Psychometric validation of the Psoriasis Symptom Diary using Phase III study data from patients with chronic plaque psoriasis

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1 Report Psychometric validation of the Psoriasis Symptom Diary using Phase III study data from patients with chronic plaque psoriasis Bruce Strober 1,11, MD, PhD, Yang Zhao 2, PhD, Mary Helen Tran 3, PharmD MBA, Ari Gnanasakthy 4, PhD, Judit Nyirady 5, MD, MBA, Charis Papavassilis 6, *, MD, PhD, Lauren M. Nelson 4, PhD, Lori D. McLeod 4, PhD, Margaret Mordin 7, MS, Alice B. Gottlieb 8, MD, PhD, Boni E. Elewski 9, MD, and Mark Lebwohl 10, MD 1 Department of Dermatology, University of Connecticut Health Center, University of Connecticut, Farmington, CT, USA, 2 Department of Health Economics and Outcomes Research, Novartis Pharmaceuticals Corp., East Hanover, NJ, USA, 3 Global Value & Access PCSK9 Development and Launch Unit, Sanofi- Aventis US LLC, Bridgewater, NJ, USA, 4 Patient Reported Outcomes Division, RTI Health Solutions, Research Triangle Park, NC, USA, 5 Department of US Medical, Novartis Pharmaceuticals Corp., East Hanover, NJ, USA, 6 Department of Immunology and Dermatology, Novartis Pharma AG, Basel, Switzerland, 7 MAOS Division, RTI Health Solutions, Ann Arbor, MI, USA, 8 Chair and Dermatologist in Chief Harvey B Ansell Professor of Dermatology, Tufts Medical Center and Tufts Univ School of Medicine, Boston, MA, 9 Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL, USA, 10 Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY, USA, and 11 Probity Medical Research, Waterloo, Ontario, Canada Correspondence Lauren M. Nelson, PHD RTI Health Solutions 3040 Cornwallis Road, PO Box Research Triangle Park, NC USA lnelson@rti.org Abstract Objectives This analysis aimed to confirm the reliability, validity, and responsiveness of the Psoriasis Symptom Diary (PSD) using data from two Phase III studies in patients with moderate to severe chronic plaque psoriasis. Methods Data from two randomized, double-blind, double-dummy, placebo-controlled, multicenter Phase III studies (n = 820) assessing the efficacy and safety of secukinumab were used. The PSD (24-h recall; 0 10 numeric rating scale) was electronically administered each evening. Test retest reliability was determined using intraclass correlations. Construct validity hypotheses were evaluated via correlations with the Psoriasis Area and Severity Index (PASI), Investigator s Global Assessment (IGA), Dermatology Life Quality Index (DLQI), EuroQoL 5-Dimension Health Status Questionnaire, and Patient Global Impression of Change (PGIC). Discriminating ability and responsiveness were evaluated by estimating mean differences and effect sizes between known groups (using the PASI and IGA). Phase II-derived, anchor-based PGIC thresholds and cumulative distribution function (CDF) plots described meaningful change. Results Items on the PSD yielded high intraclass coefficients (>0.90). Correlations were in the anticipated direction and by week 12 were moderate to strong ( ) in magnitude, demonstrating construct validity. Average PSD item scores differed predictably and significantly between known groups. Responsiveness effect size estimates were moderate to large ( ), and CDF plots showed the percentage of responders to be consistently higher in treatment than in placebo arms across the range of change in PSD scores. Conclusions The PSD is reliable, valid, and responsive, and represents a valid tool to enhance treatment decisions in patients with moderate to severe plaque psoriasis. Funding: Novartis Pharmaceuticals Corp. *Correction added on 10 February 2016, after first online publication: this author s name has been corrected. Introduction Chronic plaque psoriasis is an immune-mediated disease associated with cutaneous, scaly, red patches and plaques that can affect any area of the body. 1 Global prevalence estimates for psoriasis in adults range from 1.4 to 3.3%. 2 Patients often experience symptoms such as itching and plaque-related pain (stinging and burning). Although other e147 ª 2015 The International Society of Dermatology International Journal of Dermatology 2016, 55, e147 e155

