Long-term clinical outcomes of certolizumab pegol treatment in non-radiographic axial spondyloarthritis stratified by baseline MRI and CRP status.

OBJECTIVE: There is a paucity of data on long-term clinical responses in patients with non-radiographic axial spondyloarthritis (nr-axSpA) based on their baseline objective signs of inflammation such as MRI or C-reactive protein (CRP) levels. This study reports clinical outcomes up to 3 years of the C-axSpAnd trial, including safety follow-up extension (SFE) from Weeks 52 to 156, stratified by patients' baseline MRI and CRP status. METHODS: C-axSpAnd (NCT02552212) was a phase 3, multicentre study that evaluated certolizumab pegol (CZP) in patients with active nr-axSpA who had active sacroiliitis on MRI and/or elevated CRP. In this post hoc analysis, efficacy outcomes are reported to Week 156 of C-axSpAnd for patients stratified according to their MRI and CRP status at Week 0 (MRI+/CRP-, MRI-/CRP+ and MRI+/CRP+). RESULTS: Across all outcome measures, including major improvement in Ankylosing Spondylitis Disease Activity Score (ASDAS-MI) and Assessment of SpondyloArthritis international Society criteria ≥40% response (ASAS40), outcomes were generally sustained in SFE patients from Week 52 to Week 156. MRI+/CRP+ patients showed numerically higher or comparable responses relative to MRI-/CRP+ and MRI+/CRP- patients at Weeks 52 and 156; however, all three subgroups demonstrated substantial improvements from Week 0 (in CZP-randomised patients, ASDAS-MI at Week 156 [observed case]: MRI+/CRP+: 73.1%, MRI-/CRP+: 52.2%, MRI+/CRP-: 30.4%; ASAS40: MRI+/CRP+: 76.9%, MRI-/CRP+: 62.5%, MRI+/CRP-: 65.2%). CONCLUSIONS: In patients with nr-axSpA and objective signs of inflammation, long-term clinical outcomes achieved after 1 year were generally sustained at 3 years across MRI+/CRP+, MRI-/CRP+ and MRI+/CRP- subgroups.

Effectiveness and Safety of Certolizumab Pegol in Axial Spondyloarthritis in a Real-World Setting in Greece: A Sub-Analysis of the Prospective Non-Interventional CIMAX Cohort Study.

Objectives: We report the effectiveness and safety of certolizumab pegol (CZP) treatment in a real-world Greek axial spondyloarthritis (axSpA) population, including patients with radiographic (r-axSpA) and non-radiographic (nr-axSpA) disease. Methods: We performed a sub-analysis of the Greek cohort from CIMAX (NCT02354105), a multicentre, non-interventional cohort study that prospectively investigated CZP treatment in patients with axSpA. The primary outcome was change from baseline (CfB) in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) to Week 52. Results: Across 12 sites in Greece, 126 patients (r-axSpA: 91; nr-axSpA: 35) received ≥1 dose of CZP and were included in the Safety Set (SS), with 120 patients (r-axSpA: 86; nr-axSpA: 34) included in the Full Analysis Set (FAS). The mean (standard deviation [SD]) CfB in BASDAI at Week 52 was -3.8 (2.0) in the overall axSpA population, with numerically greater improvements observed for nr-axSpA patients compared with r-axSpA (nr-axSpA: -4.2 [2.1]; r-axSpA: -3.7 [2.0]). Improvements in the axSpA population, including r-axSpA and nr-axSpA subpopulations, were observed in key secondary and additional outcomes at Week 52. Overall, 14.3% (18/126) of patients in the axSpA population experienced ≥1 adverse event (AE). There were no serious AEs or deaths reported during the study. Conclusions: Patients with r-axSpA and nr-axSpA treated with CZP in clinical practice in Greece showed improvements in disease activity and key symptoms. CZP treatment may therefore help address the substantial health burden associated with axSpA in Greece.

Certolizumab Pegol Treatment in Patients with Axial-Spondyloarthritis-Associated Acute Anterior Uveitis: a Narrative Review.

BACKGROUND: Acute anterior uveitis (AAU) affects up to 40% of patients with axial spondyloarthritis (axSpA). An effective treatment for patients with axSpA that reduces the risk of AAU flares while also targeting axial symptoms is therefore highly desirable. Tumor necrosis factor inhibitors (TNFis) have been shown effective for treatment of axSpA and AAU occurrence, with guidelines conditionally recommending treating patients with axSpA and associated AAU with TNFi monoclonal antibodies. To date, most available data on the impact of TNFis on AAU in axSpA are from observational, open-label studies without parallel comparator arms. However, there is a growing body of evidence describing the impact of the TNFi certolizumab pegol (CZP) on the incidence of axSpA-associated AAU. OBJECTIVE: Our objective was to collate data pertaining to the impact of CZP in axSpA-associated AAU in patients across the full axSpA spectrum. METHODS: Data were obtained from four industry-supported phase 3 and 4 clinical trials (C-VIEW, C-axSpAnd, C-OPTIMISE, and RAPID-axSpA). To supplement these data, a targeted literature review was performed through searches of MEDLINE, Embase, and reference lists. RESULTS: Available data from 1467 patients from the C-VIEW, C-axSpAnd, C-OPTIMISE, and RAPID-axSpA trials show CZP to be effective in AAU in patients across the full axSpA spectrum, reducing AAU flares when compared with placebo or pretreatment period. No differences in AAU outcomes were reported when stratified by axSpA subgroup age or sex. The targeted literature review identified six further studies of CZP in spondyloarthritis-associated AAU, only one of which was specific to axSpA. CONCLUSION: CZP was effective in reducing AAU incidence in clinical trials with patients with axSpA. The targeted literature review, however, highlighted that there remains a paucity of data beyond these trials. Data from comparative studies would further enhance the body of evidence on the effects of CZP in patients with axSpA who develop AAU.

