C. Birbara

Adalimumab for long-term treatment of psoriatic arthritis: 2-year data from the Adalimumab Effectiveness in Psoriatic Arthritis Trial (ADEPT)

Objective: To evaluate the long-term effectiveness and tolerability of adalimumab in the treatment of psoriatic arthritis (PsA). Methods: Patients with PsA who completed a 24-week, double-blind study of adalimumab versus placebo were eligible to enroll in an open-label extension study and receive adalimumab 40 mg subcutaneously every other week for up to an additional 120 weeks. At the time of this analysis, available efficacy evaluations throughout 2 years of treatment (n  =  245) included American College of Rheumatology (ACR) 20%, 50% and 70% improvement scores, measures of joint disease and skin disease, disability and quality of life; modified total Sharp scores (mTSS) were available for 2.75 years of treatment for patients who received adalimumab in the 24-week study. Results: After 24 weeks of double-blind treatment, the mean change in mTSS was −0.2 for the adalimumab group (N  =  144) and 1.0 for the placebo group (N  =  152; p<0.001), and outcomes for all individual ACR component variables were significantly improved in adalimumab compared with placebo-treated patients. Compared with 24-week responses, inhibition of radiographic progression and improvements in joint disease were maintained in most patients during long-term, open-label adalimumab treatment. Also, improvements in skin disease were maintained, with >20% of patients achieving the strict criterion of psoriasis area and severity index 100. The nature and frequency of adverse events during long-term adalimumab treatment were consistent with the safety profile during short-term treatment. Conclusions: The clinical and radiographic efficacy of adalimumab demonstrated during short-term treatment was sustained during long-term treatment. Adalimumab has a favourable risk–benefit profile in patients with PsA. Trial registration number: NCT00195689.

Efficacy and safety of tanezumab in the treatment of chronic low back pain.

Summary Intravenous tanezumab produces clinically and statistically superior analgesic efficacy compared to placebo and naproxen, with few adverse events in patients with chronic low back pain. Abstract Increased nerve growth factor levels are associated with chronic pain conditions, including chronic low back pain (LBP). This study examined safety and analgesic efficacy of tanezumab, a humanized anti‐nerve growth factor antibody, in adults with chronic LBP. Patients received intravenous tanezumab 200 &mgr;g/kg plus oral placebo (n = 88), intravenous placebo plus oral naproxen 500 mg twice a day (n = 88), or intravenous placebo plus oral placebo (n = 41). Primary outcome was average LBP intensity (aLBPI) at Week 6. Secondary outcomes were proportion of patients with ≥30% or ≥50% reduction in aLBPI, Roland–Morris Disability Questionnaire and Brief Pain Inventory–short form scores, Patients’ Global Assessment of LBP, Patients’ Global Evaluation of study medication, and rescue medication use. Mean aLBPI change from baseline to Week 6 was greater with tanezumab vs naproxen (P = 0.004) and placebo (P < 0.001). Greater proportions of patients reported ≥30% and ≥50% reduction in aLBPI with tanezumab vs naproxen (P ≤ 0.013) and placebo (P < 0.001), and greater improvements in Roland–Morris Disability Questionnaire (P < 0.001) and other secondary outcomes except rescue medication use. Tanezumab was associated with adverse events (AEs) of abnormal peripheral sensation that were generally mild and resolved before study completion; however, there were no serious AEs. Nine patients (4 of whom were tanezumab‐treated) discontinued due to AEs. In conclusion, tanezumab resulted in analgesic efficacy that was clinically and statistically superior to placebo and naproxen in patients with chronic LBP. Tanezumab clinical development is on regulatory hold due to AEs in osteoarthritis patients.

