Assessing the Pharmacokinetics, Safety, Tolerability and Efficacy of Continuous Oral Levodopa Via the DopaFuse® Delivery System in Parkinson's Disease Patients

Study Overview
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Brief Summary
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The purpose of this study is to evaluate whether the DopaFuse System can reduce the fluctuation of plasma levodopa levels compared to participants' standard intermittent doses of oral LD/CD tablets (background treatment). It will also assess whether the system is safe, well tolerated, and can relieve motor symptoms.

Official Title
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Assessing the Pharmacokinetics, Safety, Tolerability and Efficacy of Continuous Oral Levodopa Via the DopaFuse® Delivery System in Parkinson's Disease Patients

Conditions
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Parkinson's Disease

Intervention / Treatment
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* Combination Product: continuous oral delivery of levodopa/carbidopa


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of Parkinson's Disease consistent with UK Brain Bank Criteria Age at least 30 years old at time of consent Male and Female participants (Women of child-bearing potential (WOCB) are eligible for participation if they are not pregnant or breastfeeding and agree to follow the contraceptive guidance in Appendix 3 during the treatment period and for at least 30 days after the last dose of study treatment) Suitable for oral retainer wear A good response to Levodopa, as assessed by the Investigator At least 2 hours of wearing OFF time per day, as reported by the participant Predictable early morning OFF periods, in the judgement of the participant and the Investigator Taking 400-1,200 mg of LD/CD per day in at least 4 doses, with stable dosing for the last 28 days prior to screening. A modified Hoehn and Yahr of ≤ 3 in the ON state at screening A stable regimen of anti-PD medications for the last 28 days prior to Screening A Mini-Mental State Examination (MMSE) Score ≥26 Capable of giving signed informed consent Approved for entry into the study by the Enrollment Authorization Committee (EAC) Exclusion Criteria: Atypical or secondary Parkinson's Disease Severe Dyskinesia that might interfere with study performance in the judgement of Investigator Clinically significant dysphagia or sialorrhea that might interfere with administration of study intervention in the judgement of the Investigator Use of extended release levodopa within 28 days prior to screening Any clinically significant medical, surgical, or psychiatric condition; laboratory value or ECG result which, in the opinion of the Investigator, makes the participant unsuitable for study entry or potentially unable to complete all aspects of the study. Presence of clinically significant orthostatic hypotension at screening, in the opinion of Investigator or the EAC Suicidal ideation within 1 year prior to the Screening Visit as evidenced by answering yes to Questions 4 or 5 on the suicidal ideation portion of the Columbia Suicide Severity Rating Scale (C-SSRS) or attempted suicide within the last 5 years. History of psychosis or hallucinations in the past six months Any malignancy in the past 5 years (excluding basal cell carcinoma of the skin or cervical carcinoma in situ that have been successfully treated.) Current or previous diagnosis of malignant melanoma or the presence of any suspicious skin lesion based on physical exam findings Unable to give blood required for the study History of allergic reaction to plastics LD infusion therapy (i.e. Duodopa); current or previous continuous apomorphine infusion treatment. Participation in any other clinical trial <30 days prior to screening visit. Presence of two third molars (wisdom teeth) on the upper dentition Participants who, for any reason, are judged by the Investigator or the EAC to be inappropriate for this study, including participants who are unable to communicate or cooperate with the Investigator or who have/had a clinically significant illness or abnormal physical examination that may compromise safety of the participant during the trial or affect ability of the participant to adhere to study procedures. Participants taking non-selective monoamine oxidase (MAO) inhibitors Participants with known hypersensitivity to the active ingredients (levodopa, carbidopa) or excipients (Benzoic Acid, Disodium Edetate, Medium Chain Triglycerides, Poloxamer 188) of the drug paste Participants with narrow-angle glaucoma

