Idiopathic Parkinson's Disease
Conditions
Keywords
Rotigotine, Neupro, Depressive Symptom, Idiopathic Parkinson's disease
Brief summary
The purpose of this study was to show superiority of Rotigotine over placebo on improvement of depressive symptoms in subjects with idiopathic Parkinson's disease.
Detailed description
The study included a maximum 2-week Screening Period, a maximum 4-week Titration Period for early-stage Parkinson's disease or maximum 7-week Titration Period for advanced-stage Parkinson's disease, 8-week Maintenance Period, a maximum 6-day De-escalation Period for early-stage Parkinson's disease or maximum 12-day De-escalation Period for advanced-stage Parkinson's disease and 30-day Safety Follow-Up Period. The maximum study durations for an individual subject with early-stage Parkinson's disease and with advanced-stage Parkinson's disease were 19 weeks and 23 weeks, respectively.
Interventions
DRUGRotigotine
Transdermal Patch Content: 2 mg /24 h (10 cm\^2), 4 mg /24 h (20 cm\^2), 6 mg /24 h (30 cm\^2), 8 mg /24 h (40 cm\^2) * For early-stage Parkinson's disease, Subjects received Rotigotine patches in escalating weekly dose (starting with daily doses 2 mg/24 h to 8 mg/24 h) for a maximum 4-week Titration Period, then 8 week Maintenance period * For advanced-stage Parkinson's disease, Subjects received Rotigotine patches in escalating weekly dose (starting with daily doses 4 mg/24 h to 16 mg/24 h) for a maximum 7-week Titration Period, then 8 week Maintenance period
DRUGPlacebo
Transdermal Patch Size: 10 cm\^2, 20 cm\^2, 30 cm\^2, 40 cm\^2 Subjects randomized to placebo received matching placebo patches
Sponsors
UCB Korea Co., Ltd.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female subjects ≥ 20 years old * Subjects diagnosed with idiopathic Parkinson's disease (according to the United Kingdom Parkinson's Disease Society Brain Bank Diagnostic Criteria for Parkinson's disease) at modified Hoehn and Yahr Scale stages I-III; do not have motor fluctuations, dyskinesia, and have stable motor symptom at least 4 weeks prior to the Screening Visit as judged by the local investigator * Subject has a Beck Depression Inventory II (BDI-II) score ≥ 16 as evidenced by depression rating scale study in Parkinson's disease (Schrag A et al, 2007) * Subject has a Mini-Mental State Examination (MMSE) score ≥ 24 * If subject is taking Levodopa (L-DOPA) and derivatives, Monoamine Oxidase (MAO) B-inhibitors, anticholinergics agents, Catechol-O-Methyl Transferase (COMT) inhibitor or N-Methyl-D-Aspartate (NMDA) antagonist, he/she must have been on stable dose for at least 28 days prior to the Screening Visit * If subject is taking an antidepressant drug such as selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), bupropion, tricyclic antidepressants (TCAs), he/she must have been on a stable dose for at least 28 days prior to the Screening Visit and be maintained on that dose for the duration of the trial
Exclusion criteria
* Subject has any medical or psychiatric condition (ie, bipolar disorder, dementia, hallucinations or psychosis) that, in the opinion of the investigator, could jeopardize or would compromise the subject's ability to participate in this study * Subject has a lifetime history of suicide attempt (including an active attempt, interrupted attempt, or aborted attempt), or has suicidal ideation in the past 6 months as indicated by a positive response ('Yes') to either Question 4 or Question 5 of the C-SSRS at Screening (Visit 1) * Current psychotherapy or behavior therapy while participating in this study * Subject has received electroconvulsive therapy within 12 weeks of the Screening Visit * Subject who has received dopamine agonists within 28 days of the Screening Visit * Subject who has received neuroleptics, methylphenidate, reserpine, alpha-methyldopa, metoclopramide, levosulpiride or amphetamine derivatives within 28 days of the Screening Visit
