Results of ADAGIO trial for rasagiline suggest possible disease-modifying effect

The New England Journal of Medicine reports exciting results today regarding the ADAGIO trial for rasagiline (Azilect). A follow up to the previous TEMPO study (Arch Neurol 61:561-566, 2004), ADAGIO is one of the first true tests in Parkinson's disease of the ‘delayed start’ clinical trial design. Results suggest, not without caveats, that rasagiline may have a disease-modifying effect.

The trial randomized a whopping 1176 people with PD not yet receiving antiparkinsonian medication to receive either 1mg or 2mg rasagiline, or placebo control. An ‘early-start’ group was on active drug for the full 72-week duration of the trial, while a ‘delayed-start’ group was initially on placebo and then switched to active drug at week 36 for the remainder of the trial. Rasagiline at either 1mg or 2mg doses had to meet three pre-specified trial efficacy endpoints (a combination of slope and difference measures) to be considered ‘disease modifying’.

The authors report that 1mg rasagiline successfully acheived all three study endpoints, but 2mg rasagiline met only two of the three endpoints. A post-hoc analysis of subjects in the highest quartile of baseline UPDRS scores indicated that both doses met all three endpoints. The authors theorize that perhaps the milder subjects at baseline benefited so much symptomatically from 2mg rasagiline that it masked any possible disease-modifying effect, which could only therefore be teased out by looking at the slightly more severe subjects. Despite the intriguing hypothesis, the difference in findings between the two doses in the primary analysis led the study authors to conclude that a definitive demonstration of rasagline's disease-modifying ability could not yet be shown.

 

C. Warren Olanow, M.D., Olivier Rascol, M.D., Ph.D., Robert Hauser, M.D., Paul D. Feigin, Ph.D., Joseph Jankovic, M.D., Anthony Lang, M.D., William Langston, M.D., Eldad Melamed, M.D., Werner Poewe, M.D., Fabrizio Stocchi, M.D., and Eduardo Tolosa, M.D., for the ADAGIO Study Investigators. A Double-Blind, Delayed-Start Trial of Rasagiline in Parkinson's Disease. N Engl J Med 2009;361:1268-78.

23 Sep 2009 05:03 PM EST
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: ... 
Responses: 6
29 Sep 2009 05:40 PM EST
These recent rasagiline data (Olanow et al., 2009) represent a laudable if not heroic effort on behalf of PD patients, but unfortunately they are inconclusive and  I believe they do not warrant ... 
Responses: 4
30 Sep 2009 02:37 PM EST
Dr. Schwarzschild's analysis is very interesting and raises in my mind another key issue with interpreting these kinds of clinical trials results. How do you define clinically meaningful benefit from ... 
1 Oct 2009 04:28 PM EST
The recent publication of the ADAGIO trial raises numerous questions for the community to consider. Many of these have been outlined by Dr. Kieburtz in his discussion with MJFF and Dr. Fiske on PD ... 
2 Oct 2009 05:55 AM EST
From Nick Holford,  Jay Nutt,  Bart Ploeger ... 
Responses: 1
2 Oct 2009 06:20 PM EST
Many thanks to Drs. Holford, Nutt and Ploeger for their great analyses of the ADAGIO trial and other issues related to clinical trial design for disease modifying therapies. I hope this discussion ... 
6 Oct 2009 03:44 PM EST
As a researcher for some 25 years in Parkinson's disease, and now with oversight of clinical trials in wide-range of disciplines, some distance is helpful. First, whether or not the evidence points ... 
7 Oct 2009 10:20 AM EST
The methodology behind the identification of disease modifying effects in the ADAGIO study is good but the implementation is questionable.  Because of intrinsic characteristics of the metrics in ... 
8 Oct 2009 03:00 PM EST
The neuroprotective effect of rasagiline found in the ADAGIO is consistent with our research on 3,4-dihydroxyphenylacetaldehyde (DOPAL), the toxic monoamine oxidase (MAO) metabolite of dopamine ... 
Responses: 1
13 Oct 2009 01:33 PM EST
Dr. Schwarzschild, I read your posting on PDOnlineResearch on Adagio, etc. with interest.  I wonder if we are overlooking a fairly basic indicator of disease modification (nay, neuroprotection); ... 
Responses: 2
13 Oct 2009 04:22 PM EST
I think I understand where you’re coming from about the slopes but it’s hard to be sure by email. [Note: Dr. Schwarzschild has approved this posting of his email response to Dr. Grove, ... 
15 Oct 2009 09:27 AM EST
I am not in a position to discuss the clinical merits of ADAGIO delayed study since I was involved in the discovery and co-development of rasagiline with TEVA. However, the discrepancy between the ... 
15 Oct 2009 11:44 AM EST
In our transcriptomic and limited proteomic analysis of sporadic Parkinson’s disease  substantia nigra pars compacta (SNpc) (Grunblatt et al. 2004; Mandel et al. 2007) two  ... 
Bart Ploeger, et al.
20 Oct 2009 04:46 AM EST
The different views of Drs. Grove and Schwarzschild on whether or not slopes of the UPDRS versus time curves in the ADAGIO and ELLDOPA trial show disease modifying effects demonstrates that the ...