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Risankizumab selectively inhibits interleukin 23, a cytokine that contributes to psoriatic inflammation.To evaluate the efficacy and safety of risankizumab vs placebo and continuous treatment vs withdrawal in adults with moderate to severe plaque psoriasis.Multinational, phase 3, randomized, double-blind, placebo-controlled trial conducted from March 6, 2016, to July 26, 2018. A total of 507 eligible patients had stable moderate to severe chronic plaque psoriasis for 6 months or longer, body surface area involvement greater than or equal to 10%, Psoriasis Area and Severity Index (PASI) greater than or equal to 12, and a static Physician's Global Assessment (sPGA) score greater than or equal to 3. Intention-to-treat analysis was conducted.Patients were randomized (4:1, interactive response technology) to risankizumab, 150 mg, subcutaneously, or placebo at weeks 0 and 4 (part A1). All patients received risankizumab at week 16. At week 28, patients randomized to risankizumab who achieved an sPGA score of 0/1 were rerandomized 1:2 to risankizumab or placebo every 12 weeks (part B).Co-primary end points for the part A1 phase included proportions of patients achieving greater than or equal to 90% improvement in PASI (PASI 90) and sPGA score of 0/1 at week 16. The PASI measures severity of erythema, infiltration, and desquamation weighted by area of skin involvement over the head, trunk, upper extremities, and lower extremities; scores range from 0 (no disease) to 72 (maximal disease activity). The sPGA assesses average thickness, erythema, and scaling of all psoriatic lesions; scores range from 0 (clear) to 4 (severe), with 0/1 indicating clear or almost clear. Primary and secondary end points in part B included proportion of rerandomized patients achieving an sPGA score of 0/1 at week 52 (primary) and week 104 (secondary).Of 563 patients screened, 507 were randomized to risankizumab (n = 407) or placebo (n = 100). Most patients were men (356 [70.2%]); median age was 51 years (interquartile range, 38-60 years). At week 16, 298 patients (73.2%) in the treatment group vs 2 patients (2.0%) receiving placebo achieved a PASI 90 response, and 340 patients (83.5%) receiving risankizumab vs 7 patients (7.0%) receiving placebo achieved sPGA 0/1 scores (placebo-adjusted differences: PASI 90: 70.8%; 95% CI, 65.7%-76.0%; sPGA 0/1: 76.5%; 95% CI, 70.4%-82.5%; P .001 for both). At week 28, 336 responders were rerandomized to risankizumab (n = 111) or treatment withdrawal (n = 225). At week 52, the sPGA 0/1 score was achieved by 97 patients (87.4%) receiving risankizumab vs 138 patients (61.3%) receiving placebo. At week 104, the sPGA 0/1 score was achieved by 90 patients (81.1%) receiving risankizumab vs 16 patients (7.1%) receiving placebo (placebo-adjusted differences: week 52: 25.9%; 95% CI, 17.3%-34.6%; week 104: 73.9%; 95% CI, 66.0%-81.9%; P .001 for both). Rates of treatment-emergent adverse events were similar between risankizumab (186 [45.7%]) and placebo (49 [49.0%]) in part A1 and remained stable over time.Risankizumab showed superior efficacy compared with placebo through 16 weeks and treatment withdrawal through 2 years. Risankizumab was well tolerated, with no unexpected safety findings during the 2-year trial.ClinicalTrials.gov Identifier: NCT02672852.

PURPOSE: Report global adalimumab safety and efficacy outcomes in patients with non-infectious uveitis.METHODS: Adults with non-infectious intermediate, posterior, or panuveitis were randomized 1:1 to receive placebo or adalimumab in the VISUAL I (active uveitis) or VISUAL II (inactive uveitis) trials. Integrated global and Japan substudy results are reported. The primary endpoint was time to treatment failure (TF).RESULTS: In the integrated studies, TF risk was significantly reduced (hazard ratio [95% CI]) with adalimumab versus placebo (VISUAL I: HR = 0.56 [0.40-0.76], p < 0.001; VISUAL II: HR = 0.52 [0.37-0.74], p < 0.001). In Japan substudies, no consistent trends were observed between groups (VISUAL I: HR = 1.20 [0.41-3.54]; VISUAL II: HR = 0.45 [0.20-1.03]). Adverse event rates were similar between treatment groups in both studies (854 to 1063 events/100 participant-years).CONCLUSIONS: Adalimumab lowered time to TF versus placebo in the integrated population; no consistent trends were observed in Japan substudies. Safety results were consistent between studies.

Purpose Chronic use of corticosteroids for the treatment of uveitis has been linked with drug-associated toxicity and adverse events (AEs). This study examines the association between corticosteroid dosage and incidence rates of corticosteroid-related AEs. Design A post hoc analysis of the VISUAL-1 and VISUAL-2 placebo-controlled clinical trials. Participants The clinical trials consisted of adults with active (VISUAL-1) and inactive (VISUAL-2) noninfectious intermediate, posterior, and panuveitis. Patients were randomized to receive adalimumab or placebo and underwent a protocol-defined mandatory taper to discontinue their oral corticosteroids. Methods Adverse event data were collected at each visit and included an assessment of the corticosteroid relationship by the investigator. A longitudinal Poisson regression model was estimated controlling for time-dependent corticosteroid dose, age, sex, prior oral corticosteroid dose, prior topical corticosteroid use, and concomitant immunosuppressive drug use. Only patients randomized to placebo were considered. Main Outcome Measures The primary outcome measure was the frequency of AEs. Results The incidence rates of corticosteroid-related AEs among placebo patients during the prednisone treatment period in VISUAL-1 was statistically higher than after discontinuation (454.2 per 100 patient-years [PY] vs. 36.1 per 100 PY, incident rate ratio = 12.6, P P P P P P = 0.05) corticosteroid-related AEs per year compared with a patient taking 10 mg/day. Conclusions Evidence from VISUAL-1 and VISUAL-2 suggests that the incidence rates of corticosteroid-related AEs increase systematically with corticosteroid dose.