Certolizumab Pegol Efficacy in Patients With Non-Radiographic Axial Spondyloarthritis Stratified by Baseline MRI and C-Reactive Protein Status: An Analysis From the C-axSpAnd Study.

OBJECTIVE: Tumor necrosis factor inhibitors (TNFi) are an effective treatment for non-radiographic axial spondyloarthritis (nr-axSpA). To be eligible, however, many authorities require patients with nr-axSpA to show active sacroiliitis on magnetic resonance imaging (MRI) and/or an elevated C-reactive protein (CRP) level, possibly resulting in a perception that patients with nr-axSpA without both factors have only low responses to TNFi treatment. We evaluated clinical responses to certolizumab pegol (CZP) in patients with nr-axSpA stratified by baseline MRI/CRP status. METHODS: C-axSpAnd was a phase 3, multicenter study on CZP in adult patients with active nr-axSpA and objective signs of inflammation. This analysis assessed efficacy of CZP over the 52-week randomized, double-blind, placebo-controlled period in patients stratified into subgroups based on the presence of active sacroiliitis on MRI and CRP level at baseline. RESULTS: CZP-treated patients across all MRI/CRP subgroups achieved clinical responses greater than placebo. Across outcome measures, CZP-treated MRI+/CRP+ patients demonstrated the greatest clinical responses, but substantial improvements were also observed in CZP-treated MRI+/CRP- and MRI-/CRP+ patients. Ankylosing Spondylitis Disease Activity Score Major Improvement response rates at week 52 among CZP-treated patients (75.6% MRI+/CRP+; 47.5% MRI-/CRP+; and 29.7% MRI+/CRP-) were higher than rates in placebo groups (range: 3.9%-12.5%). Assessment of SpondyloArthritis international Society 40% response, Bath Ankylosing Spondylitis Disease Activity Index, and Bath Ankylosing Spondyloarthritis Functional Index had similar response patterns, although differences between the CZP-treated MRI/CRP subgroups were smaller. Clinical responses among CZP-treated patients were also observed in additional subgroups, including those with low Spondyloarthritis Research Consortium of Canada MRI sacroiliac joint inflammation scores and those with normal baseline CRP levels. CONCLUSION: Our findings indicate that CZP treatment benefits patients with nr-axSpA across MRI+/CRP+, MRI-/CRP+, and MRI+/CRP- subgroups.

Long-term safety and clinical outcomes of certolizumab pegol treatment in patients with active non-radiographic axial spondyloarthritis: 3-year results from the phase 3 C-axSpAnd study.

BACKGROUND: 52-week results from C-axSpAnd demonstrated the safety and efficacy of certolizumab pegol (CZP) in patients with active non-radiographic axial spondyloarthritis (nr-axSpA) and objective signs of inflammation (sacroiliitis on MRI and/or elevated C-reactive protein levels). Long-term safety and clinical outcomes, including MRI assessments, are evaluated up to 3 years for CZP-treated patients with nr-axSpA. METHODS: C-axSpAnd was a phase 3 study comprising a 1-year double-blind, placebo-controlled period and 2-year open-label safety follow-up extension (SFE). At baseline, 317 patients were randomised 1:1 to placebo or CZP 200 mg every 2 weeks. Patients completing the double-blind phase who enrolled into the SFE received open-label CZP for an additional 104 weeks. Long-term safety and clinical outcomes are reported to Week 156. Continuous outcomes are presented as observed case (OC) and dichotomous outcomes as OC and with non-responder imputation. RESULTS: 243/317 (76.7%) patients entered the SFE, during which 149 (61.3%) experienced ≥1 treatment-emergent adverse event (TEAE); 15 (3.3/100 patient-years) experienced serious TEAEs. Continuous outcome scores (including Ankylosing Spondylitis Disease Activity Score [ASDAS]: 1.8; Bath Ankylosing Spondylitis Disease Activity Index [BASDAI]: 2.7) at Week 52 were maintained at Week 156 (ASDAS: 1.8; BASDAI: 2.6) for the initial CZP-randomised group. Mean SPARCC MRI sacroiliac joint inflammation scores for these patients decreased at Week 52 (baseline: 7.6; Week 52: 1.7), remaining low at Week 156 (2.4). CONCLUSIONS: CZP treatment was well tolerated up to 3 years, with no new safety signals versus previous reports. Clinical outcomes achieved after 1 year were sustained to 3 years. TRIAL REGISTRATION NUMBER: NCT02552212.