Infliximab maintains a high degree of clinical response in patients with active psoriatic arthritis through 1 year of treatment: results from the IMPACT 2 trial

Objective: To evaluate the efficacy and safety of infliximab through 1 year in patients with psoriatic arthritis (PsA) enrolled in the IMPACT 2 trial. Methods: In this double blind, placebo controlled, phase III study, 200 patients with active PsA were randomised to receive infusions of infliximab 5 mg/kg or placebo at weeks 0, 2, 6, and every 8 weeks thereafter through 1 year. Patients with persistent disease activity could enter early escape at week 16, and all remaining placebo patients crossed over to infliximab at week 24. Patients randomised to infliximab who had no response or who lost response could escalate their dose to 10 mg/kg starting at week 38. Clinical efficacy was assessed based on the proportion of patients achieving ACR 20 and PASI 75 responses. Major clinical response (that is, maintenance of ACR 70 response for 24 continuous weeks) was assessed for the first time in PsA. Results: Through 1 year of treatment, 58.9% and 61.4% of patients in the randomised infliximab and placebo/infliximab groups, respectively, achieved ACR 20; corresponding figures for PASI 75 were 50.0% and 60.3%. At week 54, major clinical response was achieved by 12.1% of patients in the infliximab group. The safety profile of infliximab through week 54 was consistent with that seen through week 24. Two malignancies occurred: basal cell skin cancer (placebo) and stage I Hodgkin’s lymphoma (infliximab). Conclusion: Infliximab maintains a high degree of clinical efficacy and continues to be well tolerated in patients with PsA through 1 year of treatment.

Treatment of chronic low back pain with etoricoxib, a new cyclo-oxygenase-2 selective inhibitor: improvement in pain and disability—a randomized, placebo-controlled, 3-month trial☆

We evaluated etoricoxib, a novel COX-2-specific inhibitor, in 319 patients with chronic low back pain (LBP) in this double-blind, placebo-controlled trial. Patients were randomized to a 60 mg dose (n = 103) or 90 mg dose (n = 107) of etoricoxib, or placebo (n = 109), daily for 12 weeks. The primary endpoint was low back pain intensity scale (Visual Analog Scale of 0- to 100-mm) time-weighted average change from baseline over 4 weeks. Other endpoints included evaluation over 3 months of low back pain intensity scale, Roland-Morris Disability Questionnaire (RMDQ), low back pain bothersomeness scale, patient- and investigator-global assessments, Patient Health Survey (MOS SF-12), rescue acetaminophen use, and discontinuation due to lack of efficacy. Etoricoxib provided significant improvement from baseline versus placebo in pain intensity (4 weeks: 12.9 mm and 10.3 mm for 60-mg and 90-mg doses, P <.001 for each; 12 weeks: 10.5 mm and 7.5 mm for 60-mg and 90-mg doses, P =.001 and.018, respectively). Etoricoxib at either dose led to significant improvement in other endpoints, including RMDQ scores, bothersomeness scores and global assessments. Etoricoxib given once daily provided significant relief of symptoms, and disability associated with chronic LBP that was observed 1 week after initiating therapy, was maximal at 4 weeks, and was maintained over 3 months.

Long-term open-label study of tanezumab for moderate to severe osteoarthritic knee pain

OBJECTIVE This study was designed to evaluate the long-term safety and effectiveness of repeated doses of the humanized anti-nerve growth factor antibody, tanezumab, during open-label treatment of patients with OA knee pain. DESIGN The current study (clinicaltrials.gov identifier: NCT00399490) was a multicenter, phase II, open-label, multiple-dose extension of an earlier randomized clinical trial. All patients (N=281) received infusions of tanezumab 50μg/kg on Days 1 and 56 with subsequent doses administered at 8-week intervals (up to a total of eight infusions). The primary endpoint of this study was safety. Effectiveness evaluations included overall knee pain, Western Ontario and McMaster Universities Osteoarthritis (WOMAC) index subscales, and subject global assessment (SGA) of response to therapy on 0-100 point visual analog scales. RESULTS Repeated administration of tanezumab resulted in a low incidence of treatment-related adverse events (AEs; 7.5%). The rate of serious AEs was also low (2.8%) with none considered treatment-related. Few AEs of abnormal peripheral sensation were reported; hypoesthesia was reported by nine patients (3.2%), paresthesia by seven patients (2.5%), and hyperesthesia, peripheral neuropathy, and sensory disturbance were each reported by one patient (0.4% for each). Most AEs of abnormal peripheral sensation were rated as mild (95%) and the majority (65%) resolved before study completion. At Week 8, overall knee pain and SGA improved from baseline by a mean (± standard error) of -12.8 (±1.78) and 8.0 (±1.66), respectively. Similar improvements occurred for WOMAC subscales. CONCLUSIONS Repeated injections of tanezumab in patients with moderate to severe knee OA provide continued pain relief and improved function with a low incidence of side effects. Additional studies to define the efficacy and duration of pain reduction and to provide a more complete assessment of long-term safety are warranted.

