Results of a phase-I/II randomized, masked, placebo-controlled trial of recombinant human interleukin-11 (rhIL-11) in the treatment of subjects with active rheumatoid arthritis

Interleukin-11 (IL-11) is a pleiotropic cytokine that regulates the growth and development of hematopoietic stem cells and decreases the proinflammatory mediators of cytokine and nitric oxide production. In animal models of arthritis, treatment with recombinant human IL-11 (rhIL-11) reduces both the level of synovitis and the histologic lesion scores in the joints. The goal of this phase-I/II study in adults with rheumatoid arthritis (RA) was to evaluate the safety and clinical activity of different doses and schedules of rhIL-11 in patients with active RA for whom treatment with at least one disease-modifying antirheumatic drug had failed. This was a multicenter, randomized, placebo-controlled trial that evaluated the safety and tolerability of rhIL-11 in 91 patients with active RA. rhIL-11 was administered subcutaneously; patients were randomized into one of five treatment groups (ratio of rhIL-11 to placebo, 4:1). Patients were treated for 12 weeks with either 2.5 or 7.5 μg/kg of rhIL-11 or placebo twice per week or 5 or 15 μg/kg of rhIL-11 or placebo once per week. The status of each subject's disease activity in accordance with the American College of Rheumatology (ACR) criteria was assessed before, during, and after completion of administration of the study drug. Administration of rhIL-11 was well tolerated at all doses and schedules. The most frequent adverse event was a reaction at the injection site. The data suggest a statistically significant reduction in the number of tender joints (P < 0.008) at the 15 μg/kg once-weekly dose schedule but showed no overall significant benefit at the ACR criterion of a 20% response. The trial showed rhIL-11 to be safe and well tolerated at a variety of doses and schedules over a 12-week treatment period in patients with active RA. The only adverse event clearly associated with rhIL-11 administration was reaction at the injection site

Towards the Italian CSLU Toolkit

The “digits ” small-vocabulary task is important for many telephone-based applications such as computer-assisted long-distance dialing or credit-card billing, requires extremely high accuracy, and focuses research on acoustic-level processing. On the other hand, in many other tasks a speaker-independent domain-specific vocabulary (such as “collect call”, “calling card”, “operator”, or “help”) needs to be recognized. For such tasks, a “general-purpose ” (gp) recognizer that is capable of recognizing all permissible phoneme strings in a language is required. The more recent results obtained by the application of the CSLU Toolkit framebased hybrid HMM/ANN architecture on these recognition tasks for the Italian language are described. This work is inserted in a project whose aim is to contribute to the “Italianization ” of the CSLU Toolkit and to support the dissemination of these tools and technologies. 1

Efficacy and safety of intravenous golimumab plus methotrexate in patients with rheumatoid arthritis aged \u3c 65 years and those ≥ 65 years of age.

OBJECTIVE: To evaluate the safety and efficacy of intravenous golimumab + methotrexate (MTX) in patients with active rheumatoid arthritis (RA) aged \u3c 65 years and those ≥ 65 years who were enrolled in the GO-FURTHER study. METHODS: In the phase III, double-blind, randomized, placebo-controlled GO-FURTHER trial, patients with active RA were randomized to intravenous (IV) golimumab 2 mg/kg + MTX or placebo + MTX at weeks 0 and 4, then every 8 weeks thereafter (with crossover to golimumab at week 16 [early escape] or week 24 [per-protocol]). The final golimumab infusion was at week 100. Assessments included American College of Rheumatology (ACR) 20/50/70 response criteria. Efficacy and adverse events (AEs) were monitored through 2 years. Efficacy and AEs were summarized for patients aged \u3c 65 years or ≥ 65 years; AEs were also summarized for patients \u3c or ≥ 70 years and patients \u3c or ≥ 75 years. RESULTS: In GO-FURTHER, 592 patients were randomized to receive placebo (n = 197) or golimumab (n = 395), 515 were aged \u3c 65 years and 77 were ≥ 65 years. At week 24, ACR20 response rates were greater for golimumab + MTX patients compared with placebo + MTX for patients \u3c 65 years (61.6% vs 31.3%, p \u3c 0.001) and those ≥ 65 years (69.5% vs 33.3%; p \u3c 0.01). Infections were the most common AE through week 112 (51.6% in patients \u3c 65 years; 55.3% in patients ≥ 65 years); upper respiratory infections were the most common infection in patients \u3c 65 years (13.2%) and those ≥ 65 years (11.8%). Serious AEs occurred in 17.7% in patients \u3c 65 years and 25.0% of patients ≥ 65 years and included malignancies, pneumonia, fractures, acute pancreatitis, cellulitis, and bacterial arthritis. CONCLUSIONS: In GO-FURTHER, ACR response rates were similar between patients \u3c 65 years and patients ≥ 65 years within each treatment group. AEs in elderly patients were similar to the known safety profile of IV golimumab. Immunosenescence is known to increase the risk of infections in the elderly. Elderly patients had a numerically higher incidence of serious infections. Six malignancies occurred in golimumab-treated patients, all in patients \u3c 65 years. TRIAL REGISTRATION: clinicaltrials.gov: NCT00973479 . Registered September 9, 2009

Efficacy and safety of tofacitinib in patients with rheumatoid arthritis by previous treatment: post hoc analysis of phase II/III trials

Abstract Background This study sought to evaluate the efficacy and safety of tofacitinib in patients with rheumatoid arthritis with distinct treatment histories. Methods Pooled phase II/III trial data from patients who received tofacitinib 5 or 10 mg twice daily or placebo, as monotherapy or with conventional synthetic (cs) disease-modifying antirheumatic drugs (DMARDs), were analyzed post hoc. Separate evaluations were conducted for populations with a prior inadequate response (IR) to: 1) non-methotrexate (MTX) csDMARDs only (non-MTX csDMARD-IR; n = 537); 2) MTX (MTX-IR; n = 3113); and 3) biologic (b)DMARDs (bDMARD-IR; n = 782). Efficacy outcomes included rates of response (American College of Rheumatology 20/50/70% response criteria) and remission (Disease Activity Score in 28 joints derived from 4 measures, erythrocyte sedimentation rate [DAS28-4(ESR)] < 2.6) at month 3, and changes from baseline in DAS28-4(ESR) and Health Assessment Questionnaire–Disability Index scores. Safety was assessed up to month 24. Results At month 3, efficacy was generally improved with tofacitinib (both doses) vs placebo in each population. Generally, efficacy outcomes with tofacitinib were numerically more favorable in non-MTX csDMARD-IR vs MTX-IR or bDMARD-IR patients. Over 24 months, crude incidence rates for adverse events (AEs), serious AEs, and discontinuations due to AEs were generally numerically lower in non-MTX csDMARD-IR and MTX-IR vs bDMARD-IR populations; rates for AEs of special interest were generally similar across populations. Conclusions Tofacitinib provided clinical benefit across patients with rheumatoid arthritis with a range of prior treatment experience but may have greater efficacy and an improved benefit/risk profile in those with fewer prior treatments. Trial registration NCT00147498/NCT00413660/NCT00550446/NCT00603512/NCT00687193/NCT00976599/NCT01359150/NCT00847613/NCT00814307/NCT00853385/NCT00960440/NCT01039688/NCT00856544