Dominik Richard

Canakinumab for the Treatment of Acute Flares in Difficult-to-Treat Gouty Arthritis Results of a Multicenter, Phase II, Dose-Ranging Study

OBJECTIVE To assess the efficacy and tolerability of canakinumab, a fully human anti-interleukin-1β monoclonal antibody, for the treatment of acute gouty arthritis. METHODS In this 8-week, single-blind, double-dummy, dose-ranging study, patients with acute gouty arthritis whose disease was refractory to or who had contraindications to nonsteroidal antiinflammatory drugs and/or colchicine were randomized to receive a single subcutaneous dose of canakinumab (10, 25, 50, 90, or 150 mg; n = 143) or an intramuscular dose of triamcinolone acetonide (40 mg; n = 57). Patients assessed pain using a 100-mm visual analog scale. RESULTS Seventy-two hours after treatment, a statistically significant dose response was observed for canakinumab. All canakinumab doses were associated with numerically less pain than triamcinolone acetonide; thus, a dose with equivalent efficacy to triamcinolone acetonide 72 hours after treatment could not be determined. The reduction from baseline in pain intensity with canakinumab 150 mg was greater than with triamcinolone acetonide 24, 48, and 72 hours after treatment (differences of -11.5 mm [P = 0.04], -18.2 mm [P = 0.002], and -19.2 mm [P < 0.001], respectively), and 4, 5, and 7 days after treatment (all P < 0.05). Canakinumab significantly reduced the risk of recurrent flares versus triamcinolone acetonide (P ≤ 0.01 for all doses) (relative risk reduction 94% for canakinumab 150 mg versus triamcinolone acetonide). The overall incidence of adverse events was similar for canakinumab (41%) and triamcinolone acetonide (42%); most were mild or moderate in severity. CONCLUSION Our findings indicate that canakinumab 150 mg provides rapid and sustained pain relief in patients with acute gouty arthritis, and significantly reduces the risk of recurrent flares compared with triamcinolone acetonide.

Canakinumab for acute gouty arthritis in patients with limited treatment options: results from two randomised, multicentre, active-controlled, double-blind trials and their initial extensions

Objectives Gouty arthritis patients for whom non-steroidal anti-inflammatory drugs and colchicine are inappropriate have limited treatment options. Canakinumab, an anti-interleukin-1β monoclonal antibody, may be an option for such patients. The authors assessed the efficacy/safety of one dose of canakinumab 150 mg (n=230) or triamcinolone acetonide (TA) 40 mg (n=226) at baseline and upon a new flare in frequently flaring patients contraindicated for, intolerant of, or unresponsive to non-steroidal anti-inflammatory drugs and/or colchicine. Core study co-primary endpoints were pain intensity 72 h postdose (0–100 mm visual analogue scale and time to first new flare. Methods Two 12-week randomised, multicentre, active-controlled, double-blind, parallel-group core studies with double-blind 12-week extensions (response in acute flare and in prevention of episodes of re-flare in gout (β-RELIEVED and β-RELIEVED-II)). Results 82.6% patients had comorbidities. Mean 72-h visual analogue scale pain score was lower with canakinumab (25.0 mm vs 35.7 mm; difference, −10.7 mm; 95% CI −15.4 to −6.0; p<0.0001), with significantly less physician-assessed tenderness and swelling (ORs=2.16 and 2.74; both p≤0.01) versus TA. Canakinumab significantly delayed time to first new flare, reduced the risk of new flares by 62% versus TA (HR: 0.38; 95% CI 0.26 to 0.57) in the core studies and by 56% (HR: 0.44; 95% CI 0.32 to 0.60; both p≤0.0001) over the entire 24-week period, and decreased median C-reactive protein levels (p≤0.0001 at 72 h and 7 days). Over the 24-week period, adverse events were reported in 66.2% (canakinumab) and 52.8% (TA) and serious adverse events were reported in 8.0% (canakinumab) and 3.5% (TA) of patients. Adverse events reported more frequently with canakinumab included infections, low neutrophil count and low platelet count. Conclusion Canakinumab provided significant pain and inflammation relief and reduced the risk of new flares in these patients with acute gouty arthritis.