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to the End of Maintenance Period in the Score of the Hamilton Depression Scale (HAM-D) | From Baseline (Week 0) to end of Maintenance Period (up to Week 15) | The HAM-D consists of 17 items. Nine of the items are scored on a 5-point scale, ranging from 0 to 4. The remaining 8 items are scored on a 3-point scale, from 0 to 2. Therefore, the total score ranges between 0 to 52, with a cutoff score of 15/16 diagnosing major depressive disorder. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to the End of Maintenance Period in the Score of Unified Parkinson's Disease Rating Scale (UPDRS) Part II (Activities of Daily Living-ADL Subscale) | From Baseline (Week 0) to end of Maintenance Period (up to Week 15) | The UPDRS Part II is a tool to measure Activities in Daily Living - it includes speech, salivation, swallowing, handwriting, cutting food and handling utensils, dressing, hygiene, turning in bed and adjusting clothes, falling (unrelated to freezing), freezing when walking, walking, tremor, and sensory complaints related to Parkinsonism. Each of the 13 questions is measured on a scale from 0 (normal) to 4 (severe). The total score of UPDRS part II ranges from 0 (normal) to 52 (severe). |
| Change From Baseline to the End of Maintenance Period in the Score of Unified Parkinson's Disease Rating Scale (UPDRS) Part III (Motor Subscale) | From Baseline (Week 0) to end of Maintenance Period (up to Week 15) | Improvement of motor symptoms is measured by the change from Baseline in UPDRS Part III motor score. The UPDRS Part III is an accepted and validated scale for the assessment of motor function in Parkinson's disease. Each of the elements in the UPDRS Part III is measured on a scale of 0 to 4, where 0 is normal and 4 represents severe abnormalities. The total score of UPDRS part III ranges from 0 (normal) to 108 (severe abnormalities). |
| Change From Baseline to the End of Maintenance Period in the Score of Beck Depression Inventory (BDI-II) | From Baseline (Week 0) to end of Maintenance Period (up to Week 15) | The Beck Depression Inventory II (BDI-II) is a self-report instrument to measure Depression symptoms and severity. There are 21 items in the BDI-II. Scores of 0-13 are considered minimal depression; 14-19 indicates mild depression; 20-28 indicates moderate depression; and 29-63 indicates severe depression. |
| Change From Baseline to the End of Maintenance Period in the Score of Apathy Scale (AS) | From Baseline (Week 0) to end of Maintenance Period (up to Week 15) | The AS is an abbreviated version of the Apathy Scale (AS). The AS consists of 14 items phrased as questions that are to be answered on a four-point Likert scale. It was developed specifically for patients with Parkinson Disease (PD). For questions 1-8, the scoring system is the following: not at all = 3 points; slightly = 2 points; some =1 point, a lot = 0 point. For questions 9-14: the scoring system is the following: not at all = 0 points; slightly = 1 point; some = 2 points; a lot = 3 points. Adding all scores provides the final score with a range from 0 to 42. |
| Change From Baseline to the End of Maintenance Period in the Score of Snaith-Hamilton Pleasure Scale (SHAPS) | From Baseline (Week 0) to end of Maintenance Period (up to Week 15) | The SHAPS is a self-report instrument developed for the assessment of hedonic capacity. The sum of the 14 items scores ranges from 0 to 14. A higher score represents more anhedonic symptoms. |
| Change From Baseline to the End of Maintenance Period in the Combined Score of Unified Parkinson's Disease Rating Scale (UPDRS) Part II (ADL) Plus Part III (Motor Subscale) | From Baseline (Week 0) to end of Maintenance Period (up to Week 15) | The combined score of UPDRS part II and UPDRS part III is the sum of the individual scores and threfore ranges from 0 (normal) to 160 (severe). |
Countries
South Korea
Participant flow
Recruitment details
This double-blind, randomized, multicenter, placebo-controlled, in-Patient study started recruiting in April 2012.
Pre-assignment details
Participant flow refers to the Randomized Set (RS), consisting of all randomized subjects.
Participants by arm
| Arm | Count |
|---|---|
| Rotigotine Rotigotine, daily doses, treatment Group.
