Evaluation of the safety and tolerability of rasagiline in the treatment of the early stages of Parkinson’s disease

Abstract

Objective:

Rasagiline is a second-generation, irreversible MAO-B inhibitor (MAOB-I) previously shown to be efficacious and well-tolerated compared to placebo in the treatment of early Parkinson’s disease (PD). ACTOR (ACceptabilité TOlérance Rasagiline) was a 15-week, multi-center, randomized, double-blind study aimed to assess the safety and tolerability of rasagiline compared to the dopaminergic agonist pramipexole in the treatment of early PD.

Methods:

Patients with early, untreated idiopathic PD were randomized to receive 1 mg rasagiline (n = 53) or 1.5 mg pramipexole (n = 56) daily. The primary outcome was the number of patients experiencing a ‘clinically important adverse event’ (classified as a serious adverse event, an event leading to withdrawal or severe according to the patient). Safety outcomes were evaluated by the investigator and the patient. Analysis of the primary criterion was a comparative analysis using the chi-squared test. The Wilcoxon Mann–Whitney test was conducted to test the severity of patient-reported adverse events. Other tests performed include a covariance analysis and Student’s t-tests.

Results:

Mean disease duration was 3.4 months, and mean age was 62.6 years. Of patients taking pramipexole, 44.6% reported at least one ‘clinically important’ adverse event compared to 32.1% of patients taking rasagiline; non-inferiority of rasagiline was reached, with a difference in proportions of −12.6% [confidence interval of −27.8%; 2.6%]. There were no significant differences in clinical effectiveness between the treatments, measured by clinical and patient global impression of improvement (CGI-I, PGI-I) and PDQ-8 scales. A significant decrease in the incidence of gastrointestinal symptoms (p = 0.015) and sleep disorders (p = 0.027) was reported by physicians in the rasagiline group compared to the pramipexole group; the propensity to sleepiness improved significantly in the rasagiline group (p = 0.020), and worsened in the pramipexole group (p = 0.042).

Limitations:

Limitations of this study include the limited sample size due to the lower than anticipated recruitment and the accidental inclusion of a patient who had taken contraindicated medication.

Conclusions:

In this study, the safety profile of rasagiline had clinically favorable differences in gastrointestinal and sleep adverse events compared to pramipexole, whilst showing comparable clinician and patient-rated clinical effectiveness as a monotherapy for the treatment of early idiopathic PD.

Keywords::

• Parkinson’s disease
• Pramipexole
• Rasagiline
• Safety

Transparency

Declaration of funding

This study was funded in whole by Qualissima, who received a grant from Lundbeck.

Declaration of financial/other relationships

F.V. received honoraria from Qualissima for coordination of clinical centers. S.P., an employee of Qualissima received a grant from Lundbeck to carry out this study. S.L., an employee of Sylia Stat received payment from Qualissima for statistical analysis. O.B.’s official declaration of interest is available from the French Ministry of Health website www.sante.gouv.fr/declarations-publiques-d-interets.html. In addition, it should be noted that O.B. joined GSK after the study had been completed.

CMRO peer reviewers on this manuscript have no relevant financial relationships to disclose.

Acknowledgments

Editorial support was provided by Lisa Yang of Costello Medical Consulting.

Acknowledgments to the study investigators for their recruitment (alphabetic order)

Amevigbe Joséphine (Beauvais), Arguillère Sophie (Aix-en-Provence), Augustin Jérôme (Bois Guillaume), Bailbe Marc (Perpignan), Bensa Patrick (Marseille), Charif Mahmoud (Montpellier), Chassin Olivier (Vichy), Colamarino Renato (Vichy), Couratier Christophe (Aix-en-Provence), Daluzeau Nathalie (Lisieux), De Facq Pierre (Armentières), Decombe René (Troyes), Delmer Corinne (Evreux), Denis Béatrice (Marseille), Dujardin Max (Evreux), Fromager Guillaume (Caen), Galletti Patrick (Bastia), Geny Christian (Montpellier), Getenet Jean-Claude (Saint-Etienne), Hadjout Karim (Rodez), Jary Annabelle (Vesoul), Lavernhe Gilles (Gap), Le Collen Philippe (Dax), Lemaire Jean-François (Orléans), Maillet-Vioud Marcel (Montluçon), Pichot Du Mezeray Armel (Thionville), Pin Jean-Christophe (Saint Michel), Reis Jacques (Sarreguemines), Remy Pascal (Corbeil Essonnes), Renie Laurent (Aix-en-Provence), Robin Christophe (Roanne), Schmidt Nicolas (Rueil-Malmaison), Seiller Nicolas (Sarreguemines), Trefouret Sylvie (La Seyne Sur Mer), Viallet François (Aix-en-Provence).

Previous presentations

Outcomes of the ACTOR Study have previously been presented as posters at the following congresses:

1. Viallet F, Pitel S, Lancrenon S, Blin O. A comparative study on safety and tolerability of rasagiline versus pramipexole in early Parkinson's disease (PD): The ACTOR study [abstract]: 15th EFNS Congress, Budapest, Hungary; September 10–13, 2011. Eur J Neurol 2011;18:344–620.

2. Viallet F, Pitel S, Lancrenon S, Blin O. A comparative study on safety and tolerability of rasagiline versus pramipexole in early Parkinson's disease (PD): The ACTOR study [abstract]. 16th International Congress of Parkinson's Disease and Movement Disorders, Dublin, Ireland; June 17–21, 2012. Mov Disord 2012;27(Suppl 1):450.