Predictors of long-term clinical response in patients with non-radiographic axial spondyloarthritis receiving certolizumab pegol.

BACKGROUND: Identification of predictive clinical factors of long-term treatment response may contribute to improved management of non-radiographic axSpA (nr-axSpA) patients. This analysis aims to identify whether any baseline characteristics or Week 12 clinical outcomes in nr-axSpA patients with elevated C-reactive protein (CRP) and/or sacroiliitis on magnetic resonance imaging (MRI) enrolled in the C-axSpAnd study are predictive of achieving clinical response after 1 year of certolizumab pegol (CZP). METHODS: C-axSpAnd (NCT02552212) was a phase 3, multicentre study, including a 52-Week double-blind, placebo-controlled period. Enrolled patients were randomised to CZP 200 mg Q2W or placebo. Predictors of Week 12 (CZP group only) and Week 52 clinical response were identified using a multivariate stepwise logistic regression analysis. Response variables included Ankylosing Spondylitis Disease Activity Score major improvement (ASDAS-MI), Assessment of SpondyloArthritis International Society 40% response (ASAS40), Bath Ankylosing Spondylitis Disease Activity Index 50% response (BASDAI50) and ASDAS inactive disease (ASDAS-ID). Predictive factors assessed included demographic and baseline characteristics and clinical outcomes at Week 12. A p-value <0.05 was required for forward selection into the model and p ≥0.1 for backward elimination. Missing data or values collected after switching to open-label treatment were accounted for using non-responder imputation. Sensitivity analyses accounted for patients with changes in non-biologic background medication. RESULTS: Of 317 enrolled patients, 159 and 158 were randomised to CZP and placebo, respectively. Younger age and male sex were identified as predictors of Week 12 response across all assessed efficacy outcomes in CZP-treated patients. Consistent predictors of Week 52 response, measured by ASDAS-MI, ASAS40 and BASDAI50, included human leukocyte antigen (HLA)-B27 positivity and sacroiliitis on MRI at baseline. MRI positivity was also predictive of achieving ASDAS-ID at Week 52. Sensitivity analyses were generally consistent with the primary analysis. In placebo-treated patients, no meaningful predictors of Week 52 response were identified. CONCLUSIONS: In this 52-Week, placebo-controlled study in nr-axSpA patients with elevated CRP and/or active sacroiliitis on MRI at baseline, MRI sacroiliitis and HLA-B27 positivity, but not elevated CRP or responses at Week 12, were predictive of long-term clinical response to CZP. Findings may support rheumatologists to identify patients suitable for TNFi treatment. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02552212 . Registered on 15 September 2015.

Reduction of anterior uveitis flares in patients with axial spondyloarthritis on certolizumab pegol treatment: final 2-year results from the multicenter phase IV C-VIEW study.

INTRODUCTION: Acute anterior uveitis (AAU), affecting up to 40% of patients with axial spondyloarthritis (axSpA), risks permanent visual deficits if not adequately treated. We report 2-year results from C-VIEW, the first study to prospectively investigate certolizumab pegol (CZP) on AAU in patients with active axSpA at high risk of recurrent AAU. PATIENTS AND METHODS: C-VIEW (NCT03020992) was a 104-week (96 weeks plus 8-week safety follow-up), open-label, multicenter study. Eligible patients had active axSpA, human leukocyte antigen-B27 (HLA-B27) positivity and a history of recurrent AAU (⩾2 AAU flares in total; ⩾1 in the year prior to baseline). Patients received CZP 400 mg at weeks 0, 2 and 4, then 200 mg every 2 weeks to week 96. The primary efficacy endpoint was the AAU flare event rate during 96 weeks' CZP versus 2 years pre-baseline. RESULTS: Of 115 enrolled patients, 89 initiated CZP (male: 63%; radiographic/non-radiographic axSpA: 85%/15%; mean disease duration: 9.1 years); 83 completed week 96. There was a significant 82% reduction in AAU flare event rate during CZP versus pre-baseline [rate ratio (95% confidence interval): 0.18 (0.12-0.28), p < 0.001]. One hundred percent and 59.6% of patients experienced ⩾1 and ⩾2 AAU flares pre-baseline, respectively, compared to 20.2% and 11.2% during treatment. Age, sex and axSpA population subgroup analyses were consistent with the primary analysis. There were substantial improvements in axSpA disease activity with no new safety signal identified. CONCLUSION: CZP treatment significantly reduced AAU flare event rate in patients with axSpA and a history of AAU, indicating CZP is a suitable treatment option for patients at risk of recurrent AAU. TRIAL REGISTRATION CLINICALTRIALSGOV: NCT03020992, URL: https://clinicaltrials.gov/ct2/show/NCT03020992.

Effectiveness and safety of 12-month certolizumab pegol treatment for axial spondyloarthritis in real-world clinical practice in Europe.

