A Study to Assess the PK and Pharmacodynamics of IPX203 in Subjects With Advanced Parkinson's Disease

IPX203 is an investigational product containing CD-LD.

IPX203-B16-01 Study Design:

A randomized, open-label, rater-blinded, multicenter, 2-treatment, 2-period, multiple-dose crossover study.

Approximately 30 qualified IR CD-LD-experienced advanced PD subjects will be randomized.

The study duration will be approximately 8 weeks, including the screening period.

• Sinemet (Drug), also known as IR CD-LD Tablets: Immediate Release Tablet containing carbidopa-levodopa flexible dosing
• IPX203 (Drug), also known as IPX203 ER CD-LD Capsules: Extended Release capsules containing carbidopa-levodopa flexible dosing

Primary outcomes

• Levodopa Cmax Following First Dose on Day 1 [Day 1]: Single Dose predose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 5.5, 6, 6.5, 7, 7.5, and 8 hours postdose
• Levodopa Tmax Following First Dose on Day 1 [Day 1]: Single Dose predose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 5.5, 6, 6.5, 7, 7.5, and 8 hours postdose
• Levodopa t1/2 Following First Dose on Day 1 [Day 1]: Single Dose predose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 5.5, 6, 6.5, 7, 7.5, and 8 hours postdose
• Levodopa AUCt Following First Dose on Day 1 [Day 1]: Single Dose predose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 5.5, 6, 6.5, 7, 7.5, and 8 hours postdose
• Levodopa AUCinf Following First Dose on Day 1 [Day 1]: Single Dose predose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 5.5, 6, 6.5, 7, 7.5, and 8 hours postdose
• Levodopa Bioavailability Relative to IR CD/LD Following First Dose on Day 1 [Day 1]: Single Dose predose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 5.5, 6, 6.5, 7, 7.5, and 8 hours postdose
• Carbidopa Cmax Following First Dose on Day 1 [Day 1]: Single Dose predose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 5.5, 6, 6.5, 7, 7.5, and 8 hours postdose
• Carbidopa Tmax Following First Dose on Day 1 [Day 1]: Single Dose predose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 5.5, 6, 6.5, 7, 7.5, and 8 hours postdose
• Carbidopa t1/2 Following First Dose on Day 1 [Day 1]: Single Dose predose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 5.5, 6, 6.5, 7, 7.5, and 8 hours postdose
• Carbidopa AUCt Following First Dose on Day 1 [Day 1]: Single Dose predose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 5.5, 6, 6.5, 7, 7.5, and 8 hours postdose
• Carbidopa AUCinf Following First Dose on Day 1 [Day 1]: Single Dose predose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 5.5, 6, 6.5, 7, 7.5, and 8 hours postdose
• Carbidopa Bioavailability Relative to IR CD/LD Following First Dose on Day 1 [Day 1]: Single Dose predose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 5.5, 6, 6.5, 7, 7.5, and 8 hours postdose
• Levodopa Cmax Following First Dose on Day 15 [Day 15]: Multiple Dose predose and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, and 10 hours postdose.
• Levodopa Tmax Following First Dose on Day 15 [Day 15]: Multiple Dose predose and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, and 10 hours postdose.
• Levodopa AUCtau Following First Dose on Day 15 [Day 15]: Multiple Dose predose and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, and 10 hours postdose.
• Carbidopa Cmax Following First Dose on Day 15 [Day 15]: Multiple Dose predose and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, and 10 hours postdose.
• Carbidopa Tmax Following First Dose on Day 15 [Day 15]: Multiple Dose predose and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, and 10 hours postdose.
• Carbidopa AUCtau Following First Dose on Day 15 [Day 15]: Multiple Dose predose and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, and 10 hours postdose.

Sex: All, ages: 40 Years to 100 Years

Eligibility will be determined at screening and Visit 1 of the study.

Inclusion Criteria:

* Diagnosed with idiopathic PD at age ≥ 40 years who are being chronically treated with stable regimens of CD-LD but experiencing motor complications.
* Hoehn and Yahr Stages 2, 3, or 4
* Montreal Cognitive Assessment (MoCA) score ≥ 24 at Screening Visit in "on" state.
* For the 4 weeks prior to the Screening, the subject experiences daily "wearing-off" episodes with periods of bradykinesia and rigidity and experiences an "off" state upon awakening on most mornings by history.
* Responsive to CD-LD therapy and currently being treated on a stable regimen with CD-LD for at least 4 weeks prior to Visit 1
* Typically experiences an "on" response with the first dose of IR CD-LD of the day (by subject history).
* By history, efficacy of the first morning dose of IR CD-LD lasts less than 4 hours

Exclusion Criteria:

