MADRID – Rasagiline may have a disease-modifying effect for patients with Parkinson's, delaying the progression of symptoms early in the disease at least in the short term, a new placebo-controlled trial has found.
The study was designed to assess the drug's neuroprotective potential with a delayed-start design. Patients initially randomized to rasagiline showed an immediate symptomatic benefit, while those on placebo declined. After 9 months, the placebo patients also began taking rasagiline. By the end of the second 9 months, they too had improved, although their symptoms remained significantly worse than those of the early-start group.
“We can say with certainty that early treatment provided benefits that couldn't be achieved with later introduction of the exact same drug,” Dr. C. Warren Olanow said at the annual meeting of the European Federation of Neurological Societies. “The question now is, why did this occur? Even though we have to speculate, and we don't have long-term data, we believe it must be related somehow to neuroprotection. It can't be completely explained by symptomatic improvement.”
Dr. Olanow, chairman of neurology at Mount Sinai School of Medicine, New York, was the principal investigator for the trial's North American arm. He and his colleague, Dr. Olivier Rascol of Toulouse (France) University Hospital, who supervised the European arm, jointly presented the newly released results.
The 18-month study included 1,176 patients with newly diagnosed Parkinson's disease (mean time since diagnosis, 4.5 months). Their mean age was 62 years; they all had very mild symptoms at the time of enrollment, with a mean total score of just 20 on the Unified Parkinson's Disease Rating Scale (UPDRS). Their mean modified Hoehn and Yahr score was 1.5.
Patients were randomized to placebo or to 1 or 2 mg rasagiline daily for the first 36 weeks. At 36 weeks, patients taking the drug continued receiving it, while patients taking placebo were randomized to either 1 or 2 mg of rasagiline. Everyone was followed for another 36 weeks. The investigators only presented the results of the 1-mg dose, saying that by the end of the trial, the 2-mg dose did not provide significant benefit over placebo.
Within 12 weeks of starting rasagiline, patients showed a mean 2-point decrease (improvement) on the UPDRS. Placebo patients showed a slight improvement as well, but it was not statistically significant. At 12 weeks both groups began to experience increases (worsening) of the UPDRS; however, the placebo group's score increased significantly more quickly and to a higher level. By 36 weeks, the mean score in placebo patients had increased by 3 points from baseline, while the active patients had lost their initial improvement and returned to their baseline score.
At this time point, all placebo patients were randomized to 1 or 2 mg rasagiline, while the early-start patients continued with their original regimen. By 45 weeks (9 weeks after initiating rasagiline) the delayed-start group showed a significant 1-point improvement in the UPDRS.
There was a very small improvement in the early-start group as well, which Dr. Rascol attributed to a placebo effect.
At week 45, both groups started to worsen. Although the UPDRS scores remained separated by about 2 points, the trajectory of worsening was virtually identical. By week 72–the end of the trial–the mean UPDRS in the early-start group was 2, while the mean score in the delayed-start group was 3.5–a significant difference.
If both groups had eventually reached the same level of clinical improvement, the trial would have shown that rasagiline works by improving symptoms, Dr. Rascol said. The fact that the delayed-start group improved, but never as much as the early-start group, indicates that something about early dosing slowed disease progression. “It showed that starting the treatment early improves the outcome of the patients in a way that cannot be simply explained by symptomatic benefit,” he said.
He acknowledged that the 2-point separation in scores, on a scale that reaches almost 200, was quite small. “However, some of these patients were only exposed to the drug for 9 months, and it can't be expected that the separation between the scores will be very large, especially since these patients have very early disease which progresses slowly.”
The follow-up period is enough to show that rasagiline provides very early benefit, Dr. Olanow said. Whether that benefit will remain constant, improve, or decline over time is still an unknown. “If I want to know what happens to these patients after 15 years on this drug, I'd have to follow them for 15 years, and these people don't have 15 years to sit around and wait. If we can conclude the benefit of this drug is real and can't be attributed to symptomatic effect then we can impute that it has a real disease-modifying effect. If you had Parkinson's, would you rather take a drug that shows initial disease slowing–without knowing what it does in 10 years–or not? That is the choice we face.”