the second interim analysis) because the progression rate in the placebo group was unexpectedly small: it was assumed that 50% of the low tier EDSS patients would progress in a year, but only 16.1% of patients in the placebo group did so (Wolinsky 2004). This rendered it impractical to demonstrate a clear treatment effect on the primary endpoint. However, there was a trend to reduced progression, signiﬁcantly decreased enhancing lesions and lower increases in T2 lesions in the treatment group compared with the placebo group (Wolinsky et al 2007). Thus, it may be premature to use glatiramer in PPMS, since the trial was unable to demonstrate beneﬁt in the target population and the long term safety of the drug was not demonstrated in this group, unlike RRMS. Systematic reviews and the Cochrane analysis The efﬁcacy of GA in MS was examined in two meta- analyses of clinical trials, one by the Cochrane Collaboration (Munari et al 2003) and the other by Boneschi et al (2003). In the Cochrane study, the results of three published studies were pooled (Bornstein et al 1987, 1991; Johnson et al 1995). In the Boneschi study, 3 studies, only one of which was in the Cochrane list, were analyzed together (Bornstein et al 1987; Johnson et al 1998; Comi et al 2001). The published studies were used in the Munari study, while the Boneschi study used the raw data from the original trials. The outcome variables examined in these two studies are shown in the Table 1. The Munari study did not show an effect of GA on progression at 2 years, or change in disability score at fol- low up, but did show a trend to a decrease in the number Table 1 Outcome variables examined in the Munari and Bones- chi meta-analyses Munari et al Boneschi et al Primary outcomes Primary outcome Progression at 2 years Annualized relapse rate Change in disability at follow up Number of patients with at least one exacerbation Secondary outcomes Relapse-free survival On-trial total number of relapses Time to ﬁrst relapse Accumulated disability Secondary outcomes Hospitalizations at end of follow up Steroid courses at end of follow up Additional outcomes Mean number of relapses Neuropsychiatric Disease and Treatment 2007:3(2) Glatiramer acetate of patients with at least one exacerbation when a stratiﬁed analysis was done, but not when the results were pooled. Relapse-free survival was better in the GA group, as were the number of hospitalizations and steroid courses at the end of follow up. The mean number of relapses showed no sig- niﬁcant changes in years 1 and 2, but a decrease in year 3 in the GA group (Munari et al 2003). The study was criticized for using summary data rather than raw data, using results that mixed relapsing-remitting MS and “chronic progres- sive” MS patients (these latter being a mixture of primary and secondary progressive MS), redeﬁnition of some of the outcome variables (conﬁrmed progression being deﬁned at 1 year rather than the more conventional 3 or 6 months), and choice of analysis (Caramanos and Arnold 2005; Comi et al 2005). In two of the studies incorporated in the Munari study, relapse numbers were measured. In the Bornstein study (Bornstein et al 1987), the number of relapses was 16 in the GA group and 64 in the placebo group, while in the Johnson study (Johnson et al 1995) the number of relapse per patient in 2 years was 1.19 in the GA group and 1.68 in the placebo group, a clear difference in favor of GA in both studies. No such beneﬁt was seen in the combined groups, however, which seems counterintuitive (Comi et al 2005). The Boneschi meta-analysis showed signiﬁcant decreases in the annualized relapse rate, on-trial total number of relapses, time to ﬁrst relapse, and accumulated disability, favoring the GA group (Boneschi et al 2003). The different studies incorporated in the analysis had patients with a uniform diagnosis of relapsing-remitting MS but different baseline ages, disease durations, baseline EDSS, prestudy relapse rate, which were adjusted for. Glatiramer mechanisms of action including neuroprotection models Given the complexity of GA it is not surprising that there are likely several mechanisms of action. It was one of a number of compounds originally synthesized to help understand EAE, an animal model of MS. EAE was ﬁrst discovered by Rivers and Schwentker in an investigation of the inﬂammatory demyelin- ation in the brain which occurred after rabies vaccination and some viral infections such as measles (Rivers and Schwentker 1935). These compounds contained polypeptides consisting of amino acids with stoichiometry similar to that of myelin basic protein, and were expected to provide well-deﬁned antigens with which to induce EAE (Arnon 1996). It turned out that none of these compounds caused EAE in animals, and in fact, several inhibited it; copolymer 1 (the original name for GA) did this most 263