Rasagiline in Early Parkinson’s Disease
Abstract & Commentary
Source: The Parkinson Study Group. A controlled trial of rasagiline in early Parkinson Disease. Arch Neurol. 2002;59: 1937-1943.
Like its cousin selegiline, rasagiline is a selective irreversible inhibitor of monoamine oxidase type B. Rasagiline has been shown to improve the motor and cognitive signs of experimental parkinsonism, and preliminary studies have demonstrated that the compound is more potent than selegiline. A prior study of rasagiline in early Parkinson’s disease demonstrated that the drug was well tolerated up to doses of 4 mg/d. The theoretical risk of severe hypertensive crisis from nonselective inhibition of monoamine oxidase (seen with the older antidepressants Parnate and Nardil) was not observed.
Members of the Parkinson Study Group embarked on a double-blind, parallel-group, randomized, placebo-controlled trial of rasagiline in patients with early Parkinson’s disease in 1997. This trial randomized patients to receive placebo, 1 mg/d, or 2 mg/d of drug for a period of 26 weeks, after which the drug was withdrawn. Only patients afflicted with early Parkinson’s disease who did not require treatment with levodopa or dopamine agonists were allowed to enroll. They also could not have evidence of depression or dementia and were required to be in good health. The primary end point of the study was the change in total score of the Unified Parkinson Disease Rating Scale, a statistically validated clinical rating scale.
A total of 404 patients were enrolled in the trial—138 to placebo, 134 to 1 mg of drug, and 132 to 2 mg of drug. Of these, 112, 111, and 105 patients completed the 26-week trial, respectively. Both active groups showed a statistically significant benefit in the clinical rating score relative to placebo. However, the improvements were small and, in fact, were slightly better for the 1-mg than the 2-mg group. There was no difference in the rate of minor adverse events between the groups. However, 20 serious adverse events occurred during the study—4 in the placebo group, 6 in the 1-mg group, and 10 in the 2-mg group. This included 3 patients in the 2-mg group newly diagnosed with malignancies (malignant melanoma, prostate carcinoma, and squamous cell carcinoma of the skin). There was also a small but statistically significant (4 mm Hg) rise in supine systolic blood pressure in the 2-mg group relative to placebo.
Commentary
Several lessons can be learned from this well-designed, carefully performed study. First, rasagiline was well tolerated, and most patients were able to complete the study. There was no evidence that the 2-mg dose was superior to the 1-mg dose. The improvements in rating scale scores were similar to results observed in the DATATOP trial of selegiline. Compared to the robust improvement in scores seen in trials of dopamine agonist monotherapy in early Parkinson’s disease, these rating scale improvements are modest.
The incidence of adverse events was higher in the active treatment arms, particularly the 2-mg group. The development of 3 new malignancies (including 1 case of melanoma) in this group raises concerns; however, the sample size and duration of treatment are too short to draw definitive conclusions about the safety of the drug. While rasagiline likely produces its clinical effect by extending the life of endogenous dopamine, the possibility exists that the drug may be neuroprotective. Further larger and longer trials of this agent in Parkinson’s disease are in progress. — Steven Frucht
Dr. Frucht is Assistant Professor of Neurology, Movement Disorders Division, Columbia-Presbyterian Medical Center.
Like its cousin selegiline, rasagiline is a selective irreversible inhibitor of monoamine oxidase type B. Rasagiline has been shown to improve the motor and cognitive signs of experimental parkinsonism, and preliminary studies have demonstrated that the compound is more potent than selegiline.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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