2 e148 Report Validation of the Psoriasis Symptom Diary Strober et al. psoriasis-related signs such as scaling, flaking, and alterations in skin color are observable by clinicians, they can also be assessed via patient self-reporting. The Medical Advisory Board of the National Psoriasis Foundation acknowledged and highlighted the importance of including in clinical studies patients reports on the severity of the signs and symptoms of their psoriasis, as well as the impact of psoriasis symptoms on overall well-being. 1 To address this need, the 16 questions of the Psoriasis Symptom Diary (PSD) were developed in accordance with recommendations set forth in the US Food and Drug Administrations (FDA) Guidance for Patient-Reported Outcome Measures for use in global clinical studies, with the specific aim of generating patient-reported endpoints to test efficacy claims for treatments for moderate to severe chronic plaque psoriasis. 3 The content validity of the 16 PSD questions was evaluated through qualitative interviews and a review of the published literature. 4 Results determined that the PSD questions measure signs, symptoms, and impacts of plaque psoriasis that are relevant and important to patients; seven items address symptom severity, and nine items address symptom burden. Preliminary quantitative work was conducted using data collected from a Phase II study in patients with moderate to severe chronic plaque psoriasis. 5 This prior research established sound initial estimates of the reliability, validity, and sensitivity to change of the 16 PSD items and provided thresholds for responder definitions of key PSD severity items for use in the evaluation of treatment efficacy. The objective of the current analysis was to confirm the psychometric properties of the 16 PSD items, with a primary focus on the seven key items on symptom severity, using data from two pivotal Phase III clinical studies in patients with moderate to severe chronic plaque psoriasis. Materials and methods Study design Pooled data from two randomized, double-blind, double-dummy, placebo-controlled, multicenter Phase III studies (ERASURE [n = 738] and FIXTURE [n = 1306]) designed to assess the efficacy and safety of subcutaneously administered secukinumab in patients with moderate to severe chronic plaque psoriasis were used in the current analysis. Each study consisted of a 1 4-week screening period, a 12-week induction period, a 40-week maintenance period, and an 8-week followup period. Subjects in ERASURE were randomized (1 : 1 : 1) to receive secukinumab at doses of either 300 or 150 mg, or placebo; those in FIXTURE were randomized (1 : 1 : 1 : 1) to receive secukinumab at doses of either 300 or 150 mg, or etanercept or placebo. Subjects randomized to secukinumab in either study received either two 150-mg subcutaneous secukinumab injections (i.e. 300 mg) or one 150-mg injection plus one placebo injection, all of which were administered once weekly at baseline and at weeks 1, 2, and 3, and then every 4 weeks from week 4 until week 48. In FIXTURE, subjects randomized to etanercept received 50 mg administered subcutaneously twice weekly at baseline until week 12, and then 50 mg once weekly to week 51. To maintain a doubledummy design, the placebo group in FIXTURE received placebo injections corresponding to the secukinumab and the etanercept regimens, and the secukinumab and etanercept groups received placebo injections corresponding to the other active drug regimen. In ERASURE, the placebo arm received injections corresponding to the secukinumab regimens. Further study details have been reported by Langley and colleagues. 6 The clinical studies were designed, implemented, and reported in accordance with the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) Harmonised Tripartite Guidelines for Good Clinical Practice, with applicable local regulations (including those of European Directive 2001/20/EC, US Code of Federal Regulations Title 21, and the Japanese Ministry of Health, Labor and Welfare), and in line with the ethical principles laid down in the Declaration of Helsinki. Eligible subjects were included in the study only after providing written (and witnessed, where required by law or regulation) institutional review board/ independent ethics committee-approved informed consent, or, if any subject was incapable of doing so, after such consent had been provided by a legally acceptable representative of the subject. Sample Subjects included in these studies had moderate to severe plaque-type psoriasis that was poorly controlled by topical treatments and/or phototherapy and/or previous systemic therapy and of severity sufficient to justify systemic treatment. The requirements for a Psoriasis Area and Severity Index (PASI) score of at least 12 points, an Investigator s Global Assessment (modified 2011) (IGA) rating of at least 3, and evidence of disease affecting at least 10% of total body surface area reflected guidelines outlined in the Committee for Medicinal Products for Human Use and used in the inclusion criteria in ERASURE and FIXTURE. 6,7 Versions in 18 languages were provided across the 12 countries in which the PSD was administered; however, completion of the PSD, although encouraged, was not mandatory, and the electronic device used to administer the PSD was not available in one country because it was delayed in customs control. Therefore, the present evaluation was limited to subjects who completed the PSD in the screening and induction periods (i.e. baseline to week 12). This yielded 285 subjects from ERASURE and 535 subjects from FIXTURE for a total of 820 men and women aged years. International Journal of Dermatology 2016, 55, e147 e155 ª 2015 The International Society of Dermatology