Apremilast, an oral phosphodiesterase 4 inhibitor, in patients with psoriatic arthritis and current skin involvement: a phase III, randomised, controlled trial (PALACE 3)

Objective To evaluate apremilast treatment in patients with active psoriatic arthritis, including current skin involvement, despite prior therapy with conventional disease-modifying antirheumatic drugs and/or biologic agents. Methods Patients (N=505) were randomised (1:1:1) to placebo, apremilast 20 mg twice daily, or apremilast 30 mg twice daily. Rescue therapy with apremilast was designated at week 16 for placebo patients not achieving 20% improvement in swollen and tender joint counts. At week 24, the remaining placebo patients were then randomised to apremilast 20 mg twice daily or 30 mg twice daily. The efficacy and safety of apremilast were assessed over 52 weeks. Results At week 16, significantly more patients receiving apremilast 20 mg twice daily (28%) and 30 mg twice daily (41%) achieved 20% improvement in American College of Rheumatology response criteria versus placebo (18%; p=0.0295 and p<0.0001, respectively), and mean decrease in the Health Assessment Questionnaire-Disability Index score was significantly greater with apremilast 30 mg twice daily (−0.20) versus placebo (−0.07; p=0.0073). In patients with baseline psoriasis body surface area involvement ≥3%, significantly more apremilast 30 mg twice daily patients achieved 50% reduction from baseline Psoriasis Area and Severity Index score (41%) versus placebo (24%; p=0.0098) at week 16. At week 52, observed improvements in these measures demonstrated sustained response with continued apremilast treatment. Most adverse events were mild to moderate in severity; the most common were diarrhoea, nausea, headache and upper respiratory tract infection. Conclusions Apremilast demonstrated clinically meaningful improvements in psoriatic arthritis and psoriasis at week 16; sustained improvements were seen with continued treatment through 52 weeks. Apremilast was generally well tolerated and demonstrated an acceptable safety profile. Trial registration number NCT01212770.

rabeprazole for the prevention of recurrent erosive or ulcerative gastro-oesophageal reflux disease

Objectives To evaluate the efficacy and tolerability of rabeprazole 10 mg and 20 mg versus placebo for the prevention of endoscopically demonstrable relapse in patients previously diagnosed with erosive or ulcerative gastro‐oesophageal reflux disease (GORD) who had no oesophageal erosions or ulcerations at study entry. The study also assessed the effectiveness of rabeprazole in preventing GORD symptom recurrence and reductions in quality of life. Design/methods The trial used a multicentre, randomized, double‐blind, parallel‐group design and enrolled 288 male and female outpatients of ⩾ 18 years of age. Patients were assigned to treatment with either rabeprazole 10 mg or 20 mg once daily in the morning (QAM) or placebo and followed for 52 weeks. Results Both rabeprazole doses were significantly more effective than placebo in preventing endoscopically demonstrable GORD relapse (P < 0.001 versus placebo). The cumulative relapse rate for rabeprazole 10 mg at week 52 was 23%; for rabeprazole 20 mg, 14%; and for placebo, 71%. Both rabeprazole doses were also significantly superior to placebo in preventing relapse of heartburn frequency (P < 0.001 for all comparisons between rabeprazole and placebo), with no significant differences between the two doses. Rabeprazole was also significantly more effective than placebo in preventing relapse of day and night‐time heartburn severity, maintaining overall patient well‐being, and reducing antacid use. Both rabeprazole doses were well tolerated; most treatmentemergent adverse events were mild or moderate. There were no clinically significant changes in clinical laboratory values, thyroid function tests, vital signs, or electrocardiograms. Conclusion Once‐daily treatment with rabeprazole 10 mg or 20 mg is effective and well tolerated in preventing relapse of erosive or ulcerative GORD and associated symptoms and maintaining quality of life. Eur J Gastroenterol Hepatol 12:889‐897

Effects of subcutaneous and intravenous golimumab on inflammatory biomarkers in patients with rheumatoid arthritis: results of a phase 1, randomized, open-label trial

