Rasagiline and the ADAGIO trial results: what now?

The reported results from the ADAGIO trial are the culmination of a long effort to determine possible disease-modifying (or to use the less clinically favored term: ‘neuroprotective’) effects of rasagiline in people with PD using the delayed-start study design. We've know the basic message that rasagiline might be disease-modifying for a number of months now, ever since TEVA made public its initial findings earlier this year. But seeing the actual trial results published in the open literature is a good step toward verifying the accuracy of this claim.

The results show that 1mg rasagiline met all three endpoints to be considered 'disease-modifying', while 2mg rasagiline met only two of the three endpoints. So do these data prove that rasagiline is the answer to our dreams? Probably not for at least a couple of reasons. First, the authors indicate that the odd difference in effect of 1mg vs. 2mg rasagiline is difficult to explain. Although the post hoc analysis suggests that the 2mg finding may have simply been a false negative result, it is also possible that the 1mg efficacy finding is a false positive one. Second, the ‘delayed start’ design is still, at the end of the day, a trial based on clinical measures of benefit. Whether rasagiline is truly slowing loss of dopamine neurons or just helping the brain to compensate for the loss (something the authors raise as a possibility) is uncertain. Until the day we have biomarkers of disease process and neurodegeneration, answering this ultimate question will simply have to wait.

No doubt the debate on whether rasagiline is disease modifying or not (and what this means for people with PD) will continue for some time. But from a research and scientific perspective, the trial also raises some broader issues worth discussing and I invite the whole PD Online Research community to weigh in:

1. Is this trial a solid indication that the ‘delayed start’ design is the right way to go when testing drugs for possible disease-modifying effects? How should industry view these results as confirmation of a regulatory pathway for getting ‘neuroprotective’ drugs on the market?
2. An apparent assumption in this current version of the delayed start trial design is that progression of disease is linear over time. Does this fit with what is known about natural PD progression? What do the disease and trial modelers out there think? Are there ways to improve the delayed start design statistically to better measure disease progression? (We've funded a bit of work from Dr. Nick Holford in New Zealand and Jay Nutt in Oregon to play around with these ideas using mathematical modeling.)
3. The idea that a drug may act by activating compensatory processes rather than having a direct protective effect is an intriguing one. Are there markers or other relatively straightforward measures that we should consider testing in the context of drug development to help get at this question? From an industry perspective, would it even matter so long as benefit were seen?
4. Although whether a person with PD should go on rasagiline remains a decision that must be made by doctor and patient, the simple fact that many people may start to go on potentially ‘disease-modifying’ therapies soon after diagnosis raises a problematic challenge for trial design. What has been considered to date the ‘ideal’ trial subject—someone soon after diagnosis who is not yet on antiparkinsonian treatment—may soon no longer exist. How should trial designs deal with this possibility?