PK, PD and Safety of Multiple Doses of V1512 Tablets in PD Patients Compared to Standard Levodopa/Carbidopa Oral Tablets

Study Overview
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Brief Summary
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The purpose of the study is to determine if the pharmacokinetic profile of V1512 is similar or better than existing medications for the treatment of Parkinson's Disease

Detailed Description
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The pharmacokinetics of V1512 effervescent tablet has been evaluated in healthy volunteers, however not fully in PD patients. This study aims to evaluate the PK profiles in PD patients of different dosing schedules of V1512 effervescent tablet compared to the profiles after standard L-dopa/carbidopa (Sinemet) over the course of the day. Two dosing schedules have been chosen to evaluate a possible relation between dosing interval and 'ON' time, with and without associated dyskinesia. Similar dosing schedules with the comparator Sinemet are commonly employed in the treatment of fluctuating PD patients. Patients assigned to cohort 3 will also take a dose of entacapone concomitantly with each dose of V1512 or Sinemet, thereby allowing the kinetics and dynamics of.V1512 and Sinemet to be compared in the presence of COMT inhibition. Safety and tolerability of the dosing regimens in patients will also be assessed further in this double-blind study

Official Title
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Randomised, Double-blind, Double-dummy, Two-period, Cross-over Study to Determine the PK, PD and Safety of Multiple Doses of V1512 Effervescent Tablets in Parkinson's Disease Patients Compared to Sinemet® Oral Tablets

Conditions
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Parkinson's Disease

Intervention / Treatment
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* Drug: V1512
* Drug: V1512
* Drug: V1512 and Entacapone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female, >30 years of age of any race; A Body Mass Index between 18.5 and 29.9 kg/m2 (inclusive); Clinical diagnosis according to the Brain Bank diagnostic criteria of idiopathic Parkinson's Disease (2 of 3 cardinal symptoms - bradykinesia, rigidity, tremor -must be present, with a positive response to L-dopa); Presence of fluctuations in motor performance with >2 hours inclusive of daytime OFF episodes (not applicable for cohort 1 patients); At least 1 hour delay to ON time with afternoon doses; Discontinued use of COMT inhibitors (cathecol-o-methyl transferase) for at least 2 weeks prior to study entry (not applicable for cohort 3 patients); Stable doses of dopamine agonists or selegiline for at least 2 weeks before entry into the study; Stable comorbidity for 4 weeks; Female patients must be of non-childbearing potential (post-menopausal or physically incapable of childbearing); Willing and able to give informed consent according to national legal requirements prior to initiation of any study-related procedures Exclusion Criteria: Clinically relevant abnormal vital sign values or safety laboratory data. Patients who smoke and are unable to refrain from smoking during the in-clinic period Diagnosis of atypical parkinsonism; A history and/or the presence of gastro-intestinal disorders (or surgery) that could interfere with absorption of the test medication; A history of intolerance or clinically relevant allergy to L-dopa and/or carbidopa taken in any formulation or combination; A history of intolerance or clinically relevant allergy to entacapone or any ingredients of Comtan (cohort 3 patients only) Any other condition which, in the opinion of the Investigator, would interfere with optimal participation in the study e.g. inability to complete patient diary; Participation in any clinical study or receiving treatment with another investigational drug within 30 days or 5 half lives (whichever is longer) before the screening visit; Blood donation within 3 months before study participation; History of neuroleptic malignant syndrome (NMS) or NMS-like syndromes, or non-traumatic rhabdomyolysis; Patients taking non-selective MAO inhibitors; Patients with a history of, or clinical indication of, narrow angle glaucoma; Patients with a history of, or clinical indication of, malignant melanoma; Patients with a history of, or clinical indication of, depression or psychosis; Patients taking iron containing medications (ferrous sulphate, ferrous gluconate)

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: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 2-hourly dosing<br>6 Doses of IMP at 2-hourly intervals | Drug: V1512<br>* 6 doses of IMP at 2-hourly intervals<br>|
| Experimental: 3-hourly dosing<br>4 doses of IMP at 3-hourly intervals | Drug: V1512<br>* 3-hourly dosing<br>|
| Active Comparator: 3-hourly dosing plus Entacapone<br>4 doses of IMP plus Entacapone at 3-hourly intervals | Drug: V1512 and Entacapone<br>* 4 doses of IMP and Entacapone at 3-hourly intervals<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| to characterise the plasma concentrations of L-dopa after repeated doses of V1512 in fluctuating PD patients compared to standard L-dopa/carbidopa (Sinemet) over the course of the day |  | 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| correlate plasma concentrations with response to therapy; |  | 4 weeks | 
| further characterise the safety and tolerability profile for each treatment |  | 4 weeks |