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This study evaluated the pharmacokinetics, motor effects, and assessed the safety of IPX066 compared with an immediate-release cabridopa-levodopa formulation in subjects with advanced Parkinson's disease.
This was a randomized, multicenter, open-label, single and multiple oral dose, two-treatment, two-period, crossover study in LD-experienced subjects with Parkinson's disease (PD). Subjects received 7 days of one treatment (IPX066 or IR CD-LD) followed by an approximate 7-day washout period followed by another 7 days of the other treatment (IR CD-LD or IPX066). During the approximate 7-day washout period, subjects took their prestudy CD-LD regimen. Pharmacokinetic and efficacy/pharmacodynamic measurements were done on Days 1 and 8. Safety measures (electrocardiograms [ECGs], clinical laboratory tests, vital signs, adverse events [AEs], and concomitant medications) were evaluated over the course of the study.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Sequence 1 | Other | Treatment Period 1: IPX066 - 7 days; Washout Period - 7 days; Treatment Period 2: IR CD-LD- 7 days |
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| Sequence 2 | Other | Treatment Period 1: IR CD-LD - 7 days; Washout period - 7 days; Treatment Period 2: IPX066- 7 days |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| IPX066 | Drug | experimental drug product: extended-release carbidopa-levodopa capsules |
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| Measure | Description | Time Frame |
|---|---|---|
| Pharmacokinetics Measurements to Determine Cmax for Carbidopa (CD) and Levodopa (LD) Plasma Concentrations From Samples Collected Pre-dose and at Different Time Points on Day 1 and Day 8 of Periods 1 and 2 of Both Treatment Arms. | For both treatment arms: Sequence 1 (IPX066, Washout, then IR CD-LD) and Sequence 2 (IR CD-LD, Washout, IPX066), blood samples for measurement of LD and CD plasma concentrations were collected pre-dose and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, and 8 hours after dosing on Day 1 (referred to as Single-Dose data); and at pre-dose, 0.5, 1,1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 hours after dosing on Day 8 (referred to as Multiple-Dose data). Maximum (peak) drug concentration (Cmax in nanograms/milliliter) was estimated using Single-Dose data and Multiple-Dose data. | Day 1 and on Day 8 after a week of intervention in each treatment arm: Arm 1 (IPX066 first, washout, then CD-LD IR) and Arm 2 (CD-LD IR first, washout, then IPX066) |
| Pharmacokinetics Measurements to Determine Tmax for Levodopa and Carbidopa Plasma Concentrations From Samples Collected Pre-dose and at Different Time Points on Day 1 and Day 8 of Periods 1 and 2 of Both Treatment Arms. | For both treatment arms: Sequence 1 (IPX066, Washout, then IR CD-LD) and Sequence 2 (IR CD-LD, Washout, IPX066), blood samples for measurement of LD and CD plasma concentrations were collected pre-dose and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, and 8 hours after dosing on Day 1 (referred to as Single-Dose data); and at pre-dose, 0.5, 1,1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 hours after dosing on Day 8 (referred to as Multiple-Dose data). Time of maximum drug concentration (Tmax in hours) was estimated using Single-Dose data and Multiple-Dose data. | Day 1 and on Day 8 after a week of intervention in each treatment arm: Arm 1 (IPX066 first, washout, then CD-LD IR) and Arm2 (CD-LD IR first, washout, then IPX066 |
| Pharmacokinetics Measurements to Determine Area Under the Concentration-time Curve for the Dosing Interval for LD and CD Concentrations From Blood Collected Pre-dose and at Different Time Points on Day 1 and Day 8 of Periods 1 and 2 of Treatment Arms. | For both treatment arms: Sequence 1 (IPX066, Washout, then IR CD-LD) and Sequence 2 (IR CD-LD, Washout, IPX066), blood samples for measurement of LD and CD plasma concentrations were collected pre-dose and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, and 8 hours after dosing on Day 1 (referred to as Single-Dose data); and at pre-dose, 0.5, 1,1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 hours after dosing on Day 8 (referred to as Multiple-Dose data). Area under the concentration-time curve for the dosing interval (AUC Tau) in hour*nanogram/milliliter was estimated using Single-Dose data and Multiple-Dose data. |
| Measure | Description | Time Frame |
|---|---|---|
