Converting From Ropinirole Immediate Release (IR) To Ropinirole Controlled-Release for RLS (Restless Legs Syndrome)

Study Overview
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Brief Summary
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This is a multi-center, Phase III study to evaluate the safety and tolerability of proposed dose conversion recommendations for RLS subjects converting from ropinirole immediate release to ropinirole controlled-release for RLS.

Official Title
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A 4-Week, Randomized, Double-Blind, Cohort Study to Evaluate the Safety and Tolerability of Converting From Ropinirole Immediate Release (IR) to Ropinirole Controlled Release for RLS (CR-RLS) Formulation (Formerly Ropinirole Extended Release [XR]) in Patients With Restless Legs Syndrome (RLS)

Conditions
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Restless Legs Syndrome, Restless Legs Syndrome (RLS)

Intervention / Treatment
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* Drug: Ropinirole IR 1 mg
* Drug: Ropinirole IR 2 mg
* Drug: Ropinirole IR 1 mg Placebo
* Drug: Ropinirole IR 2 mg Placebo
* Drug: Ropinirole CR 2 mg
* Drug: Ropinirole CR 3 mg
* Drug: Ropinirole CR 2 mg Placebo
* Drug: Ropinirole CR 3 mg Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of RLS using IRLS Study Group (IRLSSG) diagnostic criteria. Subjects currently being treated for RLS with a stable dose (for at least 2 weeks) of ropinirole IR given once daily. Subjects with RLS symptoms during both the evening and night or night time only. Subjects who have given written informed consent to participate. Exclusion Criteria: Subjects who require treatment of daytime RLS symptoms. Signs of secondary RLS, serum ferritin level less than 10 mcg/L. Movement Disorders, Clinically significant or unstable medical conditions. Abnormal labs, electrocardiogram (ECG) or physical findings. Receiving prohibited medications. Sleeping habits incompatible with study design. Intolerance to ropinirole or other dopamine agonist. Pregnant or lactating. Women of child-bearing potential who are not practicing an acceptable method of birth control.

Ages Eligible for Study
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Minimum Age: 18 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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ropinirole cohort A1: 1 mg IR/2 mg CR-RLS/1 mg IR/1 mg IR<br>Participants received Placebo in the evening and Ropinirole 1 mg IR at bedtime on Week 1. At the end of Week 1, participants were switched to receive Ropinirole 2 mg controlled release for Restless Legs Syndrome (CR-RLS) in the evening and placebo at bedtime till the end of Week 2. At the end of Week 2, participants were converted back to receive placebo in the evening and Ropinirole 1 mg IR at bedtime and continued to receive the same till the end of Week 4. | Drug: Ropinirole IR 1 mg<br>* Ropinirole IR (SKF-101468) will be supplied in the form of a 7mm round bi-convex white film coated tablet, de-bossed with 'GS' on both faces, containing ropinirole hydrochloride equivalent to 1.0mg of active drug substance.<br>* Other names: ropinirole controlled-release for RLS;Drug: Ropinirole IR 1 mg Placebo<br>* Ropinirole IR (SKF-101468) placebo will be supplied in the form of a 7mm round bi-convex white film coated tablet, de-bossed with 'GS' on both faces, containing matching placebo tablets of 1 mg.<br>Drug: Ropinirole CR 2 mg<br>* Ropinirole CR Tablets are presented as 7 mm round, bi-convex, white film coated tablets, de-bossed with 'GS' on both faces, containing ropinirole hydrochloride equivalent to 2mg of the active drug substance.<br>Drug: Ropinirole CR 2 mg Placebo<br>* Ropinirole CR placebo Tablets are presented as 7 mm round, bi-convex, white film coated tablets, de-bossed with 'GS' on both faces, containing matching placebo tablets of 2 mg.<br>|
