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

• Register: EUCTR
• Last refreshed on: 18 January 2016
• Main ID: EUCTR2010-021860-13-PT
• Date of registration: 08/11/2010
• Prospective Registration: Yes
• Primary sponsor: BIAL - Portela & Ca, S.A.
• Public title: 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
• Scientific title: 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 - BIPARK STUDY I
• Date of first enrolment: 22/12/2010
• Target sample size: 550
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2010-021860-13
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: yes Other trial design description: double-blind period followed by open label period If controlled, specify comparator, Other Medicinial Product: yes Placebo: yes Other: no Number of treatment arms in the trial: 5

Countries of recruitment

Austria, Bosnia and Herzegovina, Bulgaria, Croatia, Czech Republic, France, Germany, Hungary, Italy, Latvia, Lithuania, Montenegro, Netherlands, Poland, Portugal, Romania, Russian Federation, Serbia, Slovakia, Spain, Ukraine

Contacts

• Name: José Francisco Rocha
• Affiliation: Bial - Portela & Cª, S.A.

• Name: José Francisco Rocha
• Affiliation: Bial - Portela & Cª, S.A.

Key inclusion & exclusion criteria

Inclusion criteria:
V1 (Screening, up to 14 days before V2)
1. Able to comprehend and willing to sign an informed consent form.
2. Male and female subjects between 30 and 83 years old, inclusive.
3. Diagnosed with idiopathic PD according to the UK Parkinson’s Disease Society Brain Bank Clinical Diagnostic Criteria for at least 3 years.
4. Disease severity Stages I-III (modified Hoehn &Yahr staging) at ON.
5. Treated with L-DOPA/DDCI for at least 1 year with clear clinical improvement as per investigator’s judgment.
6. Treated with 3 to 8 daily doses of L-DOPA/DDCI, which can include a slow-release formulation.
7. On a stable regimen of L-DOPA/DDCI and other anti-PD drugs for at least 4 weeks before screening.
8. 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).
9. Able to keep reliable diaries of motor fluctuations (alone or with family/caregiver assistance).
10. 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)
11. Have filled-in self-rating diary charts in accordance with the diary chart instructions and with =3 errors per day.
12. 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.
13. 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).

Are the trial subjects under 18? no
Number of subjects for this age range: 0
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 150
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 400

Exclusion criteria:
V1 (Screening, up to 14 days before V2)
1. Non-idiopathic PD (atypical parkinsonism, secondary [acquired or symptomatic] parkinsonism, Parkinson-plus syndrome).
2. Dyskinesia disability score >3 in the Unified Parkinson’s Disease Rating Scale (UPDRS) Sub-section IV A, item 33.
3. Severe and/or unpredictable OFF periods.
4. 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.
5. Previous use of entacapone.
6. Treatment with apomorphine, alpha-methyldopa, or reserpine within the month before screening or likely to be needed at any time during the study.
7. Dosage change of concomitant anti-PD medication within 4 weeks of screening.
8. Previous or planned (during the entire study duration, including the OL period) deep brain stimulation.
9. Previous stereotactic surgery (e.g. pallidotomy, thalamotomy) for PD or with planned stereotactic surgery during the study period.
10. Any IMP within the 3 months (or within 5 half-lives, whichever is longer) before screening.
11. Any medical condition that might place the subject at increased risk or interfere with assessments.
12. Past (within the past year) or present history of suicidal ideation or suicide attempts.
13. 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.
14. A clinically relevant electrocardiogram (ECG) abnormality (relevance should be assessed by a cardiologist if needed).
15. 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).
16. Prior renal transplant or current renal dialysis.
17. Pheochromocytoma, paraganglioma, or other catecholamine secretive neoplasm.
18. Known hypersensitivity to the ingredients of IMPs used.
19. History of neuroleptic malignant syndrome (NMS) or NMS-like syndromes, or non-traumatic rhabdomyolysis.
20. History of or current cancer disease, which in the investigator’s opinion would exclude the subject from the study (e.g. melanoma, prostate cancer).
21. Unstable active narrow-angle or unstable wide-angle glaucoma.
22. 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.
23. Pregnant or breastfeeding.
V2 (Randomisation, Day 0)
24. Any abnormality in the liver enzymes (alanine aminotransferase and/or aspartate aminotransfer

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Nervous System Diseases [C10]

Adjunct to levodopa (L-DOPA)/DDCI for use in patients with Parkinson’s disease (PD) and end-of-dose motor fluctuations.
MedDRA version: 14.1 Level: PT Classification code 10061536 Term: Parkinson's disease System Organ Class: 10029205 - Nervous system disorders

