Strengthening the Case for Early Parkinson's Treatment
Strengthening the Case for Early Parkinson's Treatment
Abstract & Commentary
By Claire Henchcliffe, MD, Assistant Professor, Department of Neurology and Neuroscience, Weill Cornell Medical College. Dr. Henchcliffe reports she is on the speaker's bureau of GlaxoSmithKline, Teva Neuroscience, Boehringer Ingelheim, Novartis, and Allergan.
Synopsis: In a delayed-start trial of rasagiline in early Parkinson's disease, 1 mg rasagiline daily met all three predetermined endpoints consistent with disease modification. However, a dose of 2 mg daily did not meet all endpoints, complicating interpretation.
Source: Olanow WC, et al. A double-blind, delayed-start trial of rasagiline in Parkinson's disease. N Engl J Med 2009;361:1268-1278.
The ADAGIO (Attenuation of Disease Progression with Azilect Given Once-Daily) study used a delayed-start design to test whether rasagiline has a disease-modifying effect in 1,176 subjects with early Parkinson's disease (PD). The 18-month total delayed-start design entailed randomising subjects to one of four arms: early- vs delayed-start rasagiline 1 mg daily, and early- vs delayed-start rasagiline 2 mg daily. The early-start arms were given rasagiline for the 18-month duration of the trial. The delayed-start arms obtained placebo for the first nine months, and only then began rasagiline. To demonstrate disease modification, as opposed to a purely symptomatic effect, the primary analysis comprised three hierarchical endpoints, meaning each had to be met before proceeding to the next endpoint determination. Rasagiline 1 mg daily met all three endpoints: 1) slower rate of change of UPDRS vs placebo (0.09 ± 0.02 vs 0.14 ± 0.01 points/week; p=0.01), in the rasagiline vs placebo phase (12-36 weeks); 2) sustained superiority of early vs delayed start rasagiline UPDRS score at 18 months (2.82 ± 0.53 vs 4.52 ± 0.56 points; p=0.02); and 3) identical rates of progression of UPDRS scores in the active phase (47-72 weeks). However, although rasagiline 2 mg daily demonstrated a slower rate of change in the rasagiline vs placebo phase (0.07 ± 0.02 vs 0.14 ± 0.01 points/week), it did not meet statistical significance for the second endpoint of a sustained superiority over placebo (3.47 ± 0.50 vs 3.11 ± 0.50 points, p=0.06), and therefore did not meet criteria consistent with disease modification.
Commentary
Despite complicated interpretation and ongoing debate, this is a landmark study in PD for several reasons. First, the ADAGIO study is the first delayed-start design trial in PD with the primary aim of demonstrating disease modification, a major yet elusive goal that would have a profound impact on patient care. Second, the unfamiliar use of slope analysis and use of three hierarchical primary endpoints is rigorous, well addressed in an accompanying editorial, and may be the best means at present for addressing potential neuroprotective treatments whose benefits are confounded by symptomatic effects.1 Third, and most importantly, rasagiline 1 mg daily met all endpoints consistent with a disease modifying, potentially neuroprotective, effect. A previous trial, nicknamed TEMPO2 was suggestive of disease modification using a dose of rasagiline 2 mg daily. Furthermore, a long-term open-label extension of TEMPO suggested that the benefit of early start was maintained. The ADAGIO study's findings would therefore be paradigm-changing in PD treatment, pushing for intervention with rasagiline at the time of diagnosis on the basis of disease-modification.
So, why is there a problem? Despite the authors' best efforts, it is difficult to explain how the 2 mg daily dose did not meet the same endpoints. Several possibilities are proposed, including the obvious that we are dealing with a false negative (2 mg) or a false positive (1 mg) error. However, in a post-hoc subgroup analysis, data from the upper (i.e., most affected) quartile in the 2 mg arm actually met all three endpoints. Was a disease-modifying effect therefore missed because of difficulties measuring effect sizes in a cohort with low baseline UPDRS scores? This is a source of current debate and controversy, and there is no firm answer from the data in hand. Rasagiline is already indicated for symptomatic benefit in PD, since as an MAO-B inhibitor it inhibits dopamine breakdown. Now, despite the questions surrounding ADAGIO's interpretation, it is likely that PD treatment will be pushed earlier in the hope of improving long term outcomes.
References
1. D'Agostino RB. The Delayed-Start Study Design. N Engl J Med 2009;361:1304-1306.
2. Parkinson Study Group. A controlled randomized, delayed-start study of rasagiline in early Parkinson disease. Arch Neurol 2002;61:561-566.
In a delayed-start trial of rasagiline in early Parkinson's disease, 1 mg rasagiline daily met all three predetermined endpoints consistent with disease modification. However, a dose of 2 mg daily did not meet all endpoints, complicating interpretation.Subscribe Now for Access
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