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

Study Overview
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Brief Summary
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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.

Detailed Description
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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).

Official Title
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A Randomized Controlled Study to Compare the Safety and Efficacy of IPX203 With Immediate-Release Carbidopa-Levodopa in Parkinson's Disease Patients With Motor Fluctuations

Conditions
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Parkinson's Disease (Disorder)

Intervention / Treatment
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* Drug: IR CD-LD
* Drug: IPX203 ER CD-LD
* Other: Placebo Matching IPX203
* Other: Placebo Matching IR CD-LD


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Multicenter, randomized, double-blind, double-dummy, active-controlled, parallel-group study.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: IR CD-LD - Dose Adjustment<br>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. | Drug: IR CD-LD<br>* Active comparator - IR CD-LD<br>* Other names: Generic for Sinemet tablets;|
| Experimental: IPX203 - Dose Conversion<br>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. | Drug: IPX203 ER CD-LD<br>* Investigational formulation - ER CD-LD<br>|
| Experimental: IPX203 - Double-Blind Maintenance<br>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. | Drug: IPX203 ER CD-LD<br>* Investigational formulation - ER CD-LD<br>Other: Placebo Matching IPX203<br>* Double dummy placebo capsules<br>|
| Active Comparator: IR CD-LD - Double -Blind Maintenance<br>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. | Drug: IR CD-LD<br>* Active comparator - IR CD-LD<br>* Other names: Generic for Sinemet tablets;Other: Placebo Matching IR CD-LD<br>* Double dummy placebo tablets<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline in Good on Time Per Day at Week 20/Early Termination (ET) | Good on time was derived from the 3-day PD Diaries. For each day, Good on time was calculated by adding the number of half-hour intervals in which either an On without dyskinesia or On with nontroublesome dyskinesia was checked. Baseline was defined as data obtained from PD Diary collected over 3 days prior to Week 7/Randomization. Least square mean (LSM), standard error (SE), confidence interval (CI), Mixed model repeated measures (MMRM), Change from baseline (CFB). | Baseline (Week 7) and Week 20/ET | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Off Time Per Day at Week 20/ET | Off time was derived from the 3-day PD Diaries. For each day, Off time was calculated by adding the number of half-hour intervals in which the Status Off was checked. Baseline was defined as data obtained from PD Diary collected over 3 days prior to Week 7/Randomization. | Baseline (Week 7) and Week 20/ET | 
| Percentage of Participants With Either Much Improved or Very Much Improved in Patient Global Impression of Change (PGI-C) Scores at Week 20/ET | The Patient Global Impression of Change (PGIC) is self assessment questionnaire which was used by participants to compare his/her condition on a 7-point scale ranging from 1-Very Much Worse, 2-Much Worse, 3-Minimally Worse, 4-No Change, 5-Minimally Improved, 6-Much Improved, 7-Very Much Improved. Percentage of participants with either Much Improved or Very Much Improved was reported. | Week 20/ET | 
| Change From Baseline in The Movement Disorders Society Version of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III at Week 20/ET | MDS-UPDRS is a multimodal scale assessing impairment and disability consisting of 4 parts. (Part I; 13 items) non-motor experiences of daily living, (Part II; 13 items) motor experiences of daily living completed by the participants, (Part III; 34 items) motor examination of PD and was administered by the rater, and (Part IV; 6 items) motor complication integrates participant-derived information with the rater's clinical observations and judgements and is completed by the rater. For each question a numeric score was assigned between 0-4, where 0 = Normal, 1 = Slight, 2 = Mild, 3 = Moderate, 4 = Severe. MDS-UPDRS Total Score equals the sum of Parts I, II, and III and IV (Range 0-234). Part III score ranges from 0 to 136. A higher score indicated more severe symptoms of PD. Baseline was defined as data obtained from PD Diary collected over 3 days prior to Week 7/Randomization. | Baseline (Week 7) and Week 20/ET | 
| Change From Baseline in The Sum of MDS-UPDRS Part II and Part III at Week 20/ET | MDS-UPDRS is a multimodal scale assessing impairment and disability consisting of 4 parts. (Part I; 13 items) non-motor experiences of daily living, (Part II; 13 items) motor experiences of daily living completed by the participants, (Part III; 34 items) motor examination of PD and was administered by the rater, and (Part IV; 6 items) motor complication integrates participant-derived information with the rater's clinical observations and judgements and is completed by the rater. For each question a numeric score was assigned between 0-4, where 0 = Normal, 1 = Slight, 2 = Mild, 3 = Moderate, 4 = Severe. MDS-UPDRS Total Score equals the sum of Parts I, II, and III and IV (Range 0-234). The scale range for Part II+III score is 0-188. A higher score indicated more severe symptoms of PD. Baseline was defined as data obtained from PD Diary collected over 3 days prior to Week 7/Randomization. | Baseline (Week 7) and Week 20/ET | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Idiopathic Parkinson's Disease, Lewy Body Parkinson's Disease, Paralysis Agitans, Primary Parkinsonism