Patients were randomly assigned to combination therapy consisting of afamelanotide implant and narrowband UV-B (NB–UV-B) phototherapy or NB–UV-B monotherapy. Treatments were administered for 6 months, followed by a 6-month observation period. Data are presented to the end of the 6 months of active treatment.
A, A relative reduction in VASI is seen at day 56 in both arms (P = .03), with a superior response in the group receiving afamelanotide and narrowband UV-B (NB–UV-B) phototherapy (combination therapy group). A decrease in VASI indicates improvement. B, A decrease in the VETF extent dimension is demonstrated in the combination therapy group at day 56 (P = .004) and in the NB–UV-B monotherapy group at day 84 (P = .02). Data points on the graph are expressed as P values.
A, Response to combination treatment with afamelanotide and narrowband UV-B (NB–UV-B) phototherapy compared with NB–UV-B monotherapy on the trunk. B, Responses to combination therapy and NB–UV-B monotherapy on the upper extremities. D indicates day; D0, baseline. Arrowheads indicate areas of repigmentation noted at day 68 in the combination therapy group.
Lim HW, Grimes PE, Agbai O, Hamzavi I, Henderson M, Haddican M, Linkner RV, Lebwohl M. Afamelanotide and Narrowband UV-B Phototherapy for the Treatment of VitiligoA Randomized Multicenter Trial. JAMA Dermatol. 2015;151(1):42-50. doi:10.1001/jamadermatol.2014.1875
Narrowband UV-B (NB–UV-B) phototherapy is used extensively to treat vitiligo. Afamelanotide, an analogue of α–melanocyte-stimulating hormone, is known to induce tanning of the skin.
To evaluate the efficacy and safety of combination therapy for generalized vitiligo consisting of afamelanotide implant and NB–UV-B phototherapy.
Design, Setting, and Participants
This study was performed in 2 academic outpatient dermatology centers and 1 private dermatology practice. We enrolled men and women 18 years or older with Fitzpatrick skin phototypes (SPTs) III to VI and a confirmed diagnosis of nonsegmental vitiligo that involved 15% to 50% of total body surface area. Vitiligo was stable or slowly progressive for 3 months. Patients were randomized to combination therapy (n = 28) vs NB–UV-B monotherapy (n = 27). After 1 month of NB–UV-B phototherapy, 16 mg of afamelanotide was administered subcutaneously to the combination therapy group monthly for 4 months while NB–UV-B phototherapy continued; the other group continued to receive NB–UV-B monotherapy.
Narrowband UV-B monotherapy vs combined NB–UV-B phototherapy and afamelanotide.
Main Outcomes and Measures
Response on the Vitiligo Area Scoring Index and Vitiligo European Task Force scoring system.
Response in the combination therapy group was superior to that in the NB–UV-B monotherapy group (P < .05) at day 56. For the face and upper extremities, a significantly higher percentage of patients in the combination therapy group achieved repigmentation, and at earlier times (face, 41.0 vs 61.0 days [P = .001]; upper extremities, 46.0 vs 69.0 days [P = .003]). In the combination therapy group, repigmentation was 48.64% (95% CI, 39.49%-57.80%) at day 168 vs 33.26% (95% CI, 24.18%-42.33%) in the NB–UV-B monotherapy group. Notable adverse events included erythema in both groups and minor infections and nausea in the combination therapy group. Comparison between Fitzpatrick SPTs showed patients with SPTs IV to VI in the combination therapy group had improvement in the Vitiligo Area Scoring Index at days 56 and 84 (P < .05); no significant difference was noted in patients with SPT III.
Conclusions and Relevance
A combination of afamelanotide implant and NB–UV-B phototherapy resulted in clinically apparent, statistically significant superior and faster repigmentation compared with NB–UV-B monotherapy. The response was more noticeable in patients with SPTs IV to VI.
