Efficacy and Safety of BIA 9-1067 in Idiopathic Parkinson's Disease Patients With "Wearing-off" Phenomenon

Efficacy and Safety of BIA 9-1067 in Idiopathic Parkinson's Disease Patients With "Wearing-off" Phenomenon Treated With Levodopa Plus a Dopa Decarboxylase Inhibitor (DDCI): a Double-blind, Randomised, Placebo- and Active-controlled, Parallel-group, Multicentre Clinical Study

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.

Study Overview

• Status: Completed
• Conditions: Parkinson's Disease
• Intervention / Treatment: Drug: Levodopa; Drug: Benserazide; Drug: BIA 9-1067; Drug: Carbidopa; Drug: Entacapone; Drug: Placebo

Detailed Description

Efficacy and safety of BIA 9-1067 in idiopathic Parkinson's disease patients with "wearing-off" phenomenon treated with levodopa plus a dopa decarboxylase inhibitor (DDCI): a double-blind, randomised, placebo- and active-controlled, parallel-group, multicentre clinical study.

• Study Type: Interventional
• Enrollment (Actual): 600
• Phase: Phase 3

Contacts and Locations

Study Locations

• Portugal
  • S. Mamede do Coronado, Portugal, 4745-457
    • Bial - Portela & Cª, S.A.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 30 years to 83 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: BIA 9-1067; OPC, Opicapone	Drug: Levodopa; Other Names: L-Dopa; Drug: Benserazide; DOPA decarboxylase inhibitor; Drug: BIA 9-1067; 5, 25 and 50 mg of BIA 9-1067 (once-daily); Other Names: OPC, Opicapone; Drug: Carbidopa; DOPA decarboxylase inhibitor
ACTIVE_COMPARATOR: Entacapone; Comtan®; Active comparator	Drug: Levodopa; Other Names: L-Dopa; Drug: Benserazide; DOPA decarboxylase inhibitor; Drug: Carbidopa; DOPA decarboxylase inhibitor; Drug: Entacapone; 200 mg entacapone (concomitantly with each L-dopa/DDCI dose); Other Names: Comtan®
PLACEBO_COMPARATOR: Placebo; PLC, Placebo	Drug: Levodopa; Other Names: L-Dopa; Drug: Benserazide; DOPA decarboxylase inhibitor; Drug: Carbidopa; DOPA decarboxylase inhibitor; Drug: Placebo; 200 mg; Other Names: PLC

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Efficacy of 3 BIA 9-1067 (5 mg, 25 mg, and 50 mg) Compared With 200 mg of Entacapone or Placebo,	The primary efficacy variable will be the change from baseline in absolute OFF-time at the end of the DB period, This results refers when administered with the existing treatment of L-DOPA plus a DDCI, in patients with PD and end-of-dose motor fluctuations	14 to 15 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Total UPDRS SCORE (I, II (ON), and III)	Total UPDRS (Part I, II (ON) and III); UPDRS I evaluation of mentation, behavior, and mood; UPDRS II self-evaluation of the activities of daily life (ADLs) including speech, swallowing, handwriting, dressing, hygiene, falling, salivating, turning in bed, walking, and cutting food; UPDRS III clinician-scored monitored motor evaluation The UPDRS I, II and III scores and subscores are calculated as the sum of all individual items. If one or two items in a scale are missing, they will be imputed with the mean of the non-missing items of that scale. Subscale has 0-4 ratings, where 0 = normal, 1 = slight, 2 = mild, 3 = moderate, and 4 = severe The final cumulative score will range from 0 (no disability) to 199 (total disability).	14 to 15 weeks
Parkinson's Disease Sleep Scale (PDSS)	The Parkinson's disease Sleep Scale (PDSS) is a specific scale for the assessment of sleep disturbances in subjects with PD. The PDSS score is calculated as the sum of all single items. If one or two items are missing, they will be imputed with the mean of the non-missing items. If three or more items are missing, no imputation will be done and the score will be set to missing. Subscale has 0-10 ratings, where 0 = severe and 10 = normal The PDSS total score is a sum score of all 15 questions and ranges from 0 to 150, with lower scores meaning more disability.	14 to 15 weeks
Non-motor Symptoms Scale (NMSS)	The Non-motor Symptoms Scale (NMSS) consists of 30 questions, covering 9 dimensions, whereby each item is scored for severity and frequency: Severity None 0 Mild (symptoms present but causes little distress) 1 Moderate (some distress or disturbance to subject) 2 Severe (major source of distress or disturbance to subject) 3 Frequency Rarely (<1/wk) 1 Often (1/wk) 2 Frequent (several times per week) 3 Very Frequent (daily or all the time) 4 The product of frequency and severity is calculated for each item and each dimension score is defined as the sum of the frequency*severity of the respective items. If frequency or severity of a single item is missing, the domain score will not be calculated. The NMSS total score is defined as the sum of all domain scores. The NMSS total score is calculated by adding all domain scores (0-360), and lower scores mean less disability.	14 to 15 weeks

Collaborators and Investigators

• Sponsor: Bial - Portela C S.A.
• Investigators: Principal Investigator: Joaquim Ferreira, MD, PhD, Centro Hospitalar de Lisboa Norte, EPE - Hospital de Staª Maria-Centro de Estudos Egas Moniz

Publications and helpful links

General Publications

• Ferreira JJ, Lees A, Rocha JF, Poewe W, Rascol O, Soares-da-Silva P; Bi-Park 1 investigators. Opicapone as an adjunct to levodopa in patients with Parkinson's disease and end-of-dose motor fluctuations: a randomised, double-blind, controlled trial. Lancet Neurol. 2016 Feb;15(2):154-165. doi: 10.1016/S1474-4422(15)00336-1. Epub 2015 Dec 23.

Study record dates

Study Major Dates

• Study Start: March 1, 2011
• Primary Completion (ACTUAL): November 1, 2013
• Study Completion (ACTUAL): November 1, 2013

Study Registration Dates

• First Submitted: March 29, 2012
• First Submitted That Met QC Criteria: March 30, 2012
• First Posted (ESTIMATE): April 2, 2012

Study Record Updates

• Last Update Posted (ESTIMATE): September 18, 2015
• Last Update Submitted That Met QC Criteria: September 1, 2015
• Last Verified: September 1, 2015

More Information

Terms related to this study

• Keywords: Parkinson; PD; Wearing-off; Levodopa/DDCI
• 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; Dopamine Agents; Antiparkinson Agents; Anti-Dyskinesia Agents; Catechol O-Methyltransferase Inhibitors; Aromatic Amino Acid Decarboxylase Inhibitors; Levodopa; Carbidopa; Opicapone; Benserazide; Entacapone
• Other Study ID Numbers: BIA-91067-301; 2010-021860-13 (EUDRACT_NUMBER)