Parkinson's Disease
Conditions
Keywords
Parkinson's, Rasagiline Mesylate
Brief summary
A 2 phase study to evaluate disease progression in Parkinson's disease patients taking rasagiline
Interventions
tablet, 1mg once daily
OTHERPlacebo
Placebo
Sponsors
Teva Branded Pharmaceutical Products R&D, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
30 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Men and women with idiopathic PD whose diagnosis is confirmed at screening, with at least two cardinal signs without any other known or suspected cause of parkinsonism. If tremor is not present, subjects must have unilateral onset and persistent asymmetry. * Subjects with a diagnosis of early idiopathic PD of less than 1½ years duration from time of documented diagnosis. * Subjects whose clinical condition at the time of enrollment does not require anti-PD treatment and will not require for the next 9 months. * Willing and able to give informed consent.
Exclusion criteria
* Subjects younger than 30 or older than 80 years. * Subjects with loss of postural reflexes. * Subjects with UPDRS Tremor score of 3 or greater in any limb. * Subjects with Hoehn &Yahr Stage III or greater at screening. * Subjects with freezing while walking. * Subjects with any of the following features that tend to exclude PD as the cause of Parkinsonism: * History of repeated strokes with stepwise progression of Parkinsonian features * History of repeated head injury or history of definite encephalitis * Sustained remission * Supranuclear gaze palsy * Cerebellar signs * Early severe autonomic involvement * Babinski's sign * Presence of a cerebral tumour or communicating hydrocephalus * MPTP exposure * Oculogyric crises * Subjects who have had previous use of rasagiline or selegiline * Subjects having used other anti-PD medication basis at any time prior to baseline * Subjects having used other anti-PD medication (including anticholinergics) for less than 3 weeks during the 3 month period prior to baseline. (not including a single L-Dopa dose as part of L-Dopa test) * Subjects having used any other anti-PD medication (including anticholinergics) for less than 3 weeks prior to the 3 month period preceding baseline whose anti-PD medication is intentionally ceased in order for the subject to enter the study. * Subjects who have a clinically significant or unstable medical or surgical condition that may preclude safe and complete participation * Hypertensive subjects whose BP is not well controlled according to the medical record or as observed during the week of home BP recording prior to baseline * Subjects diagnosed with melanoma based on the screening dermatologic examination, or with a history of melanoma. Subjects with suspicious lesions at baseline who do not undergo biopsy * Subjects with significant cognitive impairment as defined by MMSE score \< 26 * Subjects with clinically significant psychiatric illness, including major depression \[Beck Depression Inventory (short form) ≥15 * Subjects with a history of alcohol or substance abuse within the past 2 years * Subjects who have taken any experimental medications within 60 days prior to baseline * Subjects who have used coenzyme Q10 (in daily doses \> 300 mg) within 120 days prior to baseline * Subjects who have used sympathomimetics (including over-the-counter remedies - nasal or oral), dextromethorphan, pethidine or St. John's Wort within the 7 days prior to baseline * Subjects who have used antidepressants within 42 days prior to baseline * Subjects who have used ciprofloxacin, a potent CYP 1A2 inhibitor within 7 days prior to baseline * Subjects who have used MAO inhibitors including reserpine or methyldopa within the three months prior to baseline, or treatment with an anti-emetic or antipsychotic medication with central dopamine antagonist activity within the six months prior to baseline * Women who are not postmenopausal, surgically sterilized, or using adequate birth control \[oral birth control pills, IUD, or a long acting injectable form of contraception; barrier methods alone (i.e., condom) are not sufficient\]. Women of childbearing potential without a negative pregnancy test at screening. Nursing women