OBJECTIVES: The efficacy and safety of certolizumab pegol (CZP), an Fc-free, PEGylated anti-TNF, in axial spondyloarthritis (axSpA) has been established in clinical trial settings. We report CZP effectiveness and safety in European clinical practice in patients with axSpA, including radiographic (r-) and non-radiographic (nr-) axSpA. METHODS: CIMAX (NCT02354105), a European non-interventional multicentre prospective study, observed CZP treatment response and safety over 12 months in a real-world axSpA cohort. The primary outcome was change from baseline in BASDAI to week 52, with additional outcomes pertaining to effectiveness and safety. Patients who received ≥1 dose CZP were followed up for adverse events, and those with baseline and ≥1 post-baseline BASDAI assessment were included in effectiveness analyses. RESULTS: A total of 672 patients (r-axSpA: 469; nr-axSpA: 201; unconfirmed diagnosis: 2) from 101 sites received ≥1 dose of CZP, of whom 564 (r-axSpA: 384; nr-axSpA: 179; unconfirmed: 1) were included in the effectiveness analyses. The mean baseline BASDAI was 6.1 in the overall axSpA population and r-axSpA and nr-axSpA subpopulations. At week 52, the mean (s.d.) change in BASDAI was -2.9 (2.3; n = 439); for r-axSpA and nr-axSpA, it was -2.9 (2.2; n = 301) and -2.8 (2.4; n = 137), respectively (P <0.0001 for all). Similar improvements were seen across other axSpA disease measures. In total, 37.9% (255/672) patients experienced adverse events, and 1.8% (12/672) experienced ≥1 serious adverse events. CONCLUSION: Improvements observed in signs and symptoms of axSpA following one year of CZP treatment in real-world clinical practice were similar to those from previous randomized clinical trials, with no new safety concerns.

Induction of Sustained Clinical Remission in Early Axial Spondyloarthritis Following Certolizumab Pegol Treatment: 48-Week Outcomes from C-OPTIMISE.

INTRODUCTION: Achievement of remission is a key treatment goal for patients with axial spondyloarthritis (axSpA). C-OPTIMISE assessed achievement of sustained clinical remission in patients with axSpA, including radiographic (r) and non-radiographic (nr) axSpA, during certolizumab pegol (CZP) treatment, and subsequent maintenance of remission following CZP dose continuation, dose reduction or withdrawal. Here, we report outcomes from the first 48 weeks (induction period) of C-OPTIMISE, during which patients received open-label CZP. METHODS: C-OPTIMISE (NCT02505542) was a two-part, multicenter, phase 3b study in adult patients with early axSpA (r-/nr-axSpA), including a 48-week open-label induction period followed by a 48-week maintenance period. Patients with active adult-onset axSpA, < 5 years' symptom duration, and fulfilling Assessment of SpondyloArthritis international Society classification criteria, were included. During the induction period, patients received a loading dose of CZP 400 mg at weeks 0, 2, and 4, followed by CZP 200 mg every 2 weeks (Q2W) up to week 48. The main outcome of the 48-week induction period was the achievement of sustained clinical remission (defined as an Ankylosing Spondylitis Disease Activity Score [ASDAS] < 1.3 at week 32 and < 2.1 at week 36 [or vice versa], and < 1.3 at week 48). RESULTS: In total, 736 patients (407 with r-axSpA, 329 with nr-axSpA) were enrolled into the study. At week 48, 43.9% (323/736) of patients achieved sustained remission, including 42.8% (174/407) of patients with r-axSpA and 45.3% (149/329) with nr-axSpA. Patients also demonstrated substantial improvements in axSpA symptoms, MRI outcomes and quality of life measures. Adverse events occurred in 67.9% (500/736) of patients, of which 6.0% (44/736) were serious. CONCLUSIONS: Over 40% of patients with early axSpA achieved sustained remission during 48 weeks of open-label CZP treatment. Additionally, patients across the axSpA spectrum demonstrated substantial improvements in imaging outcomes and quality of life following treatment. No new safety signals were identified. TRIAL REGISTRATION: NCT02505542.

The impact of certolizumab pegol treatment on the incidence of anterior uveitis flares in patients with axial spondyloarthritis: 48-week interim results from C-VIEW.

BACKGROUND: Acute anterior uveitis (AAU) is the most common extra-articular manifestation in patients with axial spondyloarthritis (axSpA). C-VIEW investigates the impact of the Fc-free TNF inhibitor certolizumab pegol (CZP) on AAU flares in patients with active axSpA at high risk of recurrent AAU. METHODS: C-VIEW (NCT03020992) is a 96-week ongoing, multicentre, open-label, phase 4 study. Included patients had an axSpA diagnosis, a history of recurrent AAU (≥2 AAU flares, ≥1 flare in the year prior to study entry), HLA-B27 positivity, active disease, and failure of ≥2 non-steroidal anti-inflammatory drugs. Patients received CZP 400 mg at Weeks 0/2/4, then 200 mg every 2 weeks up to 96 weeks. This 48-week pre-planned interim analysis compares AAU flare incidence in the 48 weeks before and after initiation of CZP treatment, using Poisson regression to account for possible within-patient correlations. RESULTS: In total, 89 patients were included (male: 63%; radiographic/non-radiographic axSpA: 85%/15%; mean axSpA disease duration: 8.6 years). During 48 weeks' CZP treatment, 13 (15%) patients experienced 15 AAU flares, representing an 87% reduction in AAU incidence rate (146.6 per 100 patient-years (PY) in the 48 weeks pre-baseline to 18.7 per 100 PY during CZP treatment). Poisson regression analysis showed that the incidence rate of AAU per patient reduced from 1.5 to 0.2 (p<0.001). No new safety signals were identified. CONCLUSIONS: There was a significant reduction in the AAU flare rate during 48 weeks of CZP treatment, indicating that CZP is a suitable treatment option for patients with active axSpA and a history of recurrent AAU.

