A randomized, placebo controlled trial of rasagiline in levodopa-treated patients with Parkinson disease and motor fluctuations. The PRESTO study
Parkinson Study Group;
Commented by , 22 Mar 2005
Aim of the study
To determine the safety, tolerability, and efficacy of rasagiline in levodopa-treated patients with PD and motor fluctuations.
Methods
This was a multicenter, randomized, double blind, placebo controlled, parallel group study. A total of 472 patients with Parkinson's disease and at least two and a half hours of daily "off" time, despite optimized treatment with other anti-PD medications were entered into this study.
Patients were assigned to recieve either rasagiline 1.0 mg, rasagiline 0.5 mg or placebo for a period of 26 weeks. The prespecified primary outcome measure of efficacy was the change from baseline in mean total daily off time as measured by patients' home diaries, averaged during the 26 weeks of treatment.
Results
The mean adjusted total daily off time decreased from baseline by 1.85 hours (29%) in patients treated with 1.0 mg/day of rasagiline, 1.41 hours (23%) with 0.5 mg/day rasagiline, and 0.91 hour (15%) with placebo.
Compared with placebo, patients treated with 1.0 mg/day rasagiline had 0.94 hour less off time per day, and patients treated with 0.5 mg/day rasagiline had 0.49 hour less off time per day. Predefined secondary end points also improved during rasagiline tretment, including the scores on an investigator-rated clinical global impression of change scale and the UPDRS (activities of daily living in the "off" state and motor performance in the "on" state.
Rasagiline was generally well tolerated, adverse events which were more frequent than in the placebo group mostly involved the gastrointestinal system (such as weight loss, vomiting, anorexia) and balance difficulties, dyskinesias were reported as an adverse event in more patients under rasagiline (18% vs 10% under placebo).The authors concluded that rasagiline improves motor fluctuations and PD symptoms in levodopa-treated PD patients.
Professor Emre’s comments
Rasagiline is a new generation, irreversible and selective inhibitor of the enzyme monoamino oxidase type B (MAO-B). MAO-B is the main enzyme which metabolizes dopamine in the brain.In a previous randomized, placebo-controlled trial rasagiline monotherapy at doses of 1.0. and 2.0 mg, administered over 6 months, was shown to be efficacious and well tolerated in 404 patients with early, otherwise untreated PD (ref. 1).
This is the first study reporting the use of rasagiline in patients under optimized dopaminergic medication and still experiencing motor fluctuations. This large, randomized controlled study demonstrates that rasagiline is also effective in this patient population.
This therapeutic strategy has a relatively long history, at times associated with fierce controversies The older MAO-B inhibitor selegiline has been used in PD for almost thirty years, but the magnitude and the mechanism of its efficacy have been somewhat disputed.
A recent meta-analysis of MAO-B inhibitors including 13 randomised trials with selegiline, 3 with lazabemide and 1 with rasagiline revealed that they are effective in early PD, reducing disability, the need for levodopa and the incidence of motor fluctuations, without substantial side effects (ref. 2).
An evidence-based review of all studies with MAO-B inhibitors, basically confined to those with selegiline, reached the same conclusion that it is effective as monotherapy in early PD, but the data on its benefits as add-on therapy in patients with motor complications was deemed to be insufficient (ref. 3).
The current study is an important contribution to defining the full therapeutic scope of MAO-B inhibitors as it has unequivocally demonstrated that patients experiencing motor fluctuations despite optimal dopaminergic treatment obtain relevant benefits from treatment with rasagiline.
References
1. Parkinson Study Group. A controlled trial of rasagiline in early Parkinson disease: the TEMPO study. Arch Neurol 2002; 59; 1937-1943
2. Ives NJ, Stowe RL, Marro J, et al. Monoamine oxidase type B inhibitors in early Parkinson's disease: meta-analysis of 17 randomized trials involving 3525 patients. BMJ 2004; 329 (7466); 593-596 (Note: Free full text article)
3. Goetz CG, Koller WC, Poewe W, Rascol O and Sampaio C. Management of Parkinson's disease: an evidence-based review. MAO-B inhibitors for the treatment of Parkinson's disease. Mov Disord 2002; 17 (Suppl 4); S38-S44