Idiopathic Restless Legs Syndrome
Conditions
Brief summary
The aims of the trial are to assess the safety and the efficacy of SPM 962 following once-a-daily transdermal administration within a range of 2.25 to 6.75 mg/day in Japanese patients with restless legs syndrome (RLS) in a multi-center, open-label trial. The maximum treatment period is 53 weeks. The trial is an extension trial from the precedent 6-week, double-blind, randomized, placebo-controlled, parallel-group comparative trial(243-07-003). The trial is also for an exploratory investigation of incidence of augmentation, the most problematic complications in dopaminergic treatment.
Interventions
DRUGSPM 962
Tansdermal patch
Sponsors
Otsuka Pharmaceutical Co., Ltd.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
20 Years to 79 Years
Healthy volunteers
No
Inclusion criteria
* Subject completed the preceding trial 243-07-003 (NCT00666965)
Exclusion criteria
* Subject discontinued from the preceding trial 243-07-003 (NCT00666965) * Subject had a serious adverse event which association with the investigational drug is not ruled out during trial 243-07-003 * Subject had a persistent serious adverse event at the baseline, which was observed and association with the investigational drug is ruled out during trial 243-07-003. * Subject had persistent hallucination or delusion during trial 243-07-003. * Subject had psychiatric conditions such as confusion, excitation, delirium, abnormal behaviour at the baseline. * Subject had orthostatic hypotension or a systolic blood pressure (SBP) ≤ 100 mmHg and had a decrease of SBP from spine to standing position ≥ 30 mmHg at baseline. * Subject had a history of epilepsy, convulsion etc. during trial 243-07-003. * Subject developed serious ECG abnormality at the baseline. * Subject had QTc-interval ≥ 500 msec at the baseline or subject had an increase of QTc-interval ≥ 60 msec from the baseline in the trial 243-07-003 and had a QTc-interval \> 470 msec in female or \> 450 msec in male at the baseline. * Subject had a serum potassium level \< 3.5 mEq/L at the end of the taper period in trial 243-07-003. * Subject had a total bilirubin ≥ 3.0 mg/dL or AST(GOT) or ALT(GPT) greater than 2.5 times of the upper limit of the reference range (or ≥ 100 IU/L) at the end of the period in trial 243-07-003. * Subject had BUN ≥ 30 mg/dL or serum creatinine ≥ 2.0 mg/dl at the end of the taper period in trial 243-07-003. * Subject who planned pregnancy during the trial. * Subject was judged to be inappropriate for this trial by the investigator for the reasons other than above.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Incidence and Severity of Adverse Events (AEs), Vital Signs, and Laboratory Parameters | Up to 54 weeks | The safety of the long-term SPM 962 treatment was examined based on the incidence and severity of adverse events, vital signs, and laboratory parameters. AEs of special interest (1-3) are defined as below: 1. sudden onset of sleep 2. obsessive-compulsive disorder or impulse-control disorder 3. hallucination, delusion |
| Augmentation | Up to 53 weeks | Augmentation is the main complication during long-term dopaminergic treatment of restless legs syndrome (RLS) and reflects an overall increase in RLS severity. Augmentation is clinically significant when at least one of the following occurs: 1. Change in daily activities and/or behavior (e.g., the patient stops riding in cars in the afternoon) due to augmentation; 2. Negative impact on the patient's quality of life (sleep, mood, etc.) due to augmentation; 3. Need to change the treatment dose or the patienｔ needs to take the dose earlier in the day (e.g., dividing the dose); 4. Adjustments in concomitant medication are made to compensate for augmented RLS symptoms (e.g., an increased intake of analgesics or hypnotics to cover an increase in symptom intensity); 5. Any other aspect as judged by the evaluator (should be specified). |
| Change of the Pittsburgh Sleep Quality Index (PSQI) From Baseline to Each Visit | Baseline, Up to 53 weeks | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change of IRLS Sum Score From the Baseline to Each Visit | Baseline, Up to 53 weeks | 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. |
| Change of Short-Form 36-Item Health Survey (SF-36) From Baseline to Each Visit | Baseline, Up to 53 weeks | SF-36 is a scale for assessing health status in clinical practice and research. The scores of 36 questions are summarized into 7 sub-scales. In each sub-scale which range is 0-100, a higher score indicates a better health status. Thus a increase in the scores means improvement. |
| Efficacy Rate in IRLS Sum Score | Baseline, Up to 53 weeks | Efficacy rate (percentage of subjects with 50% decrease) (LOCF) in IRLS sum score. |
| Change of Augmentation Severity Rating Scale (ASRS) Sum Score From Baseline to Each Visit | Baseline, Up to 52 weeks | ASRS is a scale for assessing severity of augmentation. ASRS consists of 3 items (one item containing 4 sub-items). The sum of the score of each question serves as the scale score (each question score: 0-3, sum score 0-24). A higher score indicates a greater severity of symptoms. Thus a decrease in the scores means improvement. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| SPM 962 Rotigotine transdermal patch | 185 |
