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.

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