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: DopaFuse Delivery System 50mg LD/hr or 68mg LD/hr flow rate<br>Either 50mg/13mg LD/CD per hour or 68mg/17mg LD/CD per hour flow rate based upon Subject's standard levodopa (LD) dose. Subjects will routinely wear each container for approximately 5 hours (3 containers per day). | Combination Product: continuous oral delivery of levodopa/carbidopa<br>* The system consists of a reusable custom dental retainer, its case, and a pre-filled, single-use container which continuously releases levodopa/carbidopa into the back of the mouth.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Variability in plasma concentration of levodopa as assessed with the Levodopa Fluctuation Index (Cmax-Cmin)/Caverage) | Comparing Day 2 to Day 1 in steady state (4-12 hours). Fluctuation index will also be calculated by the hour. | pre-dose and every 30 minutes for 12 hours on Days 1 and 2. | 
| Treatment Emergent Adverse Events |  | Screening to Day 29 | 
| Serious Adverse Events |  | Screening to Day 29 | 
| Treatment Emergent Adverse Events leading to discontinuation |  | Screening to Day 29 | 
| Percent of participants that complete study |  | Screening to Day 29 | 
| Difference in OFF time between Days 1 and 15, based on in-person investigator ratings | Investigator-rated assessment of motor state (ON or OFF) pre-dose and every 30 minutes for 12 hours. | Day 1 compared to Day 15 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Coefficient of variation (CV) for plasma levodopa. | This will be calculated between 4 and 12 hours on Days 1 and 2 comparing DopaFuse and oral levodopa tablets. | pre-dose and every 30 minutes for 12 hours on Days 1 and 2. | 
| Variability in plasma concentration of levodopa as assessed with the Levodopa Fluctuation Index (Cmax-Cmin)/Caverage). | Comparing Day 3 to Day 1, as well as Day 2 (0-12 hours) to Day 1. Fluctuation index will also be calculated by the hour. | pre-dose and every 30 minutes for 12 hours on Days 1 and 2. Pre-dose and at 30 minute intervals for two hours, and at one-hour intervals for the remainder of the 12 hours on Day 3. | 
| Levodopa and Carbidopa peak plasma concentration (Cmax) |  | pre-dose and every 30 minutes for 12 hours on Days 1 and 2. Pre-dose and at 30 minute intervals for two hours, and at one-hour intervals for the remainder of the 12 hours on Day 3. | 
| Variability in plasma levodopa comparing Dopafuse and oral levodopa tablets based on fluctuation index and CV in participants who are H. pylori negative/positive |  | pre-dose and every 30 minutes for 12 hours on Days 1 and 2. Pre-dose and at 30 minute intervals for two hours, and at one-hour intervals for the remainder of the 12 hours on Day 3. | 
| Questionnaire for Impulse Control Disorders in Parkinson's Disease Rating Scale (QUIP-RS) |  | Screening to Day 29 | 
| Columbia - Suicide Severity Rating Scale (C-SSRS) |  | Screening to Day 29 | 
| Difference in OFF Time between Day 1 and Day 3 | Investigator-rated assessment of motor state (ON or OFF) pre-dose and every 30 minutes for 12 hours. | Day 1 and Day 3 | 
| Difference in ON Time without troublesome dyskinesia between Days 1, 3 and 15 | Investigator-rated assessment of motor state (ON or OFF) pre-dose and every 30 minutes for 12 hours. | Days 1, 3, and 15 | 
| Difference in ON Time with troublesome (severe) dyskinesia between Days 1, 3 and 15 | Investigator-rated assessment of motor state (ON or OFF) pre-dose and every 30 minutes for 12 hours. | Days 1, 3 and 15 | 
| Change in Unified Parkinson's Disease Rating Scale Part III at 6 hours after morning dose between Days 1, 3 and 15 |  | Days 1, 3 and 15 | 
| Levodopa and Carbidopa time to maximum plasma concentration (Tmax) |  | pre-dose and every 30 minutes for 12 hours on Days 1 and 2. Pre-dose and at 30 minute intervals for two hours, and at one-hour intervals for the remainder of the 12 hours on Day 3. | 
| Levodopa and Carbidopa area under the plasma concentration versus time curve (AUC) |  | pre-dose and every 30 minutes for 12 hours on Days 1 and 2. Pre-dose and at 30 minute intervals for two hours, and at one-hour intervals for the remainder of the 12 hours on Day 3. |