JEADV SUPPLEMENT ARTICLE

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1 DOI: /jdv JEADV SUPPLEMENT ARTICLE Effect of adapalene 0.1%/benzoyl peroxide 2.5% topical gel on quality of life and treatment adherence during long-term application in patients with predominantly moderate acne with or without concomitant medication additional results from the non-interventional cohort study ELANG H.P.M. Gollnick, 1, * M. Friedrich, 2 M. Peschen, 3 R. Pettker, 4 A. Pier, 5 V. Streit, 6 P. J ostingmeyer, 7 D. Porombka, 8 I. Rojo Pulido 8,A.J ackel 8 1 Department of Venereology and Dermatology, Otto-von-Guericke University Magdeburg, Germany 2 Dermatologist in private practice Oranienburg, Germany 3 Dermatologist in private practice Freiburg, Germany 4 Dermatologist in private practice Berlin, Germany 5 Dermatologist in private practice Lippstadt, Germany 6 Dermatologist in private practice Buchholz in der Nordheide, Germany 7 med:unit GmbH, K oln, Germany 8 Galderma Laboratorium GmbH, D usseldorf, Germany *Correspondence: H.P.M. Gollnick. Harald.Gollnick@med.ovgu.de Abstract Background In addition to physical long-lasting effects such as permanent scarring and disfigurement, acne has acute and long-term psychosocial effects that affect the individual s quality of life. As with other chronic diseases, treatment success is often compromised by poor adherence. Objective Two main objectives of this non-interventional study were to assess the long-term effect of the fixeddose combination adapalene 0.1%/benzoyl peroxide 2.5% (adapalene-bpo gel) on quality of life and treatment adherence. Methods Patients with moderate to severe facial acne receiving adapalene-bpo alone or in combination with other drugs were enrolled in this non-interventional study. Data were documented at baseline and after 3 and 9 months of adapalene-bpo treatment. The secondary outcomes reported here include quality of life determined by the Cardiff Acne Disability Index (CADI), treatment adherence assessed by the ECOB (Elaboration d un outil d evaluation de l observance des traitements medicamenteux) questionnaire, and patient satisfaction. Results In total, 5131 patients were included in the efficacy evaluation. After 9 months, mean (SD) quality of life (CADI) improved significantly from to (P < ). Patients with more severe acne at baseline tended to achieve a greater improvement in quality of life. Long-term adherence was found to be good in 83.9% of patients. Adherence had a significant effect on efficacy and quality of life (P < respectively). The vast majority of patients (92.1%) reported subjective improvement at the interim analysis. Accordingly, most patients (84.8%) were satisfied or very satisfied with adapalene-bpo by the end of the observation period. Conclusion The clinical improvement of the disease led to an increase in quality of life among acne patients. The treatment success may be a motivation factor for patients to stay adherent over the long-term treatment course, indicating the qualification of adapalene-bpo topical gel as an appropriate medication also in the long-term usage. Received: 3 April 2015; Accepted: 7 April 2015 Conflict of interest Prof. Gollnick has participated in acne-relevant clinical and experimental studies, symposia and advisory boards of Galderma, Stiefel/GSK, Intendis, Meda, Merz, Hoffmann-LaRoche, Novartis, Schering, Pierre Fabre, IMTM and Vichy. Dr. Friedrich has participated in acne-relevant clinical studies and advisory boards of Galderma. Dr. Peschen has participated in acne-relevant clinical studies and advisory boards of Galderma. Dr. Pettker has participated in acne-relevant clinical studies of Galderma. Pier has participated in acne-relevant clinical studies of Galderma. Dr. Streit has participated in acne-relevant clinical studies and advisory boards of Galderma. Dr. J ostingmeyer is employed by med:unit

2 24 Gollnick et al. GmbH, Cologne, Germany, an agency contracted by Galderma Laboratorium GmbH. Dr. Porombka, Dr. Rojo Pulido and Dr. J ackel are employed by Galderma Laboratorium GmbH, D usseldorf, Germany. Introduction Acne is a chronic and commonly relapsing condition over years, induced by multiple aetiological factors. 1 Besides follicular hyperkeratinisation, increased sebum production and bacterial proliferation, inflammatory events contribute to the production of acne lesions. Immune changes and inflammatory responses have been found to precede the hyperproliferation of keratinocytes. 2 Propionibacterium acnes (P. acnes) contributes to inflammation via different pathways of which one is activation of the toll-like receptor 2 (TLR2). 3 As acne typically has a relapsing course for years, the disease is considered to be chronic, 4 requiring long-term treatment to prevent relapses and to maintain the improvement achieved during the acute interventional therapeutic phase. 5 Therefore, a long-term treatment that is effective and safe over more than 3 months is the key to switch to a lasting maintenance treatment. 6 Furthermore, adherence to therapy plays an important role in achieving the therapeutic goal. Although few formal studies have been conducted examining medication adherence in acne, experts agree that it is poor overall, which may be a major contributor to treatment failures. 5,7 10 Factors associated with adherence to treatment in acne include patient demographics, knowledge about the disease, preferences, as well as medication characteristics. 