Rasagiline as an adjunct to levodopa in patients with Parkinson’s disease and motor fluctuations (LARGO, Lasting Effect in Adjunct therapy with Rasagiline Given Once daily, study): a randomized, double-blind, parallel group trial.
O Rascol, DJ Brooks, E Melamed, et al. for the LARGO study group.;
Commented by , 26 Jul 2005
Background
The MAO-B inhibitor rasagiline has been previously reported to be effective in the treatment of de novo patients with Parkinson disease as well as in patients with motor fluctuations. The magnitude of effect in fluctuating patients as compared to COMT inhibitors, another treatment strategy to increase the efficiency of dopaminergic treatment, has not been reported before.
Aim of the study
To investigate the efficacy and safety of rasagiline in levodopa-treated patients with PD and motor fluctuations as compared to placebo and entacapone.
Methods
The LARGO study was an 18 week, multicenter, randomised, placebo- and entacapone-controlled, double blind, double-dummy, parallel-group trial. A total of 687 outpatients in 74 centers were randomly assigned to receive rasagiline 1 mg once daily, entacapone 200 mg with every levodopa dose or placebo.
Eligible patients were those with a clinical diagnosis of idiopathic PD, who had motor fluctuations with at least 1 hour off-state every day, despite receiving optimum levodopa treatment. The primary outcome measure was change in total daily off-time. Secondary measures included the clincial global improvement (CGI) and UPDRS scores.
Results
Both rasagiline and entacapone reduced mean daily off time (-1.18 h rasagiline and -1.2 h entacapone vs placebo -0.4 h; p=0.0001 and p<0.0001, respectively) and increased daily on-time without troublesome dyskinesia (0.85 h vs placebo 0.03 h; p=0.0005 for both).
There were significant mean improvements also in the CGI scores (-0.86 rasagiline and -0.72 entacapone vs -0.37 placebo; p<0.0001, p=0.0002, respectively), UPDRS scores significantly improved for activities of daily living during off-time (-1.71 and -1.38 vs placebo; p<0.0001, p=0.0006, respectively) and motor function during on-time (-2.94 and -2.73 vs placebo; both p<0.0001).
Frequency of adverse events was similar for all treatments, discontinuations due to adverse events were less in the rasagiline group. The authors concluded that once-daily rasagiline reduces mean daily off-time and improves symptoms of PD in levodopa-treated patients with motor fluctuations, and that this effect is similar to that of entacapone.
Professor Emre's comments
This paper is the third in a series of recent articles published on the efficacy of rasagiline in various patient populations with PD.
Rasagiline is a novel monoamino oxidase type B (MAO-B) inhibitor which is expected to be the latest anti-Parkinson medication to be introduced on the market. It is an irreversible and selective inhibitor of MAO-B, which is the main enzyme metabolizing dopamine in the brain.
The efficacy of rasagiline has been previously described in "de novo" patients with PD, i.e. those who were otherwise untreated (ref. 1) and also in those with motor fluctuations (ref. 2). This study confirms and extends the earlier results.
The PRESTO trial (ref. 2), which was also published this year had already revealed that rasagiline was effective in reducing off time in patients with motor fluctuations, despite optimized levodopa treatment.
The results of the current study unequivocally confirm these earlier findings and also demonstrate that the magnitude of this effect is comparable to that of the COMT inhibitor entacapone. COMT is the enzyme which converts levodopa to 3-O-methyl-dopa in the periphery, thus reducing the amount of levodopa available to enter the central nervous system, it also breaks down dopamine in the brain, to a lesser extent than MAO-B does.
In patients with motor fluctuations both COMT and MAO-B inhibition adjunct are therapuetic strategies to improve the efficiency of levodopa treatment, through different enzymatic pathways.
That both provide significant and comparable symptomatic benefits opens the possibility of combining these two strategies, in case this is needed.
In addition to its symptomatic benefits there has been a suggestion that treatment with rasagiline may also have an effect on the disease course. The recently published results of the extension study in de novo patients revealed that after one year patients who started their treatment with rasagiline earlier seemed to have an advantage over those who started their treatment six months later (ref. 3).
It can not be taken as proven that this difference was due to a disease modfying effect of rasagiline, nevertheless the results suggest that patients who start their treatment earlier maintain a certain advantage.
Taken together the results of these large, randomized, controlled studies in various patient populations representing the clinical spectrum of PD suggest that there will soon be a revival of MAO-B inhibition as a therapeutic strategy in PD.
References
1. Parkinson Study Group. A controlled trial of rasagiline in early Parkinson disease: the TEMPO study. Arch Neurol 2002; 59; 1937-1943
2. Parkinson Study Group. A randomized, placebo controlled trial of rasagiline in levodopa-treated patients with Parkinson disease and motor fluctuations. The PRESTO study. Arch Neurol 2005; 62; 241-248
3. Parkinson Study Group. A controlled, randomized, delayed-start study of rasagiline in early Parkinson disease. Arch Neurol 2004; 61; 561-566