A Study to Evaluate the Safety and Efficacy of IPX203 in Parkinson's Disease Participants With Motor Fluctuations

Impax Laboratories

Status and phase: Completed; Phase 3

Conditions: Parkinson's Disease (Disorder)

Treatments: Drug: IR CD-LD; Drug: IPX203 ER CD-LD; Other: Placebo Matching IR CD-LD; Other: Placebo Matching IPX203

Study type: Interventional

Funder types: Industry

Identifiers

NCT03670953

2018-002233-37 (EudraCT Number)

IPX203-B16-02

Details and patient eligibility

About

To evaluate the safety and efficacy of IPX203 (carbidopa and levodopa) extended-release capsules (IPX203 ER CD-LD) in comparison to immediate release (IR) CD-LD in the treatment of CD-LD-experienced participants with Parkinson's disease (PD) who have motor fluctuations.

Full description

This was a multicenter, randomized, double-blind, double-dummy, active-controlled, parallel-group study. The study consisted of a 3-week, open-label IR CD-LD dose adjustment period; a 4-week, open-label period for conversion to IPX203; followed by a 13-week double-blind treatment period with participants randomized in a 1:1 ratio, stratified by center, to receive either IPX203 (with matching IR CD-LD placebo) or IR CD-LD (with matching IPX203 placebo).

Enrollment: 630 patients

Sex: All

Ages: 40+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Male or female participants diagnosed at age ≥ 40 years with PD, consistent with the United Kingdom Parkinson's Disease Society Brain Bank Diagnostic Criteria and who are being treated with stable regimens of CD-LD but experiencing motor fluctuations.
• Able to provide written informed consent prior to the conduct of any study-specific procedures.
• Female participants of childbearing potential must have a negative urine pregnancy test at Screening Visit.
• Negative urine screen for drugs of abuse and negative alcohol breath test at Screening.
• Hoehn and Yahr Stages 1, 2, 3, or 4 in the "On" state (part of Movement Disorders Society version of the Unified Parkinson's Disease Rating Scale [MDS-UPDRS] Part III)
• Agrees to use a medically acceptable method of contraception throughout the study and for 6 weeks after completing the study. Medically acceptable methods of contraception that may be used by the participant and/or partner include but are not limited to: abstinence, oral contraception, NuvaRing or transdermal systems, diaphragm with vaginal spermicide, intrauterine device, condom and partner using vaginal spermicide, surgical sterilization (6 months), progestin implant or injection, or postmenopausal female (no menstrual period for ˃ 2 years) or vasectomy (˃ 6 months).
• Montreal Cognitive Assessment (MoCA) score ≥ 24 at Screening Visit in "On" state.
• Able to differentiate "On" state from "Off" state as determined by at least 75% concordance with a trained rater in "On/Off" ratings for 8 ratings over a 4-hour training period. The concordance must include at least 1 "On" and 1 "Off" rating and must be achieved within two 4-hour training sessions.
• Able and willing to comply with the protocol, including completion of diaries and availability for all study visits.
• 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.
• At Screening, the participant has predictable "Off" periods.

Exclusion criteria

• Received any investigational medications within 30 days or 5 times the half-life, whichever is longer, prior to Visit 1.
• Female participants who are currently breastfeeding or lactating.
• Had prior neurosurgical treatment for PD or if such procedure is planned or anticipated during the study period.
• Allergic to any excipient in the study drugs.
• History of medical conditions or of a prior surgical procedure that would interfere with LD absorption, such as gastrectomy, proximal small-bowel resection, or bariatric surgery.
• History of upper gastrointestinal hemorrhage in participants with peptic ulcer disease within the past 5 years.
• History of glaucoma with intraocular pressures that are elevated despite appropriate medical management.
• History of seizure or epilepsy and experienced at least 1 seizure during the past 12 months or has not been compliant with medically recommended therapy or visits.
• History of myocardial infarction with residual atrial, nodal, or ventricular arrhythmias that are not controlled with medical and/or surgical interventions. A recent (≤ 12 months) history of myocardial infarction with secondary arrhythmias is exclusionary regardless of the therapeutic control.
• History of neuroleptic malignant syndrome or of nontraumatic rhabdomyolysis.
• Liver enzyme values ≥ 2.5 times the upper limit of normal; or history of severe hepatic impairment.
• Serum creatinine level ≥ 1.75 times the upper limit of normal; or requires dialysis at the time of Screening.
• Participant with a history of malignant melanoma or with a suspicious undiagnosed skin lesion which in the opinion of the investigator could be melanoma.
• History of drug or alcohol abuse within the 12 months prior to Screening.
• Received within 4 weeks of Screening or planning to take during participation in the clinical study:
• Any doses of a CR CD-LD apart from a single daily bedtime dose, 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),
• Nonselective monoamine oxidase inhibitors (MAOI), apomorphine, or antidopaminergic agents, including antiemetics.
• Employees or family members of the investigator, study site, or sponsor.
• Participants who have previously participated in an IPX203 study.
• Participants who, in the opinion of the clinical investigator, should not participate in the study.
• Based on clinical assessment, participant does not adequately comprehend the terminology needed to complete the PD diary.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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630 participants in 4 patient groups

IR CD-LD - Dose Adjustment

Active Comparator group

Description:

Participants started on the same dose as the pre-study dosing regimen of IR CD-LD and then received dose adjusted IR CD-LD tablets daily orally, for a period of 3 weeks. If the participant was taking controlled release carbidopa-levodopa (CR CD-LD), the CR CD-LD was discontinued and substituted with a 1:1 milligram-equivalent dose of IR CD-LD.

Treatment:

Drug: IR CD-LD

IPX203 - Dose Conversion

Experimental group

Description:

Participants received extended release (ER) CD-LD (IPX203) capsules orally, every 6 - 12 hours for a period of 4 weeks at a dose based on their most frequent stable dose of IR CD-LD in dose adjustment period. Participant with most frequent stable dose of 25-100 milligrams (mg) IR CD-LD received 70 - 280 mg IPX203 thrice daily (TID); \>25-100 - 37.5-150 mg IR CD-LD received 105-420 mg IPX203 TID; \>37.5-150 - 50-200 mg IR CD-LD received 140-560 mg IPX203 TID; \>50 - 200 mg IR CD-LD received 175-700 mg IPX203 TID. Participants who received a daily total dose of less than 125-500 mg IR CD-LD in dose adjustment received IPX203 every 12 hours. After initial dose conversion from IR CD-LD to IPX203 as per above mentioned dose conversion schedule, the dose of IPX203 could be further adjusted during the 4 week dose conversion period.

Treatment:

Drug: IPX203 ER CD-LD

IPX203 - Double-Blind Maintenance

Experimental group

Description:

Participants received IPX203 capsules orally, every 6 - 12 hours for 13 weeks at a stable dose established at the end of dose conversion period along with placebo matched to IR CD-LD.

Treatment:

Drug: IPX203 ER CD-LD

Other: Placebo Matching IPX203

IR CD-LD - Double -Blind Maintenance

Active Comparator group

Description:

Participants received IR CD-LD tablets daily orally, for 13 weeks at a stable dose established at the end of dose adjustment period along with placebo matched to IPX203.

Treatment:

Drug: IR CD-LD

Other: Placebo Matching IR CD-LD