OBJECTIVE: To evaluate interim 2-year efficacy and safety of peginterferon beta-1a in patients with relapsing-remitting multiple sclerosis (RRMS) in the on-going Phase 3, ADVANCE study. BACKGROUND: At Year 1 of ADVANCE, peginterferon beta-1a (125 µg subcutaneous every 2 [Q2W] or 4 [Q4W] weeks) significantly improved primary and secondary clinical and magnetic resonance imaging endpoints versus placebo; similar safety profiles were observed across regimens, which reflected that of established interferon beta-1a therapies. DESIGN/METHODS: During Year 2 all patients (18-65 years; Expanded Disability Status Scale score ≤5) received dose-blinded peginterferon beta-1a (at the end of Year 1 patients on placebo were re-randomized to peginterferon beta-1a 125 µg Q2W or Q4W). Interim analyses of 2-year efficacy and safety were conducted for patients with available data over 2 years at cut-off. Post-hoc analyses compared the efficacy of Q2W versus Q4W regimens. RESULTS: For patients continuing peginterferon beta-1a in Year 2, ARR was maintained (for Q4W) or further numerically reduced (for Q2W) relative to Year 1. New or newly-enlarging T2 lesions were numerically lower in Year 2 versus Year 1 for patients continuing Q2W and Q4W. Versus those originally assigned to placebo, reductions in ARR, risk of relapse and disability progression were seen for patients on peginterferon beta-1a during both Years 1 and 2. Peginterferon beta-1a Q2W provided numerically larger treatment effects over 2 years versus Q4W (ARR rate ratio [95% CI]: 0.793 [0.623, 1.00], p=0.059; time to first relapse hazard ratio: 0.81 [0.64, 1.04], p=0.1006; disability progression hazard ratio: 0.89 [0.58, 1.35], p=0.57; T2 lesion mean ratio: 0.36 [0.27, 0.49], p<0.0001; gadolinium-enhancing lesion odds ratio: 0.34 [0.19, 0.61], p=0.0004). Over 2 years peginterferon beta-1a was well tolerated, with a safety profile consistent with Year 1 and other beta interferons. CONCLUSIONS: Interim 2-year results support the maintained benefits of peginterferon beta-1a beyond 1 year in RRMS, with numerically greater efficacy seen for Q2W versus Q4W across the endpoints studied. Study Sponsored by: Biogen Idec Inc.
Venous thromboembolism, including deep-vein thrombosis and pulmonary embolism, is a major source of morbidity and mortality among elderly patients. To improve our understanding of elderly patients with deep-vein thrombosis, we compared 1932 patients with deep-vein thrombosis aged 70 years or older with 2554 nonelderly patients in a prospective registry of consecutive ultrasound-confirmed deep-vein thrombosis patients. The mean age of elderly patients was 78.9 +/- 6.1 years compared with 51.8 +/- 12.9 years in nonelderly (P < .0001). Elderly patients were more likely to have prior recent hospitalization (49.2% vs 44.7%, P = .03), congestive heart failure (20.5% vs 9.9%, P < .0001), chronic obstructive pulmonary disease (18.2% vs 11.7%, P < .0001), and recent immobilization (50.5% vs 39.6%, P < .0001) than the nonelderly patients. Elderly patients were less likely to present with typical deep-vein thrombosis symptoms of extremity discomfort (44.4% vs 60.6%, P < .0001) and difficulty ambulating (8.4% vs 11.2%, P = .002). Only 41% of elderly patients subsequently diagnosed with deep-vein thrombosis had received any venous thromboembolism prophylaxis. In conclusion, elderly patients with deep-vein thrombosis represent a particularly vulnerable population with numerous comorbid conditions. Diagnosis can present a challenge because typical deep-vein thrombosis symptoms may be absent. Fewer than 50% of elderly patients with deep-vein thrombosis had received any venous thromboembolism prophylaxis.
