A Study to Assess the Safety and Efficacy of the of the Gastric-retentive AP-CD/LD in Advanced Parkinson's Patients

Study Overview
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Brief Summary
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The purpose of this study is to determine whether the gastric retentive Accordion Pill™ Carbidopa/Levodopa (AP-CD/LD) is more effective than the commercially available immediate release Carbidopa/Levodopa in reducing motor fluctuations such as off time in advanced Parkinson's Disease patients.

Detailed Description
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A multi-center, global, randomized, double-blind, double-dummy, active-controlled, parallel-group study in adult subjects with fluctuating PD. The study will have 2 open label Titration periods of 6 weeks each prior to the double blind Maintenance period. In the open label periods all patients will be stabilized on the active comparator Sinemet® and then on AP-CD/LD. The double blind Maintenance period will be 13 weeks long.

Official Title
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Phase 3 Multicenter Randomized Double-Blind, Double-dummy, Active-Controlled Study Comparing Efficacy/Safety of Gastric-retentive, Controlled-release Accordion Pill Carbidopa/Levodopa to Immediate Release in Fluctuating Parkinson's Patients

Conditions
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Parkinson's Disease

Intervention / Treatment
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* Drug: Accordion Pill™ Carbidopa/Levodopa
* Drug: Sinemet®
* Drug: Placebo -AP-CD/LD
* Drug: Placebo- Sinemet


Participation Criteria
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Eligibility Criteria
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Main Inclusion Criteria: Subjects must be approved for suitability by an Enrollment Approval Committee Able and willing to give written (signed and dated) informed consent and adhere to visit schedule and available to complete the study Men or women 30 years of age and higher at initial screening assessment. (For the 100 subjects who enter the Gastroscopy sub study, the age limits are 30-80 years of age, inclusive, at initial screening assessment) Diagnosed with Parkinson's disease, consistent with UK brain bank criteria Has a good response to Levodopa and is taking at least 4 doses of a Levodopa containing medication (or 3 doses of Rytary) per day during waking hours (not including nighttime long acting levodopa) at a stable dose for at least 28 days prior to initial screening assessment Other Anti-PD treatment (such as dopamine agonists, selective MAO-B inhibitors, anticholinergic agents or Amantadine) are permitted if stable for at least 28 days prior to study entry and provided they are not anticipated to be changed during the course of the study Total LD immediate release daily dose of 400 mg to 1300 mg or equivalent prior to initial screening assessment. Specifically for Rytary, doses up to 1755 mg daily are acceptable. Able to complete a Hauser Home Diary and can tell the difference between On and Off time Achieved at least 75% diary concordance with an approved site rater in a 4-hour training session including at least one Off time assessment Returned a valid 2-day practice diary after training has been completed. At least 2.5 hours Off time per day during waking hours on Screening 2-day Practice Hauser Home Diary (morning akinesia should be incorporated into the total Off time assessment). Other than PD, the subject is in satisfactory health, as assessed by physical examination and screening tests. No clinically significant medical, psychiatric or laboratory abnormality that could compromise safety or interfere with study procedures in the opinion of either the investigator or the Enrollment Approval Committee/Sponsor. Living in an area that is within 3 hours driving distance from the study site or is willing to stay in such a place the night before each study visit Main Exclusion Criteria: Participation in another drug clinical trial within 28 days prior to initial screening assessment (calculated from the previous study's last dosing date) Atypical Parkinsonism (subjects with Parkinsonian features caused by disorder such as multiple system atrophy, progressive supranuclear palsy, dementia with Lewy bodies or multiple brain infarcts) Clinically significant cardiac, pulmonary, hepatic or renal disease or other condition or any major complication/illness which contraindicates his/her participation in the opinion of either the investigator or the Enrollment Approval Committee/Sponsor. Severe dyskinesia in the opinion of either the investigator or the Enrollment Approval Committee. Treatment with non-selective monoamine oxidase (MAO) inhibitors during the last 28 days prior to initial screening assessment or planning to take during study participation Previous or planned neurosurgical treatment for Parkinson's Disease (e.g., procedures including ablation or deep brain stimulation) during the course of the study Significant cognitive impairment as defined by the Mini-Mental State Examination (MMSE) score < 26. Clinically significant psychiatric illness, including major depression (Hamilton Depression Rating Scale-17 ≥14). Subjects with a lifetime history of suicidal attempt (including an active attempt, interrupted attempt or aborted attempt) Current or previous treatment for more than 1 month within the past 2 years with any neuroleptic drug (antipsychotic) or any other drug with anti-dopaminergic properties (e.g. metoclopramide, domperidone) Currently experiencing or any known history of psychosis or delusions within 2 years prior to Screening. Known history of substance abuse within the past 2 years Moderate or greater level of alcohol consumption Unable to swallow large pills (e.g., large vitamin pills) History of Melanoma or suspicious skin lesion which could be a Melanoma Narrow-angle Glaucoma History of small bowel or gastric surgery (Including PEG-J placement for Duopa/Duodopa) or bowel obstruction, diagnosis of small bowel narrowing, diagnosis of Crohn's disease, or frequent nausea or emesis, regardless of etiology, (Previous appendectomy or hernioplasty will not be exclusionary). Active peptic ulcer disease or a history of peptic ulcer or upper GI bleeding Regular use of opioids (Intermittent opioid use is not exclusionary) Symptomatic gastroparesis with frequent vomiting (at least once a week) Concomitant use of NSAIDs and oral steroids within the past 28 days Allergy to the study drug or any of its excipients, or to Yellow Dye #5 (tartrazine) Women who are pregnant or nursing. Women of childbearing potential who are not willing to use a medically acceptable method of contraception.

