Reweighting estimators to extend the external validity of clinical trials: methodological considerations.

Methods to extend the strong internal validity of randomized controlled trials to reliably estimate treatment effects in target populations are gaining attention. This paper enumerates steps recommended for undertaking such extended inference, discusses currently viable choices for each one, and provides recommendations. We demonstrate a complete extended inference from a clinical trial studying a pharmaceutical treatment for Alzheimer's disease (AD) to a realistic target population of European residents diagnosed with AD. This case study highlights approaches to overcoming practical difficulties and demonstrates limitations of reliably extending inference from a trial to a real-world population.

Improvement from ixekizumab treatment in patients with psoriatic arthritis who have had an inadequate response to one or two TNF inhibitors.

OBJECTIVE: To evaluate the efficacy of ixekizumab (IXE), a monoclonal antibody selectively targeting interleukin-17A, in patients with inadequate response to one or two TNF inhibitors (TNFi). METHODS: A phase 3 study (SPIRIT-P2; NCT02349295) randomized patients with PsA with inadequate response or intolerance to one or two TNFi to receive 80-mg IXE every 2 weeks (n = 123) or every 4 weeks (n = 122) after a 160-mg starting dose or placebo (PBO; n = 118) through week 24. This post hoc analysis used data from inadequate responders to one or two TNFi, measuring the percentage achieving: ≥50% improvement in ACR response criteria (ACR50) and 100% improvement from baseline in the Psoriasis Area and Severity Index (PASI 100), ACR50, improvement in HAQ-Disability Index (HAQ-DI) ≥0.35, minimal disease activity (MDA), European League Against Rheumatism (EULAR) Good Response Criteria [improvement in Disease Activity Score 28 CRP (DAS28-CRP) >1.2], and Disease Activity in PsA (DAPSA) ≤14. RESULTS: There were no significant differences in baseline characteristics between inadequate responders to one and two TNFi. At week 24, significantly more patients irrespective of previous TNFi experience receiving IXE than PBO achieved ACR50, HAQ-DI ≥0.35 improvement, MDA, EULAR good response, and DAPSA ≤14, and significantly more patients with inadequate response to one TNFi receiving IXE than PBO achieved ACR50 and PASI 100. Improvement persisted in all measures through week 52. CONCLUSION: IXE improved the signs and symptoms of PsA in a population of difficult-to-treat patients with inadequate response to one or two TNFi.

On the design and the analysis of stratified biomarker trials in the presence of measurement error.

A major emphasis in precision medicine is to optimally treat subgroups of patients who may benefit from certain therapeutic agents. And as such, enormous resources and innovative clinical trials designs in oncology are devoted to identifying predictive biomarkers. Predictive biomarkers are ones that will identify patients that are more likely to respond to specific therapies and they are usually discovered through retrospective analysis from large randomized phase II or phase III trials. One important design to consider is the stratified biomarker design, where patients will have their specimens obtained at baseline and the biomarker status will be assessed prior to random assignment. Regardless of their biomarker status, patients will be randomized to either an experimental arm or the standard of care arm. The stratified biomarker design can be used to test for a treatment-biomarker interaction in predicting a time-to event outcome. Many biomarkers, however, are derived from tissues from patients, and their levels may be heterogeneous. As a result, biomarker levels may be measured with error and this would have an adverse impact on the power of a stratified biomarker clinical trial. We present a trial design and an analysis framework for the stratified biomarker design. We show that the naïve test is biased and provide bias-corrected estimators for computing the sample size and the 95% confidence interval when testing for a treatment-biomarker interaction in predicting a time to event outcome. We propose a sample size formula that adjusts for misclassification and apply it in the design of a phase III clinical trial in renal cancer.

Rapid and sustained improvements in patient-reported signs and symptoms with ixekizumab in biologic-naive and TNF-inadequate responder patients with psoriatic arthritis.