Early-stage Parkinon´s disease for 1 week: Rotigotine dose at 2 mg/24 h. Advanced-stage Parkinson´s disease for 1 week: Rotigotine dose at 4 mg/24 h.
Afterwards the dose has been increased in the Titration Period by 2 mg/24 h each week until either the optimal or maximal dose was reached.
All subjects remained 8-weeks in the Maintenance Period. In the De-escalation Period Subjects with early-stage Parkinson´s disease de-escalated their dose by 2 mg/24 h every other day to 2 mg/24h, and then to 0 mg after 2 days. Subjects with advanced-stage Parkinson´s disease de-escalated their dose by 2 mg/24h every other day to 4 mg/24h, and then to 0 mg after 2 days.
A Safety Follow-Up Visit was scheduled for all subjects 30 days after their last dose administration. | 184 |
| Placebo Placebo, daily doses, placebo Group. Subjects randomized to placebo received matching placebo patches.
Early-stage Parkinson´s disease for 1 week: Placebo patches´ dose at 2 mg/24 h. Advanced-stage Parkinson´s disease for 1 week: Placebo patches´dose at 4 mg/24 h.
Afterwards the dose has been increased in the Titration Period by 2 mg/24 h each week until either the optimal or maximal dose was reached.
All subjects remained 8-weeks in the Maintenance Period.
In the De-escalation Period Subjects with early-stage Parkinson´s disease de-escalated their dose by 2 mg/24 h every other day to 2 mg/24h, and then to 0 mg after 2 days. Subjects with advanced-stage Parkinson´s disease de-escalated their dose by 2 mg/24h every other day to 4 mg/24h, and then to 0 mg after 2 days.
A Safety Follow-Up Visit was scheduled for all subjects 30 days after their last dose administration. | 196 |
| Total Title | 380 |
| Total | 760 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 25 | 16 |
| Overall Study | Lack of Efficacy | 0 | 2 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Other Reason | 0 | 2 |
| Overall Study | Protocol Violation | 3 | 4 |
| Overall Study | Withdrawal by Subject | 6 | 8 |
Baseline characteristics
| Characteristic | Rotigotine | Placebo | Total Title |
|---|---|---|---|
| Age, Continuous | 65.6 years STANDARD_DEVIATION 8.9 | 64.9 years STANDARD_DEVIATION 8.2 | 65.2 years STANDARD_DEVIATION 8.5 |
| Age, Customized >18-<65 years | 76 participants | 88 participants | 164 participants |
| Age, Customized <=18 years | 0 participants | 0 participants | 0 participants |
| Age, Customized >=65 years | 108 participants | 108 participants | 216 participants |
| Height | 160.04 cm STANDARD_DEVIATION 8.41 | 159.17 cm STANDARD_DEVIATION 8.14 | 159.59 cm STANDARD_DEVIATION 8.27 |
| Sex: Female, Male Female | 96 Participants | 122 Participants | 218 Participants |
| Sex: Female, Male Male | 88 Participants | 74 Participants | 162 Participants |
| Weight | 61.54 kg STANDARD_DEVIATION 9.68 | 62.24 kg STANDARD_DEVIATION 9.84 | 61.90 kg STANDARD_DEVIATION 9.76 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 112 / 184 | 91 / 196 |
| serious Total, serious adverse events | 6 / 184 | 14 / 196 |
Outcome results
Primary
Change From Baseline to the End of Maintenance Period in the Score of the Hamilton Depression Scale (HAM-D)
The HAM-D consists of 17 items. Nine of the items are scored on a 5-point scale, ranging from 0 to 4. The remaining 8 items are scored on a 3-point scale, from 0 to 2. Therefore, the total score ranges between 0 to 52, with a cutoff score of 15/16 diagnosing major depressive disorder.
