A Study to Compare Pharmacokinetics and Pharmacodynamics of IPX066 to Standard Carbidopa-Levodopa

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.

Time frame: 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

Population: 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.

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.

Time frame: 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)

Population: 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.

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.

Time frame: 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

Population: 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.

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.

Time frame: 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

Population: 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.

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.

Time frame: Pre dosing and at hourly intervals through the 8-hour measurement period on day 1

Population: 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.

Subjects recorded state of OFF time using the Parkinson's Patient Diary

Time frame: Last 3 days of each treatment period, every 30 minutes over a 24-hour day beginning at 6:00 AM

Population: All treated patients

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.

Time frame: Predose and then every 30 min upto 8 h after dosing on Day of 1 of each treatment period

Population: 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