OBJECTIVE To evaluate the effects of the anti-TNF-α monoclonal antibody golimumab, administered by s.c. injection or i.v. infusion, on markers of inflammation in patients with RA. METHODS In this phase 1, open-label study, patients with active RA were randomized to receive s.c. golimumab 100 mg at baseline and every 4 weeks through week 20 (n = 33; group 1) or i.v. golimumab 2 mg/kg at baseline and week 12 (n = 16; group 2). Serum levels of CRP, IL-6, serum amyloid A (SAA), TNF receptor II (TNFRII), MMP-3, hyaluronic acid, haptoglobin, ferritin and haemoglobin and serum/urine hepcidin were measured at various time points. Associations between the biomarkers were assessed with Spearmans correlations. RESULTS In both groups 1 and 2, decreases in mean serum levels of CRP, IL-6, SAA, TNFRII, MMP-3, haptoglobin, ferritin and hepcidin, and mean urine levels of hepcidin occurred within 1 week and were sustained through week 8. Decreases in concentrations of serum CRP, IL-6, SAA, MMP-3, hepcidin, ferritin and haptoglobin and urine hepcidin were maintained through week 24 in group 1, but began to reverse after week 8 in group 2. Among all patients, decreases in serum hepcidin correlated significantly with decreases in serum CRP and ferritin. CONCLUSION Decreases in serum and urine concentrations of markers of inflammation occurred as early as 24 h after treatment with golimumab, and most of these improvements were sustained through week 24 in group 1.

Efficacy and safety of rofecoxib 12.5 mg and celecoxib 200 mg in two similarly designed osteoarthritis studies

ABSTRACT Objective: To compare the lower osteoarthritis (OA) dose of rofecoxib to the recommended dose of celecoxib in two identically designed studies. Methods: Patients with knee OA were randomized (2:2:1 ratio: rofecoxib 12.5 mg once daily (qd), celecoxib 200 mg qd, or placebo, respectively). The primary endpoint was patient global assessment of response to therapy (PGART) averaged over 6 weeks on a five-point scale. Rofecoxib would be declared at least as effective as celecoxib if the lower bound of the 95% confidence interval (95% CI) for difference in means was no lower than –0.5. Additional endpoints included Pain and Physical Function subscales of the Western Ontario and McMaster (WOMAC) OA Index. Adverse experiences (AEs) were recorded and combined from the two studies for analysis. Results: Study 1 enrolled 395 patients (rofecoxib, n = 160; celecoxib, n = 157; placebo, n = 78). Study 2 enrolled 413 patients (rofecoxib, n = 159; celecoxib, n = 169; placebo, n = 85). Rofecoxib 12.5 mg was at least as effective as celecoxib 200 mg by PGART (Study 1 difference –0.09 [95% CI: –0.32, 0.14] and Study 2 difference 0.02 [95% CI: –0.20, 0.24]), and both were significantly ( p < 0.001) more effective than placebo. Comparable efficacy was also seen for WOMAC Pain and Physical Function subscales with the active treatments. There was a significantly higher ( p < 0.05) incidence of serious AEs with celecoxib than rofecoxib or placebo, none of which was drug-related. There were no significant differences in the pre-specified measurements of safety including drug-related AEs or discontinuations due to AEs, and the medications demonstrated similar safety as assessed by spontaneous reporting. Conclusions: Rofecoxib 12.5 mg and celecoxib 200 mg provided comparable efficacy over 6 weeks, and both were significantly more efficacious than placebo. The medications demonstrated similar safety compared to one another and placebo. The primary limitations of these studies were that they were only 6 weeks long and were powered for efficacy. Therefore, conclusions about long-term safety cannot be inferred.

SAT0408 Long-Term Safety and Tolerability of Apremilast, an Oral Phosphodiesterase 4 Inhibitor, in Patients with Psoriatic Arthritis: Pooled Safety Analysis of Three Phase 3, Randomized, Controlled Trials