| 8-Hour Efficacy Using Day 1 Tapping | Improvement in "Tapping: has been used as a surrogate endpoint for assessing subject being "On". Finger Tapping: the number of times the subject could tap two counter keys 20 cm apart alternately in 1 minute with the most affected arm assessed every 30 minutes on Day 1. Subjects performed the 60-second tapping measurement three times prior to dosing in the clinic, and at half-hour intervals through the 8-hour measurement period on Day 1 of each treatment period. More hours "On" during treatment represented better outcome. For the Tapping measurement, the protocol defined a 20% change from the average of the predose measurements as the time to "On." Each half-hour interval counted as 0.5 hour. Any measurement below a 20% improvement was considered time "Not On." If patient required redosing then primary analyses adjusted for redosing in calculating the results. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Impax Study Director | Impax Laboratories, LLC | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| IMPAX Laboratories | Hayward | California | 94544 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 21755537 | Background | Hauser RA, Ellenbogen AL, Metman LV, Hsu A, O'Connell MJ, Modi NB, Yao HM, Kell SH, Gupta SK. Crossover comparison of IPX066 and a standard levodopa formulation in advanced Parkinson's disease. Mov Disord. 2011 Oct;26(12):2246-52. doi: 10.1002/mds.23861. Epub 2011 Jul 13. |
| Label | URL |
|---|---|
| PebMed Abstract | View source |
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27 participants were enrolled, treated and completed the treatment with this protocol.
35 subjects were screened. 8 were screen failures (did to not meet inclusion/exclusion criteria) and 27 were randomized. Date of first patient enrolled: November 25, 2008 Date last patient completed: June 11, 2009 The study was conducted at 6 sites in the United States.
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| ID | Title | Description |
|---|---|---|
| FG000 | IPX066 First (7 Days), Washout (7 Days) Then IR CD-LD (7 Days) | In this arm there were 2 treatment periods of one week each. During period 1, 14 subjects received 7 days of IPX066 first. Then subjects returned to their pre-study regimen during the washout period of approximately 1 week. This was followed by Period 2. During period 2, the 14 subjects received IR CD-LD for 7 days. |
| FG001 | IR CD-LD First ( 7 Days), Washout (7 Days) Then IPX066 (7days) | In this arm there were 2 treatment periods of one week each. During period 1, 13 subjects received 7 days of IR CD-LD first. Then subjects returned to their pre-study regimen during the washout period of approximately 1 week. This was followed by Period 2. During period 2, the 13 subjects received IPX066 for 7 days. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Period 1 Treatment for 7 Days |
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| Period 2 Treatment for 7 Days |
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| ID | Title | Description |
|---|---|---|
| BG000 | All Study Participants | Participants who were randomized to receive either IPX066 or IR CD-LD |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Pharmacokinetics Measurements to Determine Cmax for Carbidopa (CD) and Levodopa (LD) Plasma Concentrations From Samples Collected Pre-dose and at Different Time Points on Day 1 and Day 8 of Periods 1 and 2 of Both Treatment Arms. | For both treatment arms: Sequence 1 (IPX066, Washout, then IR CD-LD) and Sequence 2 (IR CD-LD, Washout, IPX066), blood samples for measurement of LD and CD plasma concentrations were collected pre-dose and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, and 8 hours after dosing on Day 1 (referred to as Single-Dose data); and at pre-dose, 0.5, 1,1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 hours after dosing on Day 8 (referred to as Multiple-Dose data). Maximum (peak) drug concentration (Cmax in nanograms/milliliter) was estimated using Single-Dose data and Multiple-Dose data. | The study was designed to assess the single and multiple-dose PK and PD of IPX066 and IR CD-LD in subjects with advanced PD.14 subjects first received IPX066 (Period 1), then IR CD-LD (Period 2). 13 Subjects first received IR CD-LD (Period 1), then IPX066 (Period 2). All 27 subjects that were treated in the study were included in the PK analyses. | Posted | Mean | Standard Deviation | nanogram/milliliter | Day 1 and on Day 8 after a week of intervention in each treatment arm: Arm 1 (IPX066 first, washout, then CD-LD IR) and Arm 2 (CD-LD IR first, washout, then IPX066) |
At each of the 4 study visits and follow-up with the subject by phone within 1 week of study exit.