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Total Unified Parkinson's Disease Rating Scale (UPDRS) Score From Baseline | 12w, 24w, 36w, 42w, 48w, 54w, 60w, 66w, 72w | The primary efficacy endpoint was defined as the change in Total UPDRS from Baseline. Subjects were assessed according to the United Parkinson's Disease Rating Scale (UPDRS,(version 3;) Parts I and II are historical data and are designed to rate mentation, behavior and mood; Part III is done as a motor examination at the time of a visit. The UPDRS measures patient status on a scale 0, which is normal or none, to 4, which is severe or the worst scenario. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Unified Parkinson's Disease Rating Scale (UPDRS) Score From Baseline to Last Observed Value in the Placebo Phase | 36 weeks | Subjects were assessed according to the United Parkinson's Disease Rating Scale UPDRS,(version 3;) Parts I and II are historical data and are designed to rate mentation, behavior and mood; Part III is done as a motor examination at the time of a visit. The UPDRS measures patient status on a scale 0, which is normal or none, to 4, which is severe or the worst scenario. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 1mg Delayed Start 1mg Rasagiline tablet QD 36 week delayed start active treatment arms (36 weeks placebo followed by 36 weeks Rasagiline) | 298 |
| 1mg Early Start 1mg Rasagiline tablet QD early start active treatment arm (72 weeks active) | 288 |
| 2mg Early Start 2mg Rasagiline tablet QD early start active treatment arm (72 weeks active) | 293 |
| 2mg Delayed Start 2mg Rasagiline tablet QD 36 week delayed start active treatment arms (36 weeks placebo followed by 36 weeks Rasagiline) | 295 |
| Total | 1,174 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 10 | 14 | 16 | 14 |
| Overall Study | Death | 0 | 1 | 0 | 0 |
| Overall Study | Lost to Follow-up | 1 | 1 | 1 | 2 |
| Overall Study | Need for additional prohibited treatment | 38 | 28 | 27 | 25 |
| Overall Study | Physician Decision | 0 | 0 | 1 | 2 |
| Overall Study | Protocol Violation | 1 | 0 | 2 | 1 |
| Overall Study | Withdrawal by Subject | 17 | 6 | 7 | 5 |
Baseline characteristics
| Characteristic | 1mg Early Start | 2mg Early Start | 2mg Delayed Start | 1mg Delayed Start | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 125 Participants | 124 Participants | 122 Participants | 123 Participants | 494 Participants |
| Age, Categorical Between 18 and 65 years | 163 Participants | 169 Participants | 173 Participants | 175 Participants | 680 Participants |
| Age Continuous | 62.4 years STANDARD_DEVIATION 9.7 | 62.3 years STANDARD_DEVIATION 9.6 | 62.4 years STANDARD_DEVIATION 9.7 | 61.9 years STANDARD_DEVIATION 9.6 | 62.2 years STANDARD_DEVIATION 9.6 |
| Region of Enrollment Argentina | 17 participants | 16 participants | 18 participants | 17 participants | 68 participants |
| Region of Enrollment Austria | 2 participants | 2 participants | 2 participants | 2 participants | 8 participants |
| Region of Enrollment Canada | 27 participants | 29 participants | 25 participants | 28 participants | 109 participants |
| Region of Enrollment France | 11 participants | 12 participants | 14 participants | 11 participants | 48 participants |
| Region of Enrollment Germany | 28 participants | 26 participants | 28 participants | 27 participants | 109 participants |
| Region of Enrollment Hungary | 8 participants | 6 participants | 7 participants | 8 participants | 29 participants |
| Region of Enrollment Israel | 23 participants | 21 participants | 21 participants | 22 participants | 87 participants |
| Region of Enrollment Italy | 25 participants | 28 participants | 25 participants | 24 participants | 102 participants |
| Region of Enrollment Netherlands | 9 participants | 9 participants | 9 participants | 9 participants | 36 participants |
| Region of Enrollment Portugal | 4 participants | 4 participants | 4 participants | 4 participants | 16 participants |
| Region of Enrollment Romania | 24 participants | 25 participants | 24 participants | 25 participants | 98 participants |
| Region of Enrollment Spain | 12 participants | 12 participants | 12 participants | 12 participants | 48 participants |
| Region of Enrollment United Kingdom | 7 participants | 9 participants | 8 participants | 7 participants | 31 participants |
| Region of Enrollment United States | 91 participants | 94 participants | 98 participants | 102 participants | 385 participants |
| Sex: Female, Male Female | 113 Participants | 118 Participants | 113 Participants | 113 Participants | 457 Participants |
| Sex: Female, Male Male | 175 Participants | 175 Participants | 182 Participants | 185 Participants | 717 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 82 / 593 | 40 / 288 | 34 / 293 |
| serious Total, serious adverse events | 22 / 593 | 37 / 288 | 44 / 293 |
Outcome results
Primary
Change in Total Unified Parkinson's Disease Rating Scale (UPDRS) Score From Baseline
The primary efficacy endpoint was defined as the change in Total UPDRS from Baseline. Subjects were assessed according to the United Parkinson's Disease Rating Scale (UPDRS,(version 3;) Parts I and II are historical data and are designed to rate mentation, behavior and mood; Part III is done as a motor examination at the time of a visit. The UPDRS measures patient status on a scale 0, which is normal or none, to 4, which is severe or the worst scenario.
