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Clinical Evaluation of Ropinirole CR-RLS ( SK&F101468)Tablets in Restless Legs Syndrome

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT00530790
First Posted: September 17, 2007
Last Update Posted: February 28, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Information provided by (Responsible Party):
GlaxoSmithKline
  Purpose
This study was designed to evaluate the safety, pharmacokinetic profile and efficacy in Restless Legs Syndrome patients.

Condition Intervention Phase
Restless Legs Syndrome Drug: ropinirole controlled release (CR)-RLS Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Clinical Evaluation of Ropinirole CR-RLS Tablets in Restless Legs Syndrome-Open-Label, Uncontrolled Study. Classification: Clinical Pharmacology, Exploratory

Resource links provided by NLM:


Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:
  • Drug Related Adverse Events-On-Therapy [ Time Frame: Weeks 1 - 12 Treatment Period ]
  • Haematology Clinical Lab Values Change From Baseline [ Time Frame: Baseline - Week 13 (Follow-up) ]
    Standard units of measure vary. Therefore, Mean Change is represented in Standard Units: Hematocrit = SI unit of GSK; Hemoglobin = G/L; Platelet count, White Blood Cell count = GI/L; Red Blood Cell count = TI/L. n = number of subjects evaluated. EW = Early Withdrawal.

  • Blood Chemistry Clinical Lab Values Change From Baseline [ Time Frame: Baseline - Week 13 (Follow-up) ]
    Mean Change in Standard Units of Measure: Albumin, Total Protein=G/L; Alkaline Phosphatase, Alanine Amino Transferase, Aspartate Amino Transferase, Lactate Dehydrogenase, Creatine Phosphokinase, Gamma Glutamyl Transferase=IU/L; Total Bilirubin, Creatinine=UMOL/L; Blood Urea Nitrogen, Cholesterol, Chloride, Sodium, Potassium=MMOL/L; Prolactin=MCG/L

  • Urinalysis Clinical Lab Values [ Time Frame: Baseline - Week 13 (Follow-up) ]
    Dipstick test values: Neg Value, Trace, +1, +2, +3. No subjects tested higher than +3.

  • 12-Lead Electrocardiogram (ECG) Findings Transitions From Baseline [ Time Frame: Baseline, Week 4, 8, 12, 13 (Follow-up) ]
    Baseline Finding/Time Period Finding. Abbreviations: N = normal; A = abnormal; CS = clinically significant; NCS = not clinically significant. Options include N/N, N/ANCS, N/ACS, ANCS/N, ANCS/ANCS, ANCS/ACS, ACS/N, ACS/ANCS, and ACS/ACS.

  • Vital Signs and Body Weight Change From Baseline [ Time Frame: Baseline to Week 12/EW ]
    Units of Measure Vary: Weight = kg; Semi-supine and Standing Systolic and Diastolic BP = mmHg; Semi-supine and Standing Pulse Rate = bpm; EW = early withdrawal; Semi-supine = lying down; Orthostatic = lying, sitting, and standing.


Secondary Outcome Measures:
  • Change From Baseline to Week 12 in International Restless Leg Syndrome (IRLS) Rating Scale Total Score [ Time Frame: Baseline and after Week 12 ]
    The IRLS Scale assesses the severity of sensory and motor symptoms, sleep disturbance, daytime somnolence, and impact on activities of daily living and mood. The questionnaire scores various questions and totals them using the following scale: Very severe=31-40 points, Severe=21-30 points, Moderate=11-20 points, Mild=1-10 points, None=0 points.

  • Clinical Global Impression Scale - Severity of Illness (CGI-S) [ Time Frame: Baseline - Final assessment point ]
    The CGI-S scale measures the overall severity of illness on a 7 point scale. Normal = 1, Borderline = 2, Mildly = 3, Moderately = 4, Markedly = 5, Severely = 6, Extremely Severe = 7(no subjects scored a 7).

  • Clinical Global Impression Global Improvement (CGI-GI) [ Time Frame: Baseline - Final assessment point ]
    CGI-GI is a 7 point scale assessing Global Improvement. 1 = Very much improved, 2 = Much improved, 3 = Minimally improved, 4 = No change, 5 = Minimally worse, 6 = Much worse, 7 = Very much worse (no patients scored a 5, 6, or 7).