OBJECTIVES: To analyse the onset and sustainability of patient-reported improvements in symptoms of psoriatic arthritis (PsA) following treatment with ixekizumab (IXE) up to Week 108. METHODS: In patients with active PsA, either naive to biological DMARDs (SPIRIT-P1) or having inadequate response or intolerance to 1 or 2 prior TNF-inhibitors (TNFi­experienced; SPIRIT-P2), we analysed the change from baseline in joint pain visual analogue scale (VAS; 0-100 scale), patient global assessment (PatGA VAS; 0-100 scale), fatigue numerical rating scale (NRS; 0 [no fatigue] to 10 [worst imaginable]), and Health Assessment Questionnaire-Disability Index (HAQ-DI; 0-3), up to Week 108. RESULTS: IXE-treated patients compared to placebo reported rapid and statistically significant improvement in pain VAS, PatGA, and HAQ-DI as early as Week 1 and this benefit was sustained or increased through Week 108. Fatigue scores improved in IXE-treated patients compared to placebo in both studies; results were statistically significant at Week 24 only in SPIRIT-P2. Improvements in fatigue with IXE were sustained over 2 years. The improvements observed in these patient-reported outcomes (PROs) were consistent in biologic-naive or TNFi-experienced patients. CONCLUSIONS: Patients treated with IXE versus PBO achieved significantly greater improvements and showed faster onset of improvements in patient-reported outcomes measuring symptoms and impact of PsA. Responses were sustained over 2 years and were generally consistent regardless of prior TNFi experience.

A comparison of reweighting estimators of average treatment effects in real world populations.

Regulatory agencies typically evaluate the efficacy and safety of new interventions and grant commercial approval based on randomized controlled trials (RCTs). Other major healthcare stakeholders, such as insurance companies and health technology assessment agencies, while basing initial access and reimbursement decisions on RCT results, are also keenly interested in whether results observed in idealized trial settings will translate into comparable outcomes in real world settings-that is, into so-called "real world" effectiveness. Unfortunately, evidence of real world effectiveness for new interventions is not available at the time of initial approval. To bridge this gap, statistical methods are available to extend the estimated treatment effect observed in a RCT to a target population. The generalization is done by weighting the subjects who participated in a RCT so that the weighted trial population resembles a target population. We evaluate a variety of alternative estimation and weight construction procedures using both simulations and a real world data example using two clinical trials of an investigational intervention for Alzheimer's disease. Our results suggest an optimal approach to estimation depends on the characteristics of source and target populations, including degree of selection bias and treatment effect heterogeneity.

Clinically meaningful improvement in work productivity loss in active psoriatic arthritis: post-hoc analysis of SPIRIT-P1 and SPIRIT-P2 trials.

OBJECTIVES: To determine the proportion of patients in Phase 3 studies (SPIRIT-P1 and SPIRIT-P2) who achieved minimal clinically important difference (MCID) for work productivity loss and activity impairment domains of Work Productivity and Activity Impairment Specific Health Problem (WPAI-SHP) questionnaire. METHODS: In the SPIRIT-P1 study, comprising a 24-week double-blind treatment period, biologic-naive patients with active psoriatic arthritis (PsA) were randomised to ixekizumab 80 mg every 4 weeks (IXEQ4W) or every 2 weeks (IXEQ2W) (starting dose of 160 mg), adalimumab 40 mg every 2 weeks (ADAQ2W), or placebo. SPIRIT-P2 enrolled tumour necrosis factor inhibitor (TNFi)-experienced patients who were randomised to receive IXEQ4W, IXEQ2W or placebo for 24 weeks of double-blind treatment. In this post-hoc analysis, we investigated the proportion of patients in SPIRIT-P1 and P2 studies who achieved 15% improvement in work productivity loss and 20% improvement in activity impairment domains of WPAI-SHP during double- blind treatment period. RESULTS: In SPIRIT-P1, at Week 24, 57.1% and 55.8% of biologic-naive patients on IXEQ4W and ADAQ2W respectively, achieved MCID estimates for work productivity loss compared to 25.6% of patients treated with placebo. The proportion of ixekizumab- and adalimumab-treated patients achieving MCIDs for activity impairment were significantly higher (IXEQ4W: p<0.001; ADAQ2W: p=0.001) com- pared to placebo-treated patients at Week 24. In SPIRIT-P2, significantly more TNFi-experienced patients on IXEQ4W (p<0.001) achieved MCIDs compared to placebo at Week 24. CONCLUSIONS: Treatment with ixekizumab was associated with clinically meaningful improvements in WPAI-SHP domains in biologic-naive and TNFi- experienced patients with active PsA.

Comparison of real-world treatment patterns among patients with psoriasis prescribed ixekizumab or secukinumab.