The objective of this study was to characterize the effects of risankizumab on the in vivo activity of cytochrome P450 (CYP) 1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A in psoriasis patients using a cocktail approach. Patients with moderate to severe chronic plaque psoriasis (n = 21) received single oral doses of sensitive probe substrates for CYP1A2 (caffeine 100 mg), CYP2C9 (warfarin 10 mg), CYP2C19 (omeprazole 20 mg), CYP2D6 (metoprolol 50 mg), and CYP3A (midazolam 2 mg) on day 1, followed by 12 weeks of subcutaneous risankizumab treatment of 150 mg once every 4 weeks from day 8 to day 92, and again the same cocktail of substrates on day 98. Serial blood samples were collected for determination of the CYP probe drugs and metabolites with and without risankizumab. Trough samples were collected for risankizumab. The 90% confidence intervals (CIs) for the area under the plasma concentration–time curve (AUC) from time zero to infinity (AUC∞) ratios for the CYP probe substrates administered with risankizumab versus without risankizumab were within the default 0.8–1.25 equivalence bounds. Similar results were observed for maximum plasma concentration (Cmax), except for omeprazole, for which the lower bound of the 90% CI for Cmax (0.73) extended slightly below the default equivalence limit. No differences were observed in metabolite-to-parent drug Cmax or AUC ratios with risankizumab versus without risankizumab. Risankizumab trough plasma concentrations significantly exceeded those of the phase III regimen of risankizumab in psoriasis (150 mg subcutaneously at weeks 0 and 4 and every 12 weeks thereafter). Risankizumab did not affect the in vivo activity of CYP1A2, CYP2C9, CYP2C19, CYP2D6, or CYP3A enzymes in patients with moderate or severe plaque psoriasis and therefore has no potential for drug interactions through these enzymes. ClinicalTrials.gov Identifier: NCT02772601.

PURPOSE: To evaluate safety and efficacy of adalimumab in patients with noninfectious intermediate, posterior, or panuveitis. DESIGN: Phase 3, open-label, multicenter clinical trial extension (VISUAL III). PARTICIPANTS: Adults meeting treatment failure (TF) criteria or who completed VISUAL I or II (phase 3, randomized, double-masked, placebo-controlled) without TF. METHODS: Patients received adalimumab 40 mg every other week. Interim follow-up data were described from VISUAL III weeks 0 through 78. MAIN OUTCOME MEASURES: Disease quiescence, steroid-free quiescence, active inflammatory chorioretinal/retinal vascular lesions, anterior chamber cell grade, vitreous haze grade, best-corrected visual acuity (BCVA), and corticosteroid dose. Binary data were reported using nonresponder imputation (NRI), continuous data using last observation carried forward and as-observed analysis, and corticosteroid dose using observed-case analysis. Adverse events (AEs) were reported from first adalimumab dose in VISUAL III through interim cutoff. RESULTS: Of 424 patients enrolled, 371 were included in intent-to-treat analysis. At study entry, 242 of 371 (65%) patients had active uveitis; 60% (145/242, NRI) achieved quiescence at week 78, and 66% (95/143, as-observed) of those were corticosteroid free. At study entry, 129 of 371 (35%) patients had inactive uveitis; 74% (96/129, NRI) achieved quiescence at week 78, and 93% (89/96, as-observed) of those were corticosteroid free. Inflammatory lesions, anterior chamber grade, and vitreous haze grade showed initial improvement followed by decline in patients with active uveitis and remained stable in patients with inactive uveitis. BCVA improved in patients with active uveitis from weeks 0 to 78 (0.27 to 0.14 logMAR; left and right eyes; as-observed) and remained stable in patients with inactive uveitis. Mean corticosteroid dose decreased from 13.6 mg/day (week 0) to 2.6 mg/day (week 78) in patients with active uveitis and remained stable in those with inactive uveitis (1.5-1.2 mg/day). AEs (424 events/100 patient-years) and serious AEs (16.5 events/100 patient-years) were comparable with previous VISUAL trials. CONCLUSIONS: Patients with active uveitis at study entry who received adalimumab therapy were likely to achieve quiescence, improve visual acuity, and reduce their daily uveitis-related systemic corticosteroid use. Most patients with inactive uveitis at study entry sustained quiescence without a systemic corticosteroid dose increase. No new safety signals were identified. ispartof: OPHTHALMOLOGY vol:125 issue:7 pages:1075-1087 ispartof: location:United States status: published

