Effects of early treatment with glatiramer acetate in patients with clinically isolated syndrome

Abstract

Background: The placebo-controlled phase of the PreCISe study showed that glatiramer acetate delayed onset of clinically definite multiple sclerosis (CDMS) in patients with clinically isolated syndrome and brain lesions on MRI. Objective: To compare the effects of early versus delayed glatiramer acetate treatment in the open-label phase of PreCISe. Methods: Patients with a clinically isolated syndrome suggestive of MS with unifocal manifestation and ≥2 T2-weighted brain lesions were randomized to receive glatiramer acetate 20 mg/d (early-treatment, n=198) or placebo (delayed-treatment, n=211) for 36 months or until conversion to CDMS, followed by open-label glatiramer acetate treatment for two years. Results: Early glatiramer acetate treatment reduced CDMS conversion risk by 41% (hazard ratio 0.59, 95% confidence interval 0.44-0.80; p=0.0005) versus delayed-treatment, and was associated with a 972-day delay (185%) in conversion to CDMS, less brain atrophy (−28%, p=0.0209), fewer new T2 lesions/year (−42%, <0.0001) and lower T2 lesion volume (−22%, p=0.0005) versus delayed treatment. Adverse events were consistent with the established safety profile of glatiramer acetate. Conclusions: Effects of early glatiramer acetate treatment on the rate of conversion to CDMS and on MRI measures of disease activity and lesion burden support initiating glatiramer acetate treatment soon after the first clinical symptoms suggestive of MS and continuing treatment to sustain benefits.

Longitudinal Mixed-Effect Model Analysis of the Association between Global and Tissue-Specific Brain Atrophy and Lesion Accumulation in Patients with Clinically Isolated Syndrome

“…Other studies showed an additional correlation between T2 LV and brain-volume changes during early treatment phases. 25 In our study, however, absolute change of T2 LV was not associated with the progression of brain atrophy measures over the follow-up period, but this finding has to be interpreted with caution, given that over the 48 months of our study, the T2 LV remained stable. Overall, these results suggest that measurement of cumulative accumulation of new/enlarging T2 lesions may be a more sensitive marker of disease activity in patients with CIS than the accumulation of T2 LV.…”

The heritage of glatiramer acetate and its use in multiple sclerosis

“…Patients with CIS are also expected to benefit from GA, given the evidence of efficacy in such patients, supported by extension studies showing clear protection from brain atrophy [86,87]. Another possible use of GA is as maintenance treatment in patients who start with an induction approach because of a negative prognostic profile.…”

“…Therefore it is recommended that, in all consenting patients currently treated with the once daily formulation, the switch to the new formulation should be considered. An early start of GA treatment should be considered in the light of data on brain atrophy from the PreCISe study [87]: there was a significant (-28 %; p = 0.0209) difference when comparing early GA treatment versus delayed GA treatment.…”

“…Early treatment with GA in patients with CIS has been shown to delay onset of CDMS in the placebo-controlled study PreCISe [86] (Table 1) and during its subsequent open-label extension period [87]. The study enrolled 481 patients with one unifocal neurological event and a positive MRI scan (defined as the presence of at least two cerebral lesions ≥6 mm in diameter on T2-weighted images).…”

Reliable measurements of brain atrophy in individual patients with multiple sclerosis

“…Longitudinal methods typically try to match the two MRI scans using warping techniques and directly extract small changes in brain volume from this process (e.g., Boyes et al., 2006; Freeborough & Fox, 1997; Smith, De Stefano, Jenkinson, & Matthews, 2001). A longitudinal method that is frequently used in clinical trials (see, e.g., Comi et al., 2013) is SIENA (Smith et al., 2001), while a longitudinal processing pipeline that can take more than two time points into account is included in FreeSurfer (Reuter, Schmansky, Rosas, & Fischl, 2012). …”