BACKGROUND: Real-world data on treatment patterns associated with use of interleukin-17A inhibitors in psoriasis are lacking. OBJECTIVE: To compare treatment patterns between ixekizumab or secukinumab users in clinical practice. METHODS: A retrospective cohort study included patients with psoriasis aged ≥18 years treated with ixekizumab or secukinumab between March 1, 2016, and May 31, 2018 in IBM MarketScan (IBM Corp, Armonk, NY) databases. Inverse probability of treatment weighting and multivariable models were used to address cohort imbalances and estimate the risks of nonpersistence (60-day gap), discontinuation (≥90-day gap), switching, and the odds of adherence. RESULTS: The study monitored 645 ixekizumab users for 13.7 months and 1152 secukinumab users for 16.3 months. Ixekizumab users showed higher persistence rate (54.8% vs 45.1%, P < .001) and lower discontinuation rate (37.8% vs 47.5%, P < .001) than secukinumab. After multivariable adjustment, ixekizumab users had lower risks of nonpersistence (hazard ratio, 0.82; 95% confidence interval, 0.71-0.95) and discontinuation (hazard ratio, 0.82; 95% confidence interval, 0.70-0.96), and higher odds of high adherence to treatment measured by a medication possession ratio ≥80% (hazard ratio, 1.31; 95% confidence interval, 1.07-1.60). The risk of switching was similar between cohorts. LIMITATIONS: Disease severity and clinical outcomes were unavailable. CONCLUSION: Ixekizumab users demonstrated longer drug persistence, lower discontinuation rate and risk of discontinuation, higher likelihood of adherence, and similar risk of switching compared with secukinumab users in clinical practices.

The Validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD): The development and reliability testing of a novel clinical outcome measurement instrument for the severity of atopic dermatitis.

BACKGROUND: An Investigator Global Assessment (IGA) is recommended by health agencies for drug registration in atopic dermatitis (AD). Current IGA scales lack standardization. OBJECTIVES: To develop an IGA scale, training module, and clinical certification examination for use in AD trials; establish content validity; and assess reliability. METHODS: Expert dermatologists participated in the development of the validated IGA for AD (vIGA-ADTM). Reliability (interrater and intrarater) was assessed by 2 web-based surveys. Clinical certification for investigators consisted of a training module and examination. RESULTS: Expert consensus was achieved around a 5-point IGA scale including morphologic descriptions, and content validity was established. Survey 1 showed strong interrater reliability (Kendall's coefficient of concordance W [Kendall's W], 0.809; intraclass correlation [ICC], 0.817) and excellent agreement (weighted kappa, 0.857). Survey 2, completed 5 months after training of dermatologists, showed improvements in scale reliability (Kendall's W, 0.819; ICC, 0.852; weighted kappa, 0.889). In this study, 627 investigators completed vIGA-AD training and certification. LIMITATIONS: Ratings were assessed on photographs. CONCLUSION: A validated IGA scale and training module were developed with the intent of harmonizing assessment of disease severity in AD trials. Strong reliability and excellent agreement between assessments were observed.

Ixekizumab treatment and the impact on SF-36: results from three pivotal phase III randomised controlled trials in patients with moderate-to-severe plaque psoriasis.

PURPOSE: To assess improvements in health-related quality of life (HRQoL) with ixekizumab treatment in patients with moderate-to-severe psoriasis. METHODS: Adults with plaque psoriasis were enrolled in phase III, double-blind, randomised, controlled trials (UNCOVER-1, UNCOVER-2, or UNCOVER-3). All 3 protocols included a 12-week, placebo-controlled induction period; UNCOVER-2 and UNCOVER-3 also had an active-control group (50 mg etanercept) during induction. After induction, patients in UNCOVER-1 and UNCOVER-2 entered a 48-week withdrawal (maintenance) period (Weeks 12-60), during which Week-12 sPGA (0,1) responders were rerandomized to receive placebo, or 80 mg ixekizumab every 4 weeks (Q4W) or 12 weeks. As a secondary objective, HRQoL was measured by the generic Medical Outcomes Survey Short Form-36 (SF-36) at baseline and Weeks 12 and 60. Changes in mean SF-36 Physical and Mental Component Summary (PCS and MCS) and domain scores and proportions of patients reporting improvements ≥ minimal important differences in SF-36 scores were compared between groups. RESULTS: At Week 12, ixekizumab-treated patients (both dose groups in UNCOVER-1, -2, and -3) reported statistically significantly greater improvements in mean SF-36 PCS and MCS and all 8 SF-36 domain scores versus placebo. Further, more ixekizumab-treated patients than placebo-treated patients reported at least minimal treatment responses in SF-36 PCS and MCS scores and domain scores. Overall improvements in SF-36 PCS and MCS scores were maintained through Week 60. CONCLUSIONS: Ixekizumab-treated patients reported statistically significant improvements in HRQoL at 12 weeks that persisted through 1 year.