Canakinumab relieves symptoms of acute flares and improves health-related quality of life in patients with difficult-to-treat Gouty Arthritis by suppressing inflammation: results of a randomized, dose-ranging study

IntroductionWe report the impact of canakinumab, a fully human anti-interleukin-1β monoclonal antibody, on inflammation and health-related quality of life (HRQoL) in patients with difficult-to-treat Gouty Arthritis.MethodsIn this eight-week, single-blind, double-dummy, dose-ranging study, patients with acute Gouty Arthritis flares who were unresponsive or intolerant to - or had contraindications for - non-steroidal anti-inflammatory drugs and/or colchicine were randomized to receive a single subcutaneous dose of canakinumab (10, 25, 50, 90, or 150 mg) (N = 143) or an intramuscular dose of triamcinolone acetonide 40 mg (N = 57). Patients assessed pain using a Likert scale, physicians assessed clinical signs of joint inflammation, and HRQoL was measured using the 36-item Short-Form Health Survey (SF-36) (acute version).ResultsAt baseline, 98% of patients were suffering from moderate-to-extreme pain. The percentage of patients with no or mild pain was numerically greater in most canakinumab groups compared with triamcinolone acetonide from 24 to 72 hours post-dose; the difference was statistically significant for canakinumab 150 mg at these time points (P < 0.05). Treatment with canakinumab 150 mg was associated with statistically significant lower Likert scores for tenderness (odds ratio (OR), 3.2; 95% confidence interval (CI), 1.27 to 7.89; P = 0.014) and swelling (OR, 2.7; 95% CI, 1.09 to 6.50, P = 0.032) at 72 hours compared with triamcinolone acetonide. Median C-reactive protein and serum amyloid A levels were normalized by seven days post-dose in most canakinumab groups, but remained elevated in the triamcinolone acetonide group. Improvements in physical health were observed at seven days post-dose in all treatment groups; increases in scores were highest for canakinumab 150 mg. In this group, the mean SF-36 physical component summary score increased by 12.0 points from baseline to 48.3 at seven days post-dose. SF-36 scores for physical functioning and bodily pain for the canakinumab 150 mg group approached those for the US general population by seven days post-dose and reached norm values by eight weeks post-dose.ConclusionsCanakinumab 150 mg provided significantly greater and more rapid reduction in pain and signs and symptoms of inflammation compared with triamcinolone acetonide 40 mg. Improvements in HRQoL were seen in both treatment groups with a faster onset with canakinumab 150 mg compared with triamcinolone acetonide 40 mg.Trial registrationclinicaltrials.gov: NCT00798369.

Effect on blood pressure of lumiracoxib versus ibuprofen in patients with osteoarthritis and controlled hypertension: a randomized trial.

Objectives Nonsteroidal anti-inflammatory drugs vary in their impact on blood pressure and the effect of lumiracoxib 100 mg once daily has not been studied previously. To examine whether lumiracoxib 100 mg once daily would result in lower 24-h mean systolic ambulatory blood pressure than ibuprofen 600 mg three times daily in osteoarthritis patients with controlled hypertension, a 4-week, randomized, double-blind, parallel-group study was conducted in 79 centres in nine countries. Methods Hypertensive osteoarthritis patients of 50 years at least whose office blood pressure was less than 140/90 mmHg on stable antihypertensive treatment were randomized to lumiracoxib (n = 394) 100 mg once daily or ibuprofen 600 mg three times daily (n = 393) and 24-h ambulatory blood pressure monitoring was performed at baseline and end of study. The primary outcome measure was a comparison of the change in 24-h mean systolic ambulatory blood pressure from baseline to week 4. Secondary analyses included other blood pressure-related endpoints and efficacy (pain) measurements. Results Compared with baseline, the 24-h mean systolic ambulatory blood pressure (least square mean) decreased in lumiracoxib-treated patients (−2.7 mmHg) and increased in ibuprofen-treated patients (+2.2 mmHg) at 4 weeks, estimated difference −5.0 mmHg (95% confidence interval −6.1 to −3.8) in favour of lumiracoxib. The 24-h mean diastolic ambulatory blood pressure changes were −1.5 mmHg (lumiracoxib), +0.5 mmHg (ibuprofen), difference −2.0 mmHg (95% confidence interval −2.7 to −1.3). Efficacy results were comparable. Conclusions Treatment with lumiracoxib 100 mg once daily resulted in clinically significant lower blood pressure compared with ibuprofen 600 mg three times daily in osteoarthritis patients with well controlled hypertension.

