Rasagiline appears to slow the progression of Parkinson's disease, not just ameliorate its symptoms in the short term, according to a report in the New England Journal of Medicine.
A complex study design that incorporates several complicated statistical methods–the delayed-start study design–was used to differentiate the drug's short-term symptom effects from true disease-modifying effects, and the results were mixed. A 1-mg dose of rasagiline seemed to slow PD progression over the course of 18 months, but a 2-mg dose did not (N. Engl. J. Med. 2009;361:1268-78).
“From a practical point of view, the study findings suggest a possible benefit of the early use of rasagiline at a dose of 1 mg per day; however, given the negative findings for the 2-mg dose, we cannot definitively conclude that rasagiline at a dose of 1 mg per day has disease-modifying effects,” said Dr. C. Warren Olanow of the department of neurology, Mount Sinai School of Medicine, New York, and his associates.
“It will be important to determine whether these results can be confirmed and whether benefits seen at 18 months will endure and translate into reduced cumulative disability in clinically meaningful areas such as impairment of gait and balance and cognitive dysfunction,” they noted.
The investigators conducted the study in 1,176 PD patients aged 30-80 who had not received any treatment for the disease and were recruited from 129 medical centers in 14 countries. The mean duration of PD at baseline was 4.5 months.
In the first 36-week phase of the trial, subjects were randomly assigned to receive the 1-mg dose of rasagiline, the 2-mg dose, or matching placebos. In the second 36-week phase, subjects in the placebo groups switched to one of the active treatments, while those taking rasagiline continued their assigned treatment.
Theoretically, improvements seen in the first phase of a delayed-start study reflect the drug's symptom effects, and the difference between improvements in the early-start and delayed-start groups reflects the drug's disease-modifying effects.
In this study, subjects' mental function, activities of daily living, and motor function were assessed frequently using the Unified Parkinson's Disease Rating Scale. The mean total UPDRS score was 20.4 at baseline.
Teva Pharmaceutical Industries, manufacturer of rasagiline, funded the study and was responsible for data collection, monitoring, and statistical analysis.
The 1-mg dose of rasagiline met the three primary end points for results to be considered positive: There was less worsening in UPDRS scores during phase 1 with the drug than with placebo (0.09 points per week vs. 0.04 ppw), less worsening during phase 2 among subjects in the early-start group (2.82 ppw vs. 4.50 ppw) than in the delayed-start group, and noninferiority in the rate of worsening among the delayed-start patients during phase 2 (0.085 ppw in both).
The 2-mg dose did not meet these end points, though it did improve symptoms. “It is difficult to explain why the two doses did not provide similar results [and] to imagine that protective effects could be lost with a mere doubling of the dose,” Dr. Olanow and his colleagues said.
Dr. Olanow reported receiving consulting and lecture fees from Teva and Lundbeck; receiving consulting fees from Boehringer Ingelheim, Novartis/Orion, Solvay, Ceregene, and Merck Serona; and owning equity in Ceregene.
His colleagues also reported receiving consulting and lecture fees from Teva and other pharmaceutical companies.