Chronic use of corticosteroids for the treatment of uveitis has been linked with drug-associated toxicity and adverse events (AEs). This study examines the association between corticosteroid dosage and incidence rates of corticosteroid-related AEs.A post hoc analysis of the VISUAL-1 and VISUAL-2 placebo-controlled clinical trials.The clinical trials consisted of adults with active (VISUAL-1) and inactive (VISUAL-2) noninfectious intermediate, posterior, and panuveitis. Patients were randomized to receive adalimumab or placebo and underwent a protocol-defined mandatory taper to discontinue their oral corticosteroids.Adverse event data were collected at each visit and included an assessment of the corticosteroid relationship by the investigator. A longitudinal Poisson regression model was estimated controlling for time-dependent corticosteroid dose, age, sex, prior oral corticosteroid dose, prior topical corticosteroid use, and concomitant immunosuppressive drug use. Only patients randomized to placebo were considered.The primary outcome measure was the frequency of AEs.The incidence rates of corticosteroid-related AEs among placebo patients during the prednisone treatment period in VISUAL-1 was statistically higher than after discontinuation (454.2 per 100 patient-years [PY] vs. 36.1 per 100 PY, incident rate ratio = 12.6, P0.001). Incidence rate ratios among VISUAL-2 patients were similarly high (317.5 per 100 PY vs. 41.1 per 100 PY, incident rate ratio = 7.7, P0.001). Based on the Poisson multivariate longitudinal Generalized Estimating Equation (GEE) model, each 10 mg increase in prednisone dose is associated with a 1.5- and 2.6-fold increase (P0.001 and P0.001) in the rate of corticosteroid-related AEs in VISUAL-1 and VISUAL-2, respectively. This implies in turn that a patient with active uveitis taking 60 mg/day of prednisone will experience, on average, an additional 10.1 (95% confidence interval (CI), 6.3-14.5; P0.001) corticosteroid-related AEs per year compared with a patient taking 10 mg/day, whereas a patient with inactive uveitis taking 35 mg/day of prednisone will experience, on average, an additional 23.5 (95% CI, 7.6-52.7; P = 0.05) corticosteroid-related AEs per year compared with a patient taking 10 mg/day.Evidence from VISUAL-1 and VISUAL-2 suggests that the incidence rates of corticosteroid-related AEs increase systematically with corticosteroid dose.

Background Patients with noninfectious uveitis are at risk for long-term complications of uncontrolled inflammation, as well as for the adverse effects of long-term glucocorticoid therapy. We conducted a trial to assess the efficacy and safety of adalimumab as a glucocorticoid-sparing agent for the treatment of noninfectious uveitis. Methods This multinational phase 3 trial involved adults who had active noninfectious intermediate uveitis, posterior uveitis, or panuveitis despite having received prednisone treatment for 2 or more weeks. Investigators and patients were unaware of the study-group assignments. Patients were randomly assigned in a 1:1 ratio to receive adalimumab (a loading dose of 80 mg followed by a dose of 40 mg every 2 weeks) or matched placebo. All patients received a mandatory prednisone burst followed by tapering of prednisone over the course of 15 weeks. The primary efficacy end point was the time to treatment failure occurring at or after week 6. Treatment failure was a multicomponent outcome that was based on assessment of new inflammatory lesions, best corrected visual acuity, anterior chamber cell grade, and vitreous haze grade. Nine ranked secondary efficacy end points were assessed, and adverse events were reported. Results The median time to treatment failure was 24 weeks in the adalimumab group and 13 weeks in the placebo group. Among the 217 patients in the intention-to-treat population, those receiving adalimumab were less likely than those in the placebo group to have treatment failure (hazard ratio, 0.50; 95% confidence interval, 0.36 to 0.70; P

Background and aims Adalimumab has been shown to be efficacious and well-tolerated in Western patients with Crohn's disease. These 2 randomized, double-blind clinical trials evaluated adalimumab efficacy and safety in Japanese patients with moderate to severe Crohn's disease. Methods 90 patients enrolled in the induction trial and were randomized to receive adalimumab 160/80 mg, adalimumab 80/40 mg or placebo at Weeks 0/2. At Week 4, patients who achieved a decrease in CDAI ≥ 70 points versus Baseline entered the maintenance trial and were randomized to adalimumab 40 mg every other week or placebo for 52 weeks. All other patients received 4 more weeks of blinded adalimumab before entering the open-label portion of the maintenance trial. At/after Week 4 of the maintenance trial, blinded patients who flared/failed to respond entered the open-label portion. Open-label maintenance patients received adalimumab 40 mg every other week with the option of 80 mg every other week for flare/non-response. Results Clinical remission rates at Week 4 in the induction trial were 33.3%, 17.6% and 13.0% in the adalimumab 160/80 mg, adalimumab 80/40 mg and placebo groups, respectively. Maintenance remission rates were 38.1% for adalimumab and 9.1% for placebo at Week 52. Anti-TNF naive patients achieved greater efficacy than anti-TNF exposed patients. Patients randomized to adalimumab achieved greater quality of life improvement versus placebo. There were no clinically relevant differences in safety between adalimumab and placebo. Conclusions Adalimumab is effective and well-tolerated for inducing and maintaining clinical remission in Japanese patients with moderate to severe Crohn's disease. NCT00445939; NCT00445432.

Background: Data regarding the effectiveness of anti-tumor necrosis factor (TNF) agents for resolution of extraintestinal manifestations (EIMs) are scarce. The CARE study evaluated clinical effectiveness, EIM resolution, and safety of adalimumab in a large pan-European cohort of patients with moderate to severe Crohn's disease (CD). Methods: In all, 945 patients with a Harvey–Bradshaw Index (HBI) ≥7 enrolled in this multicenter, open-label phase IIIb trial. Patients received subcutaneous adalimumab, 160/80 mg at weeks 0/2, then 40 mg every other week. Dose adjustments were allowed for CD-related concomitant medications (from week 8) and adalimumab (from week 12). Clinical endpoints were analyzed through week 20 for all patients, and after stratification by prior infliximab exposure and by reason for discontinuing infliximab (primary nonresponse [PNR] or other). Results: The remission rate (HBI