Time frame: 12w, 24w, 36w, 42w, 48w, 54w, 60w, 66w, 72w
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 1mg Delayed Start | Change in Total Unified Parkinson's Disease Rating Scale (UPDRS) Score From Baseline | Week 60 | 1.9 Scores on a scale | Standard Deviation 7.5 |
| 1mg Delayed Start | Change in Total Unified Parkinson's Disease Rating Scale (UPDRS) Score From Baseline | Week 54 | 1.9 Scores on a scale | Standard Deviation 7.3 |
| 1mg Delayed Start | Change in Total Unified Parkinson's Disease Rating Scale (UPDRS) Score From Baseline | Week 72 | 3.3 Scores on a scale | Standard Deviation 8.9 |
| 1mg Delayed Start | Change in Total Unified Parkinson's Disease Rating Scale (UPDRS) Score From Baseline | Week 42 | 2.4 Scores on a scale | Standard Deviation 7.4 |
| 1mg Delayed Start | Change in Total Unified Parkinson's Disease Rating Scale (UPDRS) Score From Baseline | Week 36 | 3.7 Scores on a scale | Standard Deviation 7.2 |
| 1mg Delayed Start | Change in Total Unified Parkinson's Disease Rating Scale (UPDRS) Score From Baseline | Week 24 | 3.0 Scores on a scale | Standard Deviation 6.5 |
| 1mg Delayed Start | Change in Total Unified Parkinson's Disease Rating Scale (UPDRS) Score From Baseline | Week 66 | 2.5 Scores on a scale | Standard Deviation 8.1 |
| 1mg Delayed Start | Change in Total Unified Parkinson's Disease Rating Scale (UPDRS) Score From Baseline | Week 48 | 1.9 Scores on a scale | Standard Deviation 6.9 |
| 1mg Delayed Start | Change in Total Unified Parkinson's Disease Rating Scale (UPDRS) Score From Baseline | Week 12 | 0.9 Scores on a scale | Standard Deviation 4.9 |
| 1mg Early Start | Change in Total Unified Parkinson's Disease Rating Scale (UPDRS) Score From Baseline | Week 48 | 0.7 Scores on a scale | Standard Deviation 7 |
| 1mg Early Start | Change in Total Unified Parkinson's Disease Rating Scale (UPDRS) Score From Baseline | Week 60 | 1.1 Scores on a scale | Standard Deviation 7.3 |
| 1mg Early Start | Change in Total Unified Parkinson's Disease Rating Scale (UPDRS) Score From Baseline | Week 54 | 0.7 Scores on a scale | Standard Deviation 7.1 |
| 1mg Early Start | Change in Total Unified Parkinson's Disease Rating Scale (UPDRS) Score From Baseline | Week 24 | -1.1 Scores on a scale | Standard Deviation 5.6 |
| 1mg Early Start | Change in Total Unified Parkinson's Disease Rating Scale (UPDRS) Score From Baseline | Week 12 | -1.2 Scores on a scale | Standard Deviation 5.6 |
| 1mg Early Start | Change in Total Unified Parkinson's Disease Rating Scale (UPDRS) Score From Baseline | Week 36 | 0.6 Scores on a scale | Standard Deviation 5.9 |
| 1mg Early Start | Change in Total Unified Parkinson's Disease Rating Scale (UPDRS) Score From Baseline | Week 72 | 1.9 Scores on a scale | Standard Deviation 8.1 |
| 1mg Early Start | Change in Total Unified Parkinson's Disease Rating Scale (UPDRS) Score From Baseline | Week 66 | 1.5 Scores on a scale | Standard Deviation 7.7 |
| 1mg Early Start | Change in Total Unified Parkinson's Disease Rating Scale (UPDRS) Score From Baseline | Week 42 | 0.2 Scores on a scale | Standard Deviation 6.7 |
| 2mg Early Start | Change in Total Unified Parkinson's Disease Rating Scale (UPDRS) Score From Baseline | Week 48 | 0.5 Scores on a scale | Standard Deviation 7.1 |
| 2mg Early Start | Change in Total Unified Parkinson's Disease Rating Scale (UPDRS) Score From Baseline | Week 12 | -0.7 Scores on a scale | Standard Deviation 4.8 |
| 2mg Early Start | Change in Total Unified Parkinson's Disease Rating Scale (UPDRS) Score From Baseline | Week 24 | -0.5 Scores on a scale | Standard Deviation 5.6 |
| 2mg Early Start | Change in Total Unified Parkinson's Disease Rating Scale (UPDRS) Score From Baseline | Week 36 | 0.8 Scores on a scale | Standard Deviation 6.5 |