| Experimental: Ropinirole cohort A2: 1 mg IR/1 mg IR/1 mg IR/2 mg CR-RLS<br>Participants received Placebo in the evening and Ropinirole 1 mg IR at bedtime on Week 1 and continued to receive the same till the end of Week 3. At the end of Week 3, participants were switched to receive Ropinirole 2 mg CR-RLS in the evening and placebo at bedtime till the end of Week 4. | Drug: Ropinirole IR 1 mg<br>* Ropinirole IR (SKF-101468) will be supplied in the form of a 7mm round bi-convex white film coated tablet, de-bossed with 'GS' on both faces, containing ropinirole hydrochloride equivalent to 1.0mg of active drug substance.<br>* Other names: ropinirole controlled-release for RLS;Drug: Ropinirole IR 1 mg Placebo<br>* Ropinirole IR (SKF-101468) placebo will be supplied in the form of a 7mm round bi-convex white film coated tablet, de-bossed with 'GS' on both faces, containing matching placebo tablets of 1 mg.<br>Drug: Ropinirole CR 2 mg<br>* Ropinirole CR Tablets are presented as 7 mm round, bi-convex, white film coated tablets, de-bossed with 'GS' on both faces, containing ropinirole hydrochloride equivalent to 2mg of the active drug substance.<br>Drug: Ropinirole CR 2 mg Placebo<br>* Ropinirole CR placebo Tablets are presented as 7 mm round, bi-convex, white film coated tablets, de-bossed with 'GS' on both faces, containing matching placebo tablets of 2 mg.<br>|
| Experimental: Ropinirole cohort B1: 2 mg IR/3 mg CR-RLS/2 mg IR/2 mg IR<br>Participants received Placebo in the evening and Ropinirole 2 mg IR at bedtime on Week 1. At the end of Week 1, participants were switched to receive Ropinirole 3 mg CR-RLS in the evening and placebo at bedtime till the end of Week 2. At the end of Week 2, participants were converted back to receive placebo in the evening and Ropinirole 2 mg IR at bedtime and continued to receive the same till the end of Week 4. | Drug: Ropinirole IR 2 mg<br>* Ropinirole IR (SKF-101468) will be supplied in the form of a 7mm round bi-convex white film coated tablet, de-bossed with 'GS' on both faces, containing ropinirole hydrochloride equivalent to 2.0mg of active drug substance.<br>Drug: Ropinirole IR 2 mg Placebo<br>* Ropinirole IR (SKF-101468) placebo will be supplied in the form of a 7mm round bi-convex white film coated tablet, de-bossed with 'GS' on both faces, containing matching placebo tablets of 2 mg.<br>Drug: Ropinirole CR 3 mg<br>* Ropinirole CR Tablets are presented as 7 mm round, bi-convex, white film coated tablets, de-bossed with 'GS' on both faces, containing ropinirole hydrochloride equivalent to 3mg of the active drug substance.<br>Drug: Ropinirole CR 3 mg Placebo<br>* Ropinirole CR placebo Tablets are presented as 7 mm round, bi-convex, white film coated tablets, de-bossed with 'GS' on both faces, containing matching placebo tablets of 3 mg.<br>|
| Experimental: Ropinirole cohort B2: 2 mg IR/2 mg IR/2 mg IR/3 mg CR-RLS<br>Participants received Placebo in the evening and Ropinirole 2 mg IR at bedtime on Week 1 and continued to receive the same till the end of Week 3. At the end of Week 3, participants were switched to receive Ropinirole 3 mg CR-RLS in the evening and placebo at bedtime till the end of Week 4. | Drug: Ropinirole IR 2 mg<br>* Ropinirole IR (SKF-101468) will be supplied in the form of a 7mm round bi-convex white film coated tablet, de-bossed with 'GS' on both faces, containing ropinirole hydrochloride equivalent to 2.0mg of active drug substance.<br>Drug: Ropinirole IR 2 mg Placebo<br>* Ropinirole IR (SKF-101468) placebo will be supplied in the form of a 7mm round bi-convex white film coated tablet, de-bossed with 'GS' on both faces, containing matching placebo tablets of 2 mg.<br>Drug: Ropinirole CR 3 mg<br>* Ropinirole CR Tablets are presented as 7 mm round, bi-convex, white film coated tablets, de-bossed with 'GS' on both faces, containing ropinirole hydrochloride equivalent to 3mg of the active drug substance.<br>Drug: Ropinirole CR 3 mg Placebo<br>* Ropinirole CR placebo Tablets are presented as 7 mm round, bi-convex, white film coated tablets, de-bossed with 'GS' on both faces, containing matching placebo tablets of 3 mg.<br>|
| Experimental: Ropinirole cohort C1: 4 mg IR/6 mg CR-RLS/4 mg IR/4 mg IR<br>Participants received Placebo in the evening and Ropinirole 4 mg IR at bedtime on Week 1. At the end of Week 1, participants were switched to receive Ropinirole 6 mg CR-RLS in the evening and placebo at bedtime till the end of Week 2. At the end of Week 2, participants were converted back to receive placebo in the evening and Ropinirole 4 mg IR at bedtime and continued to receive the same till the end of Week 4. | Drug: Ropinirole IR 2 mg<br>* Ropinirole IR (SKF-101468) will be supplied in the form of a 7mm round bi-convex white film coated tablet, de-bossed with 'GS' on both faces, containing ropinirole hydrochloride equivalent to 2.0mg of active drug substance.<br>Drug: Ropinirole IR 2 mg Placebo<br>* Ropinirole IR (SKF-101468) placebo will be supplied in the form of a 7mm round bi-convex white film coated tablet, de-bossed with 'GS' on both faces, containing matching placebo tablets of 2 mg.<br>Drug: Ropinirole CR 3 mg<br>* Ropinirole CR Tablets are presented as 7 mm round, bi-convex, white film coated tablets, de-bossed with 'GS' on both faces, containing ropinirole hydrochloride equivalent to 3mg of the active drug substance.<br>Drug: Ropinirole CR 3 mg Placebo<br>* Ropinirole CR placebo Tablets are presented as 7 mm round, bi-convex, white film coated tablets, de-bossed with 'GS' on both faces, containing matching placebo tablets of 3 mg.<br>|