3 Strober et al. Validation of the Psoriasis Symptom Diary Report e149 Measures Assessments of the severity of plaque psoriasis symptoms were collected from two different sources: clinician observations, and patient self-reports. The clinician-reported outcome (CRO) measures were the PASI and IGA rating scale. In addition to the PSD, three patient-reported outcome (PRO) measures were administered: the Dermatology Life Quality Index (DLQI), the EuroQoL 5-Dimension Health Status Questionnaire (EQ-5D), and a Patient Global Impression of Change (PGIC). These measures were used in the current evaluation to confirm the validity and sensitivity to change, or responsiveness, of the PSD items. The Psoriasis Symptom Diary The PSD is a 16-item, psoriasis-specific PRO measure with a 24-hour recall period (Table 1). 4,5 A total of seven items evaluate the severity of the key signs and symptoms of plaque psoriasis, including psoriasis-related itching (item 1), stinging (item 3), burning (item 5), pain from skin cracking (item 7), pain (item 9), scaling (item 11), and alterations in skin color (item 13). The remaining nine PSD items evaluate patient-reported annoyance associated with experiences of those signs and symptoms and daily impacts. The PSD was electronically administered once each evening (between hours and hours) and was scheduled to be completed from screening through the induction period. Each of the 16 items was scored as a weekly average, computed as the sum of the scored item over the course of the study week divided by the number of days on which the item was completed (completion of data for 4 days was required to derive a weekly score; the missing of 1 3 days, whether they were consecutive or nonconsecutive, was allowed). Cases for which a weekly score could not be calculated (e.g. if data were completed for fewer than 4 days in a study week) were set as missing and were excluded from the analysis. Psoriasis Area and Severity Index The PASI is a CRO measure evaluating the head, trunk, upper limbs, and lower limbs for the severity and body surface area coverage of erythema, thickening (plaque elevation, induration), and scaling (desquamation). 8 Subjects were included in the studies if their PASI score was >12. Subjects achieving a 75% improvement (reduction) in PASI score at week 12 compared with baseline (PASI 75) were defined as responders. PASI 75 was identified as a co-primary efficacy endpoint in the ERASURE and FIXTURE studies. Additionally, subjects achieving a 50% but <75% improvement in PASI score at week 12 compared with baseline (PASI 50) were defined as partial responders, and subjects not achieving a 50% improvement (reduction) in PASI score at week 12 compared with baseline were defined as non-responders. Table 1 The 16-item Psoriasis Symptom Diary Item stem 1 Overall, how severe was your psoriasis-related itching over the past 24 h? 2 Overall, how bothered were you by your psoriasis-related itching over the past 24 h? 3 Overall, how severe was your psoriasis-related stinging over the past 24 h? 4 Overall, how bothered were you by your psoriasis-related stinging over the past 24 h? 5 Overall, how severe was your psoriasis-related burning over the past 24 h? 6 Overall, how bothered were you by your psoriasis-related burning over the past 24 h? 7 Overall, how severe was the pain from your psoriasis-affected skin cracking over the past 24 h? 8 Overall, how bothered were you by the pain from your psoriasisaffected skin cracking over the past 24 h? 9 Overall, how severe was your psoriasis-related pain over the past 24 h? 10 Overall, how bothered were you by your psoriasis-related pain over the past 24 h? 11 Overall, how severe was your psoriasis scaling over the past 24 h? 12 Overall, how bothered were you by your psoriasis scaling over the past 24 h? 13 Overall, how noticeable did you think the color of your psoriasisaffected skin was over the past 24 h? 14 Overall, how much did you try to hide your psoriasis-affected skin over the past 24 h? 15 Overall, how much did your psoriasis cause you to avoid activities with other people over the past 24 h? 16 Overall, how embarrassed were you because of your psoriasis over the past 24 h? Response anchors (11-point numeric rating scale) 0 = No itching 10 = Itching as bad as you 0 = No stinging 10 = Stinging as bad as you 0 = No burning 10 = Burning as bad as you 0 = No pain 10 = Pain as bad as you 0 = No pain 10 = Pain as bad as you 0 = No scaling 10 = Scaling as bad as you 0 = Not at all noticeable 10 = Noticeable as bad as 0 = Did not try to hide at all 10 = Totally avoided being seen by others 0 = You did not avoid other people 10 = Avoided other people as much as you ever have 0 = No embarrassment 10 = Embarrassment as bad as If the respondent selected a response of 0 for the severity item, the corresponding bother item was not asked and was scored as 0. ª 2015 The International Society of Dermatology International Journal of Dermatology 2016, 55, e147 e155

