Rasagiline delayed-start trial results explained
 

Rasagiline for Parkinson's Disease May Alter Disease Course
S. Andrew Josephson

http://www.medscape.com/viewarticle/711123?src=rss

Posted: 11/30/2009; AccessMedicine from McGraw-Hill © 2009 The McGraw-Hill Companies




Current therapies for Parkinson’s disease (PD) have robust effects on symptoms (until the later stages of the disorder), but none has been proven to alter the course of the disease. Previous trials of multiple PD agents have failed to demonstrate this so-called neuroprotective effect. Rasagiline is ... often prescribed in the early stages of treatment...

The authors performed a double-blind trial of rasagiline versus placebo. In order to test whether rasagiline had neuroprotective effects, a delayed-start trial design was used... Conceptually, differences between treatment and placebo after the initial 36 weeks could be explained by effects on symptoms alone, disease modification, or both; however, changes that persist after the full 72 weeks, while all patients are receiving rasagiline, would likely be consistent with neuroprotective effects.

A total of 1176 patients with untreated PD were enrolled in the study...

In the group treated with 1 mg of rasagiline, all three primary endpoints were met, including a slower rate of worsening compared with placebo between weeks 12 and 36 (p = .01), less worsening between baseline and week 72 compared with placebo (p = .02), and noninferiority of the change in score between weeks 48 and 72 compared with the delayed-start group (p < .001). However, these three endpoints were not all met in the patients taking the 2-mg rasagiline dose. Although the 2-mg dose group did show less worsening between weeks 12 and 36 compared with placebo (p < .001), the change in total UPDRS score between baseline and week 72 was not significantly different from that in the delayed-start group (p = .60). Noninferiority was demonstrated in the change in score between weeks 48 and 72 compared with the delayed-start group (p < .001).

The results of this trial are somewhat confusing. Although rasagiline at a dose of 1 mg daily did seem to provide neuroprotective benefits, this was not replicated in the higher-dose group...
...It appears as if another trial will be needed to definitively determine if indeed a disease-modifying effect is present with rasagiline. In future trials, use of patients with more advanced disease may eliminate this possible confounder of symptomatic changes masking neuroprotective effects. Until that time, clinicians should consider the use of rasagiline for PD patients only in order to provide symptomatic benefit; alas, the elusive “holy grail” of neuroprotective effects in PD has not yet been found.

Sometimes a cigar is just a cigar.
 

How many more trials or trial designs does this drug need in order for Teva to instead start pursuing other new treatments or therapies in place of chasing its tail? First, we're supposed to ooh and ahhh over the advanced innovative delayed start trial design model. The delayed start design studied the drug's neuroprotective properties in 2004- then with mixed results as well. The desperate need to find this drug as neuroprotective leaves a bad taste in my mouth; I sense Teva needs to find something fast, a new angle to hold onto this patent. They only have 3 more years; they better start cracking.

Perhaps the inconclusive results reflect that we should also find a better way to track disease progression beyond a rather incomplete, inadequate 'day in the life' type snapshot in the UPDRS scale. I don't know about you but my scores could probably fluctuate quite dramatically on any given day when we factor in stress levels. How can tallying up points on this simplistic tool translate into statistically significant differences or hard science of any sort? Why aren't brain imaging tools also being used? Until we come up with more actual visual or biochemical measures of any differences in disease progression, our research trials remain fundamentally flawed. At this point, I don't feel confident we even have a sound common baseline measure for ensuring that trial participants are at the same disease stage at the onset of the trial.

One aspirin or two.......
 

I wonder if anyone else, as I do, sees a fundamental flaw in the way many of these trials are designed. With a condition such as PD, where is is widely acknowledged that there is huge variation in presentation, progression, response to medication, and a whole host of other things, including the experience of side-effects that even to the patient maybe virtually indistinguishable from the symptoms of the disease, trial design might NEED the modifications that Laura talks about. Further to that, it does not surprise me that this trial showed better results at a lower dose. I remember reading once that many patients with PD are exquisitely sensitive to medications, something that is born out by the many patients who split medications, and vary timing and combination patterns. I simply do not see how they quantify anything through the ratings of the UPDRS scale, it is simply too subjective. This is not a condition that can be treated by the 'one aspirin, two aspirin' approach to medicine, why is there an assumption that trials should be any different..........

Another case for including patient input in trial design.............

Lindy