patients with progression (deﬁned as a one step increase in the EDSS sustained for at least 3 months). The results showed a statistically signiﬁcant decrease in relapse frequency, a trend to beneﬁt in delay to the next relapse and proportion of patients relapse-free and no sta- tistically signiﬁcant effect on progression-free proportion. Thus, the GA group had 161 relapses and the placebo group 210, giving an average number of relapses in 2 years of 1.19 and 1.68, respectively, with p = 0.0007. The median time to ﬁrst relapse after enrollment was 287 and 198 days in the treatment and placebo groups (p = 0.097). The proportion of patients relapse-free was 33.6% and 27.0% in the treatment and placebo groups, respectively (p = 0.098). The proportion of patients progression-free was 78.4% and 75.4% in the treatment and placebo groups, respectively (NS). The drug was well tolerated, causing insigniﬁcant injec- tion site reactions. In about 15% of glatiramer patients and 3% of placebo patients, a peculiar reaction occurred just after injection. This consisted of some combination of ﬂushing, chest tightness, dyspnea, palpitations, or anxiety, lasting a few seconds to half an hour, and resolved without any residual problem. The reaction usually occurred only once, but one patient had seven episodes (Johnson et al 1995). The extension study In order to continue to collect data on the effect of GA on the disease, the pivotal study was extended by up to 11 months, with the GA versus placebo arms intact and blinded allow- ing all patients to reach the 2-year time point (Johnson et al 1998). Of the 215 patients completing the original study, 203 entered the extension study and 194 completed it. The primary and secondary outcomes were the same. The relapse rates over the extended study were 1.34 and 1.98 for the GA and placebo groups, respectively (p = 0.002). The relapse- free proportions were 33.6 and 24.6 (p = 0.035), and the median times to ﬁrst relapse were 287 and 198 (p = 0.057) for the GA and placebo groups, respectively. Overall status was deﬁned by change in EDSS, with “improvement” or “worsening” deﬁned as a one step decrease or increase in EDSS. While most patients had no change in EDSS over the extended study, some improved and others worsened. In the GA more improved than worsened (27.2% vs 18.4%), while in the placebo group, fewer improved than worsened (12.0% vs 31.2). The open-label extension study At the end of the extension study, all patients were invited to continue follow-up in an open-label study on GA, so that Neuropsychiatric Disease and Treatment 2007:3(2) Glatiramer acetate further clinical data could be collected. Most of the patients in the original double blind study, 208 out of 251 originally randomized (83%), chose to continue into the open label study, which is still ongoing. At the 8-year time point, 142 patients (57% of the originally randomized and 68% of those who entered the open label phase) were still being followed (Johnson et al 2005). In order to analyze the effect of early treatment on MS, the patients were divided into two groups: group A were patients who had received GA from the begin- ning and group B patients were initially randomized into the placebo group and subsequently were on open label GA, and their relapse rates and degree of disability ascertained. At the 8-year time point of the open label study, the annualized relapse rates were 0.43 in the group A and 0.52 in the group B patients, p = 0.0459. The overall proportion of patients with stable or improved neurological status (as measured by the EDSS) was 65.3 % in group A and 50.4% in group B (p = 0.0263). Imaging studies The European/Canadian (E/C) Imaging Study examined the effect of GA on MRI disease activity (Comi et al 2001), which was only done for a short period of time on patients at one of the 11 centers in the original pivotal study. In the E/C study, 239 RRMS patients were randomized to GA or placebo, and had monthly MRI scans and neurological examinations. The primary outcome was the number of enhancing lesions on T1 weighted images. There were a number of secondary outcome variables, including other measures of imaging activity and clinical events. The total number of enhancing lesions per subject over the 9 months of the study was 33.7 in the placebo group and 21.8 in the GA group (p < 0.001). The difference between the groups became statistically signiﬁcant 5 months into the study. The relapse rate in the treated group (0.51 per subject) was less than that in the placebo group (0.76 per subject), by 33% (p = 0.012). Other imaging outcomes were favorable to GA. In particular, the T2 lesion burden, as roughly measured by the mean total number of new T2 lesions, was 13.5 in the placebo and 9.4 in the active treatment groups, a 30% dif- ference (p < 0.003). In a substudy of the E/C Imaging Study, the proportion of initial T1-hypointense lesions evolving into permanent black holes, which represent permanently damaged tissue, was compared between the GA and placebo groups (Filippi et al 2001). Of all T1-hypointense lesions, at 8 months, 15.6% in the GA group and 31.4% in the placebo group had evolved into black holes, thus suggesting a protective effect of GA 261