Ferini_EU Neurology 09/03/2010 11:51 Page 86
Restless Legs Syndrome
week duration), one placebo-controlled six-week dose-finding study, maintenance phase, which indicated freedom from disease symptoms,
one placebo-controlled six-month study and a one-year open-label was recorded for 79 of 333 patients (24%) in the rotigotine groups (21
study (see Table 1). Currently, most of the available publications on of 112 [19%] in the 1mg group, 23 of 109 [21%] in the 2mg group and
rotigotine concern the clinical effects in PD.
27
35 of 112 [31%] in the 3mg group), compared with 14 of 114 patients
(12%) in the placebo group.
Stiasny-Kolster et al. performed the first trial by using three fixed doses
(0.5, 1 and 2mg/24 hours) of rotigotine in 63 patients with idiopathic RLS Another six-month double-blind trial has been performed in the US
who had discontinued other RLS medication four weeks before and published in abstract form.
58
Five hundred and five patients with
enrolment.
54
The authors reported that after one week of therapy, as moderate to severe RLS were randomised to fixed dosages of 0.5, 1,
measured using the International Restless Legs Syndrome Scale (IRLS), 2 or 3mg/24 hours rotigotine transdermal patch or placebo. After
there was a significant dose-related improvement in restless leg uptitration to the randomised dosage, allowing for one backtitration in
symptoms from baseline scores (baseline range: 25.0±5.0–26.6±5.0). case of intolerable side effects, patients were maintained on a stable
For the 0.5, 1 and 2mg/24 hours doses, improvements in IRLS were rotigotine dosage for six months. Efficacy analysis showed significant
-10.5 (0.5mg/24 hours; p=0.41), -12.3 (1mg/24 hours; p=0.18) and -15.7 improvement on IRLS sum scores as well as CGI item 1 (severity of
points (2mg/24 hours; p<0.01) compared with 8 points for placebo. symptoms) for rotigotine doses of 2–3mg/24 hours. At baseline, the
IRLS score was 23.3±5.0 and CGI Item 1 was 4.7±0.7. After six months
A few years later, Oertel et al., in a multicentre, double-blind, of 0.5, 1, 2 and 3mg/24 hours rotigotine or placebo treatment,
placebo-controlled dose-finding study with dosages of rotigotine respective net improvements in IRLS compared with placebo were
ranging from 0.5 to 4mg/24 hours, confirmed a dose-dependent -2.2±1.2, -2.3±1.2, -4.5±1.2 (p<0.001) and -5.2±1.2 (p<0.001), and
effectiveness in idiopathic RLS patients.
55
The authors randomly net improvements for CGI Item 1 compared with placebo were
assigned 341 patients to one of five fixed dosages of rotigotine (0.5, -0.35±0.19, -0.32±0.19, -0.65±0.19 (p<0.001) and -0.90±0.19 (p<0.001).
1, 2, 3 or 4mg/24 hours) or to placebo for six weeks. The chosen
outcome measures were the total score of the IRLS, the RLS-6 scale, Apart from the clinical efficacy findings mentioned above, a sleep
the CGI, the Epworth Sleepiness Scale (ESS) and the Quality of Life laboratory study evaluated PLM index (PLMI) and the PLMI associated to
questionnaire for RLS (RLS-QoL). At baseline the IRLS score in the six arousals (PLMSAI).
59
This trial, which randomised a total of 67 patients, in
treatment groups ranged from 27.4±6.1 to 28.2±6.6. The comparison with the previous fixed dosage studies, included titration to
improvement in the IRLS score was related to the dosage of an optimal rotigotine dose of between 1 and 3mg/24 hours, followed by
rotigotine, with the following values: -10.6 (0.5mg/24 hours), -15.1 a four-week maintenance period. Polysomnography was performed at
(1mg/24 hours), -15.7 (2mg/24 hours), -17.5 (3mg/24 hours) and baseline and at the end of the maintenance period, with a significant
-14.8 (4mg/24 hours) compared with placebo (-9.2). Rotigotine was drop in PLMI score in the rotigotine recipients. The PLMSAI score also
significantly superior to placebo for all dosages except for 0.5mg/24 improved to a greater extent in the rotigotine group than in the placebo
hours. Similar results were obtained by the CGI. Since the efficacy of group. At the end of maintenance treatment, the PLMI had decreased
the lowest dose of 0.5mg/24 hours was not proved, and the highest from 50.9 at baseline to 8.1 for rotigotine versus 37.4 to 27.1 for placebo.
dose (4mg/24 hours) lacked additional benefit, the authors identifed The IRLS score in the rotigotine group was reduced from 26.3±6.4 to
the therapeutic range for a maintenance dose of rotigotine to be 9.7±9.1 and in the placebo group from 25.4±6.3 to 15.1±8.3 (p<0.02).
1–3mg/24 hours. The same authors prospectively tested the long- Twenty-six per cent of rotigotine-treated subjects had an IRLS score of 0
term efficacy and safety of rotigotine (0.5–4mg/24 hours) in a five- (no RLS symptoms).
year open extension of the six-week trial. In a one-year interim
analysis, the results from 295 of the original 341 patients with Concerning safety and tolerability, all studies showed that rotigotine
idiopathic RLS were reported. After one year of treatment, 220 transdermal patch was generally well tolerated by patients with
patients remained in the follow-up study, with a retention rate of moderate to severe RLS.
54–57
Most adverse events were of mild to
74.6%.
57
The mean daily dose of 2.8±1.2mg/24 hours improved the moderate severity, including the symptoms usually associated with
IRLS score by 17.4±9.9 points from a mean baseline score of 27.8±5.9 dopaminergic side effects such as nausea, fatigue, insomnia, dry
points. The most frequently applied dose was 4mg/24 hours, in 40.6% mouth, dizziness and vertigo. Across all trials, the most common drug-
of patients. The rotigotine patch was well tolerated by the majority of related adverse event was skin irritation at the application site. This
patients. The long-term efficacy of rotigotine was also confirmed in adverse event was reported in 43% of patients in the six-month
terms of quality of life and sleep satisfaction. European trial,
57
in 40% in the one-year open-label extension study
56
and in 54% in a three-year open-label extension study.
60
Discontinuation
Of the four trials listed in Table 1, the multicentre randomised, double- of treatment due to skin irritation was reported in approximately 13% of
blind, placebo-controlled trial by Trenkwalder et al. included the most patients in the one-year extension study.
56
The use of dopamine
patients.
57
A total of 458 patients with moderate to severe idiopathic RLS agonists in PD may sometimes be restricted by the appearance of
were randomised to receive 1, 2 or 3mg/24 hours of rotigotine or psychiatric side effects such as hallucinations, delusions or impulse
placebo for six months. At baseline, the mean IRLS score was 28.1. The control disorders;
61,62
however, information on these side effects was
mean improvement in this score from baseline at the end of the study not included in these publications.
was significant in a dose-dependent fashion: -13.7 in the 1mg group,
-16.2 in the 2mg group, -16.8 in the 3mg group and -8.6 in the placebo Recently, a specific scale for measuring the phenomenon of
group. Similar dose-related improvements were obtained by using CGI augmentation (Augmentation Severity Rating Scale [ASRS]) has been
(CGI-item 1 [severity of symptoms]: -2.09 in the 1mg group, -2.41 in the developed.
25
In the six-month European study, the ASRS scores remained
2mg group, -2.55 in the 3mg group and -1.34 in the placebo group) and low throughout the trial, with small fluctuations.
57
Retrospective re-
the quality of life questionnaire. An IRLS sum score of 0 at the end of the analysis of IRLS and ASRS data by augmentation experts showed rates of
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