| Experimental: Ropinirole cohort C2: 4 mg IR/4 mg IR/4 mg IR/6 mg CR-RLS<br>Participants received Placebo in the evening and Ropinirole 4 mg IR at bedtime on Week 1 and continued to receive the same till the end of Week 3. At the end of Week 3, participants were switched to receive Ropinirole 6 mg CR-RLS in the evening and placebo at bedtime till the end of Week 4. | Drug: Ropinirole IR 2 mg<br>* Ropinirole IR (SKF-101468) will be supplied in the form of a 7mm round bi-convex white film coated tablet, de-bossed with 'GS' on both faces, containing ropinirole hydrochloride equivalent to 2.0mg of active drug substance.<br>Drug: Ropinirole IR 2 mg Placebo<br>* Ropinirole IR (SKF-101468) placebo will be supplied in the form of a 7mm round bi-convex white film coated tablet, de-bossed with 'GS' on both faces, containing matching placebo tablets of 2 mg.<br>Drug: Ropinirole CR 3 mg<br>* Ropinirole CR Tablets are presented as 7 mm round, bi-convex, white film coated tablets, de-bossed with 'GS' on both faces, containing ropinirole hydrochloride equivalent to 3mg of the active drug substance.<br>Drug: Ropinirole CR 3 mg Placebo<br>* Ropinirole CR placebo Tablets are presented as 7 mm round, bi-convex, white film coated tablets, de-bossed with 'GS' on both faces, containing matching placebo tablets of 3 mg.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events (AEs) Post-conversion From Ropinirole IR to Ropinirole CR Over Period | AE is an unfavorable change in the health of a participant, including abnormal laboratory findings, that happens during a clinical study or within a certain time period after the study has ended. This change may or may not be caused by the intervention being studied. In each of the 6 cohorts, there were 2 conversions, one of which was IR to CR-RLS and the other one IR to IR. Two populations were defined: the first conversion population and the second conversion population. The first conversion population consisted of all participants receiving at least one dose of randomized drug during the pre-conversion 1 period and during the post-conversion 1 period. The second conversion population consisted of all participants receiving at least one dose of randomized drug during the pre-conversion 2 period and during the post-conversion 2 period. | Up to 5 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Discontinuing the Drug Due to AEs Post Conversion From Ropinirole IR to Ropinirole CR-RLS | AE is an unfavorable change in the health of a participant, including abnormal laboratory findings, that happens during a clinical study or within a certain time period after the study has ended. This change may or may not be caused by the intervention being studied. Onset of an AE was pre-Conversion 1 and discontinuation for the same AE occurred post-Conversion 1. Serious adverse event (SAE) is an adverse event that results in death, is life-threatening, requires inpatient hospitalization or extends a current hospital stay, results in an ongoing or significant incapacity or interferes substantially with normal life functions, or causes a congenital anomaly or birth defect. Medical events that do not result in death, are not life-threatening, or do not require hospitalization may be considered serious adverse events if they put the participant in danger or require medical or surgical intervention to prevent one of the results listed above. | Up to 5 weeks | 
| Number of Participants With SAEs and Severity of AEs | SAE is an adverse event that results in death, is life-threatening, requires inpatient hospitalization or extends a current hospital stay, results in an ongoing or significant incapacity or interferes substantially with normal life functions, or causes a congenital anomaly or birth defect. Medical events that do not result in death, are not life-threatening, or do not require hospitalization may be considered serious adverse events if they put the participant in danger or require medical or surgical intervention to prevent one of the results listed above. Severity was measured in terms of grades mild, moderate, and severe. SAEs data only for post-conversion has been reported. | Up to 5 weeks | 