Nail Psoriasis Does Not Affect Skin Response to Ixekizumab in Patients With Moderate-To-Severe Psoriasis.

Background: Presence of nail psoriasis in patients with plaque psoriasis may be an indicator of greater disease severity. Previously, patients with nail psoriasis have had delayed skin clearance after treatment compared to patients without nail psoriasis. Objective: This post-hoc analysis evaluated the efficacy of ixekizumab in clearance of plaque psoriasis in patients with and without nail psoriasis. Methods: Data were integrated from two phase 3 clinical trials (UNCOVER-2 and UNCOVER-3; N=2570) to assess skin response over 12 weeks of treatment with subcutaneous placebo, etanercept, or ixekizumab in patients with and without nail psoriasis. Nail response was assessed using Nail Psoriasis Severity Index (NAPSI) and skin response was assessed as the percentage of patients achieving 75%, 90%, or 100% improvement in Psoriasis Area and Severity Index (PASI 75, PASI 90, PASI 100) or a score of 0 or 1 on the static Physician Global Assessment (sPGA 0 or 0,1). Results: From baseline to week 12, progressive improvement in psoriasis occurred with ixekizumab and etanercept treatment; however, significantly more patients with nail psoriasis than without mild PASI 75 at weeks 8 and 12 and sPGA (0,1) at week 12 with ixekizumab. Significantly more patients with severe nail psoriasis than mild achieved PASI 75 at weeks 8 and 12 with ixekizumab. Conclusion: Patients with and without nail psoriasis responded well to ixekizumab. The presence of nail psoriasis did not negatively affect skin clearance in patients treated with ixekizumab. ClinicalTrials.gov: NCT01597245, NCT01646177 J Drugs Dermatol. 2020;19(8):741-746. doi:10.36849/JDD.2020.5116.

The contribution of joint and skin improvements to the health-related quality of life of patients with psoriatic arthritis: a post hoc analysis of two randomised controlled studies.

OBJECTIVE: Determine the contribution of joint and skin improvements to health-related quality of life (HRQoL) in patients with psoriatic arthritis (PsA). METHODS: SPIRIT-P1 and SPIRIT-P2 are phase 3 trials investigating ixekizumab, an interleukin-17A antagonist, in the treatment of patients with active PsA. Patients were randomised to ixekizumab or placebo. Outcomes included the Disease Activity Index for Psoriatic Arthritis (DAPSA), the Psoriasis Area and Severity Index (PASI), the European Quality of Life-Five Dimensions (EQ-5D) Visual Analogue Score (VAS), the 36-Item Short-Form Health Survey (SF-36) and the Work Productivity and Activity Impairment (WPAI) Questionnaire. The contribution of joint and skin improvements to HRQoL was modelled using a smoothing spline method and depicted with response surface graphics. RESULTS: In this integrated analysis, 402 patients with PsA had baseline psoriasis of ≥3% of body surface area. We applied response surface modelling to this patient data set to investigate the relationship between DAPSA, PASI and HRQoL improvements at week 24. The greatest improvement in EQ-5D VAS was associated with the largest per cent improvements in both DAPSA and PASI together, rather than DAPSA or PASI alone. Similar observations were made in domains of SF-36 and WPAI. CONCLUSION: Optimal improvements in patients' HRQoL were dependent on successful treatment of both joint and skin symptoms.

Ixekizumab improves patient-reported outcomes in patients with active psoriatic arthritis and inadequate response to tumour necrosis factor inhibitors: SPIRIT-P2 results to 52 weeks.