| 2mg Early Start | Change in Total Unified Parkinson's Disease Rating Scale (UPDRS) Score From Baseline | Week 42 | 0.4 Scores on a scale | Standard Deviation 7.2 |
| 2mg Early Start | Change in Total Unified Parkinson's Disease Rating Scale (UPDRS) Score From Baseline | Week 54 | 0.8 Scores on a scale | Standard Deviation 7.2 |
| 2mg Early Start | Change in Total Unified Parkinson's Disease Rating Scale (UPDRS) Score From Baseline | Week 60 | 1.2 Scores on a scale | Standard Deviation 7.9 |
| 2mg Early Start | Change in Total Unified Parkinson's Disease Rating Scale (UPDRS) Score From Baseline | Week 66 | 1.5 Scores on a scale | Standard Deviation 8 |
| 2mg Early Start | Change in Total Unified Parkinson's Disease Rating Scale (UPDRS) Score From Baseline | Week 72 | 2.2 Scores on a scale | Standard Deviation 8.1 |
| 2mg Delayed Start | Change in Total Unified Parkinson's Disease Rating Scale (UPDRS) Score From Baseline | Week 60 | 1.6 Scores on a scale | Standard Deviation 7.4 |
| 2mg Delayed Start | Change in Total Unified Parkinson's Disease Rating Scale (UPDRS) Score From Baseline | Week 42 | 1.7 Scores on a scale | Standard Deviation 6.6 |
| 2mg Delayed Start | Change in Total Unified Parkinson's Disease Rating Scale (UPDRS) Score From Baseline | Week 36 | 3.0 Scores on a scale | Standard Deviation 6.9 |
| 2mg Delayed Start | Change in Total Unified Parkinson's Disease Rating Scale (UPDRS) Score From Baseline | Week 72 | 2.3 Scores on a scale | Standard Deviation 7.8 |
| 2mg Delayed Start | Change in Total Unified Parkinson's Disease Rating Scale (UPDRS) Score From Baseline | Week 66 | 2.0 Scores on a scale | Standard Deviation 8.2 |
| 2mg Delayed Start | Change in Total Unified Parkinson's Disease Rating Scale (UPDRS) Score From Baseline | Week 24 | 2.2 Scores on a scale | Standard Deviation 6.5 |
| 2mg Delayed Start | Change in Total Unified Parkinson's Disease Rating Scale (UPDRS) Score From Baseline | Week 54 | 1.1 Scores on a scale | Standard Deviation 7 |
| 2mg Delayed Start | Change in Total Unified Parkinson's Disease Rating Scale (UPDRS) Score From Baseline | Week 48 | 1.4 Scores on a scale | Standard Deviation 6.8 |
| 2mg Delayed Start | Change in Total Unified Parkinson's Disease Rating Scale (UPDRS) Score From Baseline | Week 12 | 0.7 Scores on a scale | Standard Deviation 5.6 |
Comparison: Hypothesis #1: Slopes Superiority of 1mg Rasagiline over Placebo in the PC Phase Where slope is the model estimate of the change from baseline in total UPDRS per week.~In this analysis, all available post-baseline observations in the PC Phase of the trial are analyzed (ITT efficacy data analysis set, weeks 12, 24 and 36). The placebo groups for rasagiline 1mg (delayed-start) and 2mg (delayed-start)are combined to one placebo group.p-value: 0.0133Repeated Measures Mixed Linear Model
Comparison: Hypothesis #1: Slopes Superiority of 2mg Rasagiline over Placebo in the PC Phase Where slope is the model estimate of the change from baseline in total UPDRS per week.~In this analysis, all available post-baseline observations in the PC Phase of the trial are analyzed (ITT efficacy data analysis set, weeks 12, 24 and 36). The placebo groups for rasagiline 1mg (delayed-start)and 2mg (delayed-start) are combined to one placebo group.p-value: 0.0001Repeated Measures Mixed Linear Model
Comparison: Hypothesis #2: Superiority of Early over Delayed Start at Week 72 In this analysis, observations of subjects entering the active phase with at least 24 weeks of treatment during the PC Phase and at least one available Total UPDRS measurement during the active-treatment phase from weeks 48, 54, 60, 66 or 72, are analyzed (ACTE data analysis set).p-value: 0.025Repeated Measures
