Treatment of moderate to severe restless legs syndrome: 2-year safety and efficacy of rotigotine transdermal patch

This multicenter, multinational, single-arm, open-label extension trial (NCT00498186) started in July 2003 in 33 hospital outpatient units, sleep centers, or private neurology practices in three European countries (Austria, Germany, and Spain) and is still ongoing. It is being conducted according to the Declaration of Helsinki, Good Clinical Practice, and local regulations in each country. The trial protocol and amendments were reviewed and approved by a central institutional review board in Germany (Kommission für Ethik in der ärztlichen Forschung im Fachbereich Humanmedizin der Philipps-Universität Marburg) and in Austria (Ethikkommission der Medizinischen Universität Innsbruck). Review and approval was provided by regional institutional review boards in Spain. Written informed consent was obtained from all subjects prior to inclusion in the trial.

The trial design was described in the presentation of the first year trial data [16]. Briefly, following wash-out of the double-blind medication, rotigotine was up-titrated from a starting dose of 0.5 mg/24 h to a maximum dose of 4 mg/24 h according to the individual requirements of the patients with intermediate steps of 1 mg/24 h, 2 mg/24 h, or 3 mg/24 h. The patch was administered once-daily in the morning using rotating application sites within 14 days of treatment. During the trial, patients remained on their optimum dosage; however, dose adjustments were allowed for efficacy or tolerability reasons at the discretion of the investigators. Patients were withdrawn if higher doses than the maximum of 4 mg/24 h rotigotine were required. Visits throughout the maintenance phase were scheduled at 3-monthly intervals during the second trial year. In the event of premature discontinuation, a 1-week taper period and a 2-week surveillance period for safety follow-up was planned.

Safety and tolerability were determined by adverse event (AE) documentation, patch application site assessment, changes in vital signs, body weight, 12-lead electrocardiogram (ECG), and safety laboratory parameters throughout the second trial year. 'Global rating of tolerability by the subject' was assessed using a 5-point scale (1 = 'very good' to 5 = 'very bad'); Clinical Global Impressions (CGI) item 4 'side effects' (1 = none to 4 = outweighs therapeutic effect) [17] and the Epworth Sleepiness Scale (ESS) [18] were also evaluated. In addition, the rate of patients who completed the entire 2 years of long-term treatment (retention rate), as well as the rate and reasons of those patients who prematurely withdrew from the trial, were assessed. Patch adhesiveness was also evaluated using a patient questionnaire.

When the study was commenced, no validated tool for diagnosis and severity assessment for augmentation was available. Augmentation, could, however, be reported as a reason for dose adjustment.

Efficacy was evaluated using the total score of the International RLS Study Group Severity Rating scale (IRLS) [19], the RLS-6 scales to assess severity of RLS symptoms at different time periods, quality of sleep and daytime sleepiness [20], and the CGI to assess severity of symptoms, global change of condition, and therapeutic effect [17]. In addition to the analysis of changes from baseline in these variables, treatment responders were defined by a score improvement of at least 50% for the IRLS total score or CGI-1 at the end of the 2-year maintenance phase compared with baseline; a CGI-2 responder had a rating of 'much' or 'very much improved' at the end of year 2. A remitter was defined by an IRLS score of 10 or less at the end of year 2; the proportion of patients presenting with no symptoms at the end of year 2 (IRLS score = 0) was also calculated (symptom free). 'Global rating of efficacy by the subject' was assessed using a 5-point scale ('very good' to 'very bad') and quality of life (QoL) was evaluated with the total score of the QoL-RLS questionnaire [21].

Patients completing the double-blind phase of the preceding dose-finding trial [13] were offered participation in this open-label extension. They were not permitted to participate if serious adverse events (SAEs) were ongoing that were suspected to be related to the previous trial medication, if severe application site disorders had occurred, or if they had not been compliant during the double-blind trial. A full description of the inclusion and exclusion criteria to enter the preceding trial can be found elsewhere [13].

The present paper reports the 2-year interim data analysis of a 5-year trial. By nature of an interim analysis, some of the end of year 1 data in the present paper may differ slightly from the published year 1 analysis [16].

All patients treated with at least one dose of trial medication were included in the safety analysis; patients analyzed for efficacy had to have at least one efficacy value during the long-term extension trial (intention-to-treat [ITT]). Analyses included changes in variables from baseline to end of year 2 and changes from end of year 1 to end of year 2. If not otherwise stated, the baseline data of the preceding dose-finding trial for all patients entering the open-label trial (n = 295) were used [13]. All variables were analyzed descriptively based on observed cases per visit; the use of the 'Last Observation Carried Forward' (LOCF) approach for some efficacy variables is indicated with the data. With respect to the validity of the efficacy variables, only those measures that were taken within 2 days of the last patch application were used.

The mean duration of rotigotine exposure was 556 ± 256 days (median 700 days). The majority of the patients (94%) were compliant during maintenance (defined as ≥85% and ≤115% application of the planned number of patches). Withdrawal for noncompliance was documented for two patients in year 1 and two patients in year 2.