Safety measures (electrocardiograms [ECGs], clinical laboratory tests, vital signs, adverse events [AEs], and concomitant medications) were evaluated over the course of the study. The Investigators were specified in the protocol to follow each AE until resolution or stabilization and in accordance with Good Clinical Practice (GCP). Follow-up on these AEs were be recorded on the source documents and reported to IMPAX.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | IPX066 | All participants who received IPX066 in either study period |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Sleepy | Nervous system disorders | MedDRA (12.0) | Systematic Assessment |
The limitations of this study include its relatively small size, multiple statistical testing, short study durations, and open-label design.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Michelle Landolfi, PhD. Sr. Director, Regulatory Affairs | Impax Laboratories, Inc. | (510) 240-6496 | Michelle.Landolfi@impaxlabs.com |
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| ID | Term |
|---|---|
| D010300 | Parkinson Disease |
| ID | Term |
|---|---|
| D020734 | Parkinsonian Disorders |
| D001480 | Basal Ganglia Diseases |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
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| ID | Term |
|---|---|
| C009265 | carbidopa, levodopa drug combination |
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| IR CD-LD | Drug | active comparator: immediate-release carbidopa-levodopa capsules |
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| Day 1 and on Day 8 after a week of intervention in each treatment arm: Arm 1 (IPX066 first, washout, then CD-LD IR) and Arm2 (CD-LD IR first, washout, then IPX066 |
| Day 1 of each treatment period - three times prior to dosing in the clinic, and at half-hour intervals through the 8-hour measurement period |
| 8-Hour Efficacy Using Day 1 Unified Parkinson's Disease Rating Scale Part III Score | To determine efficacy on Day 1 the UPDRS (unified Parkinson's disease rating) Part III score, a clinician-scored measure of motor function, was collected immediately predose and 1, 2, 3, 4, 5, 6, 7 and 8 h post dose. The UPDRS Part III motor exam analyzes multiple motor functions like speech, facial expression, tremor, rigidity, movement, posture, gait etc. Each parameter is assigned values from 0 to 4, with 0 being normal and 4 being the most affected. The total range is 0 - 108, with lower scores indicating a better outcome.The average of post dose was calculated for day 1. | Pre dosing and at hourly intervals through the 8-hour measurement period on day 1 |
| Result Summary of Day 1 Dyskinesia Evaluated by Investigator Assessment for Each Treatment Period | To determine 8h efficacy on Day 1 the on site investigator assessments of "ON", "OFF" and "state of dyskinesia" for each subject was collected predose (-1, -0.5, and 0 hours) every 30 min for up to 8 hours after dosing . For all subjects duration of (1) OFF time (2) ON time without dyskinesia, (3) ON time with non-troublesome dyskinesia and (4) ON time with troublesome dyskinesia was calculated for both treatments. Definition of "ON" was based on a 20% change from predose measure, and the results were analyzed in the standard manner of a two way crossover design. The trial inclusion criteria included ability of subject to differentiate "ON" state from "OFF" state per investigator's assessment. | Predose and then every 30 min upto 8 h after dosing on Day of 1 of each treatment period |
| "Off" Time Hours Reported by Subjects Using Parkinson's Patient Diary | Subjects recorded state of "OFF" time using the Parkinson's Patient Diary | Last 3 days of each treatment period, every 30 minutes over a 24-hour day beginning at 6:00 AM |