Intervention(s)

Product Name: BIA 9-1067
Product Code: BIA 9-1067
Pharmaceutical Form: Capsule
INN or Proposed INN: BIA 9-1067
CAS Number: 923287-50-7
Current Sponsor code: BIA 9-1067
Other descriptive name: BIA 9-1067
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 50-
Pharmaceutical form of the placebo: Capsule
Route of administration of the placebo: Oral use

Trade Name: Comtan®
Product Name: Over-encapsulated Entacapone Tablets
Product Code: Over-encapsulated Entacapone Tablets
Pharmaceutical Form: Capsule
INN or Proposed INN: ENTACAPONE
CAS Number: 130929-57-6
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 200-
Pharmaceutical form of the placebo: Capsule
Route of administration of the placebo: Oral use

Product Name: BIA 9-1067
Product Code: BIA 9-1067
Pharmaceutical Form: Capsule
INN or Proposed INN: BIA 9-1067
CAS Number: 923287-50-7
Current Sponsor code: BIA 9-1067
Other descriptive name: BIA 9-1067
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 25-
Pharmaceutical form of the placebo: Capsule
Route of administration of the placebo: Oral use

Product Name: BIA 9-1067
Product Code: BIA 9-1067
Pharmaceutical Form: Capsule
INN or Proposed INN: BIA 9-1067
CAS Number: 923287-50-7
Current Sponsor code: BIA 9-1067
Other descriptive name: BIA 9-1067
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 5-
Pharmaceutical form of the placebo: Capsule
Route of administration of the placebo: Oral use

Primary Outcome(s)

Main Objective: To investigate the efficacy of 3 different doses of BIA 9-1067 (5 mg, 25 mg, and 50 mg) administered once a day, compared with 200 mg of entacapone or placebo, when administered with the existing treatment of L-DOPA plus a DDCI, in patients with PD and end-of-dose motor fluctuations.

Primary end point(s): Criteria for Evaluation:
Efficacy:
• Subject diary charts for ON/OFF periods.
Safety:
• Treatment-emergent adverse events (TEAEs) including serious adverse events. TEAEs are defined as all AEs with onset or worsening after first intake of IMP until 2 weeks (14 days) after last intake of IMP (PSV).
• Laboratory safety tests:
? Biochemistry: sodium, potassium, bicarbonate, chloride, calcium, phosphate, glucose, creatinine, blood urea nitrogen, aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transferase, alkaline phosphatase, creatine phosphokinase, lactic dehydrogenase, albumin, total protein, total cholesterol, low- and high-density lipoprotein cholesterol, triglycerides, total bilirubin and direct/indirect bilirubin.
? Haematology: red blood cell count, haematocrit, haemoglobin, white blood cell count (total and differential), platelet count.
? Coagulation: prothrombin time (international normalised ratio and activated partial thromboplastin time).
? Serum and urine pregnancy test: only in female subjects of childbearing potential.
? Urinalysis: pH, specific gravity, protein, blood, glucose, ketones, bilirubin, urobilinogen (local dipstick).
• Physical and neurological examinations.
• Skin examinations to screen for melanoma.
• Vital signs.
• 12-lead ECG readings.
• Columbia Suicide Severity Rating Scale (C-SSRS)
• Modified Minnesota Impulsive Disorders Interview (mMIDI).

Timepoint(s) of evaluation of this end point: After unblinding of the study data.

Secondary Objective: To investigate the safety and tolerability of the combined treatment (L DOPA/DDCI plus BIA 9-1067, entacapone, or placebo).

Secondary Outcome(s)

Secondary end point(s): • UPDRS Sections I (ON), II (ON and OFF), and III (ON).
• Modified Hoehn & Yahr staging (ON) (UPDRS V).
• Schwab and England scale (ON and OFF) (UPDRS VI).
• Change in L-DOPA/DDCI dose.
• Investigator’s and subject’s assessments of change.
• Parkinson’s Disease Sleep Scale (PDSS).
• Complications of therapy (UPDRS Sub-sections IV A, B, and C).
• Parkinson’s Disease Questionnaire (PDQ-39).
• Non-motor Symptoms Scale (NMSS).

Timepoint(s) of evaluation of this end point: After unblinding of the study data.

Secondary ID(s)

2010-021860-13-HU

BIA-91067-301

Source(s) of Monetary Support

Bial - Portela & Cª, S.A.