Gastrointestinal Tolerability of Lumiracoxib in Patients With Osteoarthritis and Rheumatoid Arthritis

BACKGROUND & AIMS The aim of this study was to evaluate the gastrointestinal safety of lumiracoxib, a novel selective cyclooxygenase-2 inhibitor. METHODS Results from 15 Phase II and III randomized studies of lumiracoxib in osteoarthritis and rheumatoid arthritis were pooled. Patients received lumiracoxib (200/400 mg/day), celecoxib (200/400 mg/day), rofecoxib (25 mg once daily), diclofenac (75 mg twice daily), ibuprofen (800 mg 3 times daily), naproxen (500 mg twice daily), or placebo. Outcome measures included the incidence of definite or probable ulcer complications (perforations, obstructions, or bleedings as confirmed by an adjudication committee) and symptomatic upper gastrointestinal ulcers, the incidence of prespecified gastrointestinal adverse events, and the discontinuation rate caused by adverse events. All suspected ulcer complications in these 15 studies were adjudicated prospectively. Data from 2 endoscopic studies were pooled separately to assess the cumulative incidence of gastroduodenal ulcers >or=3 mm in diameter. RESULTS Symptomatic upper gastrointestinal ulcers and ulcer complications were reduced nearly 10-fold with lumiracoxib (1.7 events per 100 patient-years [95% confidence interval, 1.09-2.39]) compared with nonselective nonsteroidal anti-inflammatory drugs (13.7 events per 100 patient-years [95% confidence interval, 9.47-18.82]). Symptomatic ulcer frequency was markedly lower with lumiracoxib (0.4%) than with nonselective nonsteroidal anti-inflammatory drugs (2.5%). Discontinuation rates due to gastrointestinal adverse events were higher for nonselective nonsteroidal anti-inflammatory drugs (8.4%) than for lumiracoxib (3.3%). In the endoscopy analysis, the cumulative frequency of ulcers >or=3 mm in diameter was reduced by >70% for lumiracoxib versus ibuprofen. CONCLUSIONS Lumiracoxib exhibited a gastrointestinal safety profile superior to nonselective nonsteroidal anti-inflammatory drugs.

The effects of lumiracoxib 100 mg once daily vs. ibuprofen 600 mg three times daily on the blood pressure profiles of hypertensive osteoarthritis patients taking different classes of antihypertensive agents

Aims:  To examine whether the blood pressure (BP) profiles of lumiracoxib and high‐dose ibuprofen differed in patients treated with different classes of antihypertensive medications.

Clinical trial: comparison of the gastrointestinal safety of lumiracoxib with traditional nonselective nonsteroidal anti‐inflammatory drugs early after the initiation of treatment – findings from the Therapeutic Arthritis Research and Gastrointestinal Event Trial

Background  The large (n = 18 325) Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET) study demonstrated a significant gastrointestinal benefit with lumiracoxib 400 mg o.d. (4× the recommended dose in osteoarthritis) vs. naproxen 500 mg b.d. or ibuprofen 800 mg t.d.s.