clinicaltrials.gov Identifier: NCT01430195
Vitiligo is characterized by white patches of skin due to selective loss of epidermal melanocytes.1 Vitiligo affects 1% to 2% of the general population, with devastating psychological impact.1- 3 Autoimmune, genetic, biochemical, oxidative stress, neural, and viral mechanisms have been proposed as etiologic factors.1,4,5 Although topical corticosteroids, calcineurin inhibitors, and narrowband UV-B (NB–UV-B) phototherapy can be effective treatment options, none are universally successful.5,6
The cutaneous melanocortin system consists of bioactive peptides, including α–melanocyte-stimulating hormone (α-MSH), corticotropin, β-endorphin, and other peptides derived from the precursor peptide proopiomelanocortin. The peptide α-MSH is a pivotal regulatory protein that stimulates melanogenesis and melanocyte proliferation.7- 12
Quiz Ref IDAfamelanotide is a potent synthetic linear analogue of the naturally occurring α-MSH in a controlled-release formulation.13 Subcutaneous injections result in increased skin pigmentation owing to increased expression of eumelanin. Pilot studies13- 15 have shown afamelanotide to be beneficial in the treatment of erythropoietic protoporphyria and solar urticaria. Studies16- 19 have demonstrated defects in the melanocortin system in patients with vitiligo. Thus, restoring the system by use of exogenous melanocortin peptides theoretically should benefit these patients.
A recent pilot study of afamelanotide and NB–UV-B phototherapy for repigmentation of nonsegmental vitiligo20 described repigmentation in 4 patients. The present investigation reports the results of a multicenter randomized clinical trial comparing the efficacy and safety of afamelanotide implants and NB–UV-B phototherapy (combination therapy) with NB–UV-B monotherapy for the treatment of nonsegmental vitiligo in 55 patients.
The study was designed jointly by the investigators and the sponsor, Clinuvel Pharmaceuticals, Melbourne, Australia. The protocol was approved by the institutional review boards of Henry Ford Hospital and Mount Sinai Hospital and a central institutional review board.
Eligible patients included men and women 18 years or older with a confirmed diagnosis of nonsegmental vitiligo involving 15% to 50% of total body surface area, stable or slowly progressive vitiligo during a 3-month period, and Fitzpatrick skin phototypes (SPT) III to VI. Exclusion criteria consisted of SPT I or II, vitiligo involving the hands and feet only, extensive leukotrichia, previous treatment with NB–UV-B phototherapy within 6 months, lack of response to previous NB–UV-B phototherapy, allergy to afamelanotide or the polymer contained in the implant, allergy to lidocaine hydrochloride or any other local anesthetic to be used during the administration of the implant, current or previous treatment with topical immunomodulators within 4 weeks of the screening visit, history of photosensitivity disorders or photosensitive lupus, history of claustrophobia, history of any active and/or unstable autoimmune disease judged to be clinically significant by the investigator, history of melanoma or lentigo maligna, history of dysplastic nevus syndrome, the presence of any malignant skin lesions, any skin disease that may interfere with the study evaluation, child-bearing potential (for female patients), and use of any current or prior therapy that may interfere with the objective of the study (including drugs that cause photosensitivity or skin pigmentation) within 60 days before the screening visit. All patients provided written informed consent.
The study consisted of 8 visits during a period of 7 months, including a screening period no longer than 28 days before study initiation, the visit at the onset of the study (visit 1), and monthly visits for the 6-month study period (Figure 1). The treatment was assigned according to a computer-generated randomization list for each study site. Patients were randomized in equal numbers to 1 of 2 treatment groups (combination therapy and NB–UV-B monotherapy). Both groups received NB–UV-B phototherapy 2 to 3 times weekly for 6 months, for a maximum of 72 treatments; all subjects were required to have a minimum of 10 treatments per month. The combination therapy group received 4 monthly subcutaneous afamelanotide implants (on days 28, 56, 84, and 112) (Figure 1). During the 6-month active treatment phase, participants underwent weekly evaluation for onset of repigmentation. At the end of the 6-month active treatment phase, a total of 3 follow-up visits were scheduled and participants underwent evaluation during a planned period of 6 months. We are reporting results to the end of the 6-month active treatment phase.
Time to onset of repigmentation is defined as the number of days for the first sign of repigmentation to be identified visually. Repigmentation was assessed every 7 (±3) days from day 0 until occurrence at several anatomical sites.
We used 2 validated scoring systems. The Vitiligo Area Scoring Index (VASI) is a validated quantitative assessment scale for vitiligo.21 Briefly, the body is divided into the following 6 separate and mutually exclusive sites: head/ neck, hands, upper extremities (excluding hands), trunk, lower extremities (excluding feet), and feet. The percentage of vitiligo involvement was estimated in hand units by the same investigator during the entire course of the study to eliminate variations in hand size. The degree of depigmentation for each body site was determined and estimated to the nearest of the following percentages: 0, 10%, 25%, 50%, 75%, 90%, or 100%. Any new depigmented lesions that developed during the study were also estimated and included in the VASI calculation. The VASI was then calculated using the following formula:
VASI = Sum of All Values From All Body Sites [in Hand Units] × [Residual Depigmentation].