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| Primary | Pharmacokinetics Measurements to Determine Tmax for Levodopa and Carbidopa Plasma Concentrations From Samples Collected Pre-dose and at Different Time Points on Day 1 and Day 8 of Periods 1 and 2 of Both Treatment Arms. | For both treatment arms: Sequence 1 (IPX066, Washout, then IR CD-LD) and Sequence 2 (IR CD-LD, Washout, IPX066), blood samples for measurement of LD and CD plasma concentrations were collected pre-dose and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, and 8 hours after dosing on Day 1 (referred to as Single-Dose data); and at pre-dose, 0.5, 1,1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 hours after dosing on Day 8 (referred to as Multiple-Dose data). Time of maximum drug concentration (Tmax in hours) was estimated using Single-Dose data and Multiple-Dose data. | The study was designed to assess the single and multiple-dose PK and PD of IPX066 and IR CD-LD in subjects with advanced PD. 14 subjects first received IPX066 (Period 1), then IR CD-LD (Period 2). 13 Subjects first received IR CD-LD (Period 1), then IPX066 (Period 2). All 27 subjects that were treated in the study were included in the PK analyses. | Posted | Mean | Standard Deviation | Hours | Day 1 and on Day 8 after a week of intervention in each treatment arm: Arm 1 (IPX066 first, washout, then CD-LD IR) and Arm2 (CD-LD IR first, washout, then IPX066 |
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| Primary | Pharmacokinetics Measurements to Determine Area Under the Concentration-time Curve for the Dosing Interval for LD and CD Concentrations From Blood Collected Pre-dose and at Different Time Points on Day 1 and Day 8 of Periods 1 and 2 of Treatment Arms. | For both treatment arms: Sequence 1 (IPX066, Washout, then IR CD-LD) and Sequence 2 (IR CD-LD, Washout, IPX066), blood samples for measurement of LD and CD plasma concentrations were collected pre-dose and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, and 8 hours after dosing on Day 1 (referred to as Single-Dose data); and at pre-dose, 0.5, 1,1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 hours after dosing on Day 8 (referred to as Multiple-Dose data). Area under the concentration-time curve for the dosing interval (AUC Tau) in hour*nanogram/milliliter was estimated using Single-Dose data and Multiple-Dose data. | The study was designed to assess the single and multiple-dose PK and PD of IPX066 and IR CD-LD in subjects with advanced PD. 14 subjects first received IPX066 (Period 1), then IR CD-LD (Period 2). 13 Subjects first received IR CD-LD (Period 1), then IPX066 (Period 2). All 27 subjects that were treated in the study were included in the PK analyses. | Posted | Mean | Standard Deviation | hour*nanogram/milliliter | Day 1 and on Day 8 after a week of intervention in each treatment arm: Arm 1 (IPX066 first, washout, then CD-LD IR) and Arm2 (CD-LD IR first, washout, then IPX066 |
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| Secondary | 8-Hour Efficacy Using Day 1 Tapping | Improvement in "Tapping: has been used as a surrogate endpoint for assessing subject being "On". Finger Tapping: the number of times the subject could tap two counter keys 20 cm apart alternately in 1 minute with the most affected arm assessed every 30 minutes on Day 1. Subjects performed the 60-second tapping measurement three times prior to dosing in the clinic, and at half-hour intervals through the 8-hour measurement period on Day 1 of each treatment period. More hours "On" during treatment represented better outcome. For the Tapping measurement, the protocol defined a 20% change from the average of the predose measurements as the time to "On." Each half-hour interval counted as 0.5 hour. Any measurement below a 20% improvement was considered time "Not On." If patient required redosing then primary analyses adjusted for redosing in calculating the results. | Analysis of covariance was the primary analysis conducted on the mean total Taps across the 8-hour measurement period, with the average of the three predose Tapping measurement values as a covariate. | Posted | Mean | Standard Deviation | Hours | Day 1 of each treatment period - three times prior to dosing in the clinic, and at half-hour intervals through the 8-hour measurement period |
