Advanced Parkinson's Disease
Conditions
Keywords
Rotigotine, Neupro
Brief summary
This study is to investigate the safety and efficacy of Rotigotine add-on therapy with low doses of Pramipexole or Ropinirole in patients with advanced-stage Parkinson's Disease (PD) who have insufficient response to L-dopa and low doses dopamine receptor agonists.
Interventions
DRUGRotigotine
Application of Rotigotine up to 8 mg/24 h patches for 24 hours.
Sponsors
Otsuka Pharmaceutical Co., Ltd.
UCB BIOSCIENCES GmbH
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
30 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Subject is male or female, aged ≥ 30 and \< 80 years at informed consent * Subject has idiopathic Parkinson's Disease, of more than 3 years duration, as defined by the cardinal sign, bradykinesia, and the presence of at least 1 of the following: resting tremor, rigidity, impairment of postural reflexes, and without any known or suspected cause of Parkinsonism * Subject has motor fluctuations such as wearing, dyskinesia * Subject has experienced nocturias for at least 3 nights within 7 days prior to Baseline * Subject is taking levodopa (L-DOPA, immediate and/or controlled release) in combination with benserazide or carbidopa and has been on a stable dose of L-DOPA for at least 28 days prior to Baseline (Visit 2) * Subject is taking a non-ergot dopamine agonist (pramipexole ≤ 1.5 mg/day or ropinirole ≤ 6.0 mg/day) and has been on a stable dose of non-ergot dopamine agonist for at least 28 days prior to Baseline (Visit 2)
Exclusion criteria
* Subject is receiving therapy with tolcapone or budipine * Subject is receiving therapy with one of the following drugs either concurrently or within 28 days prior to Baseline (Visit 2): alpha-methyl dopa, metoclopramide, reserpine, neuroleptics (except specific atypical neuroleptics: olanzapine, ziprasidone, aripiprazole, clozapine, quetiapine), monoamine oxidase A (MAO-A) inhibitors, methylphenidate, or amphetamine * Subject has a history of symptomatic (not asymptomatic) orthostatic hypotension within the 6 months prior to Baseline (Visit 2) * Subject has a known hypersensitivity to any components of the study medication, such as a history of significant skin hypersensitivity to adhesives, known hypersensitivity to other transdermal medications, or has unresolved contact dermatitis * Subject is pregnant or nursing, or is of child-bearing potential (ie, is (i) not surgically sterile, or, (ii) not using adequate birth control methods \[including at least one barrier method\] or, (iii) not sexually abstinent, or (iv) not at least 2 years post menopausal) * Subject had a previous diagnosis of narcolepsy, sleep apnea syndrome, restless legs syndrome, or periodic limb movement disorder
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Global Impression (CGI) Item 4 (Side Effects) at the End of the Treatment Period | Week 8 (Visit 8) of the 8 weeks Treatment Period (Titration and Maintenance Period) | The CGI Item 4 was used to assess side effects. It ranges from 0 to 4 as follows: 0 = Side effects not assessable 1. = No side effects 2. = Side effects do not significantly interfere with subject's functioning 3. = Side effects significantly interfere with the subject's functioning 4. = Side effects outweigh therapeutic efficacy. |
| Change From Baseline to the End of the Treatment Period in the Unified Parkinson's Disease Rating Scale (UPDRS) Part III (on State) Total Score | From Baseline (Week 0) to Week 8 (Visit 8) of the 8 weeks Treatment Period (Titration and Maintenance Period) | The Unified Parkinson´s Disease Rating Scale Part III is an accepted and validated scale for the assessment of motor function in Parkinson´s disease. Each of the 27 sub-items in the UPDRS III is measured on a scale of 0 to 4, where 0 is normal and 4 represents severe abnormalities. The total scores therefore ranges from 0 to 108. A negative value in Change from Baseline to Week 8 indicates an improvement in motor functions from Baseline. |
| Change From Baseline to the End of the Treatment Period in the Unified Parkinson's Disease Rating Scale (UPDRS) Part II (Average of on and Off State) Total Score | From Baseline (Week 0) to Week 8 (Visit 8) of the 8 weeks Treatment Period (Titration and Maintenance Period) | UPDRS Part II measures 'Activities in Daily Living'. The total score ranges from 0 (Best score possible) to 52 (Worst score possible). UPDRS Part II total score (average of on and off state) is the average of UPDRS Part II total score (on state) and Part II total score (off state). A negative value in Change from Baseline to Week 8 indicates an improvement in activities in daily living from Baseline. |
