Parkinson's Disease
Conditions
Keywords
Azilect, Motor fluctuations, Parkinson´s Disease, Rasagiline
Brief summary
To evaluate the efficacy of a fixed dose of Azilect® (1 mg/day) vs placebo as assessed by the change from baseline in mean total daily OFF time during 18 weeks of treatment in levodopa-treated Parkinson's Disease (PD) patients with motor fluctuations in Korea.
Detailed description
Levodopa has been the mainstay therapy for PD for decades, and it is considered to be one of the most effective medications for relief of the symptoms of PD. However, within few months to few years the majority of levodopa-treated patients notice a decline in the duration of benefit of each dose and develop motor-complications. A major problem is the appearance of fluctuations in mobility, cycles of ON and OFF periods. The administration of Azilect®, a monoamine oxidase type B (MAO-B) inhibitor, can slow the elimination of the endogenous dopamine supplies or the dopamine produced from the exogenous levodopa therapy and may therefore improve ON-OFF fluctuations. Azilect® is approved for treatment of PD in Europe and the US. The objective of this study is to evaluate the efficacy, tolerability, and safety of Azilect® compared to placebo in Korean PD patients with motor fluctuations on levodopa therapy.
Interventions
DRUGPlacebo
Once daily; tablet; orally; 18 weeks
DRUGAzilect®
1 mg daily; tablet; orally; 18 weeks
Sponsors
H. Lundbeck A/S
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
30 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients with idiopathic PD * Patients with motor fluctuations averaging at least 1 hour daily in the OFF state during the waking hours (not including morning akinesia) * Patients with a Modified Hoehn and Yahr stage \<5 in the OFF state * Patients taking optimised levodopa/DOPA decarboxylase inhibitor (DDI) therapy for at least 14 days prior to baseline * Patients receiving at least 3 daily doses of levodopa, not including a bedtime dose, and not more than 8 daily doses of levodopa * Patient who have demonstrated the ability to keep accurate 24-hour diaries prior to randomisation
Exclusion criteria
* Patients with a clinically significant or unstable medical or surgical condition that would preclude his/her safe and complete study participation * Patients taking any disallowed medication according to the Azilect® approved label * Patients taking MAO inhibitors within 3 months prior to baseline visit * Patients with a known serious adverse reaction to selegiline * Patients with a clinically significant psychiatric illness, including a major depression, which compromises their ability to provide consent or participate fully in the study * Patients with a Mini Mental State Examination (MMSE) score \<=24 * Patients with a diagnosis of melanoma or a history of melanoma, or a suspicious lesion
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Mean Total Daily OFF Time Using Parkinson's Disease Patient Diary | Baseline and Weeks 6, 10, 14, and 18 | Parkinson's Disease Patient Diary is a self-administered diary designed to assess motor fluctuations throughout the day. It is divided into 30-minute intervals, and the patient selects one of four options for each interval: asleep; off; on with no dyskinesia or without troublesome dyskinesia; or on with troublesome dyskinesia. The Change From Baseline in Mean Total Daily OFF Time is calculated by taking the difference between the average of the total daily OFF time at Weeks 6, 10, 14 and 18, and the Baseline Total Daily OFF Time. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Status Using CGI-I Score During ON Time | Week 18 | Clinical Global Impression - Global Improvement (CGI-I) is a single-item rating scale used to evaluate a patient's condition relative to baseline on a 7-point scale, regardless of whether the improvement is related to the investigational medicinal product (IMP). The scale ranges from 1 (very much improved) to 7 (very much worse). |
| Change From Baseline in UPDRS-ADL Score During OFF Time | Baseline and Week 18 | Unified Parkinson's Disease Rating Scale (UPDRS) is a 42-item rating scale designed to assess Parkinson's Disease-related disability and impairment using a patient interview and a physical examination. It has 4 parts and 4 subsection scores. A higher score indicates a worst outcome. I: mentation, behaviour and mood symptoms - 0 to 16; II: activities of daily living (ADL) - 0 to 52; III: motor function - 0 to 108; IV: complications of dopaminergic therapy - 0 to 23. Subsection scores for I to III are used to calculate a total score that ranges from 0 (no disability) to 176 (total dependence). |
| Change From Baseline in UPDRS Motor Score During ON Time | Baseline and Week 18 | UPDRS is a 42-item rating scale designed to assess Parkinson's Disease-related disability and impairment using a patient interview and a physical examination. It has 4 parts and 4 subsection scores. A higher score indicates a worst outcome. I: mentation, behaviour and mood symptoms - 0 to 16; II: ADL - 0 to 52; III: motor function - 0 to 108; IV: complications of dopaminergic therapy - 0 to 23. Subsection scores for I to III are used to calculate a total score that ranges from 0 (no disability) to 176 (total dependence). |
Participant flow
Pre-assignment details
The study consisted of a 2-week Screening Period during which the levodopa dose was optimised (if required), a 2-week Screening Period during which the levodopa dose was stabilised, an 18-week double-blind treatment period with rasagiline or placebo once daily (patients were randomised in a 1:1 ratio), and a 4-week Safety Follow-up Period.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Once daily; tablet; orally; 18 weeks | 66 |