AB0847 Efficacy and Safety of Canakinumab Pre-Filled Syringe in Acute Gouty Arthritis Patients with Chronic Kidney Disease Stage ≥3

Background Chronic kidney disease (CKD) limits the treatment options in acute gouty arthritis (GA) patients due to intolerance and contraindications to available therapies. Efficacy and safety of canakinumab (CAN), a selective, fully human, anti-IL-1β monoclonal antibody, formulated as a lyophilized (CAN-LYO) powder requiring reconstitution with water vs triamcinolone acetonide (TA) in patients with acute GA was demonstrated in previous phase III trials. Objectives To evaluate efficacy and safety of CAN liquid formulation (CAN-PFS) vs TA in a subgroup of patients with CKD stage ≥3. Methods This was a 12-week, multicenter, double-blind, active controlled study. The design and methodology of the study have been reported earlier1. Here, we report results from a post-hoc analysis of the 12-week data for GA patients with CKD stage ≥3 (estimated Glomerular Filtration Rate (eGFR) <60ml/min). The primary endpoint was pain intensity in the target joint, measured on 0-100 mm VAS scale at 72 h post-dose. Secondary endpoints included time to first new attack, and safety over 12 weeks. Results Of 388 patients, 76 had CKD stage ≥3 at baseline (CAN-PFS, n=24; CAN-LYO, n=28; TA, n=24). CAN-PFS provided a statistically significant reduction in pain intensity in the target joint vs TA from 72 h post-dose (estimated difference, -14.6mm; 95% CI:-29.0, -0.1, p≤0.05) until 7 days post-dose (-16.1mm; 95% CI: -28.4, -3.7, p=0.0115). The two CAN treatment arms were comparable. Over 12 weeks, a single dose of CAN-PFS showed a significant relative risk reduction of 90% for time to first new gout attack vs TA [HR 0.10, 95% CI (0.01, 0.78); p≤0.05]. Adverse events (AEs) were reported in 12 (50%), 11 (39.3%) and 10 (41.7%) patients in CAN-PFS, CAN-LYO and TA groups, respectively. The most frequent AEs were infections (CAN-PFS, n=3 (12.5%); CAN-LYO, n=6 (21.4%); TA, n=2 (8.3%). Serious AEs were reported in a total of 7 patients (CAN-PFS, n=2 (8.3%); CAN-LYO, n=4 (14.3%); TA, n=1 (4.2%), with infections (CAN-PFS, n=1 (4.2%); CAN-LYO, n=2 (7.1%); TA, n=0), being the most common SAEs. No deaths were reported during the study. Conclusions This post-hoc analysis provides evidence for the efficacy of CAN-PFS compared with a potent long-acting corticosteroid in providing significant pain relief and reducing incidence of new attacks in GA patients with CKD stage ≥3 with limited treatment options. The safety profile in this sub population was consistent with that of the overall study population and with that known from previous studies. References Sunkureddi et al. Arthirits & Rheum 2013; 65. Disclosure of Interest P. Sunkureddi Consultant for: Novartis, Bristol Myers Squibb, Speakers bureau: Pfizer, Takeda, Bristol Myers Squibb, UCB, Amgen, Abbott, Shinogi, Savient, E. Toth: None declared, J. Brown Grant/research support: Amgen, Bristol Myers Squibb, Eli Lilly, Novartis, Merck, Pfizer, Roche, Servier, Sanofi-Aventis, Takeda, Warner Chilcott, Consultant for: Amgen, Eli Lilly, Merck, Warner Chilcott, Sanofi–Aventis, Speakers bureau: Amgen, Eli Lilly, Novartis, Merck, A. Kivitz Grant/research support: Novartis, A. Stancati Shareholder of: Novartis, Employee of: Novartis, D. Richard Shareholder of: Novartis, Employee of: Novartis, K. Lheritier Shareholder of: Novartis, Employee of: Novartis, R. Möricke: None declared DOI 10.1136/annrheumdis-2014-eular.1850

AB0848 Canakinumab Pre-Filled Syringe VS Triamcinolone Acetonide in the Treatment of Acute Gouty Arthritis Attacks: Results from A Post-Hoc Analysis in Difficult-To-Treat Patients

Background Canakinumab (CAN), a selective, fully human anti-IL-1β monoclonal antibody, is the only approved biologic in the European Union for the symptomatic treatment of adult patients (pts) with difficult-to-treat gouty arthritis (GA). A liquid formulation, presented as pre-filled syringe (CAN-PFS) has been developed to improve upon the lyophilized form (CAN-LYO) that requires reconstitution. Here, we report results from a post-hoc analysis of the 12-week data of a Phase III trial. Objectives To evaluate the efficacy and safety of CAN-PFS vs triamcinolone acetonide (TA) in a subset of difficult-to-treat GA pts defined as a) unable to use NSAIDs and colchicine due to contraindication, intolerance or lack of efficacy, and b) currently on urate-lowering therapy (ULT), or previously failed ULT or in whom ULT is otherwise contraindicated. Methods This was a 12-week, multicenter, double-blind, active controlled study. The design and methodology of the study have been reported earlier1. The primary efficacy measure was overall pain intensity in the most affected joint measured on VAS scale (0-100 mm) at 72 h post-dose. Secondary endpoints included time to first new attack and safety over 12 weeks. Results Of the 397 GA pts randomized, 106 (CAN-PFS, n=34; CAN-LYO, n=43; TA, n=29) met the subgroup definition. CAN-PFS provided a statistically significant reduction in pain intensity at 72 h post dose vs TA (estimated difference, -30.7mm; 95%CI: -42.1, -19.3, p≤0.05). The least square mean pain scores at 72 h post-dose for CAN -PFS and LYO, were14.7mm and 19.3mm, respectively; both lower than that for TA (45.4mm). CAN-PFS treatment significantly delayed time to first new attack vs TA with a relative risk reduction of 92% (HR, 0.08; 95%CI: 0.01, 0.63, p≤0.05) over 12 weeks. Adverse events (AEs) were reported in 12 (35.3%), 16 (37.2%) and 14 (48.3%) pts in CAN-PFS, CAN-LYO and TA groups, respectively. Serious AEs were reported in 7 pts [CAN-PFS, n=1 (2.9%); CAN-LYO, n=5 (11.6%); TA, n=1 (3.4%)], with infections [CAN-PFS, n=1 (2.9%); CAN-LYO, n=2 (4.7%); TA, n=0)] being the most common SAEs. One patient in the CAN-LYO group had serious aortitis, which was coded under vascular disorders system organ class, but adjudicated as an opportunistic infection by the independent adjudication committee. No deaths were reported during the study. Conclusions This analysis provides evidence for the efficacy of CAN in difficult-to-treat GA pts either in pre-filled syringe or lyophilized formulation compared to a potent long acting systemic corticosteroid. CAN-PFS provided better pain relief and reduced the risk of new attacks compared to TA. The safety profile in this population was consistent with that of the overall study population and with that known from previous studies. References Sunkureddi et al. Arthirits & Rheum 2013; 65. Disclosure of Interest P. Sunkureddi Consultant for: Novartis, Bristol Myers Squibb, Speakers bureau: Pfizer, Takeda, Bristol Myers Squibb, UCB, Amgen, Abbott, Shinogi, Savient, E. Toth: None declared, J. Brown Grant/research support: Amgen, Bristol Myers Squibb, Eli Lilly, Novartis, Merck, Pfizer, Roche, Servier, Sanofi-aventis, Takeda, Warner Chilcott, Consultant for: Amgen, Eli Lilly, Merck, Warner Chilcott, Sanofi-aventis, Speakers bureau: Amgen, Eli Lilly, Novartis, Merck, A. Kivitz Grant/research support: Novartis, A. Stancati Shareholder of: novartis, Employee of: novartis, D. Richard Shareholder of: Novartis, Employee of: Novartis, K. Lheritier Shareholder of: Novartis, Employee of: Novartis, R. Möricke: None declared DOI 10.1136/annrheumdis-2014-eular.1846