  • Change From Baseline at Week 12/Early Withdrawal (EW) in Pittsburgh Sleep Quality Index (PSQI) Total Score [ Time Frame: Baseline - Week 12/EW ]
    The PSQI generates seven scores that correspond to different domains. Each component score ranges from 0 (no difficulty) to 3 (severe difficulty). The domain scores are totaled to produce a global score (range of 0-21). A PSQI global score > 5 is considered to be suggestive of significant sleep disturbance.

  • Change From Baseline to Week 12/EW in Pittsburgh Sleep Quality Index (PSQI) Total Score by Domains [ Time Frame: Baseline - Week 12/EW ]
    The PSQI generates seven scores that correspond to different domains. Each component score ranges from 0 (no difficulty) to 3 (severe difficulty). The domain scores are totaled to produce a global score (range of 0-21). A PSQI global score > 5 is considered to be suggestive of significant sleep disturbance.

  • Change From Baseline at Week 12/Early Withdrawal (EW) in Johns Hopkins Restless Leg Syndrome Quality of Life Questionnaire (RLSQOL) on the Overall Life Impact Score [ Time Frame: Baseline and Week 12/EW ]
    The RLSQOL scale consists of 18 items, 13 of which are scored on a 5-point scale. Ten of the items can be summed to the overall life impact score, which can be transformed to a 0-100 score. Mild = 84.48, Moderate = 62.93, or Severe = 37.47

  • Change From Baseline at Week 12/Early Withdrawal (EW) in Profile of Mood Status (POMS) [ Time Frame: Baseline and Week 12/EW ]

    The POMS Standard form contains 65 items (0-232). The respondent rates each item on a 5-point scale, ranging from "Not at all (0)" to "Extremely (4)." The assessment measures six identified mood factors:

    • Tension-Anxiety
    • Depression-Dejection
    • Anger-Hostility
    • Vigor-Activity
    • Fatigue-Inertia
    • Confusion-Bewilderment

  • Change From Baseline at Week 12/Early Withdrawal (EW) in Hospital Anxiety and Depression Scale (HADS) [ Time Frame: Baseline - Week 12/EW ]
    Self screening questionnaire that requires the first response to questions. Questionnaire consists of 14 questions, seven for anxiety "0-21" and seven for depression "0-21". Questions are answered on a four point scale from 0-3; Items 1, 3, 5, 6, 8, 10, 11, and 13 are reversed for summation.

  • Pharmacokinetic Analysis: Plasma Concentrations of SK&F101468, an Unchanged Form of Ropinirole. [ Time Frame: Weeks 1-12 ]
    Plasma samples taken at 24 hours after dosing had been administered for 3 days or longer. This was repeated if the dose was escalated. Lower Limits of Quantitation (LLQ) for SK&101468 = 20 pg/mL. The lowest concentration of analyte can be measured with established acceptable accuracy and precision.

  • Pharmacokinetic Analysis: Plasma Concentrations of SK&F104557, a Circulating Metabolite of Ropinirole. [ Time Frame: Weeks 1 -12 ]
    Plasma samples taken at 24 hours after dosing had been administered for 3 days or longer. This was repeated if the dose was escalated. Lower Limits of Quantitation (LLQ) for SK&104557 = 20 pg/mL. The lowest concentration of analyte can be measured with established acceptable accuracy and precision.

  • Pharmacokinetic Analysis: Plasma Concentrations of SK&F89124, a Circulating Metabolite of Ropinirole. [ Time Frame: Weeks 1-12 ]
    Plasma samples taken at 24 hours after dosing had been administered for 3 days or longer. This was repeated if the dose was escalated. Lower Limits of Quantitation (LLQ) for SK&89124 = 20 pg/mL. The lowest concentration of analyte can be measured with established acceptable accuracy and precision.