4 e150 Report Validation of the Psoriasis Symptom Diary Strober et al. Investigator s Global Assessment (modified 2011) The IGA rating scale is a CRO measure intended to give an overall assessment of a person s psoriatic disease state in terms of coloration, thickness, and scaling of the psoriatic lesions (Table 2). 9 A co-primary efficacy endpoint in the ERASURE and FIXTURE studies was based on the IGA as follows: a subject was considered as an IGA 0 or 1 responder if the subject achieved a score of 0 (clear) or 1 (almost clear) and had improved by at least 2 points on the IGA scale compared with baseline. Dermatology Life Quality Index The DLQI is a widely used general dermatology PRO measure. It is a 10-item disability index designed to assess health-related quality of life (HRQoL) in adult subjects with skin diseases such as eczema, psoriasis, acne, and viral warts. 10 The DLQI addresses six domains: symptoms and feeling; sleep; leisure and daily activities; school and holidays; personal relationships; and treatment. Each question refers to the past week and offers four categories of response (not at all, a little, a lot, very much). EuroQoL 5-Dimension Health Status Questionnaire The EQ-5D is a generic PRO measure that is widely used to assess subjects health status on five dimensions (mobility, selfcare, usual activity, pain/discomfort, and anxiety/depression). 11 This study uses the health index of the EuroQoL questionnaire based on a visual analog scale (VAS) ranging from 0 (worst health state) to 100 (best health state). Table 2 Investigator Global Assessment (modified 2011) rating scale Score Short description Detailed description 0 Clear No signs of psoriasis; postinflammatory hyperpigmentation may be present 1 Almost clear Normal to pink coloration of lesions; no thickening; no to minimal focal scaling 2 Mild Pink to light red coloration; just detectable to mild thickening; predominantly fine scaling 3 Moderate Dull bright red, clearly distinguishable erythema; clearly distinguishable to moderate thickening; moderate scaling 4 Severe Bright to deep dark red coloration; severe thickening with hard edges; severe/coarse scaling covering almost all or all lesions Nail involvement is not assessed. Patient Global Impression of Change The PGIC question Since the start of this study, how would you rate the overall impact of psoriasis on your life right now? was administered at the end of each week via the electronic device to capture patient-reported change using a 7-point response scale (1 = a great deal worse, 2 = moderately worse, 3 = a little worse, 4 = about the same, 5 = a little better, 6 = moderately better, and 7 = a great deal better). Additionally, for the responsiveness analysis, categories 1 and 2 were combined to indicate moderately to a great deal worse, and categories 6 and 7 were combined to indicate moderately to a great deal better. Analytic methods Test retest reliability Test retest reliability provides an evaluation of reliability by comparing scores for a subgroup of subjects who are classified as stable in the constructs measured across two time periods of no anticipated change. Intraclass correlation coefficients (ICCs) were computed for each of the 16 PSD items using data from screening week 1 as the test administration and data from screening week 2 as the retest administration. 12 Although no standards exist for judging the magnitude of reliability coefficients for individual items, it is generally recommended that ICCs be at least 0.70 for multiitem scales. 13 Convergent and discriminant validity One of the most important aspects of validity is construct validity, which describes the relationships among multiple indicators of a construct and the degree to which they follow predictable patterns. 