BackgroundNon-infectious uveitis is a potentially sight-threatening ocular disorder caused by chronic inflammation and its complications. Therapeutic success is limited by systemic adverse effects associated with long-term corticosteroid and immunomodulator use if topical medication is not sufficient to control the inflammation. We aimed to assess the efficacy and safety of adalimumab in patients with inactive, non-infectious uveitis controlled by systemic corticosteroids.MethodsWe did this multicentre, double-masked, randomised, placebo-controlled phase 3 trial at 62 study sites in 21 countries in the USA, Canada, Europe, Israel, Australia, and Latin America. Patients (aged ≤18 years) with inactive, non-infectious intermediate, posterior, or panuveitic uveitis controlled by 10–35 mg/day of prednisone were randomly assigned (1:1), via an interactive voice and web response system with a block size of four, to receive either subcutaneous adalimumab (loading dose 80 mg; biweekly dose 40 mg) or placebo, with a mandatory prednisone taper from week 2. Randomisation was stratified by baseline immunosuppressant treatment. Sponsor personnel with direct oversight of the conduct and management of the study, investigators, study site personnel, and patients were masked to treatment allocation. The primary efficacy endpoint was time to treatment failure, a multicomponent endpoint encompassing new active inflammatory chorioretinal or inflammatory retinal vascular lesions, anterior chamber cell grade, vitreous haze grade, and visual acuity. Analysis was done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01124838.FindingsBetween Aug 10, 2010, and May 14, 2015, we randomly assigned 229 patients to receive placebo (n=114) or adalimumab (n=115); 226 patients comprised the intention-to-treat population. Median follow-up time was 155 days (IQR 77–357) in the placebo group and 245 days (119–564) in the adalimumab group. Treatment failure occurred in 61 (55%) of 111 patients in the placebo group compared with 45 (39%) of 115 patients in the adalimumab group. Time to treatment failure was significantly improved in the adalimumab group compared with the placebo group (median not estimated [>18 months] vs 8·3 months; hazard ratio 0·57, 95% CI 0·39–0·84; p=0·004). The 40th percentile for time to treatment failure was 4·8 months in the placebo group and 10·2 months in the adalimumab group. No patients in either group had opportunistic infections (excluding oral candidiasis and tuberculosis). No malignancies were reported in the placebo group whereas one (1%) patient in the adalimumab group reported non-serious squamous cell carcinoma. The most common adverse events were arthralgia (12 [11%] patients in the placebo group and 27 [23%] patients in the adalimumab group), nasopharyngitis (16 [17%] and eight [16%] patients, respectively), and headache (17 [15%] patients in each group).InterpretationAdalimumab significantly lowered the risk of uveitic flare or loss of visual acuity upon corticosteroid withdrawal in patients with inactive, non-infectious intermediate, posterior, or panuveitic uveitis controlled by systemic corticosteroids. No new safety signals were observed and the rate of adverse events was similar between groups. These findings suggest that adalimumab is well tolerated and could be an effective treatment option in this patient population. An open-label extension study (NCT01148225) is ongoing to provide long-term safety data for adalimumab in patients with non-infectious uveitis.FundingAbbVie

Background Tumor necrosis factor-alpha (TNF-α) is pivotal in the pathogenesis of psoriasis, an immune-mediated disease. Adalimumab is a fully human, IgG1 monoclonal antibody that inhibits TNF-α. Objectives The aims of this study were to assess the efficacy and safety of adalimumab therapy for patients with moderate to severe plaque psoriasis and evaluate the duration of treatment response after withdrawal from or dosage reduction of adalimumab therapy. Methods In this multicenter, randomized, double-blind, placebo-controlled study, patients with moderate to severe plaque psoriasis received 12-week, open-label therapy with subcutaneous adalimumab, consisting of 80 mg of adalimumab at weeks 0 and 1, followed by 40 mg weekly at weeks 2–11. At week 12, patients who had an improvement in Psoriasis Area and Severity Index (PASI) score of ≥50% were randomized to blinded therapy and received either adalimumab 40 mg every other week (eow) or placebo for an additional 12 weeks. Results A total of 148 patients enrolled. Clinical response was rapid, with a PASI 50 response rate of 28% at week 2 of adalimumab therapy. At week 12, 91.9% (136/148) of patients had achieved ≥50% reduction in PASI (PASI 50) vs. baseline, 76.4% (113/148) had achieved PASI 75, and 47.3% (70/148) had achieved PASI 90. Of patients who were randomized to placebo at week 12, 30.9% (21/68) experienced a relapse (Conclusions Weekly adalimumab therapy rapidly improved psoriasis during an initial 12-week period. Improvement was sustained in most, but not all patients, despite dosage reduction to every other week. No patients randomized to adalimumab withdrawal (placebo at week 12) experienced rebound, and most maintained >PASI 50 improvement, relative to baseline, during the 3 months following adalimumab discontinuation. Overall, greater efficacy rates at week 24 were observed for patients randomized to continuous adalimumab therapy than for patients who were withdrawn from therapy at week 12.

OBJECTIVES The purpose of this study was to compare recombinant hirudin and heparin as adjuncts to streptokinase thrombolysis in patients with acute myocardial infarction (AMI). BACKGROUND Experimental studies and previous small clinical trials suggest that specific thrombin inhibition improves early patency rates and clinical outcome in patients treated with streptokinase. METHODS In a randomized double-blind, multicenter trial, 1,208 patients with AMI ≤6 h were treated with aspirin and streptokinase and randomized to receive recombinant hirudin (lepirudin, IV bolus of 0.2 mg/kg, followed by subcutaneous (SC) injections of 0.5 mg/kg b.i.d. for 5 to 7 days) or heparin (IV placebo bolus, followed by SC injections of 12,500 IU b.i.d. for 5 to 7 days). A total of 447 patients were included in the angiographic substudy in which the primary end point, 90-min Thrombolysis in Myocardial Infarction (TIMI) flow grade 3 of the infarct-related artery, was evaluated, while the other two-thirds served as “safety group” in which only clinical end points were evaluated. As an additional efficacy parameter the ST-segment resolution at 90 and 180 min was measured in all patients. RESULTS TIMI flow grade 3 was observed in 40.7% in the lepirudin and in 33.5% in the heparin group (p = 0.16), respectively. In the entire study population the proportion of patients with complete ST resolution at 90 min (28% vs. 22%, p = 0.05) and at 180 min (52% vs. 48%, p = 0.18) after start of therapy tended to be higher in the lepirudin group. There was no significant difference in the incidence of hemorrhagic stroke (0.2% vs. 0.3%) or total stroke (1.2% vs. 1.5%), reinfarction rate (4.6% vs. 5.1%) and total mortality rate (6.8% vs. 6.4%) at 30 days, as well as the combined end point of death, nonfatal stroke, nonfatal reinfarction, rescue-percutaneous transluminal coronary angioplasty and refractory angina (22.7 vs. 24.3%) were not statistically different between the two groups. CONCLUSIONS Lepirudin as adjunct to thrombolysis with streptokinase did not significantly improve restoration of blood flow in the infarct vessel as assessed by angiography, but was associated with an accelerated ST resolution. There was no increase in the risk of major bleedings with lepirudin compared to heparin.