Enrollment: 35
Study Start Date: August 2007
Study Completion Date: February 2008
Primary Completion Date: February 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: ropinirole CR-RLS
Subjects will orally take ropinirole CR-RLS tablet(s) once daily 1-2 hours before the onset of RLS symptoms at about the same time of the day. The time of taking ropinirole must be after 16:00.Adjustment of the Ropinirole CR-RLS tablets should be completed after the Week 1 visit up to the Week 10 visit. The dose will be increased at intervals of at least one week until sufficient efficacy is obtained (use "much improved" as a guide) without safety problem. Dose escalation will start at the initial dose 0.5 mg/day to 1 mg/day; after 1 mg/day, the dose will be increased by 1 mg/day to the maximum 6 mg/day.
Drug: ropinirole controlled release (CR)-RLS
White film-coated round-shaped tablet
Other Name: Ropinirole CR-RLS (SK&F101468)

  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years to 79 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • A subject will be considered eligible for inclusion in this study only if all of the following criteria apply:

At Week -1 (at the start of Screening period)

  • Patients who are diagnosed with RLS according to the International RLS Study Group's (IRLSSG) Diagnostic Criteria.
  • Age: Patients aged at least 18 years and under 80 years.
  • Patients who have had RLS symptoms in the evening or nighttime (17:00 to 7:00 next day) for at least 20 days within one month before the start of the screening period. Patients treated for RLS before the start of the Screening period and who do not meet this criterion are considered eligible if the previous therapy can be discontinued from the Screening period.
  • Patients who experience RLS symptoms requiring treatment after 17:00 but prior to bedtime.
  • Gender: male and female Female of child-bearing potential will be eligible for inclusion in this study. However they must have a negative pregnancy test at the Screening visit. They agree are perform pregnancy test at the time determined and practice one of the following method of contraception from the Screening visit till the end of follow-up examination.

    • Abstinence
    • Oral Contraceptive, either combined or progestogen alone
    • Injectable progestogen
    • Implants of levonorgestrel
    • Estrogenic vaginal ring
    • Percutaneous contraceptive patches
    • Intrauterine device (IUD) or intrauterine system (IUS) that meets the SOP effectiveness criteria as stated in the product label
    • Male partner sterilization (vasectomy with documentation of azoospermia) prior to the female subject's entry into the study, and this male is the sole partner for that subject
    • Double barrier method: condom or occlusive cap (diaphragm or cervical / vault caps) plus spermicidal agent (foam /gel / film / cream / suppository
  • Inpatient or outpatient status: Outpatient status
  • Patients who are able to give informed written consent in person. For patients aged under 20 years, their legally acceptable representatives are able to give informed written consent.

At Week 0 (at the start of treatment period)

  • Patients who experience RLS symptoms in the evening and nighttime (17:00 to 7:00 next day) for at least 4 days within 7 days before the start of the treatment period.
  • Patients who have sleep impairment associated with RLS. Patients who answered as 3 (severe) or 4 (very severe) to Question 4 (Sleep disturbance) in the IRLS Rating Scale
  • Patients whose IRLS Rating Scale total scores are 15 points or more.

Exclusion Criteria:

  • Patients requiring treatment for daytime RLS symptoms (7:00 to 17:00).
  • Patients with signs of secondary RLS (e.g. chronic renal failure, iron-deficiency anemia, pregnancy, rheumatoid arthritis and Parkinson's disease).
  • Patients whose serum ferritin level is <10 μg/L (ng/mL) at the start of Screening period.
  • Patients with following sleep disorder not associated with RLS e.g. narcolepsy, sleep terror disorder, sleep walking disorder, breathing related sleep disorder (Patients with obvious apnea in nighttime sleeping when they do not have alcohol drinking or over 15 times/hour is used to a target for apnea hypopnea index,in which case to implement polysomnography), etc.
  • Patients with complication of movement disorder (e.g. Parkinson's disease, dyskinesia, dystonia, etc.).
  • Patients with severe hepatic/renal/cardiac/pulmonary disorder or hematopoietic disorder.

The severity refers to Grade 3 according to "the Classification of the Severity of Adverse Experiences" (Pharmaceutical affairs Bureau/Safety Division (PAB/SD) Notification No. 80, dated 29 June 1992).

  • Patients with the medical history or complication of cancer or malignant tumour.
  • Patients with the medical history or complication of substance abuse (e.g. alcohol or drug) or dependency of substance for the last one year
  • Patients whose diastolic blood pressure (BP) is >110 mmHg or <50 mmHg or whose systolic BP is >180 mmHg or <90 mmHg at the start of Screening period and Week0.
  • Patients intolerant for ropinirole hydrochloride (HCl) or other dopamine agonists.
  • Patients with the medical history of allergy to ropinirole HCl in the past.
  • Patients with the medical history of Augmentation to ropinirole HCl or other dopamine agonists in the past and those who have experienced early morning RLS symptoms.