Time frame: From Baseline (Week 0) to end of Maintenance Period (up to Week 15)
Population: Efficacy Evaluable Set (EES) consisted of all subjects from the Full Analysis Set (FAS) with a baseline total HAM-D score of 12 or larger.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Efficacy Evaluable Set (Rotigotine Treated Subjects) | Change From Baseline to the End of Maintenance Period in the Score of the Hamilton Depression Scale (HAM-D) | -4.79 units on a scale |
| Efficacy Evaluable Set (Placebo Treated Subjects) | Change From Baseline to the End of Maintenance Period in the Score of the Hamilton Depression Scale (HAM-D) | -3.68 units on a scale |
Comparison: The change from Baseline to the end of the Maintenance period in the score of the HAM-D of rotigotine-treated subjects has been compared with those subjects on placebo in the EES. The null hypothesis (H0) was that there was no difference in the change of the HAM-D score between the active treatment and the placebo group. The alternative hypothesis (H1) was that there was a difference in the change of HAM-D score between the rotigotine and the placebo arm.p-value: =0.128695% CI: [-2.56, 0.33]ANCOVA
Secondary
Change From Baseline to the End of Maintenance Period in the Combined Score of Unified Parkinson's Disease Rating Scale (UPDRS) Part II (ADL) Plus Part III (Motor Subscale)
The combined score of UPDRS part II and UPDRS part III is the sum of the individual scores and threfore ranges from 0 (normal) to 160 (severe).
Time frame: From Baseline (Week 0) to end of Maintenance Period (up to Week 15)
Population: Efficacy Evaluable Set (EES) consisted of all subjects from the Full Analysis Set (FAS) with a baseline total HAM-D score of 12 or larger.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Efficacy Evaluable Set (Rotigotine Treated Subjects) | Change From Baseline to the End of Maintenance Period in the Combined Score of Unified Parkinson's Disease Rating Scale (UPDRS) Part II (ADL) Plus Part III (Motor Subscale) | -4.20 units on a scale |
| Efficacy Evaluable Set (Placebo Treated Subjects) | Change From Baseline to the End of Maintenance Period in the Combined Score of Unified Parkinson's Disease Rating Scale (UPDRS) Part II (ADL) Plus Part III (Motor Subscale) | -1.81 units on a scale |
Secondary
Change From Baseline to the End of Maintenance Period in the Score of Apathy Scale (AS)
The AS is an abbreviated version of the Apathy Scale (AS). The AS consists of 14 items phrased as questions that are to be answered on a four-point Likert scale. It was developed specifically for patients with Parkinson Disease (PD). For questions 1-8, the scoring system is the following: not at all = 3 points; slightly = 2 points; some =1 point, a lot = 0 point. For questions 9-14: the scoring system is the following: not at all = 0 points; slightly = 1 point; some = 2 points; a lot = 3 points. Adding all scores provides the final score with a range from 0 to 42.
Time frame: From Baseline (Week 0) to end of Maintenance Period (up to Week 15)
Population: Efficacy Evaluable Set (EES) consisted of all subjects from the Full Analysis Set (FAS) with a baseline total HAM-D score of 12 or larger.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Efficacy Evaluable Set (Rotigotine Treated Subjects) | Change From Baseline to the End of Maintenance Period in the Score of Apathy Scale (AS) | -1.93 units on a scale |
| Efficacy Evaluable Set (Placebo Treated Subjects) | Change From Baseline to the End of Maintenance Period in the Score of Apathy Scale (AS) | -0.67 units on a scale |
Secondary
Change From Baseline to the End of Maintenance Period in the Score of Beck Depression Inventory (BDI-II)
The Beck Depression Inventory II (BDI-II) is a self-report instrument to measure Depression symptoms and severity. There are 21 items in the BDI-II. Scores of 0-13 are considered minimal depression; 14-19 indicates mild depression; 20-28 indicates moderate depression; and 29-63 indicates severe depression.
