SALT LAKE CITY—“Don’t delay” is the message of a delayed-start trial of rasagiline in early Parkinson’s disease, presented at the 133rd Annual Meeting of the American Neurological Association. The findings suggest that early use of this monoamine oxidase B (MAO-B) inhibitor slows decline, a benefit that cannot be made up by starting the drug later on, reported C. Warren Olanow, MD, Professor and Chair of Neurology at Mount Sinai School of Medicine in New York City. The results from the trial are consistent with a disease-modifying effect, he said.
Potential for Disease Modification?
Almost 20 years ago, another MAO‑B inhibitor, selegiline, was the subject of the first large-scale trial seeking a disease-modifying effect in Parkinson’s disease. While that trial showed that treatment delayed the need for levodopa, the results were equally explainable by the long-lasting symptomatic benefit of MAO-B inhibition, preventing any firm conclusion about the potential for disease modification.
To address this issue, the researchers used a “delayed-start” trial design for the current ADAGIO (Attenuation of Disease Progression With Azilect Given Once-Daily) study, which enrolled 1,176 Parkinson’s disease patients ages 30 to 80 within 1.5 years of their diagnosis who were not currently on other antiparkinson therapy. Patients were randomized to receive either 1 or 2 mg of rasagiline (early-start) or placebo (delayed-start) for nine months, after which placebo-treated patients were switched to either of the two rasagiline doses for an additional nine months. The low rate of dropouts during the long study—only 15%—was “remarkable,” Dr. Olanow said.
The researchers set three sequential hurdles that the early-start treatment would need to overcome to demonstrate a true disease-modifying effect. First, it would need to prove superior to placebo in the initial phase of the trial, reflected in a lower slope (less decline over time) on the Unified Parkinson’s Disease Rating Scale (UPDRS). Second, the overall change in UPDRS from baseline to the end of the study would need to favor rasagiline. Third, in the second phase, the slopes for the early- versus delayed-start groups should not begin to converge, suggesting a catch-up effect in the delayed-start group. More simply put, the benefit of early treatment should show up at the start and remain strong at the end.
Early Treatment Is Beneficial
Rasagiline at 1 mg per day passed all three tests, Dr. Olanow reported, with statistically significant superiority of treatment versus placebo for each. At the end of the trial, the slopes of change for the two groups were “completely parallel, with nothing to suggest the two groups were coming together,” he said.
Surprisingly, rasagiline at 2 mg per day did not pass this three-part test. It was superior to placebo early on, but at the end of the trial, the early- and delayed-start groups were similar. Dr. Olanow suggested that any difference between the groups that might have been due to disease modification might have been swamped by a larger symptomatic effect of the higher dose. A similar masking of differential benefit might occur, he suggested, if patients were tested after receiving a dose of levodopa, which, working purely symptomatically, might prevent detection of smaller differences in underlying disability.
As seen in other trials of rasagiline, side effects were mild and “nonnoteworthy,” Dr. Olanow said. No patients developed a serotonin syndrome, despite concomitant antidepressant use, and none displayed a tyramine reaction, even though there were no dietary restrictions imposed during the study.
“We can conclude that early treatment with rasagiline 1 mg provides a benefit that cannot be achieved with later introduction of the exact same drug,” Dr. Olanow asserted. “It is interesting to speculate on what the mechanism might be to account for this remarkable finding. Could it be that it is disease-modifying and has a neuroprotective effect, as we’ve seen in the laboratory? Is this simply early symptomatic treatment that is benefiting compensatory mechanisms, which, if not present, cause a decompensation to occur that cannot be recaptured with later reintroduction of the same drug? Or could it be that a maladaptive compensatory reaction is occurring that is prevented by early treatment? Finally, could it be simply a cumulative symptomatic effect that hasn’t caught up after nine months of drug?—something I feel is probably quite unlikely.”
Longitudinal Follow-Up Is Needed
This isn’t the end of the line for this patient cohort, Dr. Olanow said. “It’s important to know what this difference translates into over the next five to 10 years. Clearly, it is crucial to know if early treatment not only retards a decline on the UPDRS but also has an effect on gait dysfunction and cognitive dysfunction,” later-stage symptoms that are resistant to conventional antiparkinson treatments.