Rasagiline as an adjunct to levodopa in patients with Parkinson's disease and motor fluctuations (LARGO, Lasting effect in Adjunct therapy with Rasagiline Given Once daily, study): a randomised, double-blind, parallel-group trial.
BACKGROUND
Rasagiline mesylate is a novel drug for Parkinson's disease with selective, irreversible monoamine oxidase B (MAO-B) inhibitor activity, and is effective as monotherapy in early disease. This study investigated rasagiline efficacy and safety in levodopa-treated patients with Parkinson's disease and motor fluctuations.


METHODS
In an 18-week, double-blind, multicentre (74 hospitals and academic centres in Israel, Argentina, and Europe) trial, 687 outpatients were randomly assigned to oral rasagiline (231 individuals; 1 mg once daily), entacapone (227; 200 mg with every levodopa dose), or placebo (229). Primary outcome was change in total daily off-time (intention-to-treat population). Other measures included the clinical global improvement (CGI) score and unified Parkinson's disease rating scale (UPDRS) scores. Analysis was by intention to treat.


RESULTS
88 (13%) patients who were assigned treatment did not complete the study (23 rasagiline, 30 entacapone, 35 placebo), mainly because of withdrawal of consent (n=34) and adverse events (n=34). Both rasagiline and entacapone reduced mean daily off-time (-1.18 h rasagiline and -1.2 h entacapone vs placebo -0.4 h; p=0.0001, p<0.0001, respectively) and increased daily on-time without troublesome dyskinesia (0.85 h vs placebo 0.03 h; p=0.0005 for both). We recorded significant mean improvements in CGI scores (-0.86 rasagiline and -0.72 entacapone vs -0.37 placebo; p<0.0001, p=0.0002, respectively). Changes in UPDRS scores also significantly improved for activities of daily living during off-time (-1.71 and -1.38 vs placebo; p<0.0001, p=0.0006, respectively) and motor function during on-time (-2.94 and -2.73 vs placebo; both p<0.0001). Frequency of adverse events was similar for all treatments.


CONCLUSIONS
Once-daily rasagiline reduces mean daily off-time and improves symptoms of Parkinson's disease in levodopa-treated patients with motor fluctuations, an effect similar to that of entacapone.
Rascol
O
O
Clinical Investigation Centre, Department of Clinical Pharmacology, University Hospital, Toulouse, France. rascol@cict.fr
Brooks
D J
DJ
Melamed
E
E
Oertel
W
W
Poewe
W
W
Stocchi
F
F
Tolosa
E
E
D000284:Administration, Oral; D000368:Aged; D000978:Antiparkinson Agents / Q000008:administration & dosage* / Q000009:adverse effects; D065098:Catechol O-Methyltransferase Inhibitors; D002396:Catechols / Q000008:administration & dosage / Q000009:adverse effects; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D004409:Dyskinesia, Drug-Induced / Q000209:etiology / Q000517:prevention & control*; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D006801:Humans; D007189:Indans / Q000008:administration & dosage* / Q000009:adverse effects; D007980:Levodopa / Q000008:administration & dosage* / Q000009:adverse effects; D008996:Monoamine Oxidase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D009570:Nitriles; D010300:Parkinson Disease / Q000188:drug therapy*
D000978:Antiparkinson Agents; D065098:Catechol O-Methyltransferase Inhibitors; D002396:Catechols; D004791:Enzyme Inhibitors; D007189:Indans; D008996:Monoamine Oxidase Inhibitors; D009570:Nitriles; C031967:rasagiline; D007980:Levodopa; C071192:entacapone