Maintenance of clinical remission in early axial spondyloarthritis following certolizumab pegol dose reduction.

BACKGROUND: The best strategy for maintaining clinical remission in patients with axial spondyloarthritis (axSpA) has not been defined. C-OPTIMISE compared dose continuation, reduction and withdrawal of the tumour necrosis factor inhibitor certolizumab pegol (CZP) following achievement of sustained remission in patients with early axSpA. METHODS: C-OPTIMISE was a two-part, multicentre phase 3b study in adults with early active axSpA (radiographic or non-radiographic). During the 48-week open-label induction period, patients received CZP 200 mg every 2 weeks (Q2W). At Week 48, patients in sustained remission (Ankylosing Spondylitis Disease Activity Score (ASDAS) <1.3 at Weeks 32/36 and 48) were randomised to double-blind CZP 200 mg Q2W (full maintenance dose), CZP 200 mg every 4 weeks (Q4W; reduced maintenance dose) or placebo (withdrawal) for a further 48 weeks. The primary endpoint was remaining flare-free (flare: ASDAS ≥2.1 at two consecutive visits or ASDAS >3.5 at any time point) during the double-blind period. RESULTS: At Week 48, 43.9% (323/736) patients achieved sustained remission, of whom 313 were randomised to CZP full maintenance dose, CZP reduced maintenance dose or placebo. During Weeks 48 to 96, 83.7% (87/104), 79.0% (83/105) and 20.2% (21/104) of patients receiving the full maintenance dose, reduced maintenance dose or placebo, respectively, were flare-free (p<0.001 vs placebo in both CZP groups). Responses in radiographic and non-radiographic axSpA patients were comparable. CONCLUSIONS: Patients with early axSpA who achieve sustained remission at 48 weeks can reduce their CZP maintenance dose; however, treatment should not be completely discontinued due to the high risk of flare following CZP withdrawal. TRIAL REGISTRATION NUMBER: NCT02505542, ClinicalTrials.gov.

A Fifty-Two-Week, Randomized, Placebo-Controlled Trial of Certolizumab Pegol in Nonradiographic Axial Spondyloarthritis.

OBJECTIVE: The natural history of nonradiographic axial spondyloarthritis (SpA) is incompletely characterized, and there are concerns that nonsteroidal antiinflammatory drugs provide inadequate disease control in patients with active disease. This study was undertaken to investigate the effects of certolizumab pegol (CZP), an anti-tumor necrosis factor treatment, in patients with nonradiographic axial SpA with objective signs of inflammation. METHODS: In this ongoing parallel-group double-blind study, adults with active disease were recruited from 80 centers in Australia, Europe, North America, and Taiwan, and were randomized 1:1 to receive placebo or CZP (400 mg at weeks 0, 2, and 4, followed by 200 mg every 2 weeks) in addition to nonbiologic background medication (NBBM). Switching to open-label CZP (or other biologic) or making background medication changes was permitted at any point during the trial, although changes before week 12 were discouraged. The primary end point was the proportion of patients achieving major improvement (MI) (i.e., a ≥2.0-point decrease in the score from baseline or achievement of the lowest possible score [0.6]) in the Ankylosing Spondylitis Disease Activity Score (ASDAS) at week 52. RESULTS: A total of 317 patients were randomized to receive placebo plus NBBM (n = 158) or CZP plus NBBM (n = 159). ASDAS-MI at week 52 was achieved in 47.2% (75 of 159) of CZP plus NBBM patients, which was significantly greater (P < 0.0001) than the 7.0% (11 of 158) of placebo plus NBBM patients in whom ASDAS-MI was achieved. Of the placebo plus NBBM patients, 60.8% (96 of 158) switched to open-label treatment before week 52 compared to 12.6% (20 of 159) of the CZP plus NBBM patients. CONCLUSION: Adding CZP to background medication is superior to adding placebo in patients with active nonradiographic axial SpA. These results indicate that remission in nonradiographic axial SpA treated without biologics occurs infrequently, demonstrating the need for treatment beyond nonbiologic therapy.

Pharmacokinetics, Tolerability, and Bioequivalence of Two Formulations of Rotigotine in Healthy Chinese Subjects.