SummaryThe aim of this multicentre, prospective, randomised, dose-ranging study was to compare the safety and efficacy of subcutaneous recombinant hirudin (HBW 023) against intravenous sodium heparin in acute lower limb deep venous thrombosis (DVT). Patients were randomized to treatment with either HBW 023 or heparin for 5 ±1 days. HBW 023 was given according to body-weight in three dose groups. Thromboembolic disease was assessed by phlebography and ventilation/perfusion (V/Q) scanning on Bay 1 and Day 5±1. One hundred and fifty-five patients were enrolled, of these 121 were evaluable for efficacy analysis. Significantly fewer patients on HBW 023 developed new V/Q abnormalities during the treatment period, (p = 0.006). There was no difference between the groups in thrombus extension or regression, major bleeding complications or serious adverse events. There were significantly fewer findings of new V/Q mismatch after treatment with HBW 023, and anticoagulant control was superior in these patients.

Background Uveitis causes an estimated 10–15% of cases of blindness in western countries and there is an unmet need for effective therapies for patients (pts) with non-infectious uveitis who are at risk for long-term side effects from chronic corticosteroid use. Objectives To assess adalimumab (ADA) efficacy and safety in patients with active and inactive, non-infectious uveitis. Methods Adults with non-infectious intermediate, posterior, or panuveitis were enrolled in two global phase 3, double-masked trials, VISUAL I (pts with active uveitis despite ≥2 weeks (wks) of prednisone (PS), 10–60 mg/d) and VISUAL II (pts with inactive disease dependent on 10–35 mg/d of PS, to maintain inactivity). Pts were randomized 1:1 to receive placebo (PBO) or ADA subcutaneously (80 mg wk 0, followed by 40 mg every other wk from wk 1 up to 80 wks). In VISUAL I, all pts received a PS burst followed by taper to 0 mg by wk 15. In VISUAL II, PS taper to 0 mg was mandatory by wk 19. Integrated data (main study and Japan sub-study) from VISUAL I and VISUAL II trials are reported. The primary endpoint was time to treatment failure (TF) at or after wk 6 for VISUAL I or at or after wk 2 for VISUAL II. Nine ranked secondary endpoints were assessed and adverse events (AEs) were monitored. Results The intent-to-treat (ITT) analyses included 233 (217 main study, 16 Japan sub-study) and 258 (226 main study, 32 Japan sub-study) pts from VISUAL I and VISUAL II, respectively (VISUAL I and VISUAL II: female: 58% and 61%; mean age, 43.2 years (y) and 43.1 y; mean duration of uveitis, 46 months (mt) and 59 mt). Risk of TF was reduced by 44% (VISUAL I) and 48% (VISUAL II) in ADA-treated pts compared to PBO group (VISUAL I: HR=0.56, 95% CI, 0.40–0.76, P P 18 mt, as more than half of the pts did not achieve TF by wk 80; VISUAL II). ADA-treated pts had fewer TF criteria than PBO in both studies and treatment effects were numerically in favor of ADA for most of the secondary efficacy variables (Table). ADA and PBO AE rates were similar (VISUAL I: 1063 vs 960 events/100 pt-y, VISUAL II: 854 vs 884 events/100 pt-y) in both studies, respectively. Conclusions ADA lowered the risk of uveitic flare or visual acuity loss in pts with active and inactive disease when off PS. The safety profile was consistent with the known safety profile across the approved ADA indications. Acknowledgement AbbVie funded the studies (VISUAL I [NCT01138657] and VISUAL II [NCT01124838]). All authors contributed to the development of the content. The authors and AbbVie reviewed and approved the abstract. The authors maintained control over the final content. Medical writing assistance was provided by Gaurav Patki, PhD of AbbVie Inc. Disclosure of Interest A. P. Brezin Consultant for: AbbVie, A. D. Dick Consultant for: AbbVie, G. J. Jaffe Consultant for: AbbVie, S. Ohno Employee of: AbbVie, Santen, K. Namba Consultant for: AbbVie, H. Goto Consultant for: AbbVie, N. Inomata Shareholder of: AbbVie, Employee of: AbbVie, A. P. Song Shareholder of: AbbVie, Employee of: AbbVie, M. Kron Shareholder of: AbbVie, Employee of: AbbVie, A. Camez Shareholder of: AbbVie, Employee of: AbbVie, S. Tari Shareholder of: AbbVie, Employee of: AbbVie, Q. D. Nguyen Consultant for: AbbVie, Santen, XOMA, Bausch & Lomb