OBJECTIVES: To report patient-reported outcomes (PROs) of ixekizumab-treated patients with psoriatic arthritis (PsA) and an inadequate response (IR) or intolerance to tumour necrosis factor inhibitors (TNFi) to 52 weeks. METHODS: In SPIRIT-P2, patients with active PsA and an IR or intolerance to TNFi were randomised to ixekizumab 80 mg every 4 weeks (IXEQ4W; N=122) or every 2 weeks (IXEQ2W; N=123), or placebo (PBO; N=118) during the initial 24-week double-blind treatment period. At Week 16, background therapy was modified for IRs; additionally, IRs in the placebo group were re-randomised (1:1) to IXEQ2W or IXEQ4W. Patients receiving ixekizumab at Week 24 received the same dose during the study remainder. Patients completed several PROs for PsA disease activity, skin, health-related quality of life (HRQOL, and work through Week 52. RESULTS: Ixekizumab-treated patients reported significant improvements versus PBO in 36-Item Short Form Health Survey version 2, European Quality of Life 5 Dimensions visual analogue scale, Bath Ankylosing Spondylitis Disease Activity Index (total score and question 2), and Work Productivity and Activity Impairment Questionnaire-Specific Health Problem (3 of 4 domains) through Week 24. At Week 24, 9% (PBO), 52% (IXEQ4W), and 50% (IXEQ2W) of patients reported Dermatology Life Quality Index scores of 0 or 1; 0% (PBO) and 24% (IXEQ4W and IXEQ2W) reported Itch Numeric Rating Scale score of 0. Where data were collected, improvements persisted through Week 52. CONCLUSIONS: In patients with PsA and an IR or intolerance to TNFi, ixekizumab significantly improved disease activity, skin symptoms, HRQOL, and work productivity to 52 weeks.

Thioridazine Enhances P62-Mediated Autophagy and Apoptosis Through Wnt/ß-Catenin Signaling Pathway in Glioma Cells.

Thioridazine (THD) is a common phenothiazine antipsychotic drug reported to suppress growth in several types of cancer cells. We previously showed that THD acts as an antiglioblastoma and anticancer stem-like cell agent. However, the signaling pathway underlying autophagy and apoptosis induction remains unclear. THD treatment significantly induced autophagy with upregulated AMPK activity and engendered cell death with increased sub-G1 in glioblastoma multiform (GBM) cell lines. Notably, through whole gene expression screening with THD treatment, frizzled (Fzd) proteins, a family of G-protein-coupled receptors, were found, suggesting the participation of Wnt/ß-catenin signaling. After THD treatment, Fzd-1 and GSK3ß-S9 phosphorylation (inactivated form) was reduced to promote ß-catenin degradation, which attenuated P62 inhibition. The autophagy marker LC3-II markedly increased when P62 was released from ß-catenin inhibition. Additionally, the P62-dependent caspase-8 activation that induced P53-independent apoptosis was confirmed by inhibiting T-cell factor/ß-catenin and autophagy flux. Moreover, treatment with THD combined with temozolomide (TMZ) engendered increased LC3-II expression and caspase-3 activity, indicating promising drug synergism. In conclusion, THD induces autophagy in GBM cells by not only upregulating AMPK activity, but also enhancing P62-mediated autophagy and apoptosis through Wnt/ß-catenin signaling. Therefore, THD is a potential alternative therapeutic agent for drug repositioning in GBM.

Ixekizumab improves patient-reported outcomes up to 52 weeks in bDMARD-naïve patients with active psoriatic arthritis (SPIRIT-P1).

Objective: To report patient-reported outcomes of patients with PsA treated with ixekizumab up to 52 weeks. Methods: In SPIRIT-P1, biologic-naïve patients with active PsA were randomized to ixekizumab 80 mg every 4 weeks (IXEQ4W; N = 107) or every 2 weeks (IXEQ2W; N = 103) following a 160 mg starting dose, adalimumab 40 mg every 2 weeks (ADA; N = 101) or placebo (PBO; N = 106) during the initial 24-week double-blind treatment period. At week 24 (week 16 for inadequate responders), ADA (8-week washout before starting ixekizumab) and PBO patients were re-randomized to IXEQ2W or IXEQ4W. Patients receiving ixekizumab at week 24 received the same dose during the extension period (EP) to week 52. Patients completed measures including the Dermatology Life Quality Index (DLQI), Itch Numeric Rating Scale, 36-Item Short Form Health Survey version 2, European Quality of Life 5 Dimensions Visual Analogue Scale and Work Productivity and Activity Impairment Questionnaire-Specific Health Problem. Results: The IXEQ4W, IXEQ2W and ADA groups reported significant improvements in DLQI at week 24; 22% (PBO), 53% (IXEQ4W), 63% (IXEQ2W) and 54% (ADA) of patients reported DLQI scores of 0/1. The IXEQ4W, IXEQ2W and ADA groups reported significant improvements in Itch Numeric Rating Scale, 36-Item Short Form Health Survey version 2 physical component summary and some domain scores, and European Quality of Life 5 Dimensions Visual Analogue Scale at weeks 12 and 24; and in three of four Work Productivity and Activity Impairment Questionnaire-Specific Health Problem domains at week 24. Results are also presented through week 52 for the EP. Conclusion: In biologic-naïve patients with active PsA, ixekizumab significantly improved skin symptoms, health-related quality of life and work productivity. Trial Registration: ClinicalTrials.gov, http://clinicaltrials.gov, NCT01695239; EU Clinical Trials Register, https://www.clinicaltrialsregister.eu, EudraCT2011-002326-49.