| Total | 185 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 29 |
| Overall Study | Discontinuation criteria | 2 |
| Overall Study | Lack of Efficacy | 3 |
| Overall Study | Lost to Follow-up | 2 |
| Overall Study | Physician Decision | 2 |
| Overall Study | Protocol Violation | 1 |
| Overall Study | Withdrawal by Subject | 13 |
Baseline characteristics
| Characteristic | SPM 962 |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 28 Participants |
| Age, Categorical Between 18 and 65 years | 157 Participants |
| Age, Continuous | 49.8 years STANDARD_DEVIATION 13.1 |
| Region of Enrollment Japan | 185 participants |
| Sex: Female, Male Female | 113 Participants |
| Sex: Female, Male Male | 72 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 165 / 185 |
| serious Total, serious adverse events | 5 / 185 |
Outcome results
Primary
Augmentation
Augmentation is the main complication during long-term dopaminergic treatment of restless legs syndrome (RLS) and reflects an overall increase in RLS severity. Augmentation is clinically significant when at least one of the following occurs: 1. Change in daily activities and/or behavior (e.g., the patient stops riding in cars in the afternoon) due to augmentation; 2. Negative impact on the patient's quality of life (sleep, mood, etc.) due to augmentation; 3. Need to change the treatment dose or the patienｔ needs to take the dose earlier in the day (e.g., dividing the dose); 4. Adjustments in concomitant medication are made to compensate for augmented RLS symptoms (e.g., an increased intake of analgesics or hypnotics to cover an increase in symptom intensity); 5. Any other aspect as judged by the evaluator (should be specified).
Time frame: Up to 53 weeks
Population: SS
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| SPM 962 | Augmentation | Subjects with augmentation | 11 participants |
| SPM 962 | Augmentation | Subjects with clinically significant augmentation | 5 participants |
Primary
Change of the Pittsburgh Sleep Quality Index (PSQI) From Baseline to Each Visit
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.
Time frame: Baseline, Up to 53 weeks
Population: FAS, LOCF
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| SPM 962 | Change of the Pittsburgh Sleep Quality Index (PSQI) From Baseline to Each Visit | Week 8 | -2.2 Scores on a scale | Standard Deviation 3.3 |
| SPM 962 | Change of the Pittsburgh Sleep Quality Index (PSQI) From Baseline to Each Visit | Week 16 | -2.2 Scores on a scale | Standard Deviation 2.9 |
| SPM 962 | Change of the Pittsburgh Sleep Quality Index (PSQI) From Baseline to Each Visit | Week 44 | -2.0 Scores on a scale | Standard Deviation 3.1 |
Primary
The Incidence and Severity of Adverse Events (AEs), Vital Signs, and Laboratory Parameters
The safety of the long-term SPM 962 treatment was examined based on the incidence and severity of adverse events, vital signs, and laboratory parameters. AEs of special interest (1-3) are defined as below: 1. sudden onset of sleep 2. obsessive-compulsive disorder or impulse-control disorder 3. hallucination, delusion
Time frame: Up to 54 weeks
Population: Safety set (SS)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| SPM 962 | The Incidence and Severity of Adverse Events (AEs), Vital Signs, and Laboratory Parameters | Any AEs | 175 participants |
| SPM 962 | The Incidence and Severity of Adverse Events (AEs), Vital Signs, and Laboratory Parameters | Treatment-related AEs | 139 participants |
| SPM 962 | The Incidence and Severity of Adverse Events (AEs), Vital Signs, and Laboratory Parameters | SAEs | 5 participants |
| SPM 962 | The Incidence and Severity of Adverse Events (AEs), Vital Signs, and Laboratory Parameters | Treatment-related SAEs | 1 participants |
| SPM 962 | The Incidence and Severity of Adverse Events (AEs), Vital Signs, and Laboratory Parameters | Death | 0 participants |
| SPM 962 | The Incidence and Severity of Adverse Events (AEs), Vital Signs, and Laboratory Parameters | AEs of special interest 1 | 0 participants |
| SPM 962 | The Incidence and Severity of Adverse Events (AEs), Vital Signs, and Laboratory Parameters | AEs of special interest 2 | 0 participants |
| SPM 962 | The Incidence and Severity of Adverse Events (AEs), Vital Signs, and Laboratory Parameters | AEs of special interest 3 | 0 participants |
| SPM 962 | The Incidence and Severity of Adverse Events (AEs), Vital Signs, and Laboratory Parameters | Severe AEs | 3 participants |
| SPM 962 | The Incidence and Severity of Adverse Events (AEs), Vital Signs, and Laboratory Parameters | Discontinuation due to AEs | 29 participants |
| SPM 962 | The Incidence and Severity of Adverse Events (AEs), Vital Signs, and Laboratory Parameters | Valvular disease of the heart | 0 participants |
Secondary
Change of Augmentation Severity Rating Scale (ASRS) Sum Score From Baseline to Each Visit
ASRS is a scale for assessing severity of augmentation. ASRS consists of 3 items (one item containing 4 sub-items). The sum of the score of each question serves as the scale score (each question score: 0-3, sum score 0-24). A higher score indicates a greater severity of symptoms. Thus a decrease in the scores means improvement.