Background and aims: Crohn's disease negatively affects patients’ quality of life and ability to work. We investigated the impact of adalimumab on work productivity, daily activities, and quality of life in an open-label trial ( N = 945). The population comprised both infliximab-naive and -exposed patients, including infliximab primary non-responders. Methods: Patients received adalimumab induction therapy (160 mg/80 mg at Weeks 0/2), followed by adalimumab 40 mg every other week for up to 20 weeks (patients with flares/non-response could receive 40 mg weekly at/after Week 12). The Work Productivity and Activity Impairment Questionnaire and Short Inflammatory Bowel Disease Questionnaire were assessed. Indirect cost savings were estimated based on the average work productivity improvements at Week 20. Results: Mean baseline scores indicated severe productivity impairment and poor quality of life. At Week 20, 60% of infliximab-naive and 47% of infliximab primary non-responders achieved clinically important improvements (≥ 9 points) on the Short Inflammatory Bowel Disease Questionnaire, and 51% and 43%, respectively, achieved the minimum clinically important difference (improvement ≥ 7 percentage points) for total work productivity impairment (non-responder imputation). At Week 20, 64% of infliximab-naive and 55% of infliximab primary non-responders achieved clinically important improvements in total activity impairment. Estimated 20-week total indirect productivity-related cost savings were €3070 per infliximab-naive patient and €2059 per infliximab-exposed patient. Conclusions: Adalimumab therapy significantly improved work productivity and disease-specific quality of life for patients with moderate to severe Crohn's disease. Patients who failed prior infliximab therapy and patients naive to infliximab benefited from adalimumab, with potentially greater benefits for infliximab-naive patients ([NCT00409617][1]). * Abbreviations : CARE : Crohn's treatment with adalimumab, patient response to a safety and efficacy study CD : Crohn's disease CRP : C-reactive protein EIMs : extraintestinal manifestations HBI : Harvey Bradshaw Index HRQOL : health-related quality of life MCID : minimum clinically important difference PNR : primary non-responder PRO : patient-reported outcome SIBDQ : Short Inflammatory Bowel Disease Questionnaire TAI : total activity impairment TNF : tumor necrosis factor TWPI : total work productivity impairment WPAI:CD : Work Productivity and Activity Impairment Questionnaire for CD [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00409617&atom=%2Feccojc%2F7%2F1%2F34.atom

Background Corticosteroids, currently the mainstay of uveitis treatment, are associated with unwanted side effects, and are not always fully effective. Accordingly, there is a clear unmet need for steroid-sparing treatments. Multiple reports describe the use of biologics, including adalimumab (ADA), in the management of non-infectious uveitis as steroid-sparing agents, but there is a paucity of level 1 evidence to support efficacy of these drugs. Objectives To assess ADA efficacy and safety in patients with active, sight-threatening, non-infectious uveitis despite systemic high-dose corticosteroid therapy. Methods This multinational, double-masked trial included patients aged ≥18 years with active, non-infectious intermediate, posterior, or panuveitis on ≥2 weeks of prednisone (10–60 mg/d). Patients with active uveitis had ≥1 of: active, inflammatory chorioretinal or retinal vascular lesion; anterior chamber (AC) cell grade ≥2+; or vitreous haze (VH) grade ≥2+. Patients were randomized 1:1 to receive placebo or ADA. The ADA group received an 80-mg baseline loading dose and 40 mg every other week for up to 80 weeks; all patients received prednisone 60 mg/d that was tapered to 0 mg by week 15. Primary endpoint was time to treatment failure (TF) in ≥1 eye. TF was defined as ≥1 of: new, active, inflammatory vascular lesions; worsening of BCVA by ≥15 letters at or after week 6; inability to achieve ≤0.5+ AC cell grade or ≤0.5+ VH grade (at week 6); or 2-step increase in AC cell grade or VH grade (after week 6). Ranked secondary endpoints included change in AC cell grade, VH grade, and BCVA from the best state achieved before week 6 to the final visit. Safety was monitored during the trial. Results 217 patients were enrolled (female, 57%; mean age, 42.7 y; mean uveitis duration, 46 mo); 22% had intermediate, 33% had posterior, and 45% had panuveitis. Patients on ADA were less likely to have TF (hazard ratio=0.5; 95% CI, 0.36–0.70; P P Conclusions In patients with active, non-infectious intermediate, posterior, or pan uveitis despite the use of corticosteroids, ADA significantly lowered the risk for uveitic flare or BCVA loss. The safety profile was consistent with the known safety profile across approved ADA indications. Acknowledgements Writing assistance was provided by Jillian Gee and Katherine Groschwitz of Complete Publication Solutions, LLC (CPS), Horsham, PA and Peter Rittenhouse of Complete Healthcare Communications, Inc (CHC), Chadds Ford, PA, on behalf of AbbVie. AbbVie provided funding to CPS and CHC for medical writing assistance. AbbVie funded the study (NCT01138657), contributed to its design and the data analyses, and was involved in the drafting, review, and approval of the abstract. Disclosure of Interest G. Jaffe, MD Consultant for: AbbVie, J. Thorne, MD, PhD Grant/research support from: National Eye Institute and Allergen, Inc., Consultant for: AbbVie, Gilead, and XOMA, D. Scales, MD Consultant for: AbbVie Steering Committee, P. Franco, MD: None declared, S. Tari, MD Shareholder of: May hold AbbVie stock or options, Employee of: AbbVie, A. Camez, MD Shareholder of: May hold AbbVie stock or options, Employee of: AbbVie, A. Song, MD, MPH Shareholder of: May hold AbbVie stock or options, Employee of: AbbVie, M. Kron, PhD Shareholder of: May hold AbbVie stock or options, Employee of: AbbVie, T. Barisani-Asenbauer, MD, PhD Consultant for: AbbVie Advisory Board, A. Dick, MBBS, MD, FMedSci Consultant for: AbbVie Advisory Board