* History of medical conditions or of a prior surgical procedure that would interfere with LD absorption, such as gastrectomy or proximal small-bowel resection.
* Liver enzyme values ≥ 2.5 x the upper limit of normal; or history of severe hepatic impairment.
* History of drug or alcohol abuse within the 12 months prior to Screening.
* Received within 4 weeks of Visit 1 or planning to take during participation in the clinical study: any doses of a controlled-release (CR) LD apart from a single daily bedtime dose or any doses of Rytary, additional CD (eg, Lodosyn) or benserazide (eg, Serazide), or catechol-O-methyl transferase inhibitors (entacapone or tolcapone) or medications containing these inhibitors (Stalevo). Received within 4 weeks of Visit 1 or planning to take during participation in the clinical study: nonselective monoamine oxidase (MAO) inhibitors, apomorphine, or dopaminergic blocking agents including antiemetics.
* History of psychosis within the past 10 years.
* Treatment with any dopamine antagonist antipsychotics for the purposes of psychosis or bipolar disorder within the last 2 years.
* Based on clinical assessment, subject does not adequately comprehend the terminology needed to complete the PD Diary.

Participant flow

Outcome results

• Levodopa Cmax Following First Dose on Day 1 (Primary), Mean, ng/mL: IPX203 2857.56 +/- 1204.506; Sinemet 2173.30 +/- 1240.774
• Levodopa Tmax Following First Dose on Day 1 (Primary), Mean, hour: IPX203 2.07 +/- 0.997; Sinemet 0.94 +/- 0.560
• Levodopa t1/2 Following First Dose on Day 1 (Primary), Mean, hour: IPX203 1.658 +/- 0.4838; Sinemet 1.420 +/- 0.3194
• Levodopa AUCt Following First Dose on Day 1 (Primary), Mean, ng.h/mL: IPX203 12107.60 +/- 5793.881; Sinemet 3747.61 +/- 1819.141
• Levodopa AUCinf Following First Dose on Day 1 (Primary), Mean, ng.h/mL: IPX203 13968.57 +/- 7606.901; Sinemet 4308.37 +/- 2123.057
• Levodopa Bioavailability Relative to IR CD/LD Following First Dose on Day 1 (Primary), Mean, Percentage: IPX203 88.965 +/- 21.7583; Sinemet 0 +/- 0
• Carbidopa Cmax Following First Dose on Day 1 (Primary), Mean, ng/mL: IPX203 500.35 +/- 316.299; Sinemet 151.50 +/- 103.225
• Carbidopa Tmax Following First Dose on Day 1 (Primary), Mean, hour: IPX203 2.61 +/- 0.655; Sinemet 2.07 +/- 0.675
• Carbidopa t1/2 Following First Dose on Day 1 (Primary), Mean, hour: IPX203 2.015 +/- 0.5159; Sinemet 1.969 +/- 0.7187
• Carbidopa AUCt Following First Dose on Day 1 (Primary), Mean, ng.h/mL: IPX203 1940.51 +/- 1095.449; Sinemet 436.63 +/- 286.286
• Carbidopa AUCinf Following First Dose on Day 1 (Primary), Mean, ng.h/mL: IPX203 2239.61 +/- 1232.234; Sinemet 610.44 +/- 407.305
• Carbidopa Bioavailability Relative to IR CD/LD Following First Dose on Day 1 (Primary), Mean, Percentage: IPX203 117.442 +/- 43.4176; Sinemet 0 +/- 0
• Levodopa Cmax Following First Dose on Day 15 (Primary), Mean, ng/mL: IPX203 2767.96 +/- 1258.525; Sinemet 2356.85 +/- 1178.628
• Levodopa Tmax Following First Dose on Day 15 (Primary), Mean, hour: IPX203 1.91 +/- 1.241; Sinemet 0.83 +/- 0.439
• Levodopa AUCtau Following First Dose on Day 15 (Primary), Mean, ng.h/ML: IPX203 11213.76 +/- 4887.246; Sinemet 3879.39 +/- 1744.328
• Carbidopa Cmax Following First Dose on Day 15 (Primary), Mean, ng/mL: IPX203 478.66 +/- 290.584; Sinemet 145.67 +/- 82.541
• Carbidopa Tmax Following First Dose on Day 15 (Primary), Mean, hour: IPX203 2.52 +/- 0.74; Sinemet 2.20 +/- 0.639
• Carbidopa AUCtau Following First Dose on Day 15 (Primary), Mean, ng.h/mL: IPX203 1892.39 +/- 1017.537; Sinemet 415.83 +/- 279.487

Adverse events

Time frame: 15 days for each intervention plus 1 week washout up to a total of 37 days

Serious adverse events by term

Other adverse events by term

• Study Protocol (PDF, 2016-10-05)
• Statistical Analysis Plan (PDF, 2017-09-29)

• Impax Study Director, Study director, Impax Laboratories, LLC