Ixekizumab Improved Patient-Reported Genital Psoriasis Symptoms and Impact of Symptoms on Sexual Activity vs Placebo in a Randomized, Double-Blind Study.

INTRODUCTION: Genital psoriasis (GenPs) is common and distressing for patients, but is often not discussed with physicians, and no previous clinical trials have assessed the effects of biologics specifically on GenPs and its associated symptoms. AIM: To report results for novel patient-reported outcomes (PROs) for the assessment of symptoms and the sexual impact of GenPs before and after treatment in the IXORA-Q study. METHODS: IXORA-Q (NCT02718898) was a phase III, randomized, double-blind, placebo-controlled study of ixekizumab (80 mg/2 weeks after 160-mg initial dose) vs placebo for GenPs. Men and women ≥18 years old with moderate-to-severe GenPs and body surface area (BSA) ≥1% were assessed through 12 weeks. MAIN OUTCOME MEASURE: GenPs symptoms were assessed using the 8-item Genital Psoriasis Symptoms Scale (GPSS), Genital Psoriasis Sexual Frequency Questionnaire (GenPs-SFQ), and Genital Psoriasis Sexual Impact Scale (GPSIS) (validation data presented in the supplemental materials), and the Dermatology Life Quality Index (DLQI) item 9. RESULTS: For patients receiving ixekizumab (N = 75) vs placebo (N = 74), statistically significant improvement in GenPs symptoms were seen from week 1 onward (GPSS total and individual items, all P < .005). Sexual activity avoidance owing to GenPs symptoms (GPSIS) decreased significantly with ixekizumab from week 4 onward (all P <.005), whereas impact of sexual activity on GenPs improved significantly with ixekizumab at weeks 2-8 (all P < 0.05). Ixekizumab resulted in significant improvement vs placebo by week 1 onward in limitations on frequency of sexual activity owing to GenPs (GenPs-SFQ item 2). Sexual difficulties caused by skin (DLQI item 9) decreased significantly with ixekizumab from week 2 onward (all P < .001). CLINICAL IMPLICATIONS: Both GenPs symptoms and impact on sexual activity improved rapidly and significantly with ixekizumab vs placebo through 12 weeks in patients with moderate-to-severe GenPs and BSA ≥1%. STRENGTH & LIMITATIONS: To our knowledge, this is the first phase III, randomized, placebo-controlled, double-blinded clinical trial to evaluate the effect of any treatment on the symptoms and sexual impact related to GenPs. The study did not include an active comparator owing to the lack of any well-established treatment for moderate-to-severe GenPs, and the period assessed herein was of relatively short duration. CONCLUSION: These validated PRO measures may aid in future clinical studies of GenPs and in facilitating discussions of GenPs symptoms and their impact between patients and clinicians. Yosipovitch G, Foley P, Ryan C. Ixekizumab improved patient-reported genital psoriasis symptoms and impact of symptoms on sexual activity vs placebo in a randomized, double-blind study. J Sex Med 2018;15:1645-1652.

Long-term Impact of Ixekizumab on Psoriasis Itch Severity: Results from a Phase III Clinical Trial and Long-term Extension.

