A double-blind, delayed-start trial of rasagiline in Parkinson's disease.
BACKGROUND
A therapy that slows disease progression is the major unmet need in Parkinson's disease.


METHODS
In this double-blind trial, we examined the possibility that rasagiline has disease-modifying effects in Parkinson's disease. A total of 1176 subjects with untreated Parkinson's disease were randomly assigned to receive rasagiline (at a dose of either 1 mg or 2 mg per day) for 72 weeks (the early-start group) or placebo for 36 weeks followed by rasagiline (at a dose of either 1 mg or 2 mg per day) for 36 weeks (the delayed-start group). To determine a positive result with either dose, the early-start treatment group had to meet each of three hierarchical end points of the primary analysis based on the Unified Parkinson's Disease Rating Scale (UPDRS, a 176-point scale, with higher numbers indicating more severe disease): superiority to placebo in the rate of change in the UPDRS score between weeks 12 and 36, superiority to delayed-start treatment in the change in the score between baseline and week 72, and noninferiority to delayed-start treatment in the rate of change in the score between weeks 48 and 72.


RESULTS
Early-start treatment with rasagiline at a dose of 1 mg per day met all end points in the primary analysis: a smaller mean (+/-SE) increase (rate of worsening) in the UPDRS score between weeks 12 and 36 (0.09+/-0.02 points per week in the early-start group vs. 0.14+/-0.01 points per week in the placebo group, P=0.01), less worsening in the score between baseline and week 72 (2.82+/-0.53 points in the early-start group vs. 4.52+/-0.56 points in the delayed-start group, P=0.02), and noninferiority between the two groups with respect to the rate of change in the UPDRS score between weeks 48 and 72 (0.085+/-0.02 points per week in the early-start group vs. 0.085+/-0.02 points per week in the delayed-start group, P<0.001). All three end points were not met with rasagiline at a dose of 2 mg per day, since the change in the UPDRS score between baseline and week 72 was not significantly different in the two groups (3.47+/-0.50 points in the early-start group and 3.11+/-0.50 points in the delayed-start group, P=0.60).


CONCLUSIONS
Early treatment with rasagiline at a dose of 1 mg per day provided benefits that were consistent with a possible disease-modifying effect, but early treatment with rasagiline at a dose of 2 mg per day did not. Because the two doses were associated with different outcomes, the study results must be interpreted with caution. (ClinicalTrials.gov number, NCT00256204.)
Department of Neurology and Neuroscience, Mount Sinai School of Medicine, New York, NY 10029, USA. warren.olanow@mssm.edu
C Warren
CW
Olanow
Olivier
O
Rascol
Robert
R
Hauser
Paul D
PD
Feigin
Joseph
J
Jankovic
Anthony
A
Lang
William
W
Langston
Eldad
E
Melamed
Werner
W
Poewe
Fabrizio
F
Stocchi
Eduardo
E
Tolosa
D000328:Adult; D000368:Aged; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007189:Indans / Q000008:administration & dosage* / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D008996:Monoamine Oxidase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000009:adverse effects; D010300:Parkinson Disease / Q000145:classification / Q000188:drug therapy*; D012107:Research Design; D012720:Severity of Illness Index
D007189:Indans; D008996:Monoamine Oxidase Inhibitors; D018696:Neuroprotective Agents; C031967:rasagiline