5 For instance, the negative correlation found between age and medication adherence is of particular relevance in the context of acne due to the majority of patients being adolescents. 9 A study based on a so-called co-joint analysis, evaluating patient preferences with topical acne therapies, indicated that patients preferred gel formulations with easy spreading that could be applied once daily, stored at room temperature and which are stable over a couple of months. 11 These characteristics are combined in the fixed-dose preparation adapalene 0.1%/benzoyl peroxide 2.5% (adapalene-bpo). Consistently, a previous non-interventional study confirmed a high degree of adherence in adolescent patients with moderate acne receiving adapalene- BPO. 12 In addition to physical effects such as permanent scarring and disfigurement, acne has long-lasting psychosocial effects that affect the individual s quality of life. 5 The higher the level of impairment in quality of life due to acne, the greater the level of anxiety and depression. 13 As a consequence, patients with severe acne are often characterised by reduced self-confidence and symptoms of depression. 14 Studies indicated that acne improvement after therapeutic intervention is associated with increased self-esteem, body image and self-confidence. 15,16 Taken together, a successful treatment is expected to affect patient-related outcomes such as quality of life and treatment adherence in a positive way. Recent data from a randomized, double-blinded clinical study demonstrated a significant improvement in quality of life in patients with severe acne after 9 months of adapalene- BPO treatment, initially in combination with oral antibiotics. 17 Whether this effect can be reproduced under daily clinical conditions where treatment success is affected by various additional parameters including patient adherence, has not been investigated in such a large cohort. The ELANG-study was therefore launched in one part to evaluate the effect of acne treatment on quality of life and treatment adherence under long-term conditions in daily practice. Materials and methods Study design The effect of adapalene-bpo on quality of life and treatment adherence among patients with moderate to severe inflammatory acne was evaluated in a multicentre, open-label, prospective non-interventional observational cohort study conducted in 189 centres in Germany between June 2012 and September A detailed description of the study protocol and statistics used in the evaluation has been published. 18 Study population In brief, patients with moderate to severe facial inflammatory acne were selected from dermatology practices when topical therapy of acne with adapalene-bpo alone or in combination with other drugs was indicated, and the decision about treating the patient with adapalene-bpo was made independently from this study. Criteria for non-selection were pregnancy or breastfeeding, hypersensitivity to the medication or any of the ingredients. In line with the common clinical acne treatment practice, an interim documentation was scheduled 3 months after the start of initial treatment. To examine long-term effects, the full observation time per patient was 9 months. Assessments Quality of life was assessed at baseline, and after 3 and 9 months of treatment using the Cardiff Acne Disability Index (CADI), 19 a questionnaire comprised of five questions regarding psychological and social consequences of acne, the psychological condition of the patient during the previous months and the patient s subjective assessment of the current severity of acne. The CADI score was calculated by summing the score of each question resulting in a possible maximum score of 15 and a minimum of 0. A higher score indicated

3 Effect of long-term adapalene-bpo on quality of life and treatment adherence 25 impaired quality of life. Unanswered questions were scored zero, consequently the CADI score was calculated by summing the scores of four items only. If more than one item was not scored, the questionnaire could not be evaluated and the entire score was set to missing. Treatment adherence was assessed after 9 months using the ECOB (Elaboration d un outil d evaluation de l observance des traitements medicamenteux) questionnaire consisting of four questions. 20 One inappropriate answer indicated poor adherence. In addition, 4-step scales were used for the assessment of patient satisfaction with the treatment (very satisfied, satisfied, hardly satisfied, not satisfied) and the physician s overall assessment of adapalene-bpo (very good, good, satisfactory, poor) at each follow-up visit. Statistical analysis All data analyses were carried out according to a pre-established analysis plan. The sample size was chosen to gain a large patient collective that would allow the discovery of rare adverse drug reactions. The collected data were analysed with epidemiological methods, using the SPSS (IBM Deutschland GmbH, Ehningen, Germany) for Windows programme package. For continuous variables, statistic parameters including arithmetic mean, standard deviation and range were calculated. Frequency distributions for discrete variables were provided as percentage in relation to the total sample. Free text answers were transferred post hoc into adequate coding schemes and analysed as frequency distribution. Evaluation of parameters measuring the clinical course were performed by intraindividual difference analysis (first vs. last examination) using the Wilcoxon signedrank test. Difference was calculated per patient and subsequently averaged. Patients with missing data for one or both variables were not imputed. In case patients had not returned after their unscheduled visit, assessment was based on data obtained from the unscheduled visit (LOCF). For post hoc analyses of variables affecting outcome measures, subgroups were compared using Mann Whitney-U-Test. Correlations were calculated using Spearman correlation. All tests were twosided, and significance was declared at the 0.05 level. Treatment with adapalene-bpo The majority of patients (78.8%) applied adapalene-bpo alone. The remaining 21.2% received adapalene-bpo in combination with another agent, mostly topical (8.8%) or systemic antibiotics (8.7%). Efficacy and safety Detailed efficacy and safety data have been reported previously in this supplement. 17 In brief, facial acne severity according to the Leeds Revised Acne Grading System improved significantly from at baseline to at the final visit (P < ). Adapalene-BPO was well tolerated by the majority of patients. In addition to local skin irritations of mostly mild nature, experienced by about 50% of patients, a total of 42 adverse drug reactions (ADRs) were documented in 40 patients. None of these were serious. Overall, only 1.7% of patients discontinued adapalene-bpo treatment due to tolerability issues. Quality of life Over the course of the study quality of life according to the mean (SD) CADI score improved from at baseline to at the final visit (P < ) (Fig. 1). Assessment after 3 months showed significant improvement already ( ), which continued to increase over the whole course of the study. Stratification by Leeds grade at baseline revealed significant improvement in quality of life at all baseline Leeds grades. There was a trend towards a positive correlation between acne severity and improvement in quality of life: the higher the Leeds grade at baseline, the greater the improvement (Fig. 2). However, this correlation did not reach statistical significance (P = 0.086). Treatment adherence According to the ECOB questionnaire, treatment adherence over 9 months was considered as good for the majority of patients Results Patient disposition and baseline characteristics Of 6036 enrolled patients, a total of 5131 patients (56.5% male, 42.8% female, 0.7% unknown; median age 18.0 years, range 10 74) from 178 centres were included in the efficacy evaluation (895 patients were lost to follow-up). The majority of patients (86.3%) suffered from moderate facial acne (grade 4 7 according to the Leeds Revised Acne Grading System 21 ) at baseline patients (36.6%) had their acne treated prior to study start, predominantly with topical antibiotics (17.9%). Figure 1 Changes in quality of life according to the Cardiff Acne Disability Index. All P-values (baseline vs. interim visit, baseline vs. final visit, interim vs. final visit) <

4 26 Gollnick et al. Figure 2 Correlation between Leeds grade at baseline and improvement of the CADI score. Data from Leeds grades 11 and 12 were pooled due to the low number of patients. Figure 4 Effect of adherence on the CADI score at the final visit. The size of the bubbles represents the number of patients per category. (83.9%) (Fig. 3). Among the patients with poor adherence, the question regarding the name of the drug received the highest percentage of inappropriate answers (10.1%). A subgroup analysis comparing patients with good adherence vs. patients with poor adherence revealed a significant effect on efficacy outcome (P < ) as well as on quality of life (P < ) (Fig. 4), particularly in patients with moderate acne at baseline. In patients with severe acne at baseline, the impact of adherence on the CADI score was still visible, but no longer statistically significant. Patient satisfaction and overall assessment of adapalene- BPO The vast majority of patients (92.1%) reported subjective improvement after interim analysis at 3 months (Fig. 5). Accordingly, most patients (84.8%) were satisfied or very satisfied with adapalene-bpo by the end of the observation period (Fig. 6a). There was a significant correlation (r = 0.945, P < 0.001) between patient satisfaction and baseline Leeds grade (Fig. 6b). Patients with moderate acne at baseline were more satisfied than patients with severe clinical manifestations. To Figure 5 Treatment success after 3 months assessed by the patient. examine whether the observed comparatively better patient satisfaction at higher Leeds grades (1.9 at Leeds 4 vs. 2.2 at Leeds 10 in correspondence to a scale of 1 4 for very good, good, satisfactory, poor) resulted from acne severity or lack of additional chest and back affection, the following subgroups were evaluated posthoc: A. adapalene-bpo alone without chest/back affected, B. adapalene-bpo alone with chest/back affected, C. Figure 3 Treatment adherence after 9 months. The assessment tool for adherence to acne treatment was designed to detect the possibility of poor adherence. If at least one answer is different from the expected answers (written in turquoise), the patient s adherence is considered to be poor.