14 In traditional construct validity evaluations, a priori hypotheses are tested through correlation analyses demonstrating stronger relationships among measures addressing similar concepts (convergent validity) and weaker relationships with measures addressing disparate concepts (divergent validity). The following construct validity hypotheses were tested using the absolute magnitude of the correlation coefficient at least as large as 0.50 (r 0.50) as the threshold defining a strong correlation: (i) correlations were expected to be strongest between each PSD severity item and its corresponding annoyance item; (ii) stronger correlations were expected between items on symptom severity, and somewhat weaker correlations were expected between items on severity and items addressing the impact of psoriasis (i.e. the need to avoid activities and embarrassment); (iii) the PSD severity items were expected to be more strongly associated with the PASI and DLQI than with the EQ-5D VAS; and (iv) relatively weak correlations (r < 0.20) were anticipated between the PSD items and the other outcome measures at baseline as a result of restricted ranges in the outcome scores (PASI, IGA, EQ-5D, International Journal of Dermatology 2016, 55, e147 e155 ª 2015 The International Society of Dermatology

5 Strober et al. Validation of the Psoriasis Symptom Diary Report e151 and DLQI). However, by week 12, moderate to strong correlations were anticipated. Known-groups validity Known-groups validity is an aspect of construct validity that evaluates whether an item is able to distinguish between groups that are known to differ based on auxiliary information. Differences in average PSD items by subgroups based on PASI tertiles and the IGA (0 and 1) were compared using analysis of variance. Sensitivity to change It is important to provide evidence regarding the sensitivity of PSD items to detect change, or responsiveness, where expected. Therefore, correlations of item-level PSD change scores (baseline to week 12) with changes in the validating measures were computed (PASI, IGA, EQ-5D and DLQI). Cohen provided the following guideline for interpreting correlation coefficients: absolute values of correlations of 0.50 or greater are considered strong, correlations that fall between 0.10 and 0.50 are moderate, and those of less than 0.10 are weak. 15 Interpretation of change To identify subjects who experienced a significant change in their disease state over the course of treatment and who reported that they responded to treatment, a threshold, or responder definition characterizing a meaningful change in the scores of the measure should be determined. For the PSD, Strober and colleagues used two methods recommended in the final PRO guidance to establish responder definitions: the anchor-based method, and cumulative distribution function (CDF) plots depicting the range of the change in scores by treatment arm. 3,5 The proportion of patients in the Phase III studies who achieved the thresholds previously identified from the Phase II data for the PGIC anchor a little better was computed, and the CDF plots were used to facilitate the evaluation of treatment response across a range of potential responder definitions. The finding that the treatment group has the highest percentage of responders at a selected responder definition, or change score, will be considered the most beneficial. Results A total of 820 men and women aged years and diagnosed with moderate to severe psoriasis (baseline mean standard deviation PASI score: ; 36.5% of patients were rated as having severe disease on the IGA at baseline) were included in the psychometric evaluation. Patients, on average, had reported their first diagnosis of psoriasis 18.1 years prior to the study. The evaluation was conducted on the full 16 items of the diary. Because the seven PSD items on severity were the primary focus and the remaining nine PSD items assessing burden and daily impact performed similarly and as anticipated, the data presented here focus on the seven key PSD items on severity. Overall, the reliability, validity, and responsiveness of the PSD items using data from the two Phase III trials were comparable with the psychometric properties observed using data from the Phase II trial. 5 Notably, the psychometric analyses from Phase II and Phase III strongly support the reliability, construct validity, discriminating ability, and responsiveness of itching, pain, and scaling. The mean of the seven PSD severity items was higher at baseline than at week 12, indicating considerable improvement in symptoms (Appendix). The PSD severity items yielded high test retest reliability coefficients with ICCs of >0.91, well above the recommended threshold of 0.70 for test retest evaluations of multi-item tools (data not shown). 