The other validated scoring system, the Vitiligo European Task Force (VETF) score, assesses 3 dimensions of the disease (extent, staging, and spreading/progression).22 The body is divided into the following 5 separate and mutually exclusive sites: head/ neck, trunk, arms, legs, and hands/feet. At each study visit, the extent of vitiligo was estimated as the percentage of vitiligo involvement of each body site and assessed in hand units by the same investigator during the entire course of the study to eliminate variations in hand size. Stage of vitiligo was assessed as 0 (normal pigmentation), 1 (incomplete depigmentation), 2 (complete depigmentation), 3 (partial hair whitening [<30%]), and 4 (complete hair whitening). Spreading of vitiligo was scored as 0 (stable disease), −1 (observed ongoing subclinical repigmentation), and +1 (additional patches in a given area or observed ongoing subclinical depigmentation). The VETF score for each dimension of the disease (extent, staging, and spreading) was then calculated as follows:
VETF Extent or Staging or Spreading = Sum of All Values From All Body Sites [% of Area or Staging or Spreading].
A basic ophthalmoscopic examination was performed by a qualified ophthalmologist. Any lesions, vascular malformations, anomalies, or retinopathies were recorded and discussed with the principal investigator.
The afamelanotide implant is a sterile biodegradable and biocompatible poly(d,l-lactide-co-glycolide) polymer implant core (Sigma-Aldrich Corp) containing 16 mg of afamelanotide. The drug is a subcutaneous dissolving implant approximately the size of a grain of rice. Implants were placed subcutaneously above the suprailiac crest, using a sterile technique with a 14-gauge catheter after injection of 1% lidocaine hydrochloride as anesthesia.
The primary efficacy outcome is the change from day 0 to day 168 in the pigmentation of the full body, face, trunk, and extremities between the 2 treatment groups, assessed using the VASI and the VETF scoring system. A Wood’s lamp was used to assess subclinical repigmentation and determine the VASI and VETF score. Furthermore, we analyzed a secondary efficacy outcome measure, time to onset of repigmentation. Because hands and feet are sites known to be recalcitrant to treatment, these sites were not included in this part of the analysis.
Safety end points included treatment-emergent adverse events, defined as clinically significant changes in laboratory values summarized by the Medical Dictionary for Regulatory Activities. Treatment-emergent adverse events were further summarized by intensity, seriousness, outcome, and relationship to the study drug.
We compared treatment groups by means of the nonparametric Mann-Whitney test for continuous variables and the χ2 test or Fisher exact test (if >20% of the cells in a contingency table had expected counts of <5) for categorical variables.23,24 Unless otherwise stated, hypothesis testing was performed at the α = .05 level (2 sided) when comparing treatments.25 For all inferential analyses, the P value was rounded to 3 decimal places. Unless otherwise stated, a rounded P value of less than or equal to .05 indicated statistical significance. Comparison within treatment groups was also performed using the Wilcoxon signed rank test.26 The comparison between treatment groups in the time to onset of repigmentation of the full body, face, trunk, and extremities was performed by means of the log-rank test.27
The demographic and baseline characteristics of all patients are shown in Table 1. A total of 28 patients (8 from Detroit, 10 from Los Angeles, and 10 from New York) were enrolled in the combination therapy group (afamelanotide and NB–UV-B) and 27 were enrolled in the NB–UV-B monotherapy group (8 from Detroit, 10 from Los Angeles, and 9 from New York). The intent-to-treat population consisted of all participants who received at least 1 treatment and underwent an efficacy evaluation at 28 days. One patient from each group failed to fulfill these criteria, resulting in the intent-to-treat populations of 27 and 26, respectively. We found no statistically significant differences in age, body weight, height, body mass index, race, or Fitzpatrick SPT among patients in both groups. On day 0, the VASI and VETF score of both groups were similar.
Response in the intent-to-treat population in the combination therapy group compared with the NB–UV-B monotherapy group is shown in Figure 2. In both groups, the degree of repigmentation improved (P < .001), as reflected by the decreased VASI observed from day 56 until the end of the observation period (day 168). Repigmentation in both groups was noted to be peripheral and follicular. The between-groups comparison showed that response in the combination therapy group was superior to that in the NB–UV-B monotherapy group (P < .05), starting at day 56; the improvement in the combination therapy group compared with the NB–UV-B monotherapy group was more marked at day 168 than day 56. Quiz Ref IDSimilar findings were observed by analyzing data from patients who completed the treatment (n = 17 in the combination therapy group and n = 24 in the NB–UV-B monotherapy group). We found a statistically significant response in both groups (P < .001), starting from day 56; the between-groups comparison showed a superior response in the combination therapy group with repigmentation (represented by a relative reduction in the VASI) of 48.64% (95% CI, 39.49%-57.80%) at day 168 vs 33.26% (95% CI, 24.18%-42.33%) in the NB–UV-B monotherapy group.
