Intermittent Oral Administration vs. Semi-continuous Intra-oral Administration of Levodopa/Carbidopa in Fluctuating Parkinsonian Patients (LDCD-001)

A Phase IIa Study to Assess the Safety, Tolerability, Plasma Pharmacokinetics and Efficacy of Intermittent Oral Administration of Standard Levodopa/Carbidopa vs. Semi-continuous Intra-oral Administration of Levodopa/Carbidopa in Patients With Advanced Parkinson's Disease Who Suffer Motor Fluctuations

This is a phase IIa study to assess the safety, tolerability, plasma pharmacokinetics and efficacy of intermittent oral administration of standard levodopa/carbidopa (LD/CD) vs.semi-continuous intra-oral administration of levodopa/carbidopa in patients with advanced Parkinson's disease (PD) who suffer motor fluctuations.The objective of this study is to assess the plasma pharmacokinetics (PK) of continuous intra-oral administration of LD/CD vs. intermittent administration of standard oral LD/CD. For purposes of this study continuous intra-oral administration of LD/CD is defined as oral administration of LD/CD at 5-10 minute intervals.

Secondary objectives are to assess the safety and tolerability of continuous intra-oral administration of LD/CD and the effect on PD motor function of continuous intra-oral administration of LD/CD vs. intermittent administration of standard oral LD/CD.

Study Overview

• Status: Completed
• Conditions: Parkinson Disease
• Intervention / Treatment: Drug: Standard LD/CD; Drug: Semi continuous intra-oral administration of LD/CD

Detailed Description

18 PD subjects with motor fluctuations on stable doses of standard levodopa/carbidopa +/- other dopaminergic therapy who meet entry criteria and sign an Institutional Ethical Committee approved informed consent will participate in this study. The study will be conducted at the San Raffaele IRCCS in Rome, Italy.

Subjects who successfully complete the screening activities to confirm eligibility and are approved by an enrollment steering committee will be admitted to hospital on the evening of day 1 to undergo baseline evaluations. Standard oral levodopa/carbidopa (LD/CD) medication will be stopped at midnight. On day 2, a standardized low protein breakfast will be provided and treatment will be initiated with their usual dose of standard oral LD/CD. All subsequent doses will be administered at their pre-baseline dosing intervals; other anti-parkinson medications will not be stopped and will be maintained at their usual dose. If rescue therapy is required, treatment with apomorphine sc will be administered as a first preference. Plasma levels of levodopa and metabolites will be measured over the course of the ensuing 8 hours. Physicians will assess motor status (off, on without dyskinesia, or on with dyskinesia) at 30-minute intervals throughout the 8-hour observation period and perform UPDRS motor exams at 0, 2, 4, and 8 hours. Patients will then resume their standard oral LD/CD anti-parkinsonian medications (if any), which will be stopped at midnight. On day 3 subjects will receive continuous intra-oral administration of standard LD/CD at a dose equal to the total dose of standard oral LD/CD that they would normally consume over the time course of the study period. For the purposes of this study continuous intra-oral administration will refer to oral dosing at 5-10 minute intervals. To achieve this, the drug will be chopped and administered with water so that the same total dose of levodopa that would normally be taken intermittently will be divided up and administered as small doses at 5-10 minute intervals. Patients will undergo all of the same PK blood sampling as on Day 2. If the patient is taking Stalevo, a dose of entacapone will be administered at the usual time intervals that Stalevo otherwise would have been taken. Patients will then resume their standard oral LD/CD anti-parkinsonian medication (if any), which will be stopped at midnight. On Day 4 of the study subjects will receive their first LD/CD dose orally, and the balance of the total dose they would normally take over the next 8 hours by way of continuous intra-oral administration of LD/CD over the course of the 8 hour study period. If taking Stalevo, entacapone will be administered by itself at the time Stalevo would normally have been taken.

Physicians will assess motor status (off, on without dyskinesia, or on with dyskinesia) at 30-minute intervals throughout the continuous intra-oral administration and perform UPDRS motor exams at 0, 2, 4, and 8 hours. At the completion of the study, patients will be discharged from the clinic on their standard medication. Patients will return on day 18 for a safety evaluation.

