Efficacy and Safety of BIA 9-1067 in Idiopathic Parkinson's Disease Patients With "Wearing-off" Phenomenon
Condition: Parkinson's Disease
MeSH terms: Parkinson Disease
Intervention: BIA 9-1067; Entacapone; Placebo; Levodopa; Carbidopa; Benserazide
Intervention description: 5, 25 and 50 mg of BIA 9-1067 (once-daily); 200 mg entacapone (concomitantly with each L-dopa/DDCI dose); 200 mg; DOPA decarboxylase inhibitor; DOPA decarboxylase inhibitor
Intervention MeSH terms: Levodopa; Carbidopa; Opicapone; Entacapone; Benserazide
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Enrollment: 600.0
Sex: All
Minimum age: 30 Years
Maximum age: 83 Years
Healthy volunteers: No
Keywords: Parkinson; PD; Wearing-off; Levodopa/DDCI

Summary:

      This study aims to demonstrate the efficacy and safety of BIA 9-1067, compared with
      entacapone or placebo, when administered with the existing treatment of L-DOPA plus a Dopa
      Decarboxylase Inhibitor (DDCI), in patients with Parkinson's Disease (PD) and end-of-dose
      motor fluctuations.
    

Eligibility criteria:

        Inclusion Criteria:

        V1 (Screening, up to 14 days before V2)

          -  Able to comprehend and willing to sign an informed consent form.

          -  Male and female subjects between 30 and 83 years old, inclusive.

          -  Diagnosed with idiopathic PD according to the UK Parkinson's Disease Society Brain
             Bank Clinical Diagnostic Criteria for at least 3 years.

          -  Disease severity Stages I-III (modified Hoehn &Yahr staging) at ON.

          -  Treated with L-DOPA/DDCI for at least 1 year with clear clinical improvement as per
             investigator's judgment.

          -  Treated with 3 to 8 daily doses of L-DOPA/DDCI, which can include a slow-release
             formulation.

          -  On a stable regimen of L-DOPA/DDCI and other anti-PD drugs for at least 4 weeks before
             screening.

          -  Signs of "wearing-off" phenomenon (end-of-dose deterioration) for a minimum of 4 weeks
             before screening, with average total daily OFF time while awake of at least 1.5 hours,
             excluding the early morning pre-first dose OFF, despite optimal anti-PD therapy (based
             on the investigator's judgment).

          -  Able to keep reliable diaries of motor fluctuations (alone or with family/caregiver
             assistance).

          -  Amenorrheic for at least 1 year or surgically sterile for at least 6 months before
             screening. Females of childbearing potential must be using an effective non-hormonal
             contraceptive method.

        V2 (Randomisation, Day 0)

          -  Have filled-in self-rating diary charts in accordance with the diary chart
             instructions and with ≤ 3 errors per day.

          -  At least 1.5 OFF hours per day, excluding the early morning pre-first dose OFF period
             (i.e. the time between wake-up and response to the first L DOPA/DDCI dosage), as
             recorded in the self-rating diary for at least 2 of the 3 days preceding V2.

          -  Results of the screening laboratory tests are considered acceptable by the
             investigator (i.e. not clinically relevant for the well-being of the subject or for
             the purpose of the study).

        Exclusion Criteria:

        V1 (Screening, up to 14 days before V2)

          -  Non-idiopathic PD (atypical parkinsonism, secondary [acquired or symptomatic]
             parkinsonism, Parkinson-plus syndrome).

          -  Dyskinesia disability score > 3 in the Unified Parkinson's Disease Rating Scale
             (UPDRS) Sub-section IV A, item 33.

          -  Severe and/or unpredictable OFF periods.

          -  Treatment with prohibited medication: tolcapone, neuroleptics, venlafaxine, monoamine
             oxidase inhibitors (except selegiline up to 10 mg/day in oral formulation or 1.25
             mg/day in buccal absorption formulation or rasagiline up to 1 mg/day), or antiemetics
             with antidopaminergic action (except domperidone) within the month before screening.

          -  Previous use of entacapone.

          -  Treatment with apomorphine, alpha-methyldopa, or reserpine within the month before
             screening or likely to be needed at any time during the study.

          -  Dosage change of concomitant anti-PD medication within 4 weeks of screening.

          -  Previous or planned (during the entire study duration, including the OL period) deep
             brain stimulation.

          -  Previous stereotactic surgery (e.g. pallidotomy, thalamotomy) for PD or with planned
             stereotactic surgery during the study period.

          -  Any IMP within the 3 months (or within 5 half-lives, whichever is longer) before
             screening.

          -  Any medical condition that might place the subject at increased risk or interfere with
             assessments.

          -  Past (within the past year) or present history of suicidal ideation or suicide
             attempts.

          -  Current or previous (within the past year) diagnosis of major depressive disorder,
             mania, bipolar disorder, psychosis, dysthymia, generalised anxiety disorder, alcohol
             or substance abuse excluding caffeine or nicotine, impulse control disorders (e.g.
             pathological gambling), dementia or eating disorders according to Diagnostic and
             Statistical Manual of Mental Disorders, 4th edition, text revision (DSM-IV) American
             Psychiatric Association, 2000 criteria, as determined by the investigator.

          -  A clinically relevant electrocardiogram (ECG) abnormality (relevance should be
             assessed by a cardiologist if needed).

          -  Current evidence of unstable cardiovascular disease, including but not limited to
             uncontrolled hypertension, myocardial infarction with important systolic or diastolic
             dysfunction, unstable angina, congestive heart failure (New York Heart Association
             class ≥ III), and significant cardiac arrhythmia (Mobitz II 2nd or 3rd degree AV block
             or any other arrhythmia causing haemodynamic repercussions as symptomatic bradycardia
             or syncope).

          -  Prior renal transplant or current renal dialysis.

          -  Pheochromocytoma, paraganglioma, or other catecholamine secretive neoplasm.

          -  Known hypersensitivity to the ingredients of IMPs used.

          -  History of neuroleptic malignant syndrome (NMS) or NMS-like syndromes, or
             non-traumatic rhabdomyolysis.

          -  History of or current cancer disease, which in the investigator's opinion would
             exclude the subject from the study (e.g. melanoma, prostate cancer).

          -  Unstable active narrow-angle or unstable wide-angle glaucoma.

          -  History of or current evidence of any relevant disease in the context of this study,
             i.e. with respect to the safety of the subject or related to the study conditions,
             e.g. which may influence the absorption or metabolism (such as a relevant liver
             disease) of the IMP.

          -  Pregnant or breastfeeding. V2 (Randomisation, Day 0)

          -  Any abnormality in the liver enzymes (alanine aminotransferase and/or aspartate
             aminotransferase) > 2 times the upper limit of the normal range, in the screening
             laboratory tests results.

          -  Plasma sodium < 130 mmol/L, white blood cell count < 3000 cells/mm3, or any other
             relevant clinical laboratory abnormality in the screening laboratory tests results
             that, in the investigator's opinion, may compromise the subject's safety.

          -  Inadequate compliance to concomitant L-DOPA/DDCI and other anti-PD drugs during the
             Screening period.