Study of SPM 962 in Patients With Restless Legs Syndrome (RLS)

Study Overview
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Brief Summary
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The objective of this study is to evaluate the clinical efficacy and safety of SPM962 in patients with restless legs syndrome (RLS) with once-daily repeated doses of 4.5mg and 6.75mg during a 13-week dose-titration and maintenance period. This is a multi-center, randomized, placebo-controlled, double-blind, 3-armed parallel group comparison study. Efficacy will be determined by investigating the superiority of SPM962 to placebo in terms of the primary efficacy variable, change in International Restless Legs Syndrome Rating Scale (IRLS) total score from baseline to the end of the dose-maintenance period.

Official Title
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A Phase 3 Multi-Center, Placebo-Controlled, Double Blind, 3-Armed Parallel Group, Comparative Study of SPM 962 4.5 and 6.75 mg/Day to Investigate Superiority to Placebo in Patients With Restless Legs Syndrome

Conditions
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Idiopathic Restless Legs Syndrome

Intervention / Treatment
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* Drug: SPM 962
* Drug: SPM 962
* Drug: Placebo of SPM 962


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients whose condition has been diagnosed as RLS by meeting all 4 of the International Restless legs Syndrome Study Group/ National Institute of Health (IRLSSG/NIH) criteria Patients who meet any of the following criteria relating to RLS treatment: Patients who have never received treatment for RLS Patients who have received treatment for RLS in the past and responded to L-dopa or dopamine agonists (Response to other RLS medicines is irrelevant.) Patients who have an IRLS total score of >=15 at baseline Patients who experience symptoms in the evening or during the night on at least two days a week within 14 days prior to commencement of study treatment Patients and their partners can practice contraception at the end of follow-up observation period or by 1 week after the end of treatment Exclusion Criteria: Patients who have previously participated in a clinical trial of SPM962 and taken the investigational product (IP) Patients with secondary RLS induced by renal impairment (uremia), iron deficiency anemia, drugs, pregnancy, etc. Patients who currently suffer, are at risk of developing, or have a history of sleep disorder such as sleep apnea syndrome, narcolepsy, and sleep attacks/sudden onset of sleep Patients who have concomitant diseases or symptoms which may affect the symptoms of RLS, such as polyneuropathy (including diabetic neuropathy), akathisia, claudication, varicoses, muscle fasciculation, painful legs and moving toes syndrome, radiculopathy and folate deficiency Patients who have other CNS diseases such as Parkinson's disease, dementia, progressive supranuclear paresis, multisystem atrophy, Huntington's Chorea, amyotrophic lateral sclerosis, and Alzheimer's disease Patients who have psychiatric conditions such as confusion, hallucination, delusion, and excitation, or patients who have abnormal behavior such as delirium, obsessive compulsive disorder, and impulse control disorder at the time of the screening test or baseline examination Patients whose SBP declines by at least 30 mmHg from supine to standing position based on the orthostatic hypotension assessment, or patients who develop orthostatic hypotension at baseline Patients who have a history of epilepsy, convulsion, etc Patients who have complications or a history of serious cardiac diseases or arrhythmia (eg, congestive heart failure of class 3 or 4 in the NYHA classification, second or third degree atrioventricular block, complete left bundle branch block, sick sinus syndrome, ventricular fibrillation, myocardial infarction within 12 months prior to the screening test, or a complication of angina pectoris) Patients with arrhythmia who have been taking Class 1a antiarrhythmic drugs (eg., quinidine, procainamide) or Class 3 antiarrhythmic drugs (eg., amiodarone, sotalol) Patients who have a serious ECG abnormality at the screening test and at the baseline examination Patients who show QTc intervals exceeding 450 ms in both ECGs in the screening test Patients who have an average QTc interval from the two ECGs in the baseline assessment that exceeds 470 ms (for females) or 450 ms (for males) Patients with congenital long QT syndrome Patients whose serum potassium level is < 3.5mEq/L at the screening test Patients whose total bilirubin is >= 3.0mg/dL, or whose AST(GOT) and ALT(GPT) are equal or more than 2.5 times the reference range of the clinical site (or >= 100IU/L) at the screening test Patients whose BUN level is >= 30mg/dL, or whose serum creatinine level is >= 2.0mg/dL at the screening test Patients who have a history of allergy to topical agents such as transdermal patch Patients who are pregnant or nursing or who wish to become pregnant during the study period Patients who habitually drink alcohol or smoke excessively Patients who engage in evening shift work or other such shift work, or whose work or circumstances makes it difficult to maintain a regular period of sleep Patients who engage in hazardous work such as driving a vehicle, operating machinery, or working in a high location. Patients with autoimmune disease, chronic active hepatitis, or immune deficiency disorder Patients who have a complication or history of malignant neoplastic disease, or received treatment for the disease within 12 months prior to the screening test Patients who are unable to properly record information in a patient diary Patients who received other IPs within 12 weeks prior to commencement of study treatment Patients who have been judged by the investigator or the sub-investigator to be inappropriate for inclusion in the study for any other reasons