16 The magnitude and direction of the observed correlation coefficients were generally supportive of the hypothesized relationships between the PSD items on severity and the CRO (PASI and IGA) and additional PRO (DLQI and EQ-5D) measures (Table 3). Correlations were strongest between each PSD item on severity and its corresponding item on annoyance at baseline, ranging from 0.93 for the severity annoyance pair to 0.99 for the stinging, burning, and pain pairs (data not shown). Stronger correlations (r 0.74) were observed between the seven PSD severity items, and weaker correlations were observed between the seven PSD items on severity and items addressing the impact of psoriasis (items 2, 4, 6, 8, 10, and 12; r 0.60). Correlations between the PSD items on severity and the PASI, IGA, EQ-5D VAS, DLQI total, and DLQI items were found to lie in the anticipated direction and by week 12 were moderate to strong (ranging from 0.41 to 0.73 for all PSD items) in magnitude. Results from the known-group analysis were consistent with anticipated findings and provided evidence to support the discriminating ability of the PSD: the means of the PSD items on severity differed predictably and significantly in the PASI and IGA subgroups for all items on severity at baseline and at week 12. For example, mean scores on the items were lower in the subgroup characterized by the lowest PASI scores and higher in the subgroup characterized by the highest PASI scores. The responsiveness of the PSD was further confirmed by the Phase III data. Table 4 shows that changes in the seven PSD items on severity were moderately to strongly correlated with changes in the PASI, IGA, and DLQI ( ). ª 2015 The International Society of Dermatology International Journal of Dermatology 2016, 55, e147 e155

6 e152 Report Validation of the Psoriasis Symptom Diary Strober et al. Table 3 Construct validity correlations using the Psoriasis Area and Severity Index (PASI), the Investigator s Global Assessment (modified 2011) (IGA), the EuroQoL 5-Dimension Health Status Questionnaire (EQ-5D), and the Dermatology Life Quality Index (DLQI) at week 12 (n = ) PSD item PASI IGA EQ-5D VAS DLQI total 1 Itching Stinging Burning Pain/cracking Pain Scaling Notice color PSD, Psoriasis Symptom Diary; VAS, visual analog scale. Annoyance-related and daily impact items are not presented. Absolute values of correlations of 0.50 are strong; correlations of are moderate; and correlations of <0.10 are weak. All correlations are significant (P 0.01). In addition to generating data to support the psychometric properties of the PSD, the Phase III data were used to further inform the interpretability of scores produced by the instrument. Using the Phase II-derived anchorbased PGIC thresholds to define meaningful change, the Phase III analysis estimated that a larger proportion of subjects in the secukinumab treatment arms experienced meaningful change in key items on symptom severity than in the placebo arm (Table 5). For example, the percentage of patients in the secukinumab 300 mg group classified as a little better varied between 73 and 89%. This compared with percentages of 58 69% in the etanercept 50 mg group and 13 20% in the placebo group. The Table 4 Responsiveness: correlations using change from baseline to week 12 for the Psoriasis Area and Severity Index (PASI), the Investigator s Global Assessment (modified 2011) (IGA) and the Dermatology Life Quality Index (DLQI) PSD item CDF plots (Fig. 1a f) revealed that the percentage of responders was consistently higher in the secukinumab treatment arms and the etanercept treatment arm (included in FIXTURE) than in the placebo arms across the entire range of changes and percentage changes. Notably, the results of the psychometric evaluation for the remaining nine PSD items (2, 3, 4, 6, 8, 10, 12, 14, 16) were similar to the results for items on severity emphasized in this manuscript (data not shown), further supporting the reliability and validity of the PSD. Discussion PASI (n = 682) IGA (n = 682) DLQI (n = 666) 1 Itching Stinging Burning Pain/cracking Pain Scaling Notice color PSD, Psoriasis Symptom Diary. Absolute values of correlations of 0.50 are strong; correlations of are moderate; and correlations of <0.10 are weak. All correlations are significant (P 0.01). Many of the symptoms associated with chronic plaque psoriasis (e.g. itching and pain) are subjective experiences and can be assessed only by the patient. Other psoriasis- Table 5 Proportion of subjects achieving key Phase II-derived Patient Global Impression of Change (PGIC) improvement level thresholds by treatment group (baseline to week 12) Proportion of subjects achieving Phase II-derived PGIC threshold A little better, n/n, n Moderately or a great deal better, n/n, n PSD item on severity 150 mg Secukinumab 300 mg Secukinumab 50 mg Etanercept Placebo 150 mg Secukinumab 300 mg Secukinumab 50 mg Etanercept Placebo 1 Itching 0.79, , , , , , , , 10 3 Stinging 0.67, , , , , , , , 13 5 Burning 0.71, , , , , , , , 15 7 Pain/cracking 0.69, , , , , , , , 16 9 Pain 0.65, , , , , , , , Scaling 0.80, , , , , , , , 7 13 Notice color 0.83, , , , , , , , 4 PSD, Psoriasis Symptom Diary. International Journal of Dermatology 2016, 55, e147 e155 ª 2015 The International Society of Dermatology