Individually optimized flexible doses ranged from 0.5 mg/24 h (2.5 cm² patch) to 4 mg/24 h (20 cm² patch). The most frequently applied dose at the end of year 2 was 4 mg/24 h (44.5% of all patients). The number of patients sufficiently treated with a dose of 0.5 or 1 mg/24 h (13.5%) decreased by 1.3% from year 1. The average daily dose during the maintenance phase showed a slight increase from 2.85 ± 1.15 mg/24 h in year 1 to 2.93 ± 1.14 mg/24 h in year 2. Figure 1 shows the mean daily rotigotine dose over 24 months of maintenance. Dose adjustment was not required for 43.8% of patients during the 2-year maintenance; doses were adjusted once in 29% and twice in 16.9% of the patients. The remaining 10.3% needed 3 to 5 dose adjustments during maintenance. Of all patients entering year 2, 88% maintained their dose during year 2.

During the trial, 256 patients (87%) experienced at least one AE. The majority of AEs were mild or moderate in intensity; events were rated as severe in 22% of the patients.

Adverse events were documented for 75.2% of the patient population during the first trial year [16] and for 59.6% during the second year. Table 2 summarizes all incidences reported in more than 3% of all patients over the 2-year period. Application site disorders occurred most frequently; they were considered severe for 8.8% of the patients. More patients were affected by application site reactions during the first trial year (n = 100, 34.5%) whereas 16.4% (n = 36) reported them in the second year (25 patients [8.5%] had application site reactions ongoing from the preceding dose-finding study [13]). Discontinuation owing to any application site disorder was reported for 9.3% of patients (n = 27) in the first and 3.6% (n = 8) in the second trial year. The incidence of somnolence (2 cases), depression (5), syncope (1), insomnia (1), parasomnias (2), diarrhea (2), hypertension (4), and dry mouth (2) was low and sleep attacks, hallucination, dizziness, paraesthesia, and vomiting did not occur during year 2. During the second year, 21 patients (9.5%) experienced a total of 22 SAEs; none were considered to be related to trial medication. With the exception of localized osteoarthritis (4 patients), uterine leiomyoma (3), syncope (2), and goitre (2), all SAEs occurred only in single patients during the 2-year treatment period (for complete list of SAEs see Additional file 1). No deaths were reported in the 2-year study period.

There were no major changes from double-blind baseline in any of the laboratory parameters including total iron and ferritin levels. There were no patients with any post-baseline QTc ≥500 ms or post-baseline increase in QTc ≥60 ms in the ECG during the trial period.

The 'daytime tiredness' score (RLS-6 scales) improved from a double-blind baseline score of 4.8 ± 2.6 by -2.6 ± 3.1 in the first year and by -2.2 ± 3.0 in the second year resulting in a total score of 2.5 ± 2.4 after 2 years of rotigotine treatment (Table 3; negative changes in the table refer to improvements). The total ESS score improved from 6.7 ± 5.2 at double-blind baseline by -0.6 ± 4.6 after 2 years (Table 3).

Based on CGI tolerability rating, a total of 70% of the 220 patients completing year 1 and 71% of the 191 patients completing the second trial year were not impaired by side effects at all; 28.1% of the year 1 completers and 28.3% of the year 2 completers reported that side effects did not significantly interfere with their daily activities. At the end of the 2-year period, a 'significant interference' and 'side effects outweighing efficacy' were reported in 13% and 6.8%, respectively, of all patients who had entered the trial.

Rotigotine tolerability after 2 years of treatment was rated as 'very good' or 'good' by 77% of all patients (n = 295). Seventeen patients (5.8%) described tolerability as 'very bad'.

Patch adhesiveness and ease of removal were considered moderate (15%/4.5%), good (50%/58%), or excellent (31%/34%) by most patients treated in year 2 (n = 220).

Rotigotine transdermal patch rapidly improved the IRLS severity rating; the baseline sum score of 27.8 ± 5.9 was reduced by 18.8 ± 8.6 during the 4-week titration phase of the open-label trial (Figure 2). This result is comparable to the data recorded during rotigotine titration in the preceding double-blind, placebo-controlled trial [13]. Figure 3 shows the changes in IRLS severity over 2 years of rotigotine treatment. At month 12 and month 24, mean IRLS sum scores of 8.7 ± 8.0 and 10.3 ± 9.3, respectively, were calculated. Mean reduction after 2 years of rotigotine maintenance treatment was 15.4 ± 10.3 for all patients entering this extension trial (n = 295, LOCF) and 17.2 ± 9.2 for all patients completing the 2-year period (n = 190). CGI-1 and RLS-6 daytime at rest scores closely follow this pattern (Figure 2). All other efficacy variables also improved over the 2-year period (Table 3) and remained stable during the second year when compared with the year 1 results [16]. Responder rates indicate that the majority of patients benefited from rotigotine treatment (Table 4). Overall, 30% of all patients who completed the 2-year treatment were free of symptoms according to IRLS (total score = 0) and 30% were free of symptoms according to CGI-1 (not ill at all). Therapeutic efficacy of rotigotine was rated as 'good' to 'very good' in 95% (n = 209) of year 1 completers and 89% (n = 170) of year 2 completers.