PURPOSE: The pharmacokinetic (PK) profile of the rotigotine transdermal patch is well characterized in Caucasian patients with Parkinson's disease (PD) but not in Chinese subjects. This article reports the PK variables, safety, and tolerability of the rotigotine transdermal patch (2 mg/24 hours and 4 mg/24 hours cold-chain PR2.1.1 formulation) in healthy Chinese subjects (SP0913; NCT01675024). A second study (PD0011; NCT02070796) evaluated the relative bioavailability of cold-chain (PR2.1.1) and room temperature-stable (PR2.2.1) formulations of rotigotine in healthy Chinese men. METHODS: In treatment period 1 of SP0913, subjects received a single application of rotigotine 2 mg/24 hours on day 1 followed by a washout period (days 2-6); treatment period 2 (days 6-14) involved multiple doses of rotigotine 2 mg/24 hours (days 7-9) followed by multiple doses of rotigotine 4 mg/24 hours (days 10-12), with patches applied for 24 hours each. In PD0011, subjects received a single dose (2 mg/24 hours) of each rotigotine formulation (PR2.2.1 and PR2.1.1) for 24 hours each in a crossover design. Blood samples were collected at scheduled time points to determine rotigotine plasma concentrations. Safety and tolerability were evaluated by adverse events monitoring. RESULTS: Twenty-four healthy Chinese subjects (12 males, 12 females) were enrolled and completed SP0913. Geometric mean plasma concentrations of unconjugated and total rotigotine increased to a plateau beginning at ∼8 hours (multiple dose) to 16 hours (single dose) postdose; no characteristic Tmax was observed for unconjugated and total rotigotine. The respective geometric mean Cmax, Cmax,ss, AUC from zero up to the last analytically quantifiable concentration, and AUC0-24,ss values for unconjugated and total rotigotine were similar when rotigotine 2 mg/24 hours was applied as a single dose or multiple-dose regimen. During the multiple-dose period, geometric mean Cmax,ss and AUC0-24,ss of both unconjugated and total rotigotine were ∼2-fold higher for rotigotine 4 mg/24 hours than for rotigotine 2 mg/24 hours. Forty-seven of 50 male Chinese subjects completed PD0011. Primary PK parameters for the room temperature-stable formulation of rotigotine were highly comparable to the cold-chain formulation. Common adverse events included application site pruritus, nausea, dizziness, and constipation (SP0913 only), with no clinically significant changes in other safety measures. IMPLICATIONS: PK profiles and derived PK parameters of unconjugated and total rotigotine in healthy Chinese subjects were consistent with findings from other ethnic groups receiving single and multiple doses of the rotigotine transdermal patch. Single and repeated daily doses of the rotigotine transdermal patch were well tolerated. Room temperature-stable and cold-chain formulations were bioequivalent. ClinicalTrials.gov identifiers: NCT01675024 and NCT02070796.

4-year results from the RAPID-PsA phase 3 randomised placebo-controlled trial of certolizumab pegol in psoriatic arthritis.

OBJECTIVE: To report the efficacy, patient-reported, radiographic and safety outcomes of 4 years' certolizumab pegol (CZP) treatment in patients with psoriatic arthritis (PsA). METHODS: RAPID-PsA (NCT01087788) was double-blind and placebo-controlled to Week 24, dose-blind to Week 48 and open-label (OL) to Week 216. Patients were randomised 1:1:1 to either placebo or CZP 200 mg every 2 weeks (Q2W) or 400 mg every 4 weeks (Q4W) (following 400 mg at Weeks 0/2/4). Patients randomised to CZP continued their assigned dose in the OL period. Patients randomised to placebo were re-randomised to CZP 200 mg Q2W or 400 mg Q4W (post-loading dose) at Week 16 (early escape) or after the double-blind phase. We present observed and imputed data; missing values were imputed using non-responder imputation (NRI) for categorical and last observation carried forward (LOCF) for continuous measures. RESULTS: 409 patients were randomised; 20% (54/273) of Week 0 patients randomised to CZP had prior anti-tumour necrosis factor (TNF) exposure; 67% (183/273) completed 216 weeks. By Week 48, 60.4% of patients achieved Disease Activity Index for Psoriatic Arthritis low disease activity or remission, which was maintained; 66.3% achieved these outcomes at Week 216 (NRI). At Weeks 48 and 216, 39.2% of patients achieved minimal disease activity (NRI). 75% reduction in Psoriasis Area and Severity Index responses were 65% and 52% at Weeks 48 and 216 (NRI). Total resolution rates for enthesitis, dactylitis and nail psoriasis, at 4 years, were 71%, 81% and 65%, respectively (LOCF). Structural damage progression was low over 4 years' treatment. No new safety signals were identified after Week 96. CONCLUSIONS: CZP efficacy in treating PsA was maintained over 4 years, in patients both with and without prior anti-TNF exposure, with no new safety signals identified.

An observational study of rotigotine transdermal patch and other currently prescribed therapies in patients with Parkinson's disease.

Real-world data from large cohorts of patients with Parkinson's disease on the long-term effectiveness of different dopamine-substituting drug therapies are rare. The objective of this study was to obtain information on real-world management of PD with dopamine-substituting drugs. SP0854 (NCT00599339) was a prospective, multicenter, non-interventional, multiple-cohort, post-authorization safety study of rotigotine versus other dopaminergic therapies. The study was also part of a European Medicines Agency risk-management plan for the non-ergoline dopamine agonist rotigotine, focussing on cardiovalvular fibrosis. Eligible patients requiring monotherapy with a dopamine agonist, or levodopa in combination with a dopamine agonist were followed for ≤ 33 months; 1531 of 2195 patients completed the study. Mean motor scores improved for all dopamine-substituting treatments. Patients with more severe motor-symptoms/increased disability were more likely to receive levodopa alone or in combination with a DA at study onset. More patients who started on combination therapy with levodopa remained on this treatment versus those starting on dopaminergic monotherapy. This real-world study showed that the dopamine-substituting therapies were efficacious, with a safety profile consistent with that expected of dopaminergic treatments. Cardiovalvular pathology was rare and not found to be causally-related to rotigotine.