| Change From Baseline to the End of the Treatment Period in Absolute Time Spent Off | From Baseline (Week 0) to Week 8 (Visit 8) of the 8 weeks Treatment Period (Titration and Maintenance Period) | Absolute time spent off is measured in hours per day. A negative value in Change from Baseline to Week 8 indicates that the time spent off decreased from Baseline and therefore indicates an improvement from Baseline. Only subjects with time spent off at Baseline (subset of the Full Analysis Set (FAS)) are included in the analysis of this outcome measure. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to the End of Treatment Period in Parkinson's Disease Sleep Scale 2 (PDSS-2) Total Score | From Baseline (Week 0) to Week 8 (Visit 8) of the 8 weeks Treatment Period (Titration and Maintenance Period) | The Parkinson´s Disease Sleep Scale (PDSS) is a questionnaire with 15 questions to assess sleep disturbance and nocturnal disability in Parkinson´s disease. The item- scores can range between 0= never and 4= very often. The PDSS score is a sum score of all 15 questions. A negative value in Change from Baseline to Week 8 indicates an improvement from Baseline. |
| Change From Baseline to the End of Treatment Period in the Pittsburgh Sleep Quality Index (PSQI) Global Score | From Baseline (Week 0) to Week 8 (Visit 8) of the 8 weeks Treatment Period (Titration and Maintenance Period) | The Pittsburgh Sleep Quality Index (PSQI) is a questionnaire with 18 questions to assess sleep quality. The 18 questions are distributed to 7 elements with each element ranging from 0-3. The global score is the sum score of all 7 elements and ranges from 0-21 with higher values indicating worse sleep quality. A negative value in Change from Baseline to Week 8 indicates an improvement in sleep quality from Baseline. |
| Change From Baseline to the End of the Treatment Period in Time Spent on Without Troublesome Dyskinesia | From Baseline (Week 0) to Week 8 (Visit 8) of the 8 weeks Treatment Period (Titration and Maintenance Period) | Absolute time spent on without troublesome dyskinesia is measured in hours per day. A positive value in Change from Baseline to Week 8 indicates that the time spent on without troublesome dyskinesia increased from Baseline and therefore indicates an improvement from Baseline. |
Countries
Australia, Malaysia, Singapore, South Korea, Taiwan
Participant flow
Recruitment details
This multicenter study started to enroll subjects in 5 countries in October 2012.
Pre-assignment details
Participant Flow refers to the Safety Set (SS). SS consists of all subjects who were enrolled and had at least 1 patch applied during the Treatment Period.
Participants by arm
| Arm | Count |
|---|---|
| Rotigotine \- Titration Period: Weekly titration to the subject's optimal dose of Rotigotine between 2 mg/24 h and 8 mg/24 h. In case of intolerable Adverse Events (AEs) one back-titration is allowed during the Titration Period.
Duration of the Titration Period: Between 1 week and 5 weeks.
\- Maintenance Period: Starts once subject reached either optimal or maximal dose of Rotigotine. Subjects receive stable dose of Rotigotine throughout the Maintenance Period. No back-titration is allowed during the Maintenance Period.
Duration of the Maintenance Period: Between 3 weeks and 7 weeks.
Rotigotine: Application of Rotigotine up to 8 mg/24 h patches for 24 hours. | 90 |
| Total | 90 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 5 |
| Overall Study | Noncompliant | 3 |
| Overall Study | Unable to follow protocol/ judged by inv | 3 |
Baseline characteristics
| Characteristic | Rotigotine |
|---|---|
| Age, Continuous | 61.3 years STANDARD_DEVIATION 9.3 |
| Age, Customized < 65 years | 57 participants |
| Age, Customized >= 65 years | 33 participants |
| Region of Enrollment Australia | 6 participants |
| Region of Enrollment Korea, Republic of | 66 participants |
| Region of Enrollment Malaysia | 6 participants |
| Region of Enrollment Singapore | 4 participants |
| Region of Enrollment Taiwan | 8 participants |
| Sex: Female, Male Female | 43 Participants |
| Sex: Female, Male Male | 47 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 35 / 90 |
| serious Total, serious adverse events | 5 / 90 |
Outcome results
Primary
Change From Baseline to the End of the Treatment Period in Absolute Time Spent Off
Absolute time spent off is measured in hours per day. A negative value in Change from Baseline to Week 8 indicates that the time spent off decreased from Baseline and therefore indicates an improvement from Baseline. Only subjects with time spent off at Baseline (subset of the Full Analysis Set (FAS)) are included in the analysis of this outcome measure.