Data from the intent-to-treat population were analyzed using disease extent, reflecting the body surface involvement. Although both groups achieved statistically significant improvement, the combination therapy group achieved it at day 56, whereas the NB–UV-B monotherapy group achieved it at day 84 (Figure 2D). Between-groups analysis showed a superior response in the combination therapy group on days 140 and 168 (P ≤ .04).
Analysis of disease staging, which assesses severity of vitiligo, in the intent-to-treat population failed to detect differences between the 2 groups. Analysis of disease spreading, a reflection of progression, in the intent-to-treat population showed a statistically significant (P < .001) improvement of pigmentation in both groups starting on day 56. Between-groups analysis showed a statistically significant superior response (P ≤ .03) in the combination therapy group, starting from day 56.
Quiz Ref IDCompared with the NB–UV-B monotherapy group, a statistically significantly higher percentage of patients in the combination therapy group achieved repigmentation on the face and upper extremities, and they did so at earlier times (face, 41.0 vs 61.0 days [P = .001]; upper extremities, 46.0 vs 69.0 days [P = .003]). Although a similar trend was observed for the trunk and lower extremities, the differences did not reach statistical significance (P > .05).
Data from the intent-to-treat population were analyzed using the VASI system based on observed Fitzpatrick SPTs, which were categorized into groups of SPT III and SPTs IV to VI. Quiz Ref IDBetween-groups comparison showed that patients with SPTs IV to VI receiving combination treatment had a more rapid response compared with those receiving NB–UV-B monotherapy at days 56 and 84 (P < .05). No noticeable differences were found between the treatment groups for patients with SPT III. Similar analysis using the VETF scores (extent, stage, and spread) failed to detect any differences in response between the combination therapy and NB–UV-B monotherapy groups in patients with SPT III and those with SPTs IV to VI.
The most common adverse events reported were cutaneous (Table 2), including erythema noted in 19 patients in the combination therapy group (68%) and 22 in the NB–UV-B monotherapy group (82%). Other cutaneous events include hyperpigmentation of unaffected skin (2 patients [7%] in the combination therapy group and none in the NB–UV-B monotherapy group) and pruritus (2 patients [7%] in both groups). Hyperpigmentation was subjectively experienced by all participants in the combination therapy group but only included as an adverse event if the patient complained of hyperpigmentation or if the hyperpigmentation had an effect on the patient. The 2 patients who complained of hyperpigmentation withdrew from the study for this reason. Nausea was reported in 18% of the combination therapy group. No gastrointestinal tract adverse events were noted in the NB–UV-B monotherapy group. These findings are consistent with previous studies of afamelanotide in the treatment of solar urticaria and erythropoietic protoporphyria, which demonstrated nausea, headache, and increased pigmentation in existing nevi.14,15
The only serious adverse event noted was hypertension in the combination group. Two patients were noted to have hypertension during the routine examination, which qualified as severe in only 1 patient. In this case, the patient had a known history of hypertension and did not take a prescribed antihypertensive on that day; thus the hypertension was not believed to be related to the study drug.
To our knowledge, this multicenter, randomized study involving a total intent-to-treat population of 55 matched individuals with the clinical response evaluated by 2 validated scoring systems is one of the largest such studies to date. The results show an overall clinically apparent and statistically significant superior repigmentation response in the combination therapy group, compared with the NB–UV-B monotherapy group (Figure 2 and Figure 3). For the face and upper extremities, which are clinically the most apparent sites in the daily lives of the patients, the median time to onset of repigmentation in the combination therapy group was 20 days sooner than in the NB–UV-B monotherapy group. Analysis of the database SPTs showed a trend toward more rapid response in those with SPTs IV to VI who underwent combination treatment; this trend was detected using the VASI but not the VETF score. The small sample size in each of the subgroups probably was not sufficiently powered to detect consistent differences.