| Azilect® 1 mg daily; tablet; orally; 18 weeks | 66 |
| Total | 132 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Administrative or other reason(s) | 1 | 0 |
| Overall Study | Adverse Event | 3 | 7 |
| Overall Study | Lack of Efficacy | 1 | 0 |
| Overall Study | Withdrawal of Consent | 3 | 1 |
Baseline characteristics
| Characteristic | Total | Placebo | Azilect® |
|---|---|---|---|
| Age Continuous | 59.8 years STANDARD_DEVIATION 8.8 | 59.5 years STANDARD_DEVIATION 9 | 60.2 years STANDARD_DEVIATION 8.6 |
| CGI-S | 2.99 units on a scale STANDARD_DEVIATION 1.02 | 3.05 units on a scale STANDARD_DEVIATION 0.92 | 2.94 units on a scale STANDARD_DEVIATION 1.11 |
| Sex: Female, Male Female | 56 Participants | 23 Participants | 33 Participants |
| Sex: Female, Male Male | 76 Participants | 43 Participants | 33 Participants |
| Total Daily OFF Time | 6.25 hours STANDARD_DEVIATION 2.5 | 6.24 hours STANDARD_DEVIATION 2.73 | 6.26 hours STANDARD_DEVIATION 2.29 |
| UPDRS-ADL Score During OFF Time | 11.48 units on a scale STANDARD_DEVIATION 6.21 | 11.15 units on a scale STANDARD_DEVIATION 5.84 | 11.79 units on a scale STANDARD_DEVIATION 6.58 |
| UPDRS Motor Score During ON time | 18.86 units on a scale STANDARD_DEVIATION 8.57 | 19.81 units on a scale STANDARD_DEVIATION 8.39 | 17.98 units on a scale STANDARD_DEVIATION 8.71 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 12 / 66 | 19 / 66 |
| serious Total, serious adverse events | 4 / 66 | 5 / 66 |
Outcome results
Primary
Change From Baseline in Mean Total Daily OFF Time Using Parkinson's Disease Patient Diary
Parkinson's Disease Patient Diary is a self-administered diary designed to assess motor fluctuations throughout the day. It is divided into 30-minute intervals, and the patient selects one of four options for each interval: asleep; off; on with no dyskinesia or without troublesome dyskinesia; or on with troublesome dyskinesia. The Change From Baseline in Mean Total Daily OFF Time is calculated by taking the difference between the average of the total daily OFF time at Weeks 6, 10, 14 and 18, and the Baseline Total Daily OFF Time.
Time frame: Baseline and Weeks 6, 10, 14, and 18
Population: Full-analysis set (FAS); observed cases (OC)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Mean Total Daily OFF Time Using Parkinson's Disease Patient Diary | -1.24 hours | Standard Error 0.26 |
| Azilect® | Change From Baseline in Mean Total Daily OFF Time Using Parkinson's Disease Patient Diary | -1.59 hours | Standard Error 0.25 |
Comparison: The power for this study, which is designed to show a trend, that is, to show a clinical difference in the primary outcome measure, is 72%.p-value: 0.325790% CI: [-0.93, 0.23]ANCOVA
Secondary
Change From Baseline in UPDRS-ADL Score During OFF Time
Unified Parkinson's Disease Rating Scale (UPDRS) is a 42-item rating scale designed to assess Parkinson's Disease-related disability and impairment using a patient interview and a physical examination. It has 4 parts and 4 subsection scores. A higher score indicates a worst outcome. I: mentation, behaviour and mood symptoms - 0 to 16; II: activities of daily living (ADL) - 0 to 52; III: motor function - 0 to 108; IV: complications of dopaminergic therapy - 0 to 23. Subsection scores for I to III are used to calculate a total score that ranges from 0 (no disability) to 176 (total dependence).
Time frame: Baseline and Week 18
Population: FAS; LOCF
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in UPDRS-ADL Score During OFF Time | 0.13 units on a scale | Standard Error 0.42 |
| Azilect® | Change From Baseline in UPDRS-ADL Score During OFF Time | -0.57 units on a scale | Standard Error 0.41 |
p-value: 0.225895% CI: [-1.84, 0.44]ANCOVA
Secondary
Change From Baseline in UPDRS Motor Score During ON Time
UPDRS is a 42-item rating scale designed to assess Parkinson's Disease-related disability and impairment using a patient interview and a physical examination. It has 4 parts and 4 subsection scores. A higher score indicates a worst outcome. I: mentation, behaviour and mood symptoms - 0 to 16; II: ADL - 0 to 52; III: motor function - 0 to 108; IV: complications of dopaminergic therapy - 0 to 23. Subsection scores for I to III are used to calculate a total score that ranges from 0 (no disability) to 176 (total dependence).
Time frame: Baseline and Week 18
Population: FAS; LOCF
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in UPDRS Motor Score During ON Time | -1.52 units on a scale | Standard Error 0.72 |
| Azilect® | Change From Baseline in UPDRS Motor Score During ON Time | -2.87 units on a scale | Standard Error 0.69 |
p-value: 0.1795% CI: [-3.29, 0.59]ANCOVA
Secondary
Clinical Status Using CGI-I Score During ON Time
Clinical Global Impression - Global Improvement (CGI-I) is a single-item rating scale used to evaluate a patient's condition relative to baseline on a 7-point scale, regardless of whether the improvement is related to the investigational medicinal product (IMP). The scale ranges from 1 (very much improved) to 7 (very much worse).
Time frame: Week 18
Population: FAS; last observation carried forward (LOCF)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Clinical Status Using CGI-I Score During ON Time | 3.35 units on a scale | Standard Error 0.13 |
| Azilect® | Clinical Status Using CGI-I Score During ON Time | 3.05 units on a scale | Standard Error 0.13 |
p-value: 0.094695% CI: [-0.65, 0.05]ANCOVA