Abstract & Commentary
Commentary by Cliffe Henchcliffe
Synopsis: Once-daily rasagiline reduces mean daily off-time and improves symptoms of Parkinson’s disease in levodopa-treated patients with motor fluctuations, an effect similar to that of entacapone.
Source: Rascol O. et al. Rasagiline as an Adjunct to Levodopa in Patients With Parkinson’s Disease and Motor Fluctuations: The LARGO Study. Lancet. 2005;365:947-954.
The Lasting effect in Adjunct therapy with Rasagiline Given Once daily (LARGO) study is a randomized, double-blind, placebo-controlled trial of rasagiline as adjunct therapy in patients with advanced Parkinson’s disease (PD), with a parallel group taking entacapone. Advanced disease was defined by at least 1 hour per day off-time during waking hours, despite optimal treatment with levodopa, with or without dopamine agonists. Cognitive impairment and use of antidepressants were among exclusion criteria. In 74 centers in Israel, Argentina, and Europe, 687 subjects entered a 2- 4 week levodopa optimization run-in phase, and were randomized to adjunct treatment for 18 weeks with rasagiline (1 mg once daily), entacapone (200 mg with every levodopa dose), or placebo. In the rasagiline group, baseline mean age was 63.9 years old, with mean disease duration 8.7 years and mean off-time 5.6 hours per day, closely matching subjects in the other 2 arms. Change in mean total daily off-time, measured by patient diaries, was the primary end point. At 18 weeks, off-time was significantly decreased in the rasagiline (-1.18 hours, P =0.0001) and entacapone (-1.2 hours, P <0.0001) groups, compared to placebo (-0.4 hours). On-time without troublesome dyskinesia increased in rasagiline (0.85 hours, P = 0.0005 hours) and entacapone (0.85 hours, P = 0.0005) over placebo (0.03 hours). Increased on-time with troublesome dyskinesia with rasagiline (0.23 hours, P = 0.6209) or entacapone (0.18 hours, P =0.8157) was not statistically significant compared to placebo (0.14 hours). Clinical global improvement, a secondary end point on a scale ranging from -3 to +3, was better for rasagiline (-0.86, P <0.0001) and entacapone (-0.72, P =0.0003) versus placebo (-0.37). Fifty percent of patients reported adverse effects, including postural hypotension (2% taking rasagiline), nausea (3%), dyskinesias (5%), hallucinations (2%), but there was no significant difference between any group regarding type and rate of adverse reactions.
Commentary
The majority of patients taking levodopa for PD develop motor fluctuations as disease progresses, with their day divided into "on" periods when levodopa is effective, and "off" periods when the drug’s effects wane. Rasagiline, like selegiline, is a selective, irreversible MAO-B inhibitor with convincing efficacy and safety data in early PD.1 Now LARGO, hot on the heels of the PRESTO study2, convincingly demonstrates that rasagiline leads to significant decrease in off-time in advanced PD. Although not designed as a head-to-head study, rasagiline provides a reduction in off-time comparable to that of entacapone, currently approved in the United States to treat motor fluctuations. It is intriguing that in a post hoc subscale analysis, freezing of gait improved with rasagiline, but not entacapone: this should encourage more careful study. One concern is whether rasagiline increases dyskinesias, although at first glance this does not appear to be the case, LARGO was not powered to address this specific point. Nor does it address concern over potential interaction of monoamine oxidase inhibitors with serotonin reuptake inhibitors, taken by many with PD for depression. (although the TEMPO study allowed use of fluvoxamine and paroxetine, with no reported interaction). Rasagiline will be a welcome addition to treatment options in these clinically challenging patients.
References
1. Parkinson Study Group. A Controlled, Randomized, Delayed-Start Study of Rasagiline in Early Parkinson’s Disease. Arch Neurol. 2004;61:561-566.
2. Parkinson Study Group. A Randomized, Placebo-Controlled Trial of Rasagiline in Levodopa-Treated Patients With Parkinson’s Disease and Motor Fluctuations: The PRESTO Study. Arch Neurol. 2005;62: 241-248.
Once-daily rasagiline reduces mean daily off-time and improves symptoms of Parkinsons disease in levodopa-treated patients with motor fluctuations, an effect similar to that of entacapone.
You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
- Award-winning Medical Content
- Latest Advances & Development in Medicine
- Unbiased Content