Comparison: Hypothesis #2:Superiority of Early over Delayed Start at Week 72 In this analysis, observations of subjects entering the active phase with at least 24 weeks of treatment during the PC Phase and at least one available Total UPDRS measurement during the active-treatment phase from weeks 48, 54, 60, 66 or 72, are analyzed (ACTE data analysis set.)p-value: 0.6028Repeated Measures
Comparison: Hypothesis #3: Slopes Non-Inferiority of Early Start over Delayed Start in the Active Phase.~Where slope is the model estimate of the change from baseline in total UPDRS per week. In this analysis, observations of all subjects entering the active phase with at least 24 weeks of treatment during the PC Phase and at least one available Total UPDRS measurement during the active treatment phase from weeks 48, 54, 60, 66 or 72, are analyzed (ACTE data analysis set).90% CI: [-0.036, 0.036]
Comparison: Hypothesis #3: Slopes Non-Inferiority of Early Start over Delayed Start in the Active Phase.~Where slope is the model estimate of the change from baseline in total UPDRS per week. In this analysis, observations of all subjects entering the active phase with at least 24 weeks of treatment during the PC Phase and at least one available Total UPDRS measurement during the active treatment phase from weeks 48, 54, 60, 66 or 72, are analyzed (ACTE data analysis set).90% CI: [-0.005, 0.062]
Secondary
Change in Unified Parkinson's Disease Rating Scale (UPDRS) Score From Baseline to Last Observed Value in the Placebo Phase
Subjects were assessed according to the United Parkinson's Disease Rating Scale UPDRS,(version 3;) Parts I and II are historical data and are designed to rate mentation, behavior and mood; Part III is done as a motor examination at the time of a visit. The UPDRS measures patient status on a scale 0, which is normal or none, to 4, which is severe or the worst scenario.
Time frame: 36 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 1mg Delayed Start | Change in Unified Parkinson's Disease Rating Scale (UPDRS) Score From Baseline to Last Observed Value in the Placebo Phase | 3.9 Scores on a scale | Standard Deviation 7.2 |
| 1mg Early Start | Change in Unified Parkinson's Disease Rating Scale (UPDRS) Score From Baseline to Last Observed Value in the Placebo Phase | 1.0 Scores on a scale | Standard Deviation 6 |
| 2mg Early Start | Change in Unified Parkinson's Disease Rating Scale (UPDRS) Score From Baseline to Last Observed Value in the Placebo Phase | 0.8 Scores on a scale | Standard Deviation 6.5 |
Comparison: The adjusted means of the changes in Total UPDRS from baseline to LOV in the placebo-controlled phase, observed in the 1 mg and 2 mg rasagiline early-start groups are compared (two contrasts) to the combined placebo group (1 mg and 2 mg rasagiline delayed-start groups), by applying an Analysis of Covariance model. The model includes treatment group, center and baseline Total UPDRS as covariates. For this analysis, both delayed start arms are pooled as a 'placebo arm'p-value: <0.000195% CI: [-3.857, -2.153]ANCOVA
Comparison: The adjusted means of the changes in Total UPDRS from baseline to LOV in the placebo-controlled phase, observed in the 1 mg and 2 mg rasagiline early-start groups are compared (two contrasts) to the combined placebo group (1 mg and 2 mg rasagiline delayed-start groups), by applying an Analysis of Covariance model. The model includes treatment group, center and baseline Total UPDRS as covariates.~For this analysis, both delayed start arms are pooled as a 'placebo arm'p-value: <0.000195% CI: [-4.004, -2.305]ANCOVA