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Neurodegenerative Disease Parkinson’s Disease


Figure 3: Rasagiline Reduces the Need for Additional Antiparkinsonian Treatment in the Placebo-controlled Phase of the Attenuation of Disease Progression with Azilect Given Once Daily Trial


A


10 15 20


0 5


(n=96) (n=23) (n=12) Placebo B


10 15 20 25


0 5


(n=24) (n=2)


Rasagiline 1 mg/day


Early converters (n=2)


Rasagiline 2 mg/day


Early terminators


These endpoints were not met in the early- versus delayed-start rasagiline 2 mg/day comparison. A post hoc subgroup analysis of the patients with the highest quartile of UPDRS scores at baseline (UPDRS >25.5) i.e. patients more affected by the disease, however showed different results. Patients in this population who were treated with 2 mg/day early start rasagiline showed significant differences for all three primary endpoints comparedwith those who received 2 mg/day delayed start rasagiline (p<0.001, p=0.04 and p<0.001, respectively). Therefore, 2 mg/day delayed start rasagiline treatment achieved results consistent with disease modification in that population. It is possible that 2 mg/day rasagiline has a greater symptomatic effect, thus masking any potential disease-modifying effects in the more modestly affected cohort of patients studied in the ADAGIO trial. More data are required before any conclusions can be made. The different results for the two doses have been extensively discussed elsewhere.2,53–55


Analyses of Unified Parkinson's Disease Rating Scale–Activities of Daily Living Subscores in the Attenuation of Disease Progression with Azilect Given Once Daily Trial


In light of the recent evidence that the UPDRS-ADL subscale may be more sensitive in assessing disease progression in early PD,29,30,56


post


hoc analyses have been conducted using data from the ADAGIO trial.31 UPDRS-ADL subscores are derived from patients’ reports of function over the past week, and may therefore be less sensitive to short-term variability driven by environment or investigators.


0 4 Placebo


Number at risk


Placebo


Rasagiline 1 mg/day


Rasagiline 2 mg/day


593 288 293 586 287 289 573 562 282 280 286 282 Source: adapted from Rascol, et al., 2011,31 242 273 275 534 270 271 516 266 266 454 253 250 with permission from publisher.


ADAGIO trial continued to use a double-blind methodology after patients on placebo switched to rasagiline at week 36 (see Figure 1).


At baseline, patients had a mean total UPDRS score of 20.4.52 Results


showed that, compared with delayed-start rasagiline 1 mg/day treatment, early-start rasagiline 1 mg/day treatment provided benefits that indicated potential disease-modifying activity.52


met all three primary endpoints: •


Rasagiline 1 mg/day


superiority of slope suggesting a slower rate of disease worsening, as measured by a smaller change in mean UPDRS scores between week 12 and week 36 (0.09 and 0.14 with rasagiline and placebo, respectively; p=0.01);


• a difference in UPDRS scores between baseline and week 72 (2.82 and 4.52 with early- and delayed-start rasagiline, respectively; p=0.02); and





non-inferiority of slope between the early- and delayed-start groups between week 48 and week 72, as measured by the rate of change in UPDRS scores (0.085 points/week for both groups; p<0.001).52


96 435 250 246 318 185 183 8 12 16 20 Time (weeks) Rasagiline 1 mg/day Rasagiline 2 mg/day 24 28 32 36


The changes in UPDRS-ADL subscores from baseline to weeks 36 and 72, respectively, were assessed for each of the treatment groups. At week 36, estimated changes from baseline in UPDRS-ADL subscores were +1.13 (95 % confidence interval [CI] 0.95−1.31), +0.27 (95 % CI 0.02−0.52), and +0.33 (95 % CI 0.08−0.59) for placebo (n=588), rasagiline 1 mg/day (n=286), and rasagiline 2 mg/day (n=290), respectively. Rasagiline 1 mg/day also improved non-motor symptoms of the UPDRS-ADL subscale compared with placebo (mean difference -0.33; p=0.049).31


At week 72, estimated


changes from baseline in UPDRS-ADL subscores were +1.45 (95 % CI 1.04−1.85) and +2.07 (95 % CI 1.64−2.50) for early-start rasagiline 1 mg/day (n=251) and delayed-start rasagiline 1 mg/day (n=238), respectively, and +1.44 (95 % CI 1.08−1.80) and +1.66 (95 % CI 1.30−2.03) for early-start rasagiline 2 mg/day (n=258) and delayed-start rasagiline 2 mg/day (n=249), respectively (see Figure 2—which only shows data for the 1 mg/day rasagiline doses).31


In post hoc analyses, the effects of treatment on ADL subscores at week 36 and week 72 were compared with the effects of treatment on the other UPDRS subscores, in order to establish whether the UPDRS-ADL subscale is a responsive measure of disease progression over time. The percentage contribution of each UPDRS subscale was calculated by dividing the treatment effect recorded in each subscale by the sum of the three subscales (mentation, ADL, and motor).


Between baseline and week 36, rasagiline 1 mg/day significantly improved scores on each of the UPDRS subscales compared with placebo. During that period, the changes were likely to be the result of the combined effect of the short-term symptomatic and the putative long-term disease-modifying actions of the drug. At week 72, however,


US NEUROLOGY


Need for antiparkinsonian therapy (%)


Patients who needed additional antiparkinsonian therapy (%)


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