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Activities of Daily Living Subscale for Early Parkinson’s Disease


Teva Neuroscience, North Wales, PA) on early PD patients as demonstrated in the Attenuation of disease progression with Azilect given once daily (ADAGIO) trial.


Using Activities of Daily Living to Assess the Efficacy of Rasagiline in a Delayed-start Trial Currently, there are no established disease-modifying drugs for the treatment of PD. Available pharmacologic options treat symptoms, but do not have clinically proven neuroprotective properties. A major limitation in defining a disease-modifying therapy has been the lack of an outcome measure that accurately reflects the underlying disease state and is not confounded by symptomatic or pharmacologic effects of the study intervention. Some early drug studies have suggested potential mechanisms addressing underlying pathophysiology and prevention of cell loss, but subsequent clinical trials show confounding results, with difficulties in separating symptomatic improvement and neuroprotective effects.13,37


The development of a delayed-start trial design has helped overcome these confounding effects.38,39


Rasagiline—A Second-generation Monoamine Oxidase Type B Inhibitor


Rasagiline (N-propargyl-[1R]-aminoindan) is a highly selective, irreversible inhibitor of monoamine oxidase type B (MAOB) and is approved for the symptomatic treatment of PD as initial monotherapy and as adjunct therapy to L-dopa.40–42


rasagiline protects dopamine neurons in vitro43–46


Early studies have shown that and in vivo.47,48


In


primates, rasagiline has been shown to increase striatal extracellular dopamine concentrations.49


Unlike first-generation propargylamines,


rasagiline does not have an amphetamine-like structure and thus does not generate amphetamine or methamphetamine metabolites that may cause adverse effects.50


Rasagiline is metabolized by cytochrome


P-450 into its active metabolite, 1R-aminoindan, which also has in vitro and in vivo neuroprotective effects.51


The Attenuation of Disease Progression with Azilect Given Once Daily Trial Design Some retrospective analyses have tried to determine potential disease-modifying activity by comparing data from typical placebo-controlled, double-blind trials with data from the open-label, long-term extension periods in which all patients receive the study drug. Long-term extensions to clinical trials are common so that additional safety data can be collected. Any analyses that attempt to compare patients who have received the study drug throughout the double-blind and open-label phases with patients who originally received placebo and then the study drug should be interpreted with caution. For example, drop-out rates are often higher in the placebo group than in the treatment group and therefore, by the time the open-label phase begins, the two groups may be different than at the very beginning of the trial.


To determine whether rasagiline has disease-modifying potential in patients with PD, a delayed-start trial design was implemented in the prospective, double-blind, placebo-controlled ADAGIO trial using the UPDRS to evaluate patients with PD.31,39,52


The rationale for the


ADAGIO trial came from the TEMPO (Rasagiline mesylate [TVP-1012] in early monotherapy for Parkinson’s disease outpatients) trial, in which


US NEUROLOGY


Figure 2: Effects of Treatment on Mean Unified Parkinson's Disease Rating Scale Subscores and Total Scores at Week 36 (A) and Week 72 (B) in the Attenuation of Disease Progression with Azilect Given Once Daily Trial


A


6 5 4 3 2 1 0


Mental -1 B


6 5 4 3 2 1 0


Mental -1 ADL Motor


Delayed-start rasagiline 1 mg (n=238) Early-start rasagiline 1 mg (n=251)


Error bars are 95 % confidence intervals. The mean was estimated by using a mixed model repeated use. The data concerning the 2 mg/day rasagiline doses are not reproduced here. ADAGIO = Attenuation of disease progression with Azilect given once daily; ADL = Activities of Daily Living; UPDRS = Unified Parkinson’s Disease Rating Scale. Source: Rascol, et al., 2011.31


rasagiline had been shown to improve symptoms in PD patients as assessed using the UPDRS.40–42


Primary Efficacy Results from the Attenuation of Disease Progression with Azilect Given Once Daily Trial


A total of 1,176 treatment-naive patients with early, very mild PD were enrolled in the ADAGIO trial. They were randomly assigned to receive rasagiline (1 or 2 mg/day) for 72 weeks, or placebo for 36 weeks followed by rasagiline (1 or 2 mg/day) for 36 weeks. The 18-month


95 Total ADL Placebo (n=588) Motor Total Rasagiline 1 mg (n=286)


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