Intermittent Oral Administration vs. Semi-continuous Intra-oral Administration of Levodopa/Carbidopa in Fluctuating Parkinsonian Patients
Condition: Parkinson Disease
MeSH terms: Parkinson Disease
Study type: Interventional
Phase: Phase 2

Summary: 
      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.
    

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.
    

Intervention name(s): Standard LD/CD; Semi continuous intra-oral administration of LD/CD
Intervention type(s): Drug; Drug
Intervention description(s): LD/CD will be administered at patient's usual dose and frequency during 8 hours interval; 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 intervention name(s): Sinemet 25 mg/100 mg at patient's usual dose and frequency; Sinemet 25 mg/100 mg administered at 5-10 minutes intervals
Intervention MeSH terms: Carbidopa, levodopa drug combination; Carbidopa; Levodopa
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment