The LARGO (Lasting Effect in Adjunct Therapy with Rasagiline Given Once Daily) study evaluated once daily rasagiline and entacapone administered with each levodopa dose, compared with placebo as adjuncts to levodopa in patients with motor fluctuations. In this 18-week, double-blind, parallel-group trial (97), 687 subjects were randomized to receive rasagiline 1mg daily, entacapone 200 mg with each levodopa dose, or placebo. Off hours were significantly reduced in both the rasagiline (-1.2 hours; P = 0.0001) and entacapone (-1.2 hours; P < 0.0001) groups compared with placebo (-0.4 hours). In addition, both active treatment groups did better on the secondary outcomes of clinical global impression, UPDRS ADL scores in the off state and UPDRS motor scores in the on state, compared with placebo. Neither rasagiline nor entacapone caused any worsening of dyskinesia. Rasagiline, but not entacapone, improved three exploratory UPDRS subscores, postural instability/gait disorder, freezing, and motor score in the practically defined off state. Although the placebo group had a slight increase (+5 mg) in mean daily levodopa dosage at the end of 18 weeks, both rasagiline (-24 mg, P = 0.0003 vs. placebo) and entacapone (-19 mg, P = 0.0024 vs. placebo) were associated with small but significant reductions in daily levodopa requirement. Benefits of rasagi-line were independent of age and concomitant dopamine agonist therapy, and posthoc analysis revealed no increase in dopaminergic adverse effects in those over age 70 years.
Gait freezing was examined in an auxiliary study of LARGO (98). Advanced PD subjects (n=454) who had been randomized to rasagiline (1 mg/day; n = 150), entacapone (200 mg with each dose of levodopa; n = 150), or placebo (n = 154) were evaluated with a Freezing of Gait Questionnaire (FOG-Q) (98). Compared with baseline, the rasagiline and entacapone groups demonstrated a mean FOG-Q improvement of
1.2 points (P = 0.045) and 1.1 points (P = 0.066), respectively, at 10 weeks compared with a 0.5 point worsening in the placebo group.
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