7 Strober et al. Validation of the Psoriasis Symptom Diary Report e153 Figure 1 Cumulative distribution function plots for change from baseline to week 12 for (a) itching, (b) stinging, (c) burning, (d) pain from cracking, (e) pain, and (f) scaling related experiences, although observable by others (e.g. scaling, flaking, skin color), can also be assessed via patient self-report. The PSD items were developed in accordance with the recommendations put forth in the FDA s PRO guidance for measuring the severity of chronic plaque psoriasis symptoms from the patient s perspective, and included in the studies of patients with moderate to severe psoriasis as recommended by the Medical Advisory Board of the National Psoriasis Foundation. 1,3 Although several clinician-reported psoriasisspecific measures exist for assessing various aspects of observable psoriasis disease severity, such as the PASI and the IGA, the PSD provides a daily assessment of individual symptoms rated as key by patients when evaluating plaque psoriasis, including itching, stinging, burning, pain from skin cracking, skin pain, scaling, and alterations in skin color. The current analysis builds on previous work conducted to validate the PSD for use in patients with chronic plaque psoriasis. 4,5 An initial evaluation of the PSD conducted using Phase II data resulted in the removal of four items and provided preliminary evidence ª 2015 The International Society of Dermatology International Journal of Dermatology 2016, 55, e147 e155

8 e154 Report Validation of the Psoriasis Symptom Diary Strober et al. to support the reliability, validity, and ability to detect change of the seven items on severity. 5 The Phase II data were also used to inform the interpretability of scores produced by the PSD items and provided the foundation for a responder definition for evaluating treatment efficacy. 5 In the present analysis, PSD data from two pivotal Phase III studies were evaluated to provide additional support for the reliability, validity, and responsiveness of the PSD for measuring the severity, annoyance, and daily impacts of patient-reported, psoriasis-related symptoms. The Phase III psychometric evaluation results confirmed the Phase II results. The reliability coefficients were larger than the 0.70 criterion recommended in the psychometric literature. 16 Coefficients for correlations between the PSD items and the two clinician-reported psoriasis-specific measures (PASI and IGA), as well as the two generic dermatology and HRQoL measures (DLQI and EQ-5D), followed patterns that were explicitly hypothesized a priori, providing evidence of convergent and divergent validity. The correlations in the change from baseline to week 12 between the PSD items and the PASI, IGA, DLQI, and EQ-5D measures indicate that PSD items can be used to assess treatment benefit in patients with plaque psoriasis. Finally, the a priori responder threshold definitions determined in the analysis by Strober et al. 5 using Phase II data were applied in the current evaluation and demonstrated that larger proportions of subjects in the secukinumab treatment arms than in the placebo arms of the Phase III studies were characterized as indicating meaningful change on PSD severity items (measuring psoriasis-related symptoms). This finding is consistent with the results demonstrated by the co-primary endpoints, the PASI 75 and IGA, reported by Langley and colleagues. 6 Consistently, a significantly larger proportion of subjects in the secukinumab treatment arm than in the placebo arm showed improvement in the CRO and PRO. These Phase III findings, along with the Phase II psychometric evaluation reported by Strober and colleagues, 5 support the use of the PSD in future studies to monitor the severity of psoriasis, as well as to facilitate treatment comparisons. In combination with clinical measures of skin clearance, the PSD, particularly the seven key items on severity, will provide decision-makers with a more comprehensive assessment and will ultimately supply the information necessary to make more informed decisions about patient care in psoriasis. Acknowledgments The authors thank all the investigators who participated in the evaluations of the Psoriasis Symptom Diary. We also thank Theresa Coles, Patient Reported Outcomes Division RTI-HS, for her assistance with the analysis. These findings are the result of work supported by Novartis Pharmaceuticals Corp., East Hanover, NJ, USA. Conflicts of interest YZ and JN are employees of and own stocks in Novartis Pharmaceuticals Corp. CP is an employee of and owns stock in Novartis Pharma AG. AG and MHT were employees of Novartis Pharmaceuticals Corp. when these analyses were conducted. BS has served as an advisory board member for AbbVie, Amgen, Janssen, Pfizer, Novartis, UCB Pharma, Medac and Celgene, as a consultant for