Background Apremilast (APR), an oral phosphodiesterase 4 inhibitor, works intracellularly to regulate inflammatory mediators. PALACE 1, 2, and 3 compared the efficacy and safety of APR with placebo (PBO) in patients with active PsA despite prior conventional DMARDs and/or biologics. Objectives The overall safety and tolerability of APR was assessed in a pooled analysis of PALACE 1, 2, and 3, with APR exposure ≥52 wks. Methods Patients were randomized 1:1:1 to PBO, APR 20 mg BID (APR20), or APR 30 mg BID (APR30) stratified by baseline (BL) DMARD use (yes/no). Patients with <20% reduction from BL in swollen or tender joint counts were required to be re-randomized to APR20 or APR30 if initially randomized to PBO, or continued on their initial APR dose. At Wk 24, all remaining PBO patients were re-randomized to APR20 or APR30. Patients taking concurrent DMARDs were allowed to continue stable doses (MTX, sulfasalazine, leflunomide, or a combination). Results 1,493 patients received study medication (PBO: 495; APR20: 501; APR30: 497) and were included in the safety population. The APR-exposure period included 720 patients treated with APR20 (766.4 patient-yrs) and 721 with APR30 (769.0 patient-yrs). The nature, incidence, and severity of AEs were comparable through the 24-wk and 52-wk periods (Table). The most common AEs were diarrhea (14.3%), nausea (12.6%), headache (10.1%), URTI (10.3%), and nasopharyngitis (7.4%). Most AEs were mild or moderate in severity. Discontinuations due to AEs (APR20: 7.5%; APR30: 8.3%) were low, occurring primarily in the first 24 wks of treatment. Serious AEs (SAEs) occurred in 6.8% (APR20) and 7.2% (APR30) of patients. One death occurred (APR20) due to multiorgan failure not suspected to be treatment-related. Diarrhea and nausea were predominantly mild and occurred at a reduced incidence after the first month of dosing, with the highest incidence reported in the first 2 wks of treatment. Most cases resolved within 30 days despite continued therapy and without medical intervention. Discontinuation due to GI AEs was 4% through Wk 52, with nausea (1.7%) and diarrhea (1.5%) being the most common. There was 1 case of diarrhea and 1 case of nausea reported as an SAE in the 0 to ≥24-wk period, and no additional cases reported in the 0 to ≥52-wk period. Exposure-adjusted incidence rates of major adverse cardiac events, serious infections including systemic opportunistic infection, or malignancies were comparable to PBO. Laboratory abnormalities were infrequent and transient with no trends or patterns observed. Conclusions APR demonstrated an acceptable safety profile and was generally well tolerated through 52 wks; the nature, incidence, and severity of AEs were comparable through the 24-wk and 52-wk periods. These data do not indicate a need for laboratory monitoring. Disclosure of Interest P. Mease Grant/research support: Celgene Corporation, Novartis, and Roche, Consultant for: Abbott, Amgen, Biogen Idec, Bristol-Myers Squibb, Genentech, Janssen, Eli Lilly, Pfizer Inc, and UCB, A. Kavanaugh Grant/research support: Abbott, Amgen, Astra-Zeneca, Bristol-Myers Squibb, Celgene Corporation, Centocor-Janssen, Pfizer Inc, Roche, and UCB, D. Gladman Grant/research support: AbbVie, Amgen, Bristol-Myers Squibb, Celgene Corporation, Janssen, Pfizer Inc, Novartis, and UCB, A. Adebajo: None declared, J. Gomez-Reino Grant/research support: Roche and Schering-Plough, Consultant for: Bristol-Myers Squibb, Pfizer Inc, Roche, Schering-Plough, and UCB SA, Speakers bureau: Bristol-Myers Squibb, Roche, Schering-Plough, and Wyeth, J. Wollenhaupt Grant/research support: Abbott, Bristol-Myers Squibb, MSD, Pfizer Inc, and UCB, M. Cutolo Grant/research support: Actelion, Bristol-Myers Squibb, and G. Schett Grant/research support: Abbott, Celgene Corporation, Roche, E. Lespessailles Grant/research support: Amgen, Eli Lilly, Novartis, and Servier, K. Shah Employee of: Celgene Corporation, C. Hu Employee of: Celgene Corporation, R. Stevens Employee of: Celgene Corporation, C. Edwards Grant/research support: Celgene Corporation, Pfizer Inc, Roche, and Samsung, Speakers bureau: Abbott, Glaxo-SmithKline, Pfizer Inc, and Roche, C. Birbara Grant/research support: Amgen, Bristol-Myers Squibb, Incyte, Eli Lilly, Merck, and DOI 10.1136/annrheumdis-2014-eular.5589