We report a double-blind, multicenter, multinational, placebo-controlled, and well-controlled trial to prove that the sustained-release (SR) formulation of propafenone is superior to placebo in preventing symptoms of paroxysmal atrial fibrillation (AF). A total of 594 patients were enrolled in the qualifying period of the study and 293 patients were randomized at 53 centers. There were significant increases in the arrhythmia-free periods from day 5 of randomization to the first recurrence of symptomatic atrial arrhythmia in the propafenone SR 325 mg twice daily (p = 0.004) and propafenone SR 425 mg twice daily (p = 0.003) treatment groups compared with placebo. The median arrhythmia-free time was 9 days in the placebo group, 35 days in the propafenone SR 325 mg twice daily group, and 44 days in the propafenone SR 425 mg twice daily group. There was a significant reduction in average heart rate during the first recurrence of symptomatic arrhythmia after day 5 in the low-dose propafenone group compared with placebo. The median treatment failure time from day 5 (arrhythmia recurrence, adverse events, and withdrawals) was prolonged from 8 days in the placebo group to 19 days in the propafenone SR 325 mg twice daily group (p = 0.002) and to 24 days in the propafenone SR 425 mg twice daily group (p = 0.006). The percentage of patients with ≥1 serious adverse event was similar in the propafenone SR treatment groups (propafenone SR 325 mg twice daily, 10.0%; propafenone SR 425 mg twice daily, 11.2%) but lower in the placebo group (1.1%). In conclusion, the SR formulation of propafenone is superior to placebo, well-tolerated, and prevents symptoms of paroxysmal AF.

Background & Aims Patients with moderate to severe ileocolonic Crohn's disease (CD) who received adalimumab induction and maintenance therapy had greater rates of mucosal healing than patients who received placebo after adalimumab induction therapy in a 52-week trial (EXTend the Safety and Efficacy of Adalimumab Through ENDoscopic Healing). We investigated whether this treatment also induced deep remission—a composite clinical and endoscopic end point. Methods Rates of deep remission, defined as the absence of mucosal ulceration and CD Activity Index scores less than 150, were compared between patients given continuous adalimumab and those given only induction therapy followed by placebo. We assessed the relationships between deep remission and other outcomes among patients who received adalimumab. The outcomes of patients with deep remission were compared with those of patients with only the absence of mucosal ulceration or only clinical remission. Results Rates of deep remission were 16% in patients given adalimumab vs 10% in those given placebo (P = .34) at week 12, and 19% vs 0% (P Conclusions In an exploratory study of patients with moderate to severe ileocolonic CD who received adalimumab induction and maintenance therapy, patients achieving deep remission appeared to have better 1-year outcomes than those not achieving deep remission. These findings should be validated in large, prospective trials. ClinicalTrials.gov number: NCT00348283.

s of the 4th Congress of ECCO the European Crohn’s and Colitis Organisation S57 endoscopic remission in 3/3 patients at 24 months. Bowel thickness as assessed by US was slower to decrease, but improved in all patients and disappeared in 4/6 patients. Complete perianal fistulas closure was observed in 3/4 patients. No deaths or life-threatening infections occurred. Unexpected adverse events included a perianal abscess after mobilisation in one patient, pleural and pericardial effusions in another, BK virus-related macrohaematuria in one case, and acute pielonephritis in another patient, all rapidly resolved with conservative treatment. Conclusion: Unselected CD34+ cells transplantation can induce and maintain both clinical and endoscopic remission in refractory CD patients. P117 Global safety of adalimumab in trials of patients with Crohn’s disease J.F. Colombel1 *, R. Panaccione2, W.J. Sandborn3, P. Rutgeerts4, S.B. Hanauer5, W. Reinisch6, P.F. Pollack7, J.D. Kent7, A.T. Cardoso7, W. Lau8. 1Centre Hospitalier Universitaire de Lille, Lille, France, 2University of Calgary, Calgary, AB, Canada, 3Mayo Clinic, Rochester, MN, USA, 4University Hospital of Gasthuisberg, Leuven, Belgium, 5University of Chicago, Chicago, IL, USA, 6Medical University of Vienna, Vienna, Austria, 7Abbott Laboratories, Abbott Park, IL, USA, 8Abbott Laboratories, Parsippany, NJ, USA Introduction: Adalimumab, a fully human anti-tumor necrosis factor (anti-TNF) monoclonal antibody, is approved for treating patients with severely active Crohn’s disease (CD) who have had an inadequate response to conventional therapy. Methods: All patients with CD participating in the pivotal randomized controlled clinical trials, open label extensions, and Phase IIIb studies were evaluated for safety at regular intervals. Rates of adverse events (AEs) of interest to physicians prescribing anti-TNF therapy were assessed per 100-patientyears (E/100-PYs) of adalimumab exposure. Standardized mortality ratios were calculated using the World Health Organization 2003 age-and sex-matched US mortality data. These analyses are based on data available as of 15 April 2008. Rates of AEs of interest AE of interest E (E/100-PYs)

disease. The 5-, 10-, and 20-year actuarial risk of colectomy was 2.6%, 4%, and 5% respectively. Of note, 48 patients (75%) received a proctocolectomy with ileo-anal anastomosis, and 12 (25%) developed a chromic recurrent pouchitis. In addition, more than 80% of patients received maintenance therapy with mesalazine at least 1.6 gr/daily, and 43% of patients used combined oral and topical (1-2/week) maintenance therapy. Male sex (hazard ratio [HR] = 3.5; 95% confidence interval [CI] 1.5-5.5) and pancolitis (HR = 2.5; 95% CI 1.2-4.3) were predictive for EC, after adjustment for confounders. Age at diagnosis older than 40 yrs (HR = 2.5; 95% CI 1.4-3.8) and intolerance/inefficacy of thiopurines (HR = 3.1; 95% CI 1.45.1) were predictive of LC. Conclusions: Colectomy was rather infrequent in our cohort, being more often performed for chronically active disease. The incidence of cancer an dysplasia was also low, probably because the extensive use and adherence to mesalazine maintenance therapy. The introduction of anti-TNF-alpha therapy in the last five years have not changed this figure so far.