5 Effect of long-term adapalene-bpo on quality of life and treatment adherence 27 (a) (b) Figure 6 Patient satisfaction with adapalene-bpo. Overall assessment (a) and mean patient satisfaction stratified by acne severity at baseline (b) whereby the following coding was used in the calculation: very satisfied = 1, satisfied = 2, hardly satisfied = 3, not satisfied = 4. adapalene-bpo in combination with oral antibiotics without chest/back affected, D. adapalene-bpo in combination with oral antibiotics with chest/back affected. Only in the subgroup of patients receiving adapalene-bpo alone without chest/back affected, patient satisfaction was significantly higher in patients with less severe acne. In the other subgroups no correlation was shown. Discussion Here, we have reported additional outcome results of the noninterventional study ELANG that explored the long-term effect of adapalene-bpo topical gel in patients with predominantly moderate inflammatory facial acne using this topical agent alone or in combination with other drugs in daily clinical practice. In line with the observed treatment success, a 9-month-long application of adapalene-bpo gel led to a pronounced increase in quality of life at all grades of acne severity at baseline. After the initial boost at the interim visit after 3 months, quality of life continued to increase throughout the study period, which underlines the therapeutic need for long-term treatment. This observation from clinical practice was consistent with a randomized study that compared the impact of adapalene-bpo vs. vehicle on quality of life using the Acne-QoL questionnaire. 17 In our study, the Cardiff Acne Disability Index was chosen to measure the quality of life because of its patient-oriented approach. The questionnaire was developed to identify areas of particular patient concern such as psychological and social consequences of acne in general, including the additional affection of chest and back, the patient s psychological state as well as their subjective assessment of current acne severity. 19 The latter is of particular importance as several studies demonstrated an impact of acne on quality of life in relation to the patient s self-assessment of the severity of the disease, rather than on the physician s objective clinical assessment. 13,22,23 In this context, the interaction of physical and psychological factors as well as perceived treatment success is thought to be a reflection of the relationship between quality of life and treatment adherence. 9 Poor adherence to therapy is a well-known factor that can negatively impact treatment success. The ECOB questionnaire chosen for the assessment of adherence in this study is a validated tool which can be used even for children under the age of Results achieved with the ECOB questionnaire have been found comparable to those in other studies using different methods of assessment, such as tube weights, patient diaries or interviews. 24 Analysis of different topical therapies by means of the ECOB questionnaire yielded rates for poor adherence of 50% for the class of retinoids, 44% for topical antibiotics, and 40% for BPO. 5 In contrast, after 9 months of treatment with the fixeddose combination adapalene-bpo gel adherence was rated as good for the majority of patients, also under long-term applica-

6 28 Gollnick et al. tion. In this context, patient beliefs have been shown to have a big impact on the adherence rate. 25 Studies have suggested that the majority of acne patients expect significant treatment results to become apparent within 4 6 weeks. 26,27 In our study, patients already observed a therapeutic effect after a median time of 3 weeks, 18 which might be a beneficial factor in the promotion of adherence. Furthermore, the convenient once daily application and fixed-dose gel preparation are factors known to enhance adherence, 11 and therefore may have further contributed to the achievement of the observed high adherence rate. A positive correlation between treatment adherence and improved quality of life has been demonstrated for several cutaneous diseases including psoriasis 8,28 and acne. 9 In an open prospective study, the positive relationship between quality of life assessed by the Dermatology Quality of Life Index and medication adherence was shown for 403 acne patients treated predominantly with oral isotretinoin. 