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

Impax Laboratories, LLC27 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Parkinson's Disease

Interventions

IPX066DRUG

experimental drug product: extended-release carbidopa-levodopa capsules

IR CD-LDDRUG

active comparator: immediate-release carbidopa-levodopa capsules

Eligibility

Sex: ALLMin age: 30 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Male or female diagnosed with idiopathic PD, without any known cause for Parkinsonism. 2. If female and of childbearing potential, subject should be abstinent or continuing to practice and willing to continue throughout the study with appropriate contraceptives (defined as Nova ring, oral, injected, transdermal patch, implanted, or barrier). The subject must agree to take every precaution to ensure that pregnancy will not occur during the study. 3. At least 30 years old at the time of diagnosis of PD. 4. Mini Mental State Examination (MMSE) ≥ 26 at Screening Visit. 5. A responder to LD and currently being chronically treated with stable dosage of commercially available standard, orally disintegrating, or controlled-release CD LD for at least 1 month. 6. Must have predictable fluctuations between "on" and "off" states. 7. Hoehn and Yahr Stage I-IV when "on". 8. Able to provide informed consent and willing to sign Health Insurance Portability and Accountability Act (HIPAA) authorization. 9. Able and willing to comply with the protocol, including availability for all scheduled study visits and blood sample collections. Exclusion Criteria: 1. Pregnant or breastfeeding. 2. Diagnosed with atypical parkinsonism. 3. History, physical findings or laboratory results suggesting a diagnosis other than PD. 4. Allergic or nonresponsive to previous CD-LD therapy. 5. Any medical (e.g., liver or kidney impairment, peptic ulcer) or condition/history that, in the Investigator's opinion, may jeopardize the subject's safety. 6. Exposure to any investigational agent within 30 days prior to Visit 1. 7. Donated blood or plasma within 28 days. 8. Had prior functional neurosurgical treatment for PD (ablation or Deep Brain Stimulation).

Locations (1)

IMPAX Laboratories

Hayward, California, United States

Outcomes

Primary Outcomes

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.

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)

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.

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

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.

Data from ClinicalTrials.gov

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Secondary Outcomes

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.

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

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.

Time frame: 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.

Time frame: 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

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