Time frame: Baseline, Up to 52 weeks
Population: FAS, LOCF
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| SPM 962 | Change of Augmentation Severity Rating Scale (ASRS) Sum Score From Baseline to Each Visit | Week 8 | 1.4 Scores on a scale | Standard Deviation 2.5 |
| SPM 962 | Change of Augmentation Severity Rating Scale (ASRS) Sum Score From Baseline to Each Visit | Week 16 | 1.4 Scores on a scale | Standard Deviation 2.6 |
| SPM 962 | Change of Augmentation Severity Rating Scale (ASRS) Sum Score From Baseline to Each Visit | Week 32 | 1.6 Scores on a scale | Standard Deviation 2.7 |
| SPM 962 | Change of Augmentation Severity Rating Scale (ASRS) Sum Score From Baseline to Each Visit | Week 44 | 1.4 Scores on a scale | Standard Deviation 2.6 |
Secondary
Change of IRLS Sum Score From the Baseline to Each Visit
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.
Time frame: Baseline, Up to 53 weeks
Population: Full analysis set (FAS), last observation carried forward (LOCF)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| SPM 962 | Change of IRLS Sum Score From the Baseline to Each Visit | Weeks 8 | -11.4 Scores on a scale | Standard Deviation 8.8 |
| SPM 962 | Change of IRLS Sum Score From the Baseline to Each Visit | Week 16 | -9.7 Scores on a scale | Standard Deviation 9.6 |
| SPM 962 | Change of IRLS Sum Score From the Baseline to Each Visit | Week 32 | -9.5 Scores on a scale | Standard Deviation 9.1 |
| SPM 962 | Change of IRLS Sum Score From the Baseline to Each Visit | Week 44 | -10.4 Scores on a scale | Standard Deviation 9.1 |
Secondary
Change of Short-Form 36-Item Health Survey (SF-36) From Baseline to Each Visit
SF-36 is a scale for assessing health status in clinical practice and research. The scores of 36 questions are summarized into 7 sub-scales. In each sub-scale which range is 0-100, a higher score indicates a better health status. Thus a increase in the scores means improvement.
Time frame: Baseline, Up to 53 weeks
Population: FAS, LOCF
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| SPM 962 | Change of Short-Form 36-Item Health Survey (SF-36) From Baseline to Each Visit | Role physical | 3.7 Scores on a scale | Standard Deviation 17.4 |
| SPM 962 | Change of Short-Form 36-Item Health Survey (SF-36) From Baseline to Each Visit | Bodily pain | 5.1 Scores on a scale | Standard Deviation 22.3 |
| SPM 962 | Change of Short-Form 36-Item Health Survey (SF-36) From Baseline to Each Visit | Physical functioning | -0.2 Scores on a scale | Standard Deviation 8 |
| SPM 962 | Change of Short-Form 36-Item Health Survey (SF-36) From Baseline to Each Visit | General health | 1.8 Scores on a scale | Standard Deviation 12.8 |
| SPM 962 | Change of Short-Form 36-Item Health Survey (SF-36) From Baseline to Each Visit | Vitality | 4.9 Scores on a scale | Standard Deviation 15.8 |
| SPM 962 | Change of Short-Form 36-Item Health Survey (SF-36) From Baseline to Each Visit | Social functioning | 3.0 Scores on a scale | Standard Deviation 16.2 |
| SPM 962 | Change of Short-Form 36-Item Health Survey (SF-36) From Baseline to Each Visit | Role emotional | 5.6 Scores on a scale | Standard Deviation 14.5 |
Secondary
Efficacy Rate in IRLS Sum Score
Efficacy rate (percentage of subjects with 50% decrease) (LOCF) in IRLS sum score.
Time frame: Baseline, Up to 53 weeks
Population: FAS, LOCF
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| SPM 962 | Efficacy Rate in IRLS Sum Score | Weeks 8 | 64.1 Percentage of participants |
| SPM 962 | Efficacy Rate in IRLS Sum Score | Week 16 | 54.9 Percentage of participants |
| SPM 962 | Efficacy Rate in IRLS Sum Score | Week 32 | 57.6 Percentage of participants |
| SPM 962 | Efficacy Rate in IRLS Sum Score | Week 44 | 60.3 Percentage of participants |