rizvi et al Clinical trials Copolymer 1 was initially studied in a small group of patients with advanced MS and acute disseminated encephalomyelitis (ADE). Even though there was no clear benefit noted it was found to be safe and well tolerated (Abramsky et al 1977). Another preliminary trial (Phase 1, open-label) suggested a beneficial effect and no significant toxicity (Bornstein et al 1982). The first randomized study of copolymer 1 involved 48 patients in 24 pairs matched for age, sex, and disability. Two additional unmatched patients were also enrolled, raising the total number of patients to 50. Patients on copolymer had fewer relapses and more patients remained relapse-free (Bornstein et al 1987). Copolymer was then tested in a more disabled chronic progressive population consisting of both secondary progressive and primary progressive patients. After a pretrial observation period, 106 out of 169 patients were noted to have progression and were entered in the trial. Although the results were not statistically significant there was a trend favoring the patients who received copolymer (Bornstein et al 1991). In 1991, a Phase 3, double-blinded, placebo-controlled study began with 251 patients. The primary endpoint was the mean number of relapses in subjects receiving GA compared with placebo. The Expanded Disability Status Scale (EDSS) range was 0–5.0. The mean annualized relapse rate was 0.59 for patients receiving GA and 0.84 for patients receiving placebo (29% reduction) (Johnson et al 1995). On the basis of this trial, GA was approved for treatment of RRMS. After 10 years of open label extension, patients originally randomized to GA continue to do better than patients who were originally on placebo. Patients continuing GA for 10 years had an average disease duration of 18 years, yet nearly all remained ambulatory. Only 108 of the original 251 patients remained in the study and the annualized relapse rate in both (GA-GA, placebo-GA) declined to 0.2 (Ford et al 2006). MRI effects of GA therapy MRI provides a non-invasive surrogate marker of pathology, and is the only way subclinical disease activity can be detected. MRI has improved diagnostic accuracy, advanced the understanding of immunopathology of MS, and has become an essential tool in clinical drug trials. The first study of the effects of GA on serial MRI involved 10 RRMS patients compared before and after treatment. GA reduced both frequency and area of new lesions (Mancardi et al 1998). The larger US Pivotal Trial included only a few patients undergoing MRI but did demonstrate a reduction in 286 enhancing lesions, and it also showed that delay in treatment was associated with increased progression on MRI (Wolinsky et al 2001). Since the Phase 3 trial of GA did not include a significant MRI component, a large randomized, double- blinded, placebo-controlled MRI trial was initiated in Canada and Europe. A total of 239 patients were randomized to GA or placebo for 9 months followed by an open-label phase for an additional 9 months. The European/Canadian MRI study demonstrated a reduction in frequency and volume of new enhancing lesions, with a 29% reduction in the number of enhancing lesions for the treatment arm. This study also observed an intriguing difference in the rapidity of resolution of gadolinium (Gd)-enhancing activity between GA-treated patients and interferon-β-treated patients. Enhancing activity resolved much more slowly in the GA-treated group (Comi et al 2001; Wolinsky et al 2002). This slower resolution may provide further support for current theories on the differential mechanisms of GA and interferon-β. Gd- enhancing MRI activity generally corresponds with BBB disruption (Bakshi et al 2004). While interferon-β functions by reducing lymphocytic infiltration across the BBB, GA activity is dependent upon the entry of GA-reactive Th2 cells beyond an intact BBB. From within the CNS, GA-reactive Th2 cells then decrease inflammation and repair the BBB. This mechanism of repair from within the CNS is proposed to take a longer time, as reflected by the delayed change in MRI activity (Dhib-Jalbut 2002). Several recent MRI studies raise the possibility of neuroprotection as a potential mechanism of GA. Axonal degeneration in MS is represented on MRI by atrophy and the conversion of hyperintense T2 lesions into persistent hypointense T1 lesions. In the natural history of MS, 20%–60% of new lesions will degenerate into persistent hypointense T1 lesions (van Waesberghe et al 1998). The European/Canadian study demonstrated that the percentage of new lesions evolving into so called “T1-black holes” was more than 50% lower in the GA-treated group (Filippi et al 2001). Thus, in addition to slowing the formation of new MS lesions, GA may also limit permanent damage of new lesions by protecting axons and promoting lesion recovery. The effects of GA on generalized brain atrophy in RRMS have also come under recent attention. The pilot study (27 patients from the pivotal Phase III trial) to assess MRI- measured atrophy demonstrated a significantly lower mean reduction in brain volume in patients on GA. The placebo group had a three-fold greater decline in brain volume compared with the GA group (Ge et al 2000). This study was limited because of relatively small number of patients and international Journal of Nanomedicine 2006:1(3)