| Number of Participants With Positive Scores (Improved) on Clinical Global Impression Improvement Scale (CGI-I) Pre-conversion and One Week Post-conversion | Global Improvement Scale (CGI-I) allows the Investigator to rate the participants' global improvement or worsening compared with the condition at Baseline (Day 0), whether or not the change is thought to be due to treatment with study drug. The scale is rated from 1 to 7 (1=Very much improved to 7=Very much worse). Typically, a participant with a score of 1 were considered as Very much improved and 2 as Much improved responder. Positive response was given in terms of worsen to stable or stable to improved. | Up to 4 weeks | 
| Change From Pre-conversion in International RLS (IRLS) Rating Scale Total Score to One Week Post-conversion | The IRLS Rating Scale was developed to measure disease severity for clinical assessment, research, and therapeutic studies an also to show relationship between responses and overall RLS severity. The IRLS Rating Scale is a disease-specific 10-item scale that is based on the IRLSSG consensus of clinical features and associated sleep problems. The investigator asked the participant to rate his/her symptoms for each of the ten questions contained in the IRLS Rating Scale from 0 to 4, with 0 representing the absence of a problem and 4 a very severe problem. The best and worst possible scores are 0 and 40, respectively; higher scores represent a greater severity of symptoms. Changes from pre- to one-week post-conversion in the IRLS rating scale total score was obtained by subtracting the Week 1 total score from the Week 2 total score for the first conversion and the Week 3 total score from the Week 4 total score for the second conversion. | Up to 5 weeks | 
| Number of Participants With pre-and One Week Post-conversion Values of Vital Signs of Potential Clinical Concern (PCC) | The number of participants with pre- and post- conversion orthostatic systolic blood pressure (SBP), diastolic blood pressure (DBP) and pulse rate values of PCC were summarized. Both conversions (drug and dummy) were considered. High and low values of only orthostatic SBP and DBP of PCC are presented. | Up to 5 weeks | 
| Change From Pre-conversion in Systolic and Diastolic Orthostatic SBP and DBP to One Week Post-conversion | Both conversions 1 and 2 (drug and dummy) were considered for analysis. High and low values of only orthostatic SBP and DBP of PCC are presented. Change from pre-conversion in BP is the value of BP at post-conversion minus the value at pre-conversion. For orthostatic changes (standing minus semi-supine vital signs values), pre-conversion measurements were compared with the post-conversion measurements. Positive values are indicative of less orthostatic decrease in blood pressure. The first conversion relates to the Week 1 visit, with pre- to post-conversion changes computed as Week 2 values minus the Week 1 values, and the second conversion relates to the Week 3 visit with pre- to post-conversion changes computed as the Week 4 values minus the Week 3 values. | Up to 5 weeks | 
| Change From Pre-conversion in Pulse Rate to One Week Post-conversion | Both conversions 1 and 2 (drug and dummy) were considered for analysis. High and low values of only orthostatic pulse of PCC are presented. Change from pre-conversion in pulse rate is the value of pulse rate at post-conversion minus the value at pre-conversion. For orthostatic changes (standing minus semi-supine vital signs values), pre-conversion measurements were compared with the post-conversion measurements. Positive values are indicative of less orthostatic decrease in pulse. The first conversion relates to the Week 1 visit, with pre- to post-conversion changes computed as Week 2 values minus the Week 1 values, and the second conversion relates to the Week 3 visit with pre- to post-conversion changes computed as the Week 4 values minus the Week 3 values. | Up to 5 weeks | 
| Change From Pre-conversion to Post-conversion in Ambulatory Blood Pressure | Blood pressure (both systolic and diastolic) measurements were made just prior to the first dose of study medication ('evening' dose, ropinirole CR-RLS or matching placebo) and then every hour afterwards up to bedtime (when the device was removed). The changes for the first conversion were calculated as the post evening dose values minus the pre evening dose values at the Week 1 visit and the changes for the second conversion were the post evening dose values minus the pre evening dose values at the Week 3 visit. | Up to 5 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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RLS, Ropinirole, Restless Legs Syndrome