Time frame: From Baseline (Week 0) to Week 8 (Visit 8) of the 8 weeks Treatment Period (Titration and Maintenance Period)
Population: Subjects with time spent off at Baseline in the FAS with Last Observation Carried Forward (LOCF) as a method of imputation for missing observations. FAS includes all subjects with at least 1 patch application during Treatment Period, and with an evaluable UPDRS Part III total score at Baseline and at least 1 valid value after Baseline to Day 64.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Rotigotine | Change From Baseline to the End of the Treatment Period in Absolute Time Spent Off | -2.1 hours/day | Standard Deviation 2.9 |
Primary
Change From Baseline to the End of the Treatment Period in the Unified Parkinson's Disease Rating Scale (UPDRS) Part II (Average of on and Off State) Total Score
UPDRS Part II measures 'Activities in Daily Living'. The total score ranges from 0 (Best score possible) to 52 (Worst score possible). UPDRS Part II total score (average of on and off state) is the average of UPDRS Part II total score (on state) and Part II total score (off state). A negative value in Change from Baseline to Week 8 indicates an improvement in activities in daily living from Baseline.
Time frame: From Baseline (Week 0) to Week 8 (Visit 8) of the 8 weeks Treatment Period (Titration and Maintenance Period)
Population: Full Analysis Set (FAS) with Last Observation Carried Forward (LOCF) as a method of imputation for missing observations. FAS includes all subjects with at least 1 patch application during Treatment Period, and with an evaluable UPDRS Part III total score at Baseline and at least 1 valid value after Baseline to Day 64.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Rotigotine | Change From Baseline to the End of the Treatment Period in the Unified Parkinson's Disease Rating Scale (UPDRS) Part II (Average of on and Off State) Total Score | -1.5 units on a scale | Standard Deviation 3.8 |
Primary
Change From Baseline to the End of the Treatment Period in the Unified Parkinson's Disease Rating Scale (UPDRS) Part III (on State) Total Score
The Unified Parkinson´s Disease Rating Scale Part III is an accepted and validated scale for the assessment of motor function in Parkinson´s disease. Each of the 27 sub-items in the UPDRS III is measured on a scale of 0 to 4, where 0 is normal and 4 represents severe abnormalities. The total scores therefore ranges from 0 to 108. A negative value in Change from Baseline to Week 8 indicates an improvement in motor functions from Baseline.
Time frame: From Baseline (Week 0) to Week 8 (Visit 8) of the 8 weeks Treatment Period (Titration and Maintenance Period)
Population: Full Analysis Set (FAS) with Last Observation Carried Forward (LOCF) as a method of imputation for missing observations. FAS includes all subjects with at least 1 patch application during Treatment Period, and with an evaluable UPDRS Part III total score at Baseline and at least 1 valid value after Baseline to Day 64.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Rotigotine | Change From Baseline to the End of the Treatment Period in the Unified Parkinson's Disease Rating Scale (UPDRS) Part III (on State) Total Score | -5.3 units on a scale | Standard Deviation 8.3 |
Primary
Clinical Global Impression (CGI) Item 4 (Side Effects) at the End of the Treatment Period
The CGI Item 4 was used to assess side effects. It ranges from 0 to 4 as follows: 0 = Side effects not assessable 1. = No side effects 2. = Side effects do not significantly interfere with subject's functioning 3. = Side effects significantly interfere with the subject's functioning 4. = Side effects outweigh therapeutic efficacy.