9 This study used the CADI for the measurement of quality of life, also confirmed this correlation for acne patients on adapalene-bpo gel. The assessment of patient satisfaction added another valuable variable from the patient s perspective to the effort of gaining a more complete picture of a successful treatment outcome. While a high degree of patient satisfaction was achieved in general over a long-term period, which is consistent with data from clinical trials, 29 there was an inverse relationship between facial acne severity at baseline and patient satisfaction patients with moderate acne severity were more satisfied with adapalene-bpo treatment. To investigate whether the relatively lower satisfaction experienced by acne patients with more severe clinical manifestations resulted from additional trunk affection or from potential undertreatment of patients with severe acne whereof only a low proportion received a combination with systemic antibiotics further subgroup analysis were conducted. Since neither a correlation with additional chest or back affection nor with combined prescription of oral antibiotics could be shown, the causal relation is still outstanding. Although it has been shown that acne improvement was greater in cases of more severe cases 18 it could be assumed that patients with severe acne suffer more from either residual acne lesions or from aftereffects of formerly severe acne, for example from scarring. To shed more light on these psycho emotional aspects of the disease, future analysis should investigate the correlation of acne severity and patient satisfaction in a more multifactorial way. The study is limited by its non-interventional design and lack of a control group which precludes the conclusion of causality. The outcomes reported by patients presented here are subjective and may lead to an underrepresentation of actual results. However, due to the large number of more than 5000 participants, the study is sufficiently powered to provide statistically conclusive data representing the clinical situation of acne patients who receive long-term topical adapalene-bpo gel in a real-world setting. In conclusion, our findings indicate beneficial effects of longterm treatment with adapalene-bpo that go beyond mere acne improvement. Patients quality of life continued to increase over the course of 9 months. This, along with the previously reported treatment success, may be a motivational factor for patients to stay adherent over the long-term course of treatment. Acknowledgement This study was funded by Galderma Laboratorium GmbH. References 1 Pawin H, Beylot C, Chivot M et al. Physiopathology of acne vulgaris: recent data, new understanding of the treatments. Eur J Dermatol 2004; 14: Jeremy AH, Holland DB, Roberts SG, Thomson KF, Cunliffe WJ. Inflammatory events are involved in acne lesion initiation. J Invest Dermatol 2003; 121: Kim J, Ochoa MT, Krutzik SR et al. Activation of toll-like receptor 2 in acne triggers inflammatory cytokine responses. J Immunol 2002; 169: Gollnick HP, Finlay AY, Shear N. Can we define acne as a chronic disease? If so, how and when? 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7 Effect of long-term adapalene-bpo on quality of life and treatment adherence Gollnick H, Friedrich M, Peschen M et al. Safety and efficacy of adapalene 0.1%/benzoyl peroxide 2.5% in the long-term treatment of predominantly moderate acne with or without concomitant medication results from the non-interventional cohort study ELANG. Published previously in this current JEADV-supplement. 19 Motley RJ, Finlay AY. Practical use of a disability index in the routine management of acne. Clin Exp Dermatol 1992; 17: Pawin H, Beylot C, Chivot M et al. Creation of a tool to assess adherence to treatments in acne. Dermatology 2009; 218: O Brien SC, Lewis JB, Cunliffe WJ. The Leeds revised acne grading system. J Dermatol Treat 1998; 9: Niemeier V, Kupfer J, Demmelbauer-Ebner M, Stangier U, Effendy I, Gieler U. Coping with acne vulgaris. Evaluation of the chronic skin disorder questionnaire in patients with acne. Dermatology 1998; 196: Mallon E, Newton JN, Klassen A, Stewart-Brown SL, Ryan TJ, Finlay AY. The quality of life in acne: a comparison with general medical conditions using generic questionnaires. Br J Dermatol 1999; 140: Dreno B, Thiboutot D, Gollnick H et al. Large-scale worldwide observational study of adherence with acne therapy. Int J Dermatol 2010; 49: McEvoy B, Nydegger R, Williams G. Factors related to patient compliance in the treatment of acne vulgaris. Int J Dermatol 2003; 42: Rasmussen JE, Smith SB. Patient concepts and misconceptions about acne. Arch Dermatol 1983; 119: Tan JK, Vasey K, Fung KY. Beliefs and perceptions of patients with acne. J Am Acad Dermatol 2001; 44: Zaghloul SS, Goodfield MJ. Objective assessment of compliance with psoriasis treatment. Arch Dermatol 2004; 140: Tan J, Stein Gold L, Schlessinger J et al. Short-term combination therapy and long-term relapse prevention in the treatment of severe acne vulgaris. J Drugs Dermatol 2012; 11: