RCT for Pregabalin in Restless Legs Syndrome in South Korea

A Randomized, Double-blind, Placebo-controlled Multicenter Study to Assess Efficacy and Safety of Pregabalin in Willis-Ekbom Disease/Restless Legs Syndrome

This randomized, double-blind, placebo-controlled, multicenter clinical trial is designed to to assess the treatment efficacy and tolerability of pregabalin in patients with idiopathic restless legs syndrome in South Korea.

Objectives: To assess the treatment efficacy and tolerability of pregabalin in patients with idiopathic restless legs syndrome (RLS) in South Korea. Study Design: A randomized, double-blind, placebo-controlled, multicenter clinical trial Study period: total 14 weeks: 2 weeks for placebo run in period and 12 weeks treatment after randomization (titration for 4 weeks and maintenance for 8 weeks). Subjects: a total number of 100 participants (randomly assigned 1:1 to pregabalin or placebo). The sample number was calculated based on a superiority design, 1-sided, alpha 0.05 with power 80% and drop rate 10%. Inclusion criteria: adults aged between 19-80 and diagnosed with idiopathic RLS with IRLS score of 15 or more. Exclusion criteria: Secondary RLS; serum ferritin < 10 μg/L or history of oral iron therapy within 3 months or intravenous iron therapy within 1 year; severe comorbid medical or psychiatric disorders; history of pregabalin or gabapentin treatment within 3 months; other comorbid sleep disorders or shift workers. Treatment schedule and dose - Placebo responders, who showed a decrease of IRLS score of 40% or more, are excluded before randomization. Subjects will randomly assigned to receive either pregabalin or placebo with a 1:1 allocation. A starting dose is 75 mg/day for 2 weeks (taken 1-2 hours before habitual bedtime). At the visit of 2 weeks and 4 weeks, a dose can be titrated by 75-150 mg according to the response and tolerability. A dose ranging 75-300 mg per day will be maintained for 8 weeks. Primary outcome: changes in IRLS score after 12-week treatment. Secondary outcomes: remission rate (decrease in IRLS score of 50% or more), CGI (clinical global impression)-improvement, changes in 10-cm visual analog scale (VAS), RLS-6, PSQI (pittsburgh sleep quality index), ISI (insomnia severity index), Johns Hopkins RLS QoL after 12-week treatment. Statistical analysis: ANCOVA for changes in IRLS score with a baseline IRLS score as a covariate. Tolerability: Safety profiles and Liverpool Adverse Event Profile (LAEP) will be assessed.

A randomized, double-blind, placebo-controlled, multicenter clinical trial. Study subjects will be recruited from 4 medical centers in South Korea.

Changes in International restless legs scale (IRLS) score after 12-week treatment. IRLS is used to assess the severity of patient's RLS symptoms. A total score ranges from 0 to 40 and higher scores mean more severe symptoms. Therefore, greater differences in IRLS scores between baseline and post-treatment mean a better outcome.

A proportion of patients who showed a decrease in IRLS score of 50% or more after treatment. Higher scores mean a better outcome.

The amount of RLS symptom improvement measured by physicians. CGI-improvement is a 7-point scale and rated as 1 (Very much improved), 2 (Much improved), 3 (Minimally improved), 4 (No change), 5 (Minimally worse), 6 (Much worse), and 7 (Very much worse).

Changes in 10-cm VAS after 12-week treatment. A VAS score ranges from 0 (no symptoms) to 10 (very severe symptoms).

Changes in RLS-6 scores after 12-week treatment. A RLS-6 consists of 6 questions for RLS symptoms and a total score ranges from 0 (no symptoms) to 60 (very severe symptoms).

Changes in PSQI scores after 12-week treatment. A total PSQI score ranges from 0 to 21, and higher scores indicate worse sleep quality.

Changes in ISI scores after 12-week treatment. A total ISI score range from 0 to 28 and categories: 0-7 (No clinically significant insomnia), 8-14 (Subthreshold insomnia), 15-21 (Moderate insomnia), and 22-28 (Severe insomnia)

Changes in Johns Hopkins Restless legs syndrome quality of life scores after 12-week treatment. A total score ranges from 0 to 100 and lower scores indicate worse quality of life.

Inclusion Criteria: IRLS (international restless legs scale) score ≥ 15 RLS symptom occurring ≥ 3 times/week and persisting over ≥ 6 months Drug-naive patients or those who stop taking RLS drugs for ≥ 1 week before screening Exclusion Criteria: Secondary RLS (including iron deficiency anemia, pregnancy, chronic kidney disease [eGFR < 60 mL/min/1.73 m2], peripheral neuropathy, others) Serum Ferritin < 10 μg/L or history of oral iron therapy within 3 months or intravenous iron therapy within 1 year Severe comorbid medical or psychiatric disorders history of pregabalin or gabapentin treatment within 3 months High risk of obstructive sleep apnea by STOP-BANG questionnaire Other comorbid sleep disorders or shift workers Hypersensitivity to pregabalin Galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption