lack of baseline data. In a larger study population (European/ Canadian trial), the findings were mixed depending on the MRI brain volume measurement techniques. When the European/Canadian MRI data were analyzed by a semi- automated segmentation technique, no significant difference in atrophy was found (Rovaris et al 2001). However, when the same MRI data were re-analyzed using a fully automated, normalized technique, the analysis demonstrated a slight but not significantly lowered brain volume change in the GA group. However, during the open-label phase, there was a significant reduction in atrophy for the group initially treated with GA (Sormani et al 2004). These data may suggest a delayed but significant effect of GA on brain atrophy. Further research may better answer this question. Meta-analysis, comparative, combination, and other trials When data from three clinical trials (Bornstein pilot trial, US pivotal trial, and European Canadian study) were compiled for meta-analysis, an annualized relapse rate reduction of 28% was noted for GA compared with placebo (Boneschi et al 2003). Several comparative open label trials have supported the use of GA as a first-line agent (Table 2). These trials should be interpreted with caution since biases are unavoidable. Controlled trials comparing the efficacy of GA and inteferon- β are underway. Data for use as combination treatment are lacking, but a large NIH-funded trial looking at the efficacy Glatiramer for MS of a combination of GA and interferon-β1a is currently underway. When all the randomized and controlled GA trials were analyzed in a Cochrane database review, GA did not show a significant effect on disease progression as measured by a worsening on EDSS score. The authors could not support GA as first-line treatment in MS (Munari et al 2004). This study’s reliability could have been limited for several reasons including the variability of disease course (a mixture of RRMS, secondary progressive MS, and primary progressive MS) and the reliability of EDSS as a primary outcome measure. GA was also studied in primary progressive MS and a large controlled trial failed to provide any evidence for benef it in this population (Wolinsky 2004b; Wolinsky et al 2004). Similarly, an oral form of GA studied in a controlled population did not show any significant evidence of efficacy. Safety The most common adverse reaction is a local injection- site reaction of erythema and induration. In one trial, 90% experienced at least one such reaction compared with 69% of placebo patients. GA is less frequently associated with a transient post-injection systemic reaction of flushing, chest tightness, dyspnea, chest palpitations, and anxiety. This self-limited systemic reaction was experienced in 15%. The reactions typically resolve within 15–30 minutes without sequelae. No significant laboratory abnormalities Duration 18 months 16 months 2 years 2 years Results relapse rate reduction was significant in the GA and iFN β1b groups Significant decline in relapse rates in all patients with the largest reduction in the GA group All patients showed similar reduction in relapse rates compared to 2 years prior to immunomodulating therapy Significant reductions from pre-study to on-study relapse rates for all of the iFN preparations with superior reduction in GA relapse rate compared with interferons at month 24 287 Table 2 Comparative open-label trials on the use of GA as a first-line agent Author Nr patients Comparative treatment groups Khan et al 2001 156 iFN β1a 30 µg/week iM (n = 40) iFN β1b 250 µg/qod SC (n=41) GA 20 mg/day SC (n=42) No treatment (n=33) Carra et al 2003 134 Fletcher et al 2002 58 Haas et al 2003 283 iFN β1a 30 µg/week iM (n=26) iFN β1a 44 µg 3x/week (n=20) iFN β1b 250 µg/qod SC (n=20) GA (n=30) daily SC No treatment (n=38) GA daily SC GA qod SC Untreated iFN β1a 30 µg/week iM (n=79) iFN β1a 22 µg 3x/week SC (n=48) iFN β1b 250 µg/qod SC (n=77) GA daily SC (n=79) Abbreviations: GA, glatiramer acetate; iFN, interferon; iM, intra-muscular; SC, subcutaneous. international Journal of Nanomedicine 2006:1(3)