Els_D1081810_Lancet

Cohen_500_1113

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Articles measures. We made treatment comparisons of all available 3 month assessments with the Wei-Lachin non-parametric test for repeated measures.24,25 We analysed changes in T2- See Online for appendix hyperintense lesion volume and brain volume with a ranked ANCOVA model. We analysed proportions of patients with new or enlarging T2-hyperintense lesions or gadolinium-enhancing lesions, and those who were free from disease activity, with logistic regression. The appendix contains additional details about the statistical methods. This study is registered with ClinicalTrials.gov, number NCT00530348. Role of the funding source The study sponsor (Genzyme) was involved in the design and undertaking of the trial, data analysis and inter pretation, writing of the manuscript, and the decision to submit the manuscript for publication. Interferon beta 1a (n=187) Alemtuzumab (n=376) Relapse Patients with any event Total number of events Rate ratio (95% CI) Risk reduction Yearly rate (95% CI) 75 (40%) 122 ·· ·· 0·39 (0·29 to 0·53) Relapse-free patients, % (95% CI)* 58·7% (51·1 to 65·5) Disability Sustained accumulation confi rmed over 6 months Patients 20 (11%) Percentage of patients (95% CI)* Hazard ratio (95% CI) Risk reduction Change in EDSS score from baseline Mean change (95% CI) MRI Median change in volume of T2-hyperintense lesions Patients with new or enlarging T2-hyperintense lesions§ Patients with gadolinium- enhancing lesions at 24 months§ Median change in brain parenchymal fraction§ –6·5% (–20·7 to 2·5) 99/172 (58%) 34/178 (19%) –9·3% (–19·6 to –0·2) 176/363 (48%) 26/366 (7%) 0·31 0·04 <0·0001 –1·488% (–2·355 to –0·567) –0·867% (–1·470 to –0·254) <0·0001 Disease-free survival Patients clinically disease-free§ 104 (56%) Odds ratio (95% CI) ·· Patients MRI and clinically disease-free§ Odds ratio (95% CI) 46/172 (27%) ·· 279 (74%) 2·36 (1·62 to 3·43) 139/360 (39%) 1·75 (1·17 to 2·61) 0·006 Data are n (%), mean (SD), median (IQR), or n/n assessed (%), unless otherwise stated. EDSS=expanded disability status scale. MSFC=multiple sclerosis functional composite. *Kaplan-Meier estimates. †As per the prespecifi ed plan for sequential testing of the four secondary endpoints and the non-signifi cant fi ndings for changes over 24 months in EDSS and T2-hyperintense lesion volume, this diff erence was not regarded as signifi cant. §Prespecifi ed tertiary endpoint. Table 2: Clinical and MRI outcomes 4 <0·0001 11·12% (7·32 to 16·71) ·· ·· –0·14 (–0·29 to 0·01) Change in MSFC score from baseline† Mean change 0·07 (0·45) 82 (22%) 119 0·45 (0·32 to 0·63) 54·9% 0·18 (0·13 to 0·23) 77·6% (72·9 to 81.6) 30 (8%) 8·00% (5·66 to 11·24) 0·70 (0·40 to 1·23) 30% –0·14 (–0·25 to –0·02) 0·15 (0·52) 0·97 0·01 0·22 <0·0001 <0·0001 p value Bayer Schering Pharma participated in the design and oversight of the trial. Clinical investigators collaborated with the sponsor to design and oversee the trial. The sponsor did the statistical analyses. All authors had full access to data, participated in the analyses, wrote the manuscript, had fi nal responsibility for the decision to submit for publication, and vouch for the accuracy and completeness of the results. Results 563 (97%) of 581 patients who were randomly assigned received at least one dose of study drug and 526 (93%) of these patients completed the study on assigned treatment (fi gure 1). Baseline char acteristics were typical for an early, active relapsing-remitting multiple sclerosis population (table 1). 17 (5%) of 376 patients received aciclovir with the fi rst course of alemtuzumab and 243 (66%) of 370 patients received aciclovir with the second course of alemtuzumab. Alemtuzumab reduced the rate of relapse compared with interferon beta 1a (table 2, fi gure 3). More patients were relapse-free at 2 years in the alemtuzumab group than were relapse-free in the interferon beta 1a group (table 2, fi gure 2). Rates of sustained accumulation of disability did not diff er between groups (table 2, fi gure 2). Mean EDSS score improved from baseline by 0·14 points in both groups (table 2). Based on the prespecifi ed plan of sequential testing of secondary endpoints to control for multiple comparisons, the diff erence in MSFC change over 24 months was not regarded as signifi cant (table 2, fi gure 3). Decreases in T2-hyperintense lesion volume by 24 months did not diff er between groups (table 2, fi gure 3). Compared with interferon beta 1a, alemtuzumab reduced the proportions of patients with gadolinium-enhancing and new or enlarging T2-hyperintense lesions, and slowed brain volume loss by about 40% (table 2, fi gure 3). More patients remained free from clinical disease activity and combined clinical and radiological disease activity in the alemtuzumab group than in the interferon beta 1a group (table 2). Masking was successful for 5172 (>99%) of 5193 EDSS assessments. Only 15 (3%) of 563 patients had one or more assessments done by an unmasked rater. Sensitivity analyses, including exclusion of unmasked assessments, supported the absence of eff ect of rater unmasking on study results (appendix). The relapse adjudication panel confi rmed 121 (81%) of 149 suspected relapses for patients in the alemtuzumab group and 125 (85%) of 147 suspected relapses for patients in the interferon beta 1a group. Much the same proportions of patients in the two treatment groups had adverse events (92–96%), most of which were mild to moderate in severity (table 3). The most frequently reported adverse events with alemtuzumab were infusion-associated reactions (headache, rash, and www.thelancet.com Published online November 1, 2012 http://dx.doi.org/10.1016/S0140-6736(12)61769-3 Electronic Distribution Only

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