BACKGROUND & AIMS: We investigated the efficacy of adalimumab for inducing and maintaining mucosal healing in patients with Crohn's disease (CD). METHODS: A randomized, double-blind, placebo-controlled trial (extend the safety and efficacy of adalimumab through endoscopic healing [EXTEND]) evaluated adalimumab for induction and maintenance of mucosal healing in 135 adults with moderate to severe ileocolonic CD. The baseline degree of mucosal ulceration was documented by ileocolonoscopy. All patients received induction therapy (subcutaneous adalimumab 160/80 mg at weeks 0/2). At week 4, patients were randomly assigned to groups given 40 mg adalimumab or placebo every other week through week 52. Open-label adalimumab was given to patients with flares or no response, starting at week 8. Mucosal healing was reassessed by ileocolonoscopy at weeks 12 and 52. RESULTS: Twenty-seven percent of patients receiving adalimumab had mucosal healing at week 12 (the primary end point) versus 13% given placebo (P

Reference(s) [1] Wolff BG (1983), The importance of disease-free margins in resections for Crohn’s disease, Diseases of the Colon & Rectum, vol. 26 (4) pp. 239 43. [2] Kotanagi H (1991), Do microscopic abnormalities at resection margins correlate with increased anastomotic recurrence in Crohn’s disease? Retrospective analysis of 100 cases, Diseases of the Colon & Rectum (1991), vol. 34 (10) pp. 909 16.

UC patients were still in remission one year after discontinuing IFX (Figure). Fifty percent of the patients were still in remission after median 680 [412 948] and 1334 [995 1673] days, respectively, p = 0.057. Univariate analyses indicated an association of longer disease duration with relapse in CD, OR 1.1 [1.0 1.1], p = 0.022; but this was not confirmed in multivariate analyses. Twenty-four of 25 CD patients (96%), and 5 of 7 UC patients (71%) experienced complete clinical remission at retreatment with IFX after relapse. Conclusions: Most IBD patients who discontinued IFX while in clinical remission later experienced relapse, with a nonsignificant trend towards a better prognosis in patients with UC. Retreatment with IFX at relapse in this particular subpopulation was followed by higher remission rates than expected from clinical trials.

Recombinant hirudin: A specific thrombin inhibiting anticoagulant for hemodialysis. The first experience with hirudin as an alternative anticoagulant for heparin in hemodialysis is reported. Recombinant hirudin (HBW 023) was administered in 20 patients as a bolus before dialysis with low flux polysulfone dialyzers (PS400), the dosage being adapted stepwise from patient to patient by 0.02 mg/kg to the occurrence of clotting or bleeding. Four different administration schedules were studied. The first three schedules (0.02 mg/kg, N = 1; 0.04 mg/kg, N = 1; 0.06 mg/kg, N = 4) were discontinued because of clotting. The 0.08 mg/kg schedule was maintained without clotting event in 14 patients. Bleeding was not observed. Plasma hirudin averaged 503.9 ± 214.0 and 527.7 ± 217.1 ng/ml after two and four hours of dialysis, and decreased during an interdialytic interval of 44 hours to 223.2 ± 86.2 ng/ml. Modified antithrombin III (P < 0.05) and activated partial thromboplastin times were lower (P < 0.01) under hirudin compared to heparin; these coagulation parameters were closer to normal during hirudin treatment. The patients developing clotting could be distinguished from those without clotting by the registration of the activated clotting times (9.2 ± 3.0 vs. 18.7 ± 3.2min after 2 hr, P < 0.01; 8.1 ± 3.0 vs. 16.2 ± 3.8min after 4hr of dialysis, P < 0.05); cut-off value below which clotting is to be expected was 12 min). It is concluded that administration of hirudin as a bolus before the start of dialysis, at a dosage of 0.08 mg/kg, is not complicated by clotting or by bleeding. Coagulation tendency can optimally be monitored by the registration of the activated clotting time. Residual hirudin in the blood 44 hours after the end of dialysis will have to be taken into consideration, if this anticoagulant is to be administered on a regular basis.

P124 Efficacy and toxicity of tacrolimus in steroid resistant ulcerative colitis cannot be predicted by genetic polymorphisms of the CYP3A4, CYP3A5, ABCB1 and NR1I2 genes K.R. Herrlinger1 *, H. Koc1, A. Teml2, J. Wehkamp2, M. Schwab2, E.F. Stange1, K. Fellermann1, E. Schaeffeler2. 1Robert-Bosch-Hospital, Stuttgart, Germany, 2Dr MargareteFischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany

Background and aims Adalimumab has been shown to be effective and well tolerated in patients with Crohn's disease. This analysis reports the results of a cohort of Japanese patients with moderate to severe Crohn's disease who were evaluated for up to 3years to assess the long-term use of adalimumab. Methods The study consisted of a double-blind part and an open-label part. Patients were included either in the 52-week double-blind, placebo-controlled part of the study followed by a 96-week open-label extension or in the open-label part from the beginning or in the event of a flare. Patients were treated with adalimumab and evaluated for up to 148weeks as 3 data cohorts: the all-adalimumab cohort (patients receiving ≥1 injection of adalimumab), the 148-week follow-up subcohort (patients who completed 148weeks of follow-up after the first adalimumab dose), and the dose-escalation subcohort (patients receiving adalimumab doses that increased to 80mg every other week). Results In the all-adalimumab cohort (n=79), clinical remission rates were approximately 30% after 36weeks of exposure to adalimumab and for the remainder of the study (35%, 33%, and 28% for weeks 48, 108, and 144, respectively). An improvement in quality of life was also maintained over the same period. In the dose-escalation subcohort (n=40), the clinical remission rate was 75% (6/8) 48weeks after dose escalation. Adalimumab was tolerated, and no deaths were reported. Conclusions Adalimumab is effective for maintaining long-term clinical remission in Japanese patients with moderate to severe Crohn's disease (NCT00445432).