Efficacy, Safety and Tolerability of E2007 in Levodopa Treated Parkinson's Disease Patients With Motor Fluctuations
Condition: Parkinson's Disease
MeSH terms: Parkinson Disease
Intervention: Placebo; E2007; E2007
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 723.0
Sex: All
Minimum age: 30 Years
Healthy volunteers: No

Summary:

      Randomised, double-blind, double dummy, parallel group design. Following the screening period
      patients will be randomised at the baseline visit, in a 1:1:1 manner, to one of three
      treatment arms; 4 mg E2007, 200 mg entacapone (with each dose of levodopa) or placebo. The
      first 4 weeks of the double blind phase will be used to titrate patients on the E2007 arm
      from 2 mg up to the maintenance dose of 4 mg. Patients randomised to entacapone or placebo
      will have dummy up titrations to maintain the blind. Following this titration phase, patients
      will remain on the maintenance dose for a further 14 weeks.

      Patients will have visits at 2, 4, 6, 10, 14 and 18 weeks after baseline. A follow up visit
      will be performed at Week 22.

      A home diary will be completed in which patients rate themselves as either:

        1. "OFF"

        2. "ON" without dyskinesias

        3. "ON" with non-troublesome dyskinesias

        4. "ON" with troublesome dyskinesias

        5. Asleep

      These entries will be completed every 30 minutes during the waking day and will be completed
      for three consecutive days immediately prior to visits at Baseline, Weeks 6, 10, 18 and 22.

      At Baseline (Day 0), week 10 and 18 the Unified Parkinson's Disease Rating Scale (UPDRS -
      Parts I, II , III and IV) will be performed.

      At the end of the treatment period (Week 18), patients will undergo final efficacy and safety
      assessments and will stop taking the study medication they were receiving. They will be seen
      4 weeks later for a follow up visit.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Male or female patients with idiopathic PD fulfilling the (United Kingdom [UK])
             Parkinson's disease Society Brain Bank diagnostic criteria, with a good response to
             levodopa.

          2. Patients must have been diagnosed with idiopathic PD at ≥ 30 years of age. In addition
             the onset of symptoms associated with Parkinson's disease must have occurred ≥ 30
             years of age.

          3. Patients must have predictable motor fluctuations of the wearing OFF type with the
             presence of at least 2 hrs of OFF time during the waking day (excluding the morning
             OFF time) as evidenced by diary cards completed at screening and confirmed by diary
             data collected in the 3 day diaries completed before randomisation.

          4. Before patients are randomised, they must be able to show that they are able to
             accurately complete the diary cards. During the diary-training period at Screening
             Visit 1, there must be diary evidence of at least one transition of OFF to ON or from
             ON to OFF.

          5. Patients must rate between II IV on the Hoehn &Yahr (8) scale when in an OFF state.

          6. Patients must be taking optimised levodopa (plus dopamine decarboxylase inhibitors
             [DDI]) therapy (according to the Investigator's opinion) at least 3 times during the
             waking day (not including bedtime/night time dose) up to a maximum of 8 doses daily
             (including bedtime/night time dose).

          7. Patients who are treated with DA or MAOB inhibitors or other anti-PD drugs must be on
             optimised and stable doses for at least 4 weeks prior to the Screening visit and must
             remain stable throughout the study. Only levodopa dosage can be adjusted downwards in
             the first 6 weeks of the double blind treatment phase.

          8. In the Investigator's opinion, patients must be able to distinguish their own motor
             states and the absence or presence of troublesome or non-troublesome dyskinesias.

          9. In the Investigator's opinion, patients are able to complete the study including the
             completion of the home diary cards and are capable of giving full written informed
             consent.

        Exclusion Criteria:

          1. Pregnant or lactating women.

          2. Women of child bearing potential unless infertile (including surgically sterile) or
             practicing effective contraception (e.g., abstinence, intrauterine device or barrier
             method plus hormonal method). These patients must have a negative serum B-human
             chorionic gonadotrophin (B-HCG) test at the initial screening visit (Visit 1) and a
             negative urine pregnancy test at the baseline visit (Visit 3). These patients must
             also be willing to remain on their current form of contraception for the duration of
             the study. Postmenopausal women may be recruited but must be amenorrhoeic for at least
             1 year to be considered of non child bearing potential as determined by the
             Investigator.

          3. Patients with a past or present history of drug or alcohol abuse as per Diagnostic and
             Statistical Manual of Mental Disorders (4th edition; DSM IV) criteria.

          4. Patients with a past (within 1 year) or present history of psychotic symptoms
             requiring anti psychotic treatment. Patients may be taking anti-depressant medication;
             however, the dose must be stable for 4 weeks prior to the Screening visit. Use of anti
             psychotic medication including clozapine and quetiapine is prohibited.

          5. Patients with a past (within 1 year) or present history of major depression, suicidal
             ideation or suicide attempts.

          6. Patients with unstable abnormalities of the hepatic, renal, cardiovascular,
             respiratory, gastro-intestinal, haematological, endocrine or metabolic systems that
             might complicate assessment of the tolerability of the study medication.

          7. Patients who have a past or present history of liver impairment, neuroleptic malignant
             syndrome, non traumatic rhabdomyolysis or pheochromocytoma.

          8. Patients with significantly elevated liver enzymes (abnormal bilirubin or serum
             transaminase levels of more than 1.5 times the upper normal limit).

          9. Patients with current or prior treatment (within 4 weeks prior to the Screening visit)
             with medication known to induce the enzyme CYP3A4.

         10. Current or prior treatment (within 4 weeks prior to the Screening visit) with
             pergolide (only applies to patients entering after April 5, 2007), cabergoline
             (effective as of the date of the IRB/IEC approval of this amendment), tolcapone,
             methyldopa, budipine, reserpine, quetiapine or intermittent use of either liquid forms
             of levodopa or subcutaneous apomorphine.

         11. Current treatment with non selective MAOA/B or combination of selective MAOA and
             selective MAOB inhibitors.

         12. Patients with a known hypersensitivity to the active substance or to any of the
             excipients of entacapone.

         13. Patients with previous stereotactic surgery (e.g., pallidotomy) for PD or with planned
             stereotactic surgery during the study period.

         14. Patients receiving or with planned (next 6 months) deep brain stimulation.

         15. Patients who have received entacapone previously or are currently using entacapone.

         16. Patients who have received an investigational product within 4 weeks prior to the
             Screening visit or patients who have participated in a previous study with E2007.

         17. Patients with clinically significant cognitive impairment (Mini Mental State
             Examination [MMSE] <24 or fulfilling DSM IV criteria for dementia due to PD).

         18. Patients with conditions affecting the peripheral or central sensory system unless
             related to PD (such as mild sensory or pain syndromes limited to OFF periods) that
             could interfere with the evaluation of any such symptoms caused by the study drug.

         19. Patients with any condition that would make the patient, in the opinion of the
             Investigator, unsuitable for the study.