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| Secondary | 8-Hour Efficacy Using Day 1 Unified Parkinson's Disease Rating Scale Part III Score | To determine efficacy on Day 1 the UPDRS (unified Parkinson's disease rating) Part III score, a clinician-scored measure of motor function, was collected immediately predose and 1, 2, 3, 4, 5, 6, 7 and 8 h post dose. The UPDRS Part III motor exam analyzes multiple motor functions like speech, facial expression, tremor, rigidity, movement, posture, gait etc. Each parameter is assigned values from 0 to 4, with 0 being normal and 4 being the most affected. The total range is 0 - 108, with lower scores indicating a better outcome.The average of post dose was calculated for day 1. | Analysis of covariance was the primary analysis conducted on the mean UPDRS Part III across the 8-hour measurement period, with the predose UPDRS Part III value as a covariate. This analysis was repeated at each timepoint for completeness. | Posted | Mean | Standard Deviation | UPDRS Part III Motor Score | Pre dosing and at hourly intervals through the 8-hour measurement period on day 1 |
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| Secondary | Result Summary of Day 1 Dyskinesia Evaluated by Investigator Assessment for Each Treatment Period | To determine 8h efficacy on Day 1 the on site investigator assessments of "ON", "OFF" and "state of dyskinesia" for each subject was collected predose (-1, -0.5, and 0 hours) every 30 min for up to 8 hours after dosing . For all subjects duration of (1) OFF time (2) ON time without dyskinesia, (3) ON time with non-troublesome dyskinesia and (4) ON time with troublesome dyskinesia was calculated for both treatments. Definition of "ON" was based on a 20% change from predose measure, and the results were analyzed in the standard manner of a two way crossover design. The trial inclusion criteria included ability of subject to differentiate "ON" state from "OFF" state per investigator's assessment. | For determining motor assessment of dyskinesia evaluated by investigator assessment a mixed-effect model was used with treatment, sequence, and period as factors and subjects within sequence as error term. The primary analysis was performed on the average of all times collected half hourly. Data for two patients was not collected, N25 instead of 27 | Posted | Mean | Standard Deviation | Hours | Predose and then every 30 min upto 8 h after dosing on Day of 1 of each treatment period |
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| Secondary | "Off" Time Hours Reported by Subjects Using Parkinson's Patient Diary | Subjects recorded state of "OFF" time using the Parkinson's Patient Diary | All treated patients | Posted | Mean | Standard Deviation | hours | Last 3 days of each treatment period, every 30 minutes over a 24-hour day beginning at 6:00 AM |
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| 0 |
| 27 |
| 3 |
| 27 |
| EG001 | CD-LD IR | All participants who received IR CD-LD in either study period | 0 | 27 | 3 | 27 |
| Choreiform Movements | Musculoskeletal and connective tissue disorders | MedDRA (12.0) | Systematic Assessment |
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| Feeling of Warth in Abdomen | Gastrointestinal disorders | MedDRA (12.0) | Systematic Assessment |
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| Headache - Frontal | Nervous system disorders | MedDRA (12.0) | Systematic Assessment |
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| Common Cold | Infections and infestations | MedDRA (12.0) | Systematic Assessment |
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| Dizziness after Taking Medication | Nervous system disorders | MedDRA (12.0) | Systematic Assessment |
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| Fatigue | General disorders | MedDRA (12.0) | Systematic Assessment |
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| Anxiety | Nervous system disorders | MedDRA (12.0) | Systematic Assessment |
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| D009422 | Nervous System Diseases |
| D009069 | Movement Disorders |
| D000080874 | Synucleinopathies |
| D019636 | Neurodegenerative Diseases |
| LD Tmax Single-Dose |
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| LD Tmax Multiple-Dose |
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| LD AUC Tau, Single-Dose |
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| LD AUC Tau, Multiple-Dose |
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| ON time with non-troublesome dyskinesia |
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| ON time with troublesome dyskinesia |
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