Time frame: Week 8 (Visit 8) of the 8 weeks Treatment Period (Titration and Maintenance Period)
Population: From the 90 subjects in the Safatey Set, 89 are included in the analysis of this outcome measure. Last Observation Carried Forward (LOCF) was used as a method of imputation for missing observations.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Rotigotine | Clinical Global Impression (CGI) Item 4 (Side Effects) at the End of the Treatment Period | CGI Item 4 score of 1 | 61 participants |
| Rotigotine | Clinical Global Impression (CGI) Item 4 (Side Effects) at the End of the Treatment Period | CGI Item 4 score of 2 | 22 participants |
| Rotigotine | Clinical Global Impression (CGI) Item 4 (Side Effects) at the End of the Treatment Period | CGI Item 4 score of 3 | 3 participants |
| Rotigotine | Clinical Global Impression (CGI) Item 4 (Side Effects) at the End of the Treatment Period | CGI Item 4 score of 4 | 3 participants |
| Rotigotine | Clinical Global Impression (CGI) Item 4 (Side Effects) at the End of the Treatment Period | CGI Item 4 score of 3 or 4 | 6 participants |
Secondary
Change From Baseline to the End of the Treatment Period in Time Spent on Without Troublesome Dyskinesia
Absolute time spent on without troublesome dyskinesia is measured in hours per day. A positive value in Change from Baseline to Week 8 indicates that the time spent on without troublesome dyskinesia increased from Baseline and therefore indicates an improvement from Baseline.
Time frame: From Baseline (Week 0) to Week 8 (Visit 8) of the 8 weeks Treatment Period (Titration and Maintenance Period)
Population: Full Analysis Set (FAS) with Last Observation Carried Forward (LOCF) as a method of imputation for missing observations. FAS includes all subjects with at least 1 patch application during Treatment Period, and with an evaluable UPDRS Part III total score at Baseline and at least 1 valid value after Baseline to Day 64.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Rotigotine | Change From Baseline to the End of the Treatment Period in Time Spent on Without Troublesome Dyskinesia | 1.9 hours/day | Standard Deviation 3.1 |
Secondary
Change From Baseline to the End of Treatment Period in Parkinson's Disease Sleep Scale 2 (PDSS-2) Total Score
The Parkinson´s Disease Sleep Scale (PDSS) is a questionnaire with 15 questions to assess sleep disturbance and nocturnal disability in Parkinson´s disease. The item- scores can range between 0= never and 4= very often. The PDSS score is a sum score of all 15 questions. A negative value in Change from Baseline to Week 8 indicates an improvement from Baseline.
Time frame: From Baseline (Week 0) to Week 8 (Visit 8) of the 8 weeks Treatment Period (Titration and Maintenance Period)
Population: Full Analysis Set (FAS) with Last Observation Carried Forward (LOCF) as a method of imputation for missing observations. FAS includes all subjects with at least 1 patch application during Treatment Period, and with an evaluable UPDRS Part III total score at Baseline and at least 1 valid value after Baseline to Day 64.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Rotigotine | Change From Baseline to the End of Treatment Period in Parkinson's Disease Sleep Scale 2 (PDSS-2) Total Score | -3.2 units on a scale | Standard Deviation 7.5 |
Secondary
Change From Baseline to the End of Treatment Period in the Pittsburgh Sleep Quality Index (PSQI) Global Score
The Pittsburgh Sleep Quality Index (PSQI) is a questionnaire with 18 questions to assess sleep quality. The 18 questions are distributed to 7 elements with each element ranging from 0-3. The global score is the sum score of all 7 elements and ranges from 0-21 with higher values indicating worse sleep quality. A negative value in Change from Baseline to Week 8 indicates an improvement in sleep quality from Baseline.
Time frame: From Baseline (Week 0) to Week 8 (Visit 8) of the 8 weeks Treatment Period (Titration and Maintenance Period)
Population: Full Analysis Set (FAS) with Last Observation Carried Forward (LOCF) as a method of imputation for missing observations. FAS includes all subjects with at least 1 patch application during Treatment Period, and with an evaluable UPDRS Part III total score at Baseline and at least 1 valid value after Baseline to Day 64.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Rotigotine | Change From Baseline to the End of Treatment Period in the Pittsburgh Sleep Quality Index (PSQI) Global Score | -0.7 units on a scale | Standard Deviation 3 |