Ropinirole Improves Symptoms in Patients with Moderate-to-Severe Primary Restless Legs Syndrome (RLS) Experiencing Reduced Daytime Alertness

Daniel Lee MD,1 Philip M Becker MD,2 Carolyn B Watson PhD3

1Sleep Disorder Center, East Carolina Neurology, Inc., Greenville, NC, USA; 2Sleep Medicine Associates of Texas, Dallas, TX, USA; 3GlaxoSmithKline, Research Triangle Park, NC, US

Introduction

Restless Legs Syndrome (RLS) is characterized by an urge to move the legs, usually accompanied by uncomfortable sensations in the legs. These symptoms begin or worsen during periods of rest or inactivity and are partially or totally relieved by movement.1 Symptoms begin or worsen in the evening or at night and can be associated with difficulty falling asleep and sleep disruption, often resulting in impaired daytime functioning.1,2 Ropinirole, a non-ergot dopamine agonist, is the only treatment approved by the FDA for moderate-to-severe primary RLS. In three pivotal, placebo-controlled clinical trials, the efficacy of ropinirole was assessed in patients with moderate-to-severe primary RLS, and effects on patients’ sleep disruption were measured using the Medical Outcomes Study (MOS) Sleep Scale.3-5 Additionally, the effects of ropinirole for patients reporting abnormal daytime alertness on the MOS Sleep Scale at baseline are described.

Patients and Methods

• Data were pooled from three similarly designed, 12-week, Phase III, double-blind, placebo-controlled studies: TREAT RLS 1, TREAT RLS 2, and TREAT RLS US (protocols 101468/190, 194, and 249, respectively).3-5
• Patients with moderate-to-severe primary RLS were randomized to receive placebo or ropinirole, 0.25-4.0 mg/day, titrated as needed and tolerated and taken once daily 1-3 hours before bedtime.
• The key inclusion criteria were as follows:
• age >18 years and <80 years
• diagnosed with primary restless legs syndrome using the International Restless Legs Syndrome Study Group (IRLSSG) diagnostic criteria
• baseline total score of > 15 on the IRLSSG rating scale, the International Restless Legs Scale (IRLS)
• at least 15 nights of RLS symptoms during the previous month

• Patients were excluded if they:

• showed signs of secondary RLS (e.g. renal failure or iron deficiency)
• experienced augmentation or rebound with previous treatment
• had daytime RLS symptoms that required treatment
• had primary sleep disorders, movement disorders, or medical conditions that could affect the assessment of RLS
• were taking medications known to affect RLS or sleep or withdrawal/introduction/dose change of medications known to inhibit or induce P450 CYP1A2.

• Efficacy was assessed using the mean change in total score from baseline to Week 12 on the validated IRLS (primary endpoint).6

• Efficacy was also assessed using the proportion of responders on the Clinical Global Impression – Improvement (CGI-I) scale; responders were defined as those rated by the investigator as ‘very much improved’ (1) or ‘much improved’ (2) on the 7-point scale (key secondary endpoint).

• The effects of ropinirole on sleep disturbance were assessed using the validated MOS Sleep Scale (Table 7),7 which measures specific aspects of sleep in patients with comorbidities during the previous 4 weeks. The answers [recorded on a 6-point scale ranging from 1 (all of the time) to 6 (none of the time)] given by patients on this 12-item scale were used to calculate scores for four domains:

• sleep disturbance
• sleep quantity
• sleep adequacy
• daytime somnolence

• Patients with abnormal daytime alertness were defined by their responses to selected questions of the MOS Sleep Scale (Table 1), as follows:

• ‘a little (5)/none of the time(6)’ on Question 4,
• ‘all (1)/ most of the time (2)’ on Question 6, or
• ‘all (1)/most of the time (2)’ on Question 9.

• Treatment response analyses post hoc, as measured by IRLS total score and CGI-I, were performed for patients with abnormal daytime alertness.

• A total of 931 patients were included in the safety population (ropinirole=464; placebo=467) and 930 patients in the intention-to-treat (ITT) population (ropinirole=464; placebo=466).
• About half of these patients reported some type of abnormal daytime alertness (as defined above) on the MOS Sleep Scale:

• 441 (47.4%, 218 randomized to ropinirole and 223 to placebo) reported not feeling rested on waking (Question 4)
• 239 (25.7%, 134 randomized to ropinirole and 105 to placebo) reported feeling drowsy or sleepy during the day (Question6)
• 88 (9.5%, 43 randomized to ropinirole and 45 to placebo) reported having trouble staying awake during the day (Question 9)

• Demographic and disease characteristics at baseline were generally similar in the whole patient group and these subgroups (Table 2).
• There were more women than men in each subgroup except for the patients with an abnormal response on MOS Sleep Scale Question 9 at baseline in the ropinirole group, in which there were marginally more men than women (Table 2).
• The mean (SD) doses at last visit for patients in the ropinirole group with abnormal responses on MOS Sleep Scale Questions 4, 6, and 9 were 2.0 (1.2), 2.0 (1.1), and1.9 (1.1) mg/day, respectively, and for the placebo group were 2.8 (1.3), 2.7 (1.3), and 2.9 (1.3) mg/day, respectively. For all subgroups, the median (range) doses at the last visit were 2.0 (0.25-4.0) mg/day in the ropinirole group and 3.0 (0.25-4.0) mg/day in the placebo group.
• For comparison, the mean (SD) and median (range) doses at the last visit for the overall population were: 2.0 (1.2) mg/day and 2.0 (0.25-4.0) mg/day, respectively, in the ropinirole group and 2.9 (1.3) mg/day and 3.0 (0.25-4.0) mg/day, respectively, in the placebo group.

