken. From those photographs, target lesion size was assessed by the transparent sheet method using ImageJ software (National Institute of Health, Bethesda, MA) for digital surface measurement (
      • van Geel N.
      • Vandendriessche D.
      • Vandersichel E.
      • De Schepper S.
      • Grine L.
      • Mertens L.
      • et al.
      Reference method for digital surface measurement of target lesions in vitiligo: a comparative analysis.
      ). The DLQI score, VIPs score (
      • Salzes C.
      • Abadie S.
      • Seneschal J.
      • Whitton M.
      • Meurant J.M.
      • Jouary T.
      • et al.
      The Vitiligo Impact Patient Scale (VIPs): development and validation of a vitiligo burden assessment tool.
      ), and both patients’ satisfaction and physicians’ global assessment scores were recorded at baseline and week 24 (see Appendix). Additional follow-up phone calls were scheduled at weeks 6 and 18 to ensure patient compliance and to ensure that side effects were recorded.
      The main objective of the study was to investigate the efficacy of twice-daily tacrolimus ointment at the atopic dermatitis label dosage of 0.1%, compared with that of the vehicle, for repigmentation after 24 weeks of treatment. The primary outcome was a therapeutic success, defined as a ≥75% change in repigmentation of the target lesion between baseline and week 24. Repigmentation was evaluated using scanned images of skin mapping technique (planimetry), with ConvaTec (Deeside, United Kingdom) transparencies of lesions under Wood’s lamp examination at baseline and week 24, as recommended (
      • van Geel N.
      • Vandendriessche D.
      • Vandersichel E.
      • De Schepper S.
      • Grine L.
      • Mertens L.
      • et al.
      Reference method for digital surface measurement of target lesions in vitiligo: a comparative analysis.
      ). Scanned lesions were then measured using a freely available software for analysis and measurements of digital images, the ImageJ 1.47d software (Image processing and analysis in Java [Oracle, Austin, TX] by the National Institute of Health; http://imagej.nih.gov/ij). All patients provided written consent to the publication of follow-up photographs. Changes were also assessed in target lesion depigmented surface (cm2) and in target lesion depigmentation score on the basis of the Vitiligo Area Scoring Index score pattern of the depigmentation descriptive atlas (e.g., 0%, 10%, 25%, 50%, 75%, 90%, or 100%) between baseline and week 24. Evaluations were performed by physicians blinded to treatment allocation.
      Secondary outcomes included QOL variations between baseline and week 24, assessed using the DLQI and VIPs. Patients’ satisfaction and physician’s global assessment scores were assessed between baseline and week 24 using 4-point Likert scales.
      Finally, tacrolimus and vehicle safety were assessed, as was the proportion of relapse among patients successfully treated with topical tacrolimus after treatment withdrawal, during the follow-up period. A relapse was defined as a depigmentation ≥25% of the repigmented area when comparing planimetry between week 24 and week 48.

      Calculation of sample size

      Sample sizes were calculated assuming therapeutic success rates of 50% in the tacrolimus group and 20% in the vehicle group, along with 80% power, an alpha risk of 5%, and a two-tailed hypothesis test. In total, 39 patients were required in each group. Considering 20% loss to follow-up within 6 months of study initiation, a target of 100 patients was sought for enrollment (50 per group).

      Statistical analysis

      Analysis of the primary objective was based on the intention-to-treat principle. Missing values were imputed as failed treatment. The rate of target lesion repigmentation ≥75% between treatment groups at weeks 12 and 24 was assessed using chi-square test or Fisher’s exact test, as appropriate. The mean changes in target lesion depigmented surface and depigmentation score between baseline and week 24 were compared between groups using Wilcoxon test. To compare patients’ and physicians’ Likert scales between groups at week 24, chi-square test was used after dichotomization of 4-point Likert scales into the following categories: satisfied and not satisfied or improved and not improved. Mean variations in VIPs and DLQI scores between treatment groups at week 24 were compared using Wilcoxon test. All statistical analyses were performed using SAS software.

      Data availability statement

      The data that support the findings of this study are available from the corresponding author KE ( [email protected] ), JS ( [email protected] ), or NA ( [email protected] ) on request. Datasets related to this article are available on request and are hosted by the University Hospital Center of Bordeaux. The data are not publicly available because they contain information that could compromise the privacy of research participants.

      Conflict of Interest

      TP has been an investigator for LEO Pharma and has received grants and honoraria from LEO Pharma for studies outside of this work. The remaining authors state no conflict of interest.

      Acknowledgments

      This study was funded by a national grant (La Direction Générale de l'Offre de Soins Programme Hospitalier de Recherche Clinique-N n° 13-0088) from the French Ministry of Health (Paris, French) and by Astellas.

      Author Contributions

      Conceptualization: JS, KE; Data Curation: NA; Formal Analysis: RL, CF; Funding Acquisition: JS, KE; Investigation: JS, AD, HM, TP, NA, RL, CF, CD, AT, KE; Methodology: JS, KE; Project Administration: JS, AD, HM, TP, CD, AT, KE; Resources: NA; Software: RL, CF; Supervision: JS, KE; Validation: JS, AD, HM, TP, NA, RL, CF, CD, AT, KE; Visualization: JS, AD, KE; Writing - Original Draft Preparation: AD, JS, KE; Writing - Review and Editing: JS, AD, HM, TP, NA, RL, CF, CD, AT, KE

      Supplementary Material

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