Randomized, double-blind, crossover study of the adhesiveness of two formulations of rotigotine transdermal patch in patients with Parkinson's disease.

OBJECTIVE: In patch-based transdermal drug delivery, adhesiveness is critical for safe and effective treatment, especially in Parkinson's disease (PD) where excessive sweating is common. This study compared the adhesiveness of two transdermal patch formulations of rotigotine (improved room temperature-stable [PR2.3.1/Treatment A] and intermediate cold storage product [PR2.1.1/Treatment B]), using the largest patch size (40 cm2). METHODS: PD0018 (NCT02230904) was a multicenter, randomized, double-blind, crossover study. PD patients received Treatments A and B in randomized order for 2 days each. Patch adhesiveness was measured immediately after patch application and 24 hours thereafter (before removal). Primary variable: change in average investigator-rated adhesiveness score between treatments, per modified European Medicines Agency scale (EMA/CHMP/QWP/911254/2011, 2012). RESULTS: Fifty-seven patients were randomized; 56 patients completed the study. Five patients were excluded from analysis for accidental unblinding. Treatment A had better average adhesiveness score (mean ± SD Treatment A - Treatment B: 1.115 ± 1.635). A higher percentage of patients on both days had patch adhesiveness ≥95% at 24 hours for Treatment A (first day: 65.4%, second day: 71.2%) vs. Treatment B (46.2%, 36.5%), and were satisfied with patch adhesiveness of Treatment A (first day: 75.0%, second day: 73.1%) vs. Treatment B (65.4%, 59.6%). Average patch-wear duration was similar between formulations (23.761 hours vs. 23.495 hours per patch). Both formulations were well tolerated with no new safety observations. CONCLUSION: Results indicated greater adhesiveness for the improved room temperature-stable formulation (PR2.3.1) vs. intermediate cold storage product (PR2.1.1) using the largest patch-size, with comparable safety and skin tolerability.

Limited radiographic progression and sustained reductions in MRI inflammation in patients with axial spondyloarthritis: 4-year imaging outcomes from the RAPID-axSpA phase III randomised trial.

OBJECTIVES: To report 4-year imaging outcomes in the RAPID-axSpA (NCT01087762) study of patients with ankylosing spondylitis (AS) and non-radiographic axial spondyloarthritis (nr-axSpA), treated with certolizumab pegol (CZP). METHODS: This phase III, randomised trial was placebo-controlled and double-blind to week 24, dose-blind to week 48 and open-label to week 204. Patients fulfilling the Assessment of Spondyloarthritis International Society (ASAS) axSpA criteria with active disease were stratified (AS/nr-axSpA) according to the modified New York (mNY) criteria at randomisation. Spinal radiographs were assessed using the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS). MRI inflammation used the Spondyloarthritis Research Consortium of Canada (SPARCC) score for sacroiliac joints (SIJ) and the Berlin spinal score (remission defined as SPARCC <2 and Berlin ≤2, respectively). RESULTS: MRI improvements from baseline (BL) to week 12 were maintained to week 204 (SPARCC BL: AS=8.5, nr-axSpA=7.5; SPARCC week 204: AS=1.3, nr-axSpA=2.4; Berlin BL: AS=7.4, nr-axSpA=4.4; Berlin week 204: AS=2.6, nr-axSpA=1.9). 66.7% of patients with AS and 69.6% of patients with nr-axSpA with BL SPARCC scores ≥2, and 65.4% of patients with AS and 57.3% of patients with nr-axSpA with BL Berlin score >2, achieved remission at week 204. Mean mSASSS change in AS from BL to week 204 was 0.98 (95% CI 0.34, 1.63); 0.67 (95% CI 0.21,1.13) from BL to week 96; and 0.31 (95% CI 0.02,0.60) from week 96 to week 204. Corresponding nr-axSpA changes were 0.06 (95% CI -0.17,0.28), -0.01 (95% CI -0.19,0.17) and 0.07 (95% CI -0.07,0.20). 4.5% of patients with nr-axSpA fulfilled the mNY criteria at week 204, while 4.3% of patients with AS no longer did so. CONCLUSIONS: In patients with CZP-treated axSpA, rapid decreases in spinal and SIJ MRI inflammation were maintained to week 204. Overall, 4-year spinal progression was low, with less progression during years 2-4 than 0-2. Radiographic SIJ grading changes demonstrated limited progression. TRIAL REGISTRATION NUMBER: NCT01087762; Post-results.

Rotigotine transdermal patch in Chinese patients with advanced Parkinson's disease: A randomized, double-blind, placebo-controlled pivotal study.