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 79 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SPM 962 4.5<br>started at 2.25 mg/day to 4.5 mg/day for 13 weeks | Drug: SPM 962<br>* once a daily transdermal administration started at 2.25 mg/day to 4.5 mg/day for 13 weeks<br>|
| Experimental: SPM 962 6.75<br>started at 2.25 mg/day to 6.75 mg/day for 13 weeks | Drug: SPM 962<br>* once a daily transdermal administration started at 2.25 mg/day to 6.75 mg/day for 13 weeks<br>|
| Placebo Comparator: placebo<br>for 13 weeks | Drug: Placebo of SPM 962<br>* once a daily transdermal administration for 13 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| International Restless Legs Syndrome Rating Scale (IRLS) Total Score | Change from the baseline to the end of dose-titration/dose-maintenance period. IRLS is a scale for assessing severity of restless legs syndrome symptoms. IRLS consists of ten questions. Each question is scored from 4 for the first (top) answer (usually 'very severe') to 0 for the last answer (usually none). The sum of the score of each question serves as the scale score. The scale scoring criteria are: Mild (score 1-10); Moderate (score 11-20); Severe (score 21-30); Very severe (score 31-40). A decrease in the scores means improvement. | Baseline, the end of dose-titration/dose-maintenance period (week 13) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Global Impression (CGI) Improvement | CGI improvement is a clinician-reported scale for assessing how much the patient's illness has improved or worsened from baseline. The scale scoring criteria are 1: very much improved, 2: much improved, 3: minimally improved, 4: no change, 5: minimally worse, 6: much worse, 7: very much worse. | Baseline, the end of dose-titration/dose-maintenance period (week 13) | 
| Patient Global Impression (PGI) Improvement | PGI improvement is a patient-reported scale for assessing how much the patient's illness has improved or worsened from baseline. The scale scoring criteria are 1: very much better, 2: much better, 3: a little better, 4: no change, 5: a little worse, 6: much worse, 7: very much worse. | Baseline, the end of dose-titration/dose-maintenance period (week 13) | 
| The Pittsburgh Sleep Quality Index (PSQI) | Change of PSQI from baseline to the end of dose-titration/dose-maintenance period. PSQI is a scale for assessing severity of sleep disorders. The score ranges from 0 to 21. 0 indicates no difficulty and 21 indicates severe difficulty. A decrease in the scores means improvement. | Baseline, the end of dose-titration/dose-maintenance period (week 13) | 
| Each Item of IRLS (10 Items) | IRLS is a scale for assessing severity of restless legs syndrome symptoms. IRLS consists of ten questions. Each question is scored from 4 for the first (top) answer (usually 'very severe') to 0 for the last answer (usually none). Numbers of subjects with -4 or -3 score change from baseline in each item of IRLS. A decrease in the scores means improvement. | Baseline, the end of dose-titration/dose-maintenance period (week 13) | 
| Incidence of RLS Symptoms | Incidence rate of RLS symptoms is calculated as the number of days with RLS symptoms in the week / the number of evaluation days in the week* 100% | Baseline, the end of dose-titration/dose-maintenance period (week 13) | 
| Average Duration of RLS Symptoms | Change of average duration of RLS symptoms in a week from baseline to the end of dose-titration/dose-maintenance period. Only the days with RLS symptoms are used for calculation. | Baseline, the end of dose-titration/dose-maintenance period (weeks 13) | 
| Incidence of RLS Symptoms in the Evening and Night | Incidence rate of RLS symptoms is calculated as the number of days with RLS symptoms / the number of days of evaluation * 100%. | Baseline, the end of dose-titration/dose-maintenance period (week 13) | 
| Average Duration of RLS Symptoms in the Evening and Night in a Week | Change of average duration of RLS symptoms in a week from baseline to the end of dose-titration/dose-maintenance period. Only the days with RLS symptoms are used for calculation. | Baseline, the end of dose-titration/dose-maintenance period (weeks 13) | 
| Nocturnal Awakenings Due to RLS Symptoms in a Week | Nocturnal awakening rate is calculated as the number of days with nocturnal awakenings / the number of days of evaluation * 100%. | Baseline, the end of dose-titration/dose-maintenance period (week 13) | 
| Average Sleep Time in a Week | Change of average sleep time in a week from baseline to the end of dose-titration/dose-maintenance period. | Baseline, the end of dose-titration/dose-maintenance period (weeks 13) |