Figure 1. Adjusted mean (2SE) change from baseline to Wek 12 last observation in the International Restless Legs Scale (RLS) total score for all patients and those showing abnormal daytime alertness at baseline, as assessed using the Medical Outcomes Study (MOS) Sleep Scale Questions 4, 6, and 9.

Figure 2. The percentage of patients classified as responders on the Clinical Global Impression - Improvement scale at Week 12 last observation carried forward for all patients and those showing abnormal daytime alertness at baseline, as assessed using the Medical Outcomes Study (MOS) Sleep Scale Questions 4, 6, and 9.

Efficacy of ropinirole

• As shown in Figure 1, at Week 12 last observation carried forward (LOCF), there was a significantly greater improvement (reduction) from baseline in IRLS total score in the ropinirole group compared with the placebo group for the entire population [adjusted mean treatment difference (AMTD): -3.2; 95% Cl: -4.3, -2.1; p<0.001].
• Ropinirole produced statistically significantly greater improvements compared with placebo in the IRLS total score at Week 12 LOCF in all three groups of patients with reduced daytime alertness (Figure 1):

• patients with abnormal baseline responses to MOS Sleep Scale Question 4 (AMTD: -4.5; 95% Cl: -6.2’ –2.7; p<0.001).
• patients with abnormal baseline responses to MOS Sleep Scale Question 6 (AMTD: -3.6; 95% Cl: -6.3, -1.0; p=0.007).
• patients with abnormal baseline responses to MOS Sleep Scale Question 9 (AMTD: -5.1; 95% Cl: -9.5, -0.8; p=0.021)

• A statistically significantly greater proportion of patients receiving ropinirole versus placebo (63% versus 47%) were classified as responders on the CGI-I scale at Week 12 LOCF [adjusted odds ratio (AOR): 2.0; 95% Cl: 1.5,2.6; p<0.001; Figure 2].
• Significantly more patients receiving ropinirole who had abnormal baseline responses to the MOS Sleep Scale Question 4 at baseline were classified as responders on the CGI-I scale than those in the placebo group (AOR: 2.1; 95% Cl: 1.5, 2.6; p<0.001; Figure 2).
• For those patients who had abnormal baseline responses to MOS Sleep Scale Questions 6 and 9, a larger proportion of ropinirole-treated patients, compared with placebo-treated patients, were classified as responders on the CGI-I scale, but the differences were not statistically significant [AOR: 1.6; 95% Cl: 1, 2.8; p=0.067 (ropinirole); AOR: 1.1; 95% Cl: 0.5, 2.6; p=0.789 (placebo); Figure 2].
• For the overall population (TREAT RLS 1, 2, and US data pooled), the change from baseline in MOS Sleep Scale score to Week 12 LOCF was significantly in favor of ropinirole (p<0.001) for all four domains (sleep disturbance, sleep quantity, sleep adequacy, and daytime somnolence).

• Ropinirole was generally well tolerated.
• In the whole patient group, the most common adverse events in the ropinirole group were:

• nausea (ropinirole 40%, placebo 7%)
• headache (ropinirole 19%, placebo 20%)
• somnolence (ropinirole 12%, placebo 6%)

• The numbers of patients who withdrew from the study due to adverse events were:

• nausea [ropinirole 8/464 (2%), placebo 1/467 (<1%)]
• headache [ropinirole 3/464 (<1%), placebo 1/467 (<1%)]
• somnolence [ropinirole 2/464 (<1%), placebo 0/467 (0%)]

• A total of 57 patients [31 (7%) in the ropinirole group and 26 (6%) in the placebo group] withdrew because of adverse events.

• Ropinirole was effective in improving the symptoms of moderate-to-severe primary RLS.
• Patients with impaired daytime alertness, as assessed using a subset of items from the MOS Sleep Scale, also benefited from ropinirole treatment, with symptom improvement demonstrated on the IRLS.
• Based on these results, ropinirole provides an effective and generally well-tolerated treatment for RLS patients, including those patients who present with abnormal daytime alertness, presumably due to their RLS symptoms.

1. Allen R, et al. Sleep Med 2003;4:101-19.
2. Hening W, et al. Sleep Med 2004;5:237-46.
3. Trenkwalder C, et al. J Neurol Neurosurg Psychiatry 2004;75:92-7
4. Walters A, et al. Mov Disord 2004;19:1414-23.
5. Bogan R, et al. Mayo Clin Proc 2006;81:17-27.
6. Walters A, et al. Sleep Med 2003;4:121-32.
7. Hays R & Stewart A. Sleep Measures. In: Stewart AL & Ware JE Jr, Eds. Durham and London: Duke University Press, 1992: pp. 235-59.

Acknowledgements and disclosures

This study was supported by GlaxoSmithKline Research and Development. Within the past year, Dr. Lee has received personal compensation (expense reimbursement) from GlaxoSmithKline for presenting current unbiased data on RLS. He has also received personal compensation from Sepracor for a speaking engagement on insomnia, and from Biogen for speaking to a multiple sclerosis support group. He has received financial support for research activities from Pfizer, GlaxoSmithKline and Janssen. Dr. Becker has received personal compensation from GlaxoSmithKline, Boehringer Ingelheim, Sanofi-Aventis, and Sepracor for consultation, scientific advisory work, and speaking engagements. Personal compensation was also received from Orphan Medical and Takeda for speaking engagements. He has also received research support for participation in multisite trials from GlaxoSmithKline, Boehringer Ingelheim, Schwarz Pharma, Kyowa and Takeda. Dr. Watson is an employee of GlaxoSmithKline.