Ages Eligible for Study
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Minimum Age: 30 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
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AP-CD/LD<br>Accordion Pill™ Carbidopa/Levodopa Capsule 50/400mg , b.i.d or t.i.d or Accordion Pill™ Carbidopa/Levodopa Capsule 50/500mg , b.i.d or t.i.d and Placebo IR Carbidopa/ levodopa | Drug: Accordion Pill™ Carbidopa/Levodopa<br>* AP-CD/LD capsule containing 50 mg carbidopa with 400 mg or 500 mg levodopa administered orally twice or 3 times a day<br>* Other names: AP-CD/LD;Drug: Placebo -AP-CD/LD<br>* Placebo for AP-CD/LD capsule<br>|
| Active Comparator: SINEMET®<br>IR Carbidopa/ levodopa tablets 25/100 mg at least 4 times a day and placebo AP-CD/LD | Drug: Sinemet®<br>* Sinemet® tables containing carbidopa and levodopa 25/100 mg will be administered orally at least 4 times a day according to patients need<br>* Other names: IR Carbidopa/Levodopa;Drug: Placebo- Sinemet<br>* Placebo for Sinemet tables<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline through study completion, an average of 27 weeks, in the percentage of daily Off time during waking hours | Change from Baseline through study completion, an average of 27 weeks, in the percentage of daily Off time during waking hours based on Hauser Home Diary assessments; Total number of Off  hours normalized to a 16- hour waking day will also be calculated but only a single p-value applicable to both the percentage and hours will be reported. | Baseline through study completion, an average of 27 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline through study completion, an average of 27 weeks, in On time without troublesome dyskinesia during waking hours |  | Baseline through study completion, an average of 27 weeks | 
| Change in the number of total daily LD doses from Baseline through study completion, an average of 27 weeks (hours) |  | Baseline through study completion, an average of 27 weeks | 
| CGI-I through study completion, an average of 27 weeks, as recorded by physician & patient |  | Baseline through through study completion, an average of 27 weeks, | 
| Change from Baseline through study completion, an average of 27 weeks, in total UPDRS Score (Sum of Parts I-III) |  | Baseline through study completion, an average of 27 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Parkinson's Disease, Fluctuating Parkinson's Disease, Advanced Parkinson's Disease, Carbidopa, Levodopa, Accordion, Accordance