INTRODUCTION: Rotigotine was demonstrated to be efficacious and well-tolerated in three placebo-controlled studies (CLEOPATRA-PD/PREFER/SP921) of patients with advanced-stage Parkinson's disease (PD), most of whom were Caucasian. This multicenter phase 3 study (SP1037; NCT01646255) was the first to investigate the efficacy and safety of rotigotine in Chinese patients with advanced-stage PD. METHODS: Chinese patients with PD, inadequately controlled on levodopa (stable dose ≥200 mg/day), with ≥2.5 h/day "off" time, and Hoehn & Yahr stage 2-4, were randomized 1:1 to receive transdermal rotigotine or placebo, titrated over ≤7 weeks, maintained at optimal/maximum dose (4-16 mg/24 h) for 12 weeks. Primary efficacy variable: mean change in absolute "off" time (according to patient diaries) from baseline to end of maintenance. Safety variables included adverse events (AEs) and discontinuations due to AEs. RESULTS: 346 patients were randomized and 89.9% completed the study (87.8% placebo; 92.0% rotigotine). All were Chinese (58.7% male; mean ± SD age: 62.2 ± 8.9 years; mean ± SD time since PD diagnosis: 6.62 ± 3.70 years). Rotigotine significantly reduced "off" time vs placebo (LS mean [95% CI] treatment difference: -1.20 h/day [-1.83, -0.57]; p = 0.0002), and resulted in more responders (≥30% decrease in "off" time: 36.9% placebo; 48.8% rotigotine; p = 0.0269). AEs were reported for 86 (50.0%) placebo- and 103 (59.2%) rotigotine-treated patients; 15 discontinued due to AEs (placebo 7; rotigotine 8). The most common AEs (≥5%) were dizziness, nausea, pruritus, and dyskinesia. CONCLUSIONS: Rotigotine was efficacious in Chinese patients with advanced-stage PD as add-on therapy to levodopa, significantly reducing "off" time vs placebo; the treatment difference was similar to that observed in previous studies of mainly Caucasian patients. Rotigotine was generally well-tolerated and had a similar AE profile to those observed in previous studies.

Switching from an oral dopamine receptor agonist to rotigotine transdermal patch: a review of clinical data with a focus on patient perspective.

INTRODUCTION: Dopamine receptor agonists (DAs) are commonly used to treat Parkinson's disease (PD) and restless legs syndrome (RLS). In certain situations, switching from oral DAs to rotigotine transdermal patch may be beneficial for the patient (e.g., optimal symptom control/side effects/perioperative management, preference for once-daily/non-oral administration, RLS augmentation treatment). Areas covered: This narrative review summarizes available data on DA dose equivalency, dose conversions, switching schedules, safety, tolerability, efficacy and patient treatment preferences of switching from oral DAs to rotigotine (and vice versa) in patients with PD/RLS. The studies were identified in a PubMed search (up to 8 November 2016) using terms ('dopamine receptor agonist' OR 'rotigotine') AND 'switch'. Expert commentary: Randomized controlled studies often do not address the challenges clinicians face in practice, e.g., switching medications within the same class when dosing is not a one-to-one ratio. The authors describe three open-label studies in PD where oral DAs were successfully switched to rotigotine, and review three studies in RLS where oral DAs/levodopa were switched to rotigotine. Finally, the authors provide a suggested tool for switching from oral DAs to rotigotine, which includes dose conversion factors and switching schedules. The authors' view is that low-dose oral DAs (equivalent to ≤8 mg/24 h rotigotine) may be switched overnight.

Sustained efficacy, safety and patient-reported outcomes of certolizumab pegol in axial spondyloarthritis: 4-year outcomes from RAPID-axSpA.

Objective: The aim was to assess the long-term safety and efficacy of certolizumab pegol over 4 years of continuous treatment in patients with axial spondyloarthritis (axSpA), including both AS and non-radiographic (nr-) axSpA. Methods: RAPID-axSpA was a phase 3 randomized trial, double blind and placebo controlled to week 24, dose blind to week 48 and open label to week 204. Patients had a clinical diagnosis of axSpA, meeting Assessment of SpondyloArthritis international Society (ASAS) criteria, and had active disease. The assessed outcomes included ASAS20, ASAS40, AS DAS (ASDAS), BASDAI, BASFI and BASMI scores, along with selected measures of remission. Further patient-reported outcomes, peripheral arthritis, enthesitis, uveitis and quality-of-life measures are also reported. Results: Two hundred and eighteen of 325 patients randomized (AS: 121; nr-axSpA: 97) received certolizumab pegol from week 0. Of these, 65% remained in the study at week 204 (AS: 67%; nr-axSpA: 63%). Across all outcomes, for AS and nr-axSpA, sustained improvements were observed to week 204 [week 204 overall axSpA: ASAS20: 54.1% (non-responder imputation); 83.7% (observed case, OC); ASAS40: 44.0% (non-responder imputation); 68.1% (OC); ASDAS inactive disease: 32.1% (last observation carried forward); 31.4% (OC)]. In the safety set (n = 315), there were 292.8 adverse events and 10.4 serious adverse events per 100 patient-years. No deaths were reported. Conclusion: In the first study to evaluate the efficacy of an anti-TNF across both axSpA subpopulations, improvements in clinical and patient-reported outcomes at 24 and 96 weeks were sustained through 4 years of treatment, with no new safety signals. Trial registration: ClinicalTrials.gov, http://clinicaltrials.gov, NCT01087762.