• Study Type: Interventional
• Enrollment (Actual): 18
• Phase: Phase 2

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 35 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion criteria

1. PD diagnosis consistent with United Kingdom Brain Bank Criteria
2. Good response to levodopa with at least 2 hours of wearing off episodes in judgment of investigator
3. Stable doses of levodopa plus/minus other dopaminergic therapy (minimum of 4 weeks for each drug)
4. Mini Mental Score Examination (MMSE): score > 26
5. Capable of providing informed consent
6. No clinically significant medical, psychiatric or laboratory abnormalities in the judgment of the investigator.
7. No history of psychosis or hallucinations in the past 6 months
8. Women who are capable of child bearing must have a negative urine pregnancy test at screening visit and use an adequate contraceptive method throughout the study.
9. Approval for entry into the study by an enrolment steering committee

Exclusion criteria

1. Atypical or secondary parkinsonism
2. Severe dyskinesia that might interfere with study performance in judgment of investigator
3. Patient receiving duodopa, apomorphine infusion or Deep Brain Stimulation (DBS)
4. Dysphagia or sialorrhea that might interfere with administration of study intervention
5. Any relevant medical, surgical, or psychiatric condition, laboratory value, or concomitant medication which, in the opinion of the Investigator, would interfere with performing a pharmacokinetic study or would interfere with drug absorption.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Standard LD/CD; Standard LD/CD administered at patient's usual dose and frequency	Drug: Standard LD/CD; LD/CD will be administered at patient's usual dose and frequency during 8 hours interval; Other Names: Sinemet 25 mg/100 mg at patient's usual dose and frequency
Experimental: Semi continuous intra-oral administration of LD/CD; Semi continuous intra-oral administration of LD/CD at a dose equivalent to the patient's regular dose of standard LD/CD	Drug: Semi continuous intra-oral administration of LD/CD; Semi continuous intra-oral administration of standard LD/CD at a dose equal to the total dose of standard oral LD/CD that patients would normally consume over 8 hours period.; Other Names: Sinemet 25 mg/100 mg administered at 5-10 minutes intervals

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Variability in the observed plasma concentration of levodopa as assessed with the fluctuation index (Fluctuation index= (Maximum Plasma Concentration (Cmax)-Minimum Plasma Concentration (Cmin))/Concentration average)	Change in fluctuation index between intermittent administration (Day 2) and intra-oral administration (Day 3)	Change in fluctuation index between Day 2 and Day 3

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Assess the safety and tolerability of continuous intra-oral administration of LD/CD: Adverse Events	Record of any adverse event	From Day 1 to Day 18
Assess the effect on number of hours of "off" time of continuous intra-oral administration of LD/CD vs. intermittent administration of standard oral LD/CD		Change in number of hours of "off" time between Day 2 and Day 3
Assess the effect on UPDRS of continuous intra-oral administration of LD/CD vs. intermittent administration of standard oral LD/CD		Change in UPDRS between Day 2 and Day 3

Collaborators and Investigators

• Sponsor: IRCCS San Raffaele Roma
• Collaborators: SynAgile Corporation
• Investigators: Principal Investigator: FABRIZIO STOCCHI, PROFESSOR, IRCCS San Raffaele

Publications and helpful links

General Publications

• Stocchi F, Vacca L, Ruggieri S, Olanow CW. Intermittent vs continuous levodopa administration in patients with advanced Parkinson disease: a clinical and pharmacokinetic study. Arch Neurol. 2005 Jun;62(6):905-10. doi: 10.1001/archneur.62.6.905.

Study record dates

Study Major Dates

• Study Start (Actual): July 30, 2014
• Primary Completion (Actual): October 1, 2015
• Study Completion (Actual): October 1, 2015

Study Registration Dates

• First Submitted: April 26, 2016
• First Submitted That Met QC Criteria: May 4, 2016
• First Posted (Estimated): May 5, 2016

Study Record Updates

• Last Update Posted (Actual): April 10, 2024
• Last Update Submitted That Met QC Criteria: April 9, 2024
• Last Verified: October 1, 2022

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; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Immunologic Factors; Dopamine Agonists; Dopamine Agents; Adjuvants, Immunologic; Antiparkinson Agents; Anti-Dyskinesia Agents; Aromatic Amino Acid Decarboxylase Inhibitors; Levodopa; Carbidopa; Carbidopa, levodopa drug combination
• Other Study ID Numbers: RP 12/14

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Publication on peer-reviewed journal