Augmentation is defined as below:

RLS appear 2 hours earlier than the pre-treatment. Symptoms become severer than the pre-treatment. Symptoms which start after less time at rest than they did before treatment. The RLS extend to other sites (e.g. arm and trunk).

  • Patients without nighttime sleeping habit (e.g. night-shift worker, etc.) and those who must drastically change the habitual bedtime during the study duration.
  • Patients who have participated in another clinical study of an investigational product or medical device within the last 12 weeks prior to the start of screening period.
  • Female patients who are pregnant or lactating, who may be pregnant, or who plan for pregnancy during the study .
  • Patients with chronic hepatitis typeB and /or typeC which is positive of hepatitis B surface antigen (HBsAg)and/or hepatitis C antibody.
  • Patients who have medical conditions which, in the opinion of investigator could affect efficacy and safety assessment. This may include, but are not limited to the following disorders: diabetes, peripheral neuropathy, fibromyalgia syndrome, symptomatic orthostatic hypotension, hepatic or renal failure, pleuro-pulmonary fibrosis.
  • Patients who have received treatment of an estrogen drug product and a drug that are known to substantially inhibit CYP1A2 and have changed the dose from baseline visit to Week 0.
  • Others whom the investigator (sub investigator) considers ineligible for the study.
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00530790


Locations
Japan
GSK Investigational Site
Fukuoka, Japan, 802-0084
GSK Investigational Site
Fukuoka, Japan, 810-0044
GSK Investigational Site
Fukuoka, Japan, 830-0011
GSK Investigational Site
Hiroshima, Japan, 733-0031
GSK Investigational Site
Kanagawa, Japan, 210-0024
GSK Investigational Site
Osaka, Japan, 550-0004
GSK Investigational Site
Osaka, Japan, 589-0022
GSK Investigational Site
Osaka, Japan, 599-8263
GSK Investigational Site
Tochigi, Japan, 321-0293
GSK Investigational Site
Tokyo, Japan, 151-0053
GSK Investigational Site
Tokyo, Japan, 187-0041
Sponsors and Collaborators
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline
  More Information

Additional Information:
Publications:
GSK has concluded that it is not feasible to publish this study in a peer-reviewed scientific journal because the nature of the study is unlikely to be of interest to a journal. GSK is providing the attached study results summary with a conclusion.

Study Data/Documents: Statistical Analysis Plan  This link exits the ClinicalTrials.gov site
Identifier: 107846
For additional information about this study please refer to the GSK Clinical Study Register
Individual Participant Data Set  This link exits the ClinicalTrials.gov site
Identifier: 107846
For additional information about this study please refer to the GSK Clinical Study Register
Dataset Specification  This link exits the ClinicalTrials.gov site
Identifier: 107846
For additional information about this study please refer to the GSK Clinical Study Register
Annotated Case Report Form  This link exits the ClinicalTrials.gov site
Identifier: 107846
For additional information about this study please refer to the GSK Clinical Study Register

Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT00530790     History of Changes
Other Study ID Numbers: 107846
First Submitted: September 14, 2007
First Posted: September 17, 2007
Results First Submitted: February 2, 2009
Results First Posted: July 24, 2009
Last Update Posted: February 28, 2017
Last Verified: January 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Patient-level data for this study will be made available through www.clinicalstudydatarequest.com following the timelines and process described on this site.

Keywords provided by GlaxoSmithKline:
Restless Legs Syndrome

Additional relevant MeSH terms:
Syndrome
Psychomotor Agitation
Restless Legs Syndrome
Disease
Pathologic Processes
Dyskinesias
Neurologic Manifestations
Nervous System Diseases
Psychomotor Disorders
Neurobehavioral Manifestations
Signs and Symptoms
Sleep Disorders, Intrinsic
Dyssomnias
Sleep Wake Disorders
Parasomnias
Mental Disorders
Ropinirole
Antiparkinson Agents
Anti-Dyskinesia Agents
Dopamine Agonists
Dopamine Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs