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Is Earlier Treatment of Parkinson's Disease Better?
Abstract & Commentary
By Claire Henchcliffe, MD, Assistant Professor, Department of Neurology and Neuroscience, Weill Medical College, Cornell University. Dr. Henchcliffe reports she is on the speaker's bureau of GlaxoSmithKline, Teva, Boehringer Ingelheim, Schwarz Pharma, and Allergan.
Synopsis: This is an open label extension of 306 subjects from a previously reported delayed-start phase III clinical trial of rasagiline in early Parkinson's disease. Clinical benefit observed at one year in the early vs. delayed-start arm was maintained over an average 3.6 ± 2.1 years observation, raising the question of whether earlier intervention with rasagiline results in better outcomes.
Source: Hauser RA, Lew MF, Hurtig HI, et al. Long-term outcome of early versus delayed rasagiline treatment in early Parkinson's disease. Mov Disord 2009:Epub ahead of print.
Rasagiline is an irreversible monoamine oxidase type B inhibitor indicated for symptomatic treatment of Parkinson's disease (PD), but laboratory data in cells and animal models has provided hope that it may also be neuroprotective. This study seeks to address its long-term use and possible disease-modifying properties, beginning from a pivotal phase III clinical trial, named "TEMPO," that demonstrated symptomatic benefit.1 In TEMPO, subjects with early, untreated PD (n = 404) were randomized to receive placebo, 1 mg, or 2 mg rasagiline daily for six months. All consenting participants (n = 371) were then assigned to rasagiline 2 mg daily, with the initial placebo arm of TEMPO therefore forming a "delayed start" group.2 Intriguingly, at 52 weeks from baseline, total Unified Parkinson's Disease Rating Scale (UPDRS) scores were superior in the early- versus delayed-start group (-2.29 points in the initial 2 mg group, p = 0.01), indicating a sustained difference in favor of the early start group that could not be accounted for purely by symptomatic benefit. In this open-label extension (n = 306), subjects have now been followed for up to 6.5 years total rasagiline treatment (average 3.6 ± 2.1 years), with 117 remaining in the study until database lock. Additional medications including levodopa and dopamine agonists were taken as clinically indicated. Once again, difference in adjusted mean change in total UPDRS from TEMPO baseline to last observation demonstrated a difference in favor of the early- versus delayed-start groups (-2.5 UPDRS points, SE 1.1, p = 0.021).
This is a timely study with long-term followup, adding to discussion of whether rasagiline could have disease-modifying properties in addition to its mild symptomatic benefits in PD. Rasagiline has various effects in vitro, including increasing expression of "pro-survival" glial-derived neurotrophic factor, and in animal models of PD it attenuates MPTP-induced loss of dopamine neurons. Unfortunately, PD research has been littered with promising data that did not translate from bench to bedside. Moreover, there are significant challenges in demonstrating neuroprotection/disease modification, such as lack of adequate biomarkers. However, by following clinical outcomes, the authors demonstrate that PD subjects starting rasagiline six months earlier sustained a long-term benefit over those starting later, as measured by UPDRS scores. This is certainly consistent with (although not proof of) a disease-modifying effect, and may stimulate reconsideration of data on the related drug, selegiline. It raises the question of, if earlier treatment is better, why don't we start all of our PD patients on rasagiline at the time of diagnosis? As the authors urge, caution should be exercised in interpretation for the time being. Only 117 of the original 404 TEMPO subjects completed the study reported here, doses of rasagiline varied during the trial, (including during the open label phase during which all switched from 2 mg to 1mg based upon new efficacy data), and the TEMPO study was originally powered to test symptomatic effects rather than disease modification. Additionally, although not statistically significant, the early-start group received more levodopa equivalents than the delayed group at all except the six years' time point, which could possibly be argued to account for better UPDRS scores. One study that will clarify some concerns is a larger delayed-start trial of rasagiline in early PD, the ADAGIO trial.3 Positive results, reported as abstracts, have already prompted discussion (although, oddly, results were positive only for the 1 mg and not the 2 mg dose). Arguments aside, this "third incarnation" of the TEMPO trial illustrates the tremendous value of long-term followup of subjects who have participated in clinical trials, and adds support to a possible intervention for disease modification in PD.
1. Parkinson Study Group. A controlled trial of rasagiline in early Parkinson disease. Arch Neurol 2002;59:1937-1943.
2. Parkinson Study Group. A controlled, randomized, delayed-start study of rasagiline in early Parkinson disease. Arch Neurol 2004;61:561-566.
3. CW Olanow et al. A randomized, double-blind, placebo-controlled, delayed start study to assess rasagiline as a disease modifying therapy in Parkinson's disease (The ADAGIO Study): Rationale, design, and baseline characteristics. Mov Disord 2008;23:2194-2201.