Can the Course of Parkinson's Disease be Modified?

As is the case with a number of chronic, progressive neurologic disorders, there is a long running debate about whether pharmacotherapy modifies the course of Parkinson's Disease (PD). The original selegiline (a monoamine oxidase inhibitor; MAOI) trials, done with the p.o. formulation, almost thirty years ago sought to address this, with limited success. In the same vein, there is also a division of opinion about whether the use of levodopa worsens PD over time. The idea of disease modification is important, since we have a number of therapies to address symptoms of PD, but none that are proven to actually affect the course of the disease.

One way to address this question is the "delayed start" trial. A recent manuscript in NEJM uses this approach with another MAOI, rasagiline (Azilect). This was a randomized, double blind, placebo controlled trial, sponsored by the drug manufacturer. The authors recruited patients with early PD, and divided them into immediate start (IS) and delayed start (DS) groups. Each group was further divided into cohorts treated with 1 mg. or 2 mg. of rasagiline per day. Patients receiving any recent PD treatment were excluded.

The trial was divided into 2 phases. In the first phase (36 weeks), patients in the IS group were started on rasagiline, while the DS patients received placebo. In phase 2 (also 36 weeks), all patients were treated with rasagiline. The primary measure was the Unified Parkinson's Disease Rating Scale (UPDRS), which is a 176 point, well validated instrument in which higher scores indicate worse disease.

The analysis is complex. Three endpoints were used: The UPDRS curve slope change between 12 and 36 weeks, the UPDRS numerical change between the beginning and end of the trial, and a non-inferiority test between groups of the change between weeks 48 and 72. All these metrics had to reach statistical significance for the study to be considered positive. These complex measures were necessary to determine whether changes were due to disease modification or simply drug efficacy. 1,176 patients in 14 countries were recruited. 1,164 patients reached the first endpoint analysis, and 996 were included in the second and third endpoint analyses.

And the results were mixed. The 1 mg. IS group showed less progression by slope of curve analysis (0.09±0.02 points per week v. placebo (0.14±0.01 points per week); p=0.01. The other 2 measures were statistically significantly different between the IS and DS groups as well. The results were, however, different for the 2 mg. groups. The first endpoint and the non-inferiority measures were statistically significant. But the total UPDRS change over 72 weeks was not. So, a post-hoc analysis, stratified into quartiles by initial UPDRS scores, was done. The highest initial score quartile met the study criteria for significance.

Adverse effects were not limiting. No tyramine reactions, a potentially serious reaction in persons taking MAOIs, were noted. One subject in the high dose group was found to have a melanoma at week 72. This is a concern with such therapy, but is also a common problem in older patients, and thus may have been an anomaly.

The authors note that both doses of rasagiline had beneficial effects on PD symptoms, of a magnitude comparable to previous trials. They are hard pressed, however, to explain the difference in study outcome between the two different doses. They ultimately posit that the efficacy on symptoms masks the disease modifying effects in less affected patients, but they do not consider this to be conclusive. I note that an accompanying paper on statistics addresses shortcomings of the delayed start trial design in great detail.

Thus, 1 mg. rasagiline may delay the progression of PD. Unfortunately, however, this trial was not definitive. The authors recommend that the results be confirmed and longer term data be obtained before this becomes a clinical treatment standard to modify the course of PD.