Objectives: A sub-study to evaluate safety, tolerability, ease-of-use and patient satisfaction with a single-use autoinjector administering subcutaneous peginterferon-β1a (a pegylated interferon-β1a in clinical development) in a subset of relapsing-remitting multiple sclerosis (MS) patients participating in ATTAIN, a long-term dose-frequency blinded extension of the Phase III randomized ADVANCE study.Methods: Over 8 weeks, patients self-administered peginterferon-β1a 125 µg or placebo every 2 weeks (two injections via manual pre-filled syringe [PFS]; two injections via single-use autoinjector). Primary end points were incidence of adverse events (AEs), patient assessment of injection pain score (10-point Visual Analog Scale), and clinician assessment of injection site reactions (ISRs). Secondary objectives included patient assessment of ease-of-use and satisfaction with the autoinjector and evaluation of autoinjector training materials.Results: In 39 patients, the safety profile of peginterferon-β1a was similar when delivered via autoinjector or PFS; AEs were mostly mild or moderate in severity. Clinicians and patients reported a similar tolerability profile using both PFS and autoinjector, and pain scores were low (< 1), with no reports of clinician-assessed ISRs after administration with the autoinjector. Patients perceived the single-use autoinjector to be easy to use and convenient; overall patient satisfaction with the autoinjector and accompanying training materials was high.Conclusion: The safety and tolerability profile of peginterferon-β1a delivered via autoinjector was similar to delivery via PFS. Patients found the autoinjector easy to use and convenient; this device may simplify the injection process for MS patients who require long-term therapy, thereby potentially improving patient’s quality of life and adherence.
Peginterferon beta-1a was efficacious in a Phase 3 relapsing multiple sclerosis trial, and its safety profile was consistent with other beta interferons. This study evaluated the impact of renal impairment on the pharmacokinetics and pharmacodynamics (neopterin elevation; a biomarker of pharmacological activity induced by interferon beta-1a) of peginterferon beta-1a following a single subcutaneous dose at 63 μg (n = 5) or 125 μg (n = 30). The results showed a fractional increase in area-under-the-concentration-time curve (AUC [30-53%]) and peak serum concentration (Cmax [26-42%]) in subjects with mild, moderate, and severe renal impairment, versus healthy subjects; AUC and Cmax were similar for healthy subjects and end-stage-renal-disease patients receiving hemodialysis. Pharmacokinetic simulation showed that the steady state concentration overlapped in the majority of healthy subjects and subjects with severe renal impairment. Neopterin baseline, peak concentration, and AUC increased as renal function decreased. Peginterferon beta-1a was well tolerated in all groups. These results do not warrant peginterferon beta-1a dose adjustment in subjects with renal impairment.
Summary Deep vein thrombosis (DVT) is a poorly understood complication of chronic kidney disease (CKD). The objective of our analysis was to profile DVT patients with and without CKD. We defined CKD as patients requiring dialysis or patients having nephrotic syndrome.We compared 268 patients with CKD (184 patients with dialysis-dependent renal disease and 84 with nephrotic syndrome) to 4,307 patients with preserved renal function from a prospective United States multicenter deep venous thrombosis (DVT) registry. Compared with non-CKD patients, CKD patients with DVT were younger (median age 62 vs. 69 years, p<0.0001), more often African- American (p<0.0001), and more often Hispanic (p=0.0003). CKD patients underwent surgery more frequently in the three months prior to developing DVT (48.9% vs. 39.0%, p=0.001) and more often had concomitant congestive heart failure (20.9% vs. 14.6%, p=0.005). CKD patients suffered upper extremity DVT more frequently (30.0% vs. 10.8%, p<0.0001). Patients with CKD presented less often with typical DVT symptoms of extremity discomfort (42.9% vs. 52.4%, p=0.003) and difficulty ambulating (5.4% vs. 10.1%, p=0.01). Prophylaxis rates prior to DVT were similarly low in CKD and non-CKD patients (44.2% vs. 38.0%, p=0.06). Future studies of DVT in CKD patients should explore novel strategies for improving prophylaxis utilization and the detection of DVT in this special population.
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