AbbVie, Amgen, Janssen, Novartis, Pfizer, Celgene, Maruho, Medac, Xenoport and Lilly, and as a paid speaker for AbbVie. ABG has served as a consultant or advisory panel member for Amgen, Astellas, Akros, Centocor (Janssen), Celgene, Bristol-Myers Squibb, Beiersdorf, Abbott Laboratories (AbbVie), TEVA, Actelion, UCB, Novo Nordisk, Novartis, Dermipsor, Incyte, Pfizer, Canfite, Lilly, Coronado, Vertex, Karyopharm, CSL Behring Biotherapies for Life, GlaxoSmithKline, Xenoport, Catabasis, Sanofi-Aventis and DUSA, and has received research and education grants (proceeds paid to Tufts Medical Center) from Centocor (Janssen), Amgen, Abbott (AbbVie), Novartis, Celgene, Pfizer, Lilly, Coronado, Levia, Merck and Xenoport. BEE has received honoraria as a consultant from Eli Lilly, Pfizer and Novartis, and has performed clinical studies for Abbvie, Amgen, Merck, Lilly, Novartis, Pfizer, Valeant and Viamet; all funds derived from her participation have been paid to her university. Mark Lebwohl is an employee of the Mount Sinai Medical Center which receives research funds from AbGenomics, AbbVie, Amgen, Anacor, Aqua, Canfite Biopharma, Celgene, Clinuvel, Coronado Biosciences, Ferndale, Lilly, Janssen Biotech, LEO Pharmaceuticals, Merz, Novartis, Pfizer, Sandoz, Sun Pharmaceuticals, and Valeant. LMN, LDM and MM are paid consultants for Novartis Pharmaceuticals. References 1 Gottlieb AB, Matheson RT, Lowe N, et al. A randomized trial of etanercept as monotherapy for psoriasis. Arch Dermatol 2003; 139: Lebwohl MG, Bachelez H, Barker J, et al. Patient perspectives in the management of psoriasis: results from the population-based Multinational Assessment of Psoriasis and Psoriatic Arthritis Survey. J Am Acad Dermatol 2014; 70: US Food and Drug Administration (FDA). Guidance for industry. Patient-reported outcome measures: use in medical product development to support labeling claims. December International Journal of Dermatology 2016, 55, e147 e155 ª 2015 The International Society of Dermatology

9 Strober et al. Validation of the Psoriasis Symptom Diary Report e155 GuidanceComplianceRegulatoryInformation/Guidances/ UCM pdf [accessed on March 18, 2015]. 4 Lebwohl M, Swensen AR, Nyirady J, et al. The Psoriasis Symptom Diary: development and content validity of a novel patient-reported outcome instrument. Int J Dermatol 2014; 53: Strober B, Gottlieb AB, Elewski B, et al. Item-level psychometric properties for a new patientreported symptom diary. Value Health 2013; 16: Langley RG, Elewski BE, Lebwohl M, et al. Secukinumab in plaque psoriasis results of two phase 3 trials. N Engl J Med 2014; 371: Committee for Medicinal Products for Human Use, European Medicines Agency for the Evaluation of Medicines for Human Use. Guideline on Clinical Investigation of Medicinal Products Indicated for the Treatment of Psoriasis. CHMP/EWP/2454/02. London: CHMP, Henseler T, Schmitt-Rau K. A comparison between BSA, PASI, PLASI, and SAPASI as measures of disease severity and improvement by therapy in patients with psoriasis. Int J Dermatol 2008; 47: Langley RG, Feldman SR, Nyirady J, et al. The 5-point Investigators Global Assessment (IGA) Scale: a modified tool for evaluating plaque psoriasis severity in clinical trials. J Dermatolog Treat 2015; 26: Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI): a simple practical measure for routine clinical use. Clin Exp Dermatol 1994; 19: Brooks R, Rabin R, de Charro F, eds. The Measurement and Valuation of Health Status Using EQ-5D: A European Perspective: Evidence from the EuroQoL BIO MED Research Programme. Rotterdam: Kluwer Academic Publishers, Schuck P. Assessing reproducibility for interval data in health-related quality of life questionnaires: which coefficient should be used? Qual Life Res 2004; 13: Nunnally JC, Bernstein IH. Psychometric Theory, 3rd edn. New York, NY: McGraw-Hill, Messick S. Validity. In: R. L. Linn (Ed.), Educational measurement, 3rd edn. (pp ). New York: Macmillan, Cohen J. Statistical Power Analysis for the Behavioral Sciences, 2nd edn. Hillsdale, NJ: Lawrence Erlbaum Associates, Streiner DL, Norman GR. Health Measurement Scales: A Practical Guide to Their Development and Use, 2nd edn. New York, NY: Oxford University Press, Appendix Descriptive statistics for items on symptom severity on the Psoriasis Symptom Diary (PSD) at baseline and at week 12 PSD item n Mean (SD) Percentile 25th 50th 75th Range Baseline 1 Itching (2.4) Stinging (3.0) Burning (3.0) Pain/cracking (3.0) Pain (3.0) Scaling (2.5) Notice color (2.3) Week 12 1 Itching (2.9) Stinging (2.7) Burning (2.7) Pain/cracking (2.7) Pain (2.8) Scaling (2.9) Notice color (3.0) SD, standard deviation. ª 2015 The International Society of Dermatology International Journal of Dermatology 2016, 55, e147 e155

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