Two vitiligo treatment outcome scoring systems are used in this study. Significant differences were detected when data were analyzed based on the VASI. Using the VETF score, significant differences were detected in disease spreading and extent, but not in staging. A possible explanation could be that the VASI has an uneven scaling system that allows it to pick up small changes at either end of the spectrum and larger changes in between. The VASI differs from the VETF system, which has a consistent system of staging with the same differences between each stage. Because smaller differences tend to occur at the extremes, the VASI may be more effective at detecting small changes in staging but lacks the ability to measure stability. In addition, most patients had stage I or II disease, which may explain a lack of significant findings in the VETF staging score.
Overall, afamelanotide was well tolerated without any serious adverse effect. As expected, erythema and pruritus were noted in both groups and hyperpigmentation in the combination therapy group. The higher frequency of nausea and abdominal pain, although not serious, is most likely related to afamelanotide administration.
This study has several limitations. The dose of afamelanotide (16 mg) and the frequency of the injection were chosen based on experience with previous studies in erythropoietic protoporphyria and solar urticaria14,15; we did not perform a dose-response study in vitiligo, and we do not know whether a monthly injection is the most optimal treatment regimen. The active treatment phase of 6 months was selected because we knew it would give more than adequate time to evaluate the response to NB–UV-B phototherapy properly; however, we do not know if this duration is optimal to evaluate fully the response to afamelanotide.
Quiz Ref IDTo ensure an adequate number of patients for analysis, we did not include an afamelanotide-only group. In addition, previous studies have shown that α-MSH acts on the melanocortin-1 receptor, which is not expressed on nascent melanoblasts. Combined use of NB–UV-B phototherapy and afamelanotide allowed for further differentiation of melanoblasts and upregulation of melanocortin-1 receptor. This study design was developed to maximize the potential therapeutic effect of afamelanotide. Future areas of investigation include evaluating any possible effect of afamelanotide as monotherapy in the treatment of vitiligo.
Patients with dark skin types (SPTs III-VI) were chosen because of our collective clinical impression that dark-skinned patients in general tend to be more responsive to all types of treatments; therefore, this study was not designed to address response in fair-skinned patients (ie, those with SPTs I and II). However, our data suggest that individuals with darker skin (SPTs IV-VI) responded more rapidly to combined treatment with afamelanotide and NB–UV-B phototherapy compared with NB–UV-B monotherapy. Because this group of patients has the most apparent visual appearance and hence psychological effect of the disease, rapidity of response for these patients would be most welcome. In the future, quality-of-life assessments may be helpful in gauging the impact of treatment.
Even with these limitations, the results of this multicenter, randomized study strongly indicate that administration of afamelanotide to patients receiving NB–UV-B phototherapy should be considered as an option that could significantly enhance the rate and the total surface area of repigmentation. Furthermore, our data suggest that patients with lesions on the face and upper extremities, and potentially those with darker skin, would have a more rapid response to the combination treatment. The results of this study offer hope to patients with vitiligo in the treatment of this disfiguring disease.
Accepted for Publication: June 17, 2014.
Corresponding Author: Henry W. Lim, MD, Multicultural Dermatology Center, Department of Dermatology, Henry Ford Hospital, New Center One, 3031 W Grand Blvd, Ste 800, Detroit, MI 48202 (firstname.lastname@example.org).
Published Online: September 17, 2014. doi:10.1001/jamadermatol.2014.1875.
Author Contributions: Drs Lim and Agbai had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Lim, Grimes, Agbai, Hamzavi, Henderson, Lebwohl.
Acquisition, analysis, or interpretation of data: Lim, Agbai, Hamzavi, Henderson, Haddican, Linkner, Lebwohl.
Drafting of the manuscript: Lim, Grimes, Agbai, Henderson, Linkner.
Critical revision of the manuscript for important intellectual content: Lim, Grimes, Agbai, Hamzavi, Henderson, Haddican, Lebwohl.
Obtained funding: Lim.
Administrative, technical, or material support: Lim, Agbai, Hamzavi, Henderson, Haddican.
Study supervision: Lim, Grimes, Lebwohl.
Conflict of Interest Disclosures: Dr Lim served as a consultant to Clinuvel Pharmaceuticals. No other disclosures were reported.
Funding/Support: This study was supported by Clinuvel Pharmaceuticals.
Role of Funder/Sponsor: Clinuvel Pharmaceuticals participated in the design and conduct of the study and the collection, management, analysis, and interpretation of the data. The funding source had no role in the preparation, review, or approval of the manuscript and decision to submit the manuscript for publication.
Additional Contributions: Silvia Barbi, MS, and Lisa Comarella, MS, provided all statistical analysis and were compensated for this work.