Itching is a prevalent plaque psoriasis symptom. Ixekizumab, an IL-17A antagonist, has demonstrated rapid, significant improvements in itch severity over 12 weeks in Phase III psoriasis trials (UNCOVER-1, UNCOVER-2). We assessed the long-term (through 60 weeks) effect of ixekizumab maintenance therapy (80-mg ixekizumab every 4 weeks [IXEQ4W]) on itch severity, using the Itch Numeric Rating Scale, in psoriasis patients who received ixekizumab, placebo, or etanercept for 12 weeks in the Phase III UNCOVER-3 trial. After 12 weeks, patients either continued or switched to IXEQ4W. Mean improvements in itch severity achieved with 12 weeks of ixekizumab (-4.7 to -5.1) were maintained through 60 weeks with IXEQ4W (-4.9 to -5.0). Patients who initially received placebo or etanercept experienced rapid itch severity improvements after switching to ixekizumab at Week 12 (Week 12, placebo: -0.6; etanercept: -3.8; Week 60, placebo/IXEQ4W: -4.9; etanercept/IXEQ4W: -4.7). Ixekizumab maintenance therapy sustained improvements in itch severity through 60 weeks.

Real-world health outcomes in adults with moderate-to-severe psoriasis in the United States: a population study using electronic health records to examine patient-perceived treatment effectiveness, medication use, and healthcare resource utilization.

BACKGROUND: Little is known regarding real-world health outcomes data among US psoriasis patients, but electronic health records (EHR) that collect structured data at point-of-care may provide opportunities to investigate real-world health outcomes among psoriasis patients. Our objective was to investigate patient-perceived treatment effectiveness, patterns of medication use (duration, switching, and/or discontinuation), healthcare resource utilization, and medication costs using real-world data from psoriasis patients. METHODS: Data for adults (≥18-years) with a dermatology provider-given diagnosis of psoriasis from 9/2014-9/2015 were obtained from dermatology practices using a widely used US dermatology-specific EHR containing over 500,000 psoriasis patients. Disease severity was captured by static physician's global assessment and body surface area. Patient-perceived treatment effectiveness was assessed by a pre-defined question. Treatment switching and duration were documented. Reasons for discontinuations were assessed using pre-defined selections. Healthcare resource utilization was defined by visit frequency and complexity. RESULTS: From 82,621 patients with psoriasis during the study period, patient-perceived treatment effectiveness was investigated in 2200 patients. The proportion of patients reporting "strongly agree" when asked if their treatment was effective was highest for biologics (73%) and those reporting treatment adherence (55%). In 16,000 patients who received oral systemics and 21,087 patients who received biologics, median treatment duration was longer for those who received biologics (160 vs. 113 days, respectively). Treatment switching was less frequent among patients on systemic monotherapies compared to those on combination therapies. The most common reason for discontinuing biologics was loss of efficacy; the most common reason for discontinuing orals was side effects. In 28,754 patients, higher disease severity was associated with increased healthcare resource utilization (increased visit frequency and complexity). When compared between treatment groups (n = 10,454), healthcare resource utilization was highest for phototherapy. Annual medication costs were higher for biologics ($21,977) than oral systemics ($3413). CONCLUSIONS: Real-world research using a widely implemented dermatology EHR provided valuable insights on patient perceived treatment effectiveness, patterns of medication usage, healthcare resource utilization, and medication costs for psoriasis patients in the US. This study and others utilizing EHRs for real-world research may assist clinical and payer decisions regarding the management of psoriasis.

Ixekizumab, an interleukin-17A specific monoclonal antibody, for the treatment of biologic-naive patients with active psoriatic arthritis: results from the 24-week randomised, double-blind, placebo-controlled and active (adalimumab)-controlled period of the phase III trial SPIRIT-P1.

