A 52- Week, Open-Label Study to Assess the Long-Term Safety and Tolerability of Ropinirole CR Extended Release Tablets in Patients with Restless Legs Syndrome (RLS)

Introduction

Restless Legs Syndrome (RLS) is a neurological disorder characterized by
an urge to move the legs, often accompanied or caused by uncomfortable
sensations (dysesthesias or paresthesias) in the legs. 1,2 The symptoms
occur primarily at rest in the evening or at night and are at least partially
relieved during movement or activity as long as the movement continues.

Although some patients experience RLS symptoms only at night, many
patients have both late afternoon/early evening and night time symptoms.
An extended release formulation - ropinirole CR - provides treatment
coverage in patients with RLS experiencing longer duration of symptoms.

Since RLS is a chronic and often progressive neurological disorder; long-term
treatment may be required in many patients. This study assesses the
long-term effects of ropinirole CR on safety, tolerability, and efficacy
measures in adults with RLS.

Objectives

Primary: To assess the safety and tolerability of ropinirole CR in the long-term
treatment of subjects with RLS.

Secondary: To assess the efficacy and effect on subject-reported outcomes of ropinirole CR in the long-term treatment of subjects with RLS.

Methods

• SK&F-101468/206 was a multicenter, 52-week. open-label study to assess
  the long-term safety and tolerability of ropinirole CR in subjects with
  moderate to severe primary RLS. The study consisted of 3 phases: a
  minimum 7-day screening/washout phase; a 52-week open-label,
  treatment phase; and a 1-week follow-up phase. The study design is
  illustrated in Figure 1.
  
  Figure 1. Study Design
  
  

• Subjects from parent studies SK&F-101468/205 and ROX104805 were
  eligible for entry into this long-term continuation study Additionally.
  subjects who did not participate in these studies who had primary RLS
  and met all eligibility criteria could also be enrolled. Key inclusion and
  exclusion criteria are presented in Table 1.

Table 1. Key entry criteria

Key inclusion criteria: - Aged ≥ 18 years. - Diagnosed with primary RLS using the international Restless Leg Syndrome Study Group (IRLSSG) diagnostic criteria - RLS symptoms experienced both evening and night - Baseline total score of ≥20 evenings and/or nights in previous month - RLS symptoms on ≥4 of 7 evenings and/or nights immediately prior to baseline Key exclusion criteria : - Secondary RLS - Daytime RLS symptoms requiring treatment - Primary sleep disorder, movement disordersm or medical conditions that can affect RLS or subject safety - History of augmentation or rebound



• Subjects were titrated to an efficacious dose of ropinirole CR based on
  individual efficacy and tolerability. The total daily dose range of ropinirole
  CR was 0.5mg to 6.0mg daily for up to 52 weeks.


• Safety and tolerability endpoints included adverse events (AE), vital signs,
  labs, and assessments of augmentation and early morning rebound (EMR)
  An external international adjudication board reviewed all potential cases of
  augmentation and EMR (identified based on the Structured Interview for the
  Diagnosis of Augmentation during RLS treatment [SIDA-RLS], EMR
  question, or AE reports) in a blinded manner.
  
  
• Efficacy and quality of life endpoints included mean change from baseline in
  the IRLS Rating Scale total score, proportion of responders on the Clinical
  Global Impression Scale-Improvement (CGI-I), mean change from baseline
  in Medical Outcomes Study 12-item (MOS) Sleep Scale calculated score.
  Johns Hopkins RLS Quality of Life Questionnaire summary score, and
  proportion of subjects satisfied with study medication.
  
  
  
• In this single arm, open-label study, no formal statistical hypotheses were
  tested. Data were summarized using descriptive statistics.
  
  
• The Safety Population defined as all subjects who took at least one dose of
  investigational product, was used for all safety analyses.  The ITT
  population, used in the analysis of efficacy data, was defined as all subjects
  who took at least one dose of investigational product, and for whom at least
  one valid post-baseline efficacy assessment was available.

Results

The Safety Population included 386 subjects. 385 subjects were included in
the ITT population Demographics and baseline characteristics are
presented in Table 2. The majority of subjects (78%) in this study were
derived from parent studies SK&F-101468/205 and ROX104805, and 22%
of subjects were non-rollover subjects. This was the first exposure to
ropinirole CR for 195 (51%) subjects; 110 (28%) subjects received placebo
in study SK&F-101468/205 and 85 (22%) subjects were non-rollover
subjects.

Table 2. Demographics and baseline characteristics (Safety population)

The mean (SD) average total daily dose of ropinirole CR was 2.55mg/day
(1.49) and the median average total daily dose was 2.18mg/day. The mean
overall duration of exposure to ropinirole CR in SK&F-101468/206 was 309 days.

Safety

• AEs were reported for 345 (89%) subjects. (Table 3) The most common AE
  was nausea (26%). On-treatment non-fatal serious AEs (SAEs) were
  reported for 19 (5%) subjects. Cellulitis (3 subjects [<1%]) and
  cholethiasis (2 subjects [<1%]) were the only SAEs reported by more than
  one subject. AEs led to withdrawal in 39 (10%) subjects; the most common
  AEs leading to withdrawal were RLS (3%) and nausea (2%). (Table 3)
  
  Table 3. Number of subjects reporting treatment-related AEs (25% of subjects)
  and withdrawals due to these AEs during treatment (Safety population).

Subjects, n (%)1 Ropinirole CR (n=386)
	Reporting AEs	Withdrawls due to AE
Any Event Nausea Somnolence RLS2 Headache Dizziness Fatigue	209 (54) 81 (21) 52 (13) 44 (11) 42 (11) 25 (6) 25 (6)	39 (10) 9 (2) 2 (<1) 11 (3) 2 (<1) 1 (<1) 2 (<1)

 

• Mean changes in vital signs, body weight, laboratory assessments and
  ECGs were generally small.

• All AEs indicative of augmentation or EMR were reviewed by the external
  international adjudication board. The adjudication board confirmed
  augmentation for 35 (9%) subjects and EMR for 6 (2%) subjects.

Efficacy

• At Week 52 last observation carried forward (LOCF) the mean change (SD),
  from baseline in the IRLS Rating Scale was -13.4 (9.48) (Figure 2) and 318
  (83%) of subjects were classified as CGI-I responders.
  
  Figure 2 Mean Change from baseline IRLS Rating Scale (ITT population)*.
  
  

• Marked improvements were evident in sleep parameters on the MOS sleep
  scale with the exception of sleep quantity for which there was little change.
  The majority of subjects (57%) at Week 52 LOCF were ‘very satisfied’ with
  their study medication.  Those responding 'very satisfied' or ‘satisfied’ and
  thus considered as being satisfied with the study medication made up 83%
  (244 out of 294) of subjects at Week 52 LOCF.

• Ropinirole CR was generally well-tolerated over the dose range 0.5-
  6.0mg/day. Ropinirole CR was efficacious in the long-term treatment of
  subjects with primary RLS.

1. Allen R. Picchietti D, Hening W, et al Restless legs syndrome:
   diagnostic criteria, special considerations, and epidemiology.  A report
   from the restless legs syndrome diagnosis and epidemiology & workshop
   at the National Institutes of Health. Steep Med 2003; 4(2): 101-119.
2. Earley CJ. Restless legs syndrome. N Engl J Med 2003;348:2103-2109.

The study was supported by GlaxoSmithKline Research and Development.

Disclosure

Dr. Hill-Zabala and Mr. Lomax are employed by GlaxoSmithKline.
D Lee has received research support from and participated in speaker’s bureaus for GlaxoSmithKline, has consulted and attended speaker’s bureaus for Pfizer, Sepracor, and Sanofi-aventis, and has taken part in speaker’s bureaus for Boehringer-Ingelheim. K Tucci-Herron has participated in research sponsored by GlaxoSmithKline. C Chiang is a salaried employee of GlaxoSmithKline.