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

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

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

Study Overview

• Status: Completed
• Conditions: Parkinson's Disease
• Intervention / Treatment: Drug: V1512; Drug: V1512; Drug: V1512 and Entacapone

Detailed Description

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

• Study Type: Interventional
• Enrollment (Anticipated): 27
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Italy
  • Rome
    • Roma, Rome, Italy, 00163
      • IRCCS San Raffaele Pisana

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 30 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Male or female, >30 years of age of any race;
2. A Body Mass Index between 18.5 and 29.9 kg/m2 (inclusive);
3. 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);
4. Presence of fluctuations in motor performance with >2 hours inclusive of daytime OFF episodes (not applicable for cohort 1 patients);
5. At least 1 hour delay to ON time with afternoon doses;
6. Discontinued use of COMT inhibitors (cathecol-o-methyl transferase) for at least 2 weeks prior to study entry (not applicable for cohort 3 patients);
7. Stable doses of dopamine agonists or selegiline for at least 2 weeks before entry into the study;
8. Stable comorbidity for 4 weeks;
9. Female patients must be of non-childbearing potential (post-menopausal or physically incapable of childbearing);
10. Willing and able to give informed consent according to national legal requirements prior to initiation of any study-related procedures

Exclusion Criteria:

1. Clinically relevant abnormal vital sign values or safety laboratory data.
2. Patients who smoke and are unable to refrain from smoking during the in-clinic period
3. Diagnosis of atypical parkinsonism;
4. A history and/or the presence of gastro-intestinal disorders (or surgery) that could interfere with absorption of the test medication;
5. A history of intolerance or clinically relevant allergy to L-dopa and/or carbidopa taken in any formulation or combination;
6. A history of intolerance or clinically relevant allergy to entacapone or any ingredients of Comtan (cohort 3 patients only)
7. 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;
8. 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;
9. Blood donation within 3 months before study participation;
10. History of neuroleptic malignant syndrome (NMS) or NMS-like syndromes, or non-traumatic rhabdomyolysis;
11. Patients taking non-selective MAO inhibitors;
12. Patients with a history of, or clinical indication of, narrow angle glaucoma;
13. Patients with a history of, or clinical indication of, malignant melanoma;
14. Patients with a history of, or clinical indication of, depression or psychosis;
15. Patients taking iron containing medications (ferrous sulphate, ferrous gluconate)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

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

Collaborators and Investigators

• Sponsor: Vernalis (R&D) Ltd
• Collaborators: Syneos Health; Cita NeuroPharmaceuticals
• Investigators: Principal Investigator: Fabrizio Stocchi, MD, PhD, IRCCS San Raffaele

Publications and helpful links

General Publications

• Stocchi F, Vacca L, Grassini P, Pawsey S, Whale H, Marconi S, Torti M. L-Dopa Pharmacokinetic Profile with Effervescent Melevodopa/Carbidopa versus Standard-Release Levodopa/Carbidopa Tablets in Parkinson's Disease: A Randomised Study. Parkinsons Dis. 2015;2015:369465. doi: 10.1155/2015/369465. Epub 2015 Jun 10.

Study record dates

Study Major Dates

• Study Start: November 1, 2006
• Primary Completion (Actual): November 1, 2007
• Study Completion (Actual): November 1, 2007

Study Registration Dates

• First Submitted: June 26, 2007
• First Submitted That Met QC Criteria: June 26, 2007
• First Posted (Estimate): June 27, 2007

Study Record Updates

• Last Update Posted (Estimate): July 25, 2011
• Last Update Submitted That Met QC Criteria: July 21, 2011
• Last Verified: July 1, 2011

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Parkinsonian Disorders; Basal Ganglia Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases; Parkinson Disease; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antiparkinson Agents; Anti-Dyskinesia Agents; Catechol O-Methyltransferase Inhibitors; Entacapone
• Other Study ID Numbers: V1512-2PD01