OBJECTIVE: To assess the safety and efficacy of ixekizumab, a monoclonal antibody that inhibits interleukin-17A, in a double-blind phase III trial enrolling patients with active psoriatic arthritis (PsA). METHODS: Patients naive to biologic therapy with active PsA were randomised to subcutaneous injections of placebo (N=106), adalimumab 40 mg once every 2 weeks (active reference; N=101), ixekizumab 80 mg once every 2 weeks (IXEQ2W) (N=103), or ixekizumab 80 mg once every 4 weeks (IXEQ4W) (N=107). Both ixekizumab regimens included a 160-mg starting dose. The primary objective was to assess the superiority of IXEQ2W or IXEQ4W versus placebo as measured by the proportion of patients achieving an American College of Rheumatology 20 (ACR20) response at week 24. RESULTS: Significantly more patients treated with ixekizumab achieved an ACR20 response with IXEQ2W (62.1%) or IXEQ4W (57.9%) than placebo (30.2%) (p≤0.001; non-responder imputation method). Disease activity and functional disability were significantly improved with both ixekizumab doses versus placebo at weeks 12 and 24, and there was significantly less progression of structural damage at week 24 (p≤0.01). Clearance of plaque psoriasis was greater with ixekizumab than placebo (p≤0.001). Efficacy results with adalimumab, the active reference arm, showed significant improvements versus placebo. Treatment-emergent adverse events were more frequent with ixekizumab (65.7-66.4%) and adalimumab (64.4%) than placebo (47.2%) (p<0.05). CONCLUSIONS: In biologic-naive patients with active PsA, ixekizumab treatment resulted in improvements in disease activity and physical function, as well as in the inhibition of structural damage progression. Overall, adverse events were more frequent in all active groups compared with placebo. TRIAL REGISTRATION NUMBER: NCT01695239; EudraCT2011-002326-49; Results.

Psychometric properties of morning joint stiffness duration and severity measures in patients with moderately to severely active rheumatoid arthritis.

BACKGROUND: To assess the measurement properties of two single-item patient-reported outcome (PRO) measures that assessed the length of time (in minutes) and severity of morning joint stiffness (MJS) experienced each day. METHODS: Data from two Phase 3, randomized placebo-controlled (and active-controlled [RA-BEAM]), clinical studies assessing the safety and efficacy of baricitinib in adults with moderately to severely active rheumatoid arthritis (RA) were used to evaluate the psychometric properties of the Duration of MJS and Severity of MJS PROs. RESULTS: Test-retest reliability of Duration of MJS and Severity of MJS was supported through large intraclass correlation coefficients among stable patients (coefficient range for both studies: 0.88 to 0.93). In support of construct validity, moderate correlations were evidenced between Duration of MJS and other related patient- and clinician-reported assessments of RA symptoms and patient functioning, whereas moderate-to-strong correlations were evidenced between these same patient- and clinician-reported assessments and Severity of MJS. Statistically significant differences between the median and mean values of Duration of MJS and Severity of MJS for differing categories of RA disease severity supported known-groups validity. Finally, large and statistically significant differences in change scores from Day 1 to Week 12 for patients defined as responders versus non-responders using the American College of Rheumatology 20 criteria supported the responsiveness of both PROs. CONCLUSION: Duration of MJS and Severity of MJS PROs demonstrated reliability, validity, and responsiveness in adults with moderately to severely active RA, supporting the measurement of these key symptoms in clinical trials.

Psychometric properties of the single-item measure, severity of worst tiredness, in patients with moderately to severely active rheumatoid arthritis.

BACKGROUND: To assess the reliability, validity, and responsiveness to treatment change of the single-item measure, Severity of Worst Tiredness, in patients with rheumatoid arthritis (RA). METHODS: Data from two Phase 3, randomized, placebo-controlled (RA-BUILD; and active-controlled [RA-BEAM]), clinical studies of the efficacy of baricitinib in adults with moderately to severely active RA were used. The psychometric properties of the single-item measure, Severity of Worst Tiredness, were assessed, including test-retest reliability, convergent and discriminant validity, known-groups validity, and responsiveness, using other patient- and clinician-reported outcomes frequently assessed in RA patients. RESULTS: Test-retest reliability of the Severity of Worst Tiredness was supported through large intraclass correlation coefficients (0.89 ≤ ICC ≤ 0.91). Moderate-to-large correlations were observed between this patient-reported outcome (PRO) and other related patient- and clinician-reported assessments of RA symptoms and patient functioning, supporting construct validity of the measure (│r│ ≥ 0.41). The instrument also displayed known-groups validity through statistically significant differences between mean values of the Severity of Worst Tiredness defined using other indicators of RA severity. Finally, responsiveness was supported by large and statistically significant differences in change scores from Day 1 to Week 12 for patients comparing responders and nonresponders using the American College of Rheumatology 20 (ACR20) criteria. CONCLUSION: The Severity of Worst Tiredness PRO demonstrated adequate reliability, validity, and responsiveness in clinical trials of adults with moderately to severely active RA and is fit for purpose in this patient population.