PHILADELPHIA – Results of the phase III clinical trial to evaluate preladenant as monotherapy for Parkinson’s disease are difficult to interpret because the lack of observed efficacy of rasagiline as an active control indicates that the study didn’t work.
"There was not a significantly greater benefit in any of the arms, compared with placebo, including all the preladenant arms, and the rasagiline arm, our active-control medication with known efficacy," Dr. Robert A. Hauser revealed to a giggling crowd, some of whom applauded, at the annual meeting of the American Academy of Neurology.
"Interestingly enough, placebo was statistically superior to the lowest dose of preladenant," said Dr. Hauser, director of the Parkinson’s Disease and Movement Disorder Center at the University of South Florida, Tampa.
Dr. Robert Hauser
The randomized, double-blind, placebo- and active-controlled, parallel-group trial was designed to cover two 26-week time periods for a total of 52 weeks, and it was conducted at multiple centers in multiple countries. More than half (58%) of the 1,022 participants were men. The average age was 63 years, and the mean baseline score on the Unified Parkinson’s Disease Rating Scale (UPDRS) parts 2 and 3 was 28.5. The study participants had been diagnosed with Parkinson’s disease within the previous 5 years, and had not yet received any levodopa or dopamine agonists.
The efficacy parameter was based on a change from baseline (CFB) in patient UPDRS scores. There was a dose-ordered response, although the patients in the preladenant 2 mg twice daily arm actually worsened, showing a significant CFB of 0.30 and a 2.60 difference when compared with placebo (P = .0033; 95% confidence interval, 0.86-4.30).
The preladenant 5 mg twice-daily group improved, showing a –1.00 CFB and a 1.30 difference from placebo (P = .1382; 95% CI, –0.41-2.94). The preladenant 10 mg twice-daily arm also improved, showing a CFB of –1.80 with a difference of 0.40 from placebo (P = .6378; 95% CI, –1.29-2.11).
Patients in the 1 mg once-daily rasagiline group improved, but not significantly, with a CFB of -1.90 when compared with placebo (P = .6923; 95% CI, –1.35-2.03), however, the placebo arm had the best results overall with a CFB of –2.20.
"I should point out that rasagiline was our active comparator, and it was included to make sure that the trial worked," said Dr. Hauser. "The fact that [the rasagiline group] did not separate from placebo indicates that this was a failed trial."
Rasagiline is a monoamine oxidase type-B inhibitor, with Food and Drug Administration approval as both monotherapy in early Parkinson’s disease an as an adjunctive treatment in moderate to advanced Parkinson’s disease.
A post hoc analyses revealed that, across the sites, the strongest rasagiline response vs. placebo (when looking at the CFB on the UPDRS parts 2 and 3) occurred in the European Union (–2.4) and North America (–1.5). In Eastern Europe, placebo performed 4 points better than did rasagiline. In Latin America, the rasagiline and placebo arms showed parity. Dr. Hauser speculated that regional differences might reflect experience and expertise of sites in those regions that participated in the trial.
Preladenant previously had been found effective as an adjunct to levodopa when dosed at either 5 mg or 10 mg twice per day.
While it is not possible to draw definitive conclusions about preladenant’s efficacy as a monotherapy for Parkinson’s disease based on this trial, Dr. Hauser stated, "One of things I think this trial demonstrates is the value of having an active-control medication known to have efficacy in a situation when you are testing a new medication."
Dr. Hauser disclosed that he and his associates had many industry relationships, including his own with Abbott Laboratories, Allergan, AstraZeneca, Biotie Therapies, Ceregene, Chelsea Therapeutics, and GE Healthcare. This trial was underwritten by Merck.
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