| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Adjunct to levodopa (L-DOPA)/DDCI for use in patients with Parkinson’s disease (PD) and end-of-dose motor fluctuations. |
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| E.1.1.1 | Medical condition in easily understood language |
| Adjunct to levodopa (L-DOPA)/DDCI for use in patients with Parkinson’s disease (PD) and end-of-dose motor fluctuations. |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10061536 |
| E.1.2 | Term | Parkinson's disease |
| E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| 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. |
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| E.2.2 | Secondary objectives of the trial |
| To investigate the safety and tolerability of the combined treatment (L DOPA/DDCI plus BIA 9-1067, entacapone, or placebo). |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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).
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| E.4 | Principal 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.
DEA #1 (Amendment #1, for Germany only): Nursing care level II or III according to German SGB XI.
V2 (Randomisation, Day 0)
24. 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.
25. 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.
26. Inadequate compliance to concomitant L-DOPA/DDCI and other anti-PD drugs during the Screening period.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Criteria for Evaluation:
Efficacy:
• Subject diary charts for ON/OFF periods.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| After unblinding of the study data. |
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| E.5.2 | Secondary end point(s) |
Criteria for Evaluation:
Efficacy:
• Subject diary charts for ON/OFF periods.
• 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).
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, 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).
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| After unblinding of the study data. |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 5 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 12 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 100 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| 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 |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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