Time frame: From Baseline (Week 0) to end of Maintenance Period (up to Week 15)
Population: Efficacy Evaluable Set (EES) consisted of all subjects from the Full Analysis Set (FAS) with a baseline total HAM-D score of 12 or larger.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Efficacy Evaluable Set (Rotigotine Treated Subjects) | Change From Baseline to the End of Maintenance Period in the Score of Beck Depression Inventory (BDI-II) | -5.87 units on a scale |
| Efficacy Evaluable Set (Placebo Treated Subjects) | Change From Baseline to the End of Maintenance Period in the Score of Beck Depression Inventory (BDI-II) | -4.68 units on a scale |
Secondary
Change From Baseline to the End of Maintenance Period in the Score of Snaith-Hamilton Pleasure Scale (SHAPS)
The SHAPS is a self-report instrument developed for the assessment of hedonic capacity. The sum of the 14 items scores ranges from 0 to 14. A higher score represents more anhedonic symptoms.
Time frame: From Baseline (Week 0) to end of Maintenance Period (up to Week 15)
Population: Efficacy Evaluable Set (EES) consisted of all subjects from the Full Analysis Set (FAS) with a baseline total HAM-D score of 12 or larger.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Efficacy Evaluable Set (Rotigotine Treated Subjects) | Change From Baseline to the End of Maintenance Period in the Score of Snaith-Hamilton Pleasure Scale (SHAPS) | -0.82 units on a scale |
| Efficacy Evaluable Set (Placebo Treated Subjects) | Change From Baseline to the End of Maintenance Period in the Score of Snaith-Hamilton Pleasure Scale (SHAPS) | -0.60 units on a scale |
Secondary
Change From Baseline to the End of Maintenance Period in the Score of Unified Parkinson's Disease Rating Scale (UPDRS) Part II (Activities of Daily Living-ADL Subscale)
The UPDRS Part II is a tool to measure Activities in Daily Living - it includes speech, salivation, swallowing, handwriting, cutting food and handling utensils, dressing, hygiene, turning in bed and adjusting clothes, falling (unrelated to freezing), freezing when walking, walking, tremor, and sensory complaints related to Parkinsonism. Each of the 13 questions is measured on a scale from 0 (normal) to 4 (severe). The total score of UPDRS part II ranges from 0 (normal) to 52 (severe).
Time frame: From Baseline (Week 0) to end of Maintenance Period (up to Week 15)
Population: Efficacy Evaluable Set (EES) consisted of all subjects from the Full Analysis Set (FAS) with a baseline total HAM-D score of 12 or larger.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Efficacy Evaluable Set (Rotigotine Treated Subjects) | Change From Baseline to the End of Maintenance Period in the Score of Unified Parkinson's Disease Rating Scale (UPDRS) Part II (Activities of Daily Living-ADL Subscale) | -1.13 units on a scale |
| Efficacy Evaluable Set (Placebo Treated Subjects) | Change From Baseline to the End of Maintenance Period in the Score of Unified Parkinson's Disease Rating Scale (UPDRS) Part II (Activities of Daily Living-ADL Subscale) | -0.10 units on a scale |
Secondary
Change From Baseline to the End of Maintenance Period in the Score of Unified Parkinson's Disease Rating Scale (UPDRS) Part III (Motor Subscale)
Improvement of motor symptoms is measured by the change from Baseline in UPDRS Part III motor score. The UPDRS Part III is an accepted and validated scale for the assessment of motor function in Parkinson's disease. Each of the elements in the UPDRS Part III is measured on a scale of 0 to 4, where 0 is normal and 4 represents severe abnormalities. The total score of UPDRS part III ranges from 0 (normal) to 108 (severe abnormalities).
Time frame: From Baseline (Week 0) to end of Maintenance Period (up to Week 15)
Population: Efficacy Evaluable Set (EES) consisted of all subjects from the Full Analysis Set (FAS) with a baseline total HAM-D score of 12 or larger.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Efficacy Evaluable Set (Rotigotine Treated Subjects) | Change From Baseline to the End of Maintenance Period in the Score of Unified Parkinson's Disease Rating Scale (UPDRS) Part III (Motor Subscale) | -3.07 units on a scale |
| Efficacy Evaluable Set (Placebo Treated Subjects) | Change From Baseline to the End of Maintenance Period in the Score of Unified Parkinson's Disease Rating Scale (UPDRS) Part III (Motor Subscale) | -1.65 units on a scale |