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    Summary
    EudraCT Number:2010-021860-13
    Sponsor's Protocol Code Number:BIA-91067-301
    National Competent Authority:Lithuania - SMCA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2010-09-28
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedLithuania - SMCA
    A.2EudraCT number2010-021860-13
    A.3Full title of the trial
    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
    BIA 9-1067 VEIKSMINGUMAS IR SAUGUMAS IDIOPATINE PARKINSONO LIGA SU “NUSIDĖVĖJIMO” FENOMENU SERGANTIEMS PACIENTAMS, GYDYTIEMS LEVODOPA IR DOPADEKARBOKSILAZĖS INHIBITORIUMI (DDCI): DVIGUBAI AKLU BŪDU ATLIEKAMAS, ATSITIKTINĖS ATRANKOS, PLACEBU IR AKTYVIU PREPARATU KONTROLIUOJAMAS, PARALELINIŲ GRUPIŲ, DAUGIACENTRINIS KLINIKINIS TYRIMAS
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    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
    BIA 9-1067 VEIKSMINGUMAS IR SAUGUMAS IDIOPATINE PARKINSONO LIGA SU “NUSIDĖVĖJIMO” FENOMENU SERGANTIEMS PACIENTAMS, GYDYTIEMS LEVODOPA IR DOPADEKARBOKSILAZĖS INHIBITORIUMI (DDCI): DVIGUBAI AKLU BŪDU ATLIEKAMAS, ATSITIKTINĖS ATRANKOS, PLACEBU IR AKTYVIU PREPARATU KONTROLIUOJAMAS, PARALELINIŲ GRUPIŲ, DAUGIACENTRINIS KLINIKINIS TYRIMAS
    A.3.2Name or abbreviated title of the trial where available
    BIPARK STUDY I
    A.4.1Sponsor's protocol code numberBIA-91067-301
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorBIAL - Portela & Ca, S.A.
    B.1.3.4CountryPortugal
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportBIAL - Portela & Ca, S.A.
    B.4.2CountryPortugal
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationBIAL - Portela & Ca, S.A.
    B.5.2Functional name of contact pointJose Francisco Rocha
    B.5.3 Address:
    B.5.3.1Street AddressÀ Av. Siderurgia Nacional
    B.5.3.2Town/ cityS. Mamede do Coronado
    B.5.3.3Post code4745-457
    B.5.3.4CountryPortugal
    B.5.4Telephone number+351 22 9866100
    B.5.5Fax number+351 229866192
    B.5.6E-mailjose.rocha@bial.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameBIA 9-1067
    D.3.2Product code BIA 9-1067
    D.3.4Pharmaceutical form Capsule
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNBIA 9-1067
    D.3.9.1CAS number 923287-50-7
    D.3.9.2Current sponsor codeBIA 9-1067
    D.3.9.3Other descriptive nameBIA 9-1067
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Comtan®
    D.2.1.1.2Name of the Marketing Authorisation holderNovartis Pharmaceuticals
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Capsule
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNENTACAPONE
    D.3.9.1CAS number 130929-57-6
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 3
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameBIA 9-1067
    D.3.2Product code BIA 9-1067
    D.3.4Pharmaceutical form Capsule
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNBIA 9-1067
    D.3.9.1CAS number 923287-50-7
    D.3.9.2Current sponsor codeBIA 9-1067
    D.3.9.3Other descriptive nameBIA 9-1067
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 4
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameBIA 9-1067
    D.3.2Product code BIA 9-1067
    D.3.4Pharmaceutical form Capsule
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNBIA 9-1067
    D.3.9.1CAS number 923287-50-7
    D.3.9.2Current sponsor codeBIA 9-1067
    D.3.9.3Other descriptive nameBIA 9-1067
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboCapsule
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    E.1.1.1Medical 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.
    Levodopa (L-DOPA)/DDCI papildymas Parkinsono liga (PL) sergantiems pacientams, patiriantiems dozės pabaigos motorines fluktuacijas
    E.1.1.2Therapeutic area Diseases [C] - Nervous System Diseases [C10]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 16.1
    E.1.2Level PT
    E.1.2Classification code 10061536
    E.1.2Term Parkinson's disease
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main 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.
    Ištirti 3-jų skirtingų BIA 9-1067 dozių (5 mg, 25 mg, ir 50 mg), vartojamų kartą per dieną, veiksmingumą lyginant su 200 mg entacapone arba placebu, kai vartojama kartu su jau taikomu L-DOPA ir DDCI gydymu PL pacientams su dozės pabaigos motorinės funkcijos svyravimais.
    E.2.2Secondary objectives of the trial
    To investigate the safety and tolerability of the combined treatment (L DOPA/DDCI plus BIA 9-1067, entacapone, or placebo).
    Ištirti kombinuoto vartojimo (L DOPA/DDCI plius BIA 9-1067, entacapone, arba placebas) saugumą ir toleravimą.
    E.2.3Trial contains a sub-study No
    E.3Principal 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 a double-barrier method of contraception. Hormonal
    contraceptives are not acceptable as a contraceptive method in this trial.
    However, their intake is not forbidden throughout the study..
    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).
    V1 (Atranka, iki 14 dienų prieš V2):
    1. Sugeba suvokti ir nori pasirašyti informuoto asmens sutikimo formą.
    2. Vyrai ir moterys nuo 30 iki 83 metų, imtinai.
    3. Idiopatinė PL diagnozuota mažiausiai prieš 3 metus pagal Jungtinės Karalystės Parkinsono ligos draugijos smegenų banko klinikinius diagnostinius kriterijus.
    4. Ligos sunkumo stadijos I-III (modifikuotos Hoehn &Yahr skalės) ĮSIJUNGIMO metu.
    5. Mažiausiai 1 metus gydyti L-DOPA/DDCI su, pagal tyrėją, aiškiai kliniškai išreikštu pagerėjimu.
    6. Gydyti L-DOPA/DDCI nuo 3 iki 8 dozių per parą, tame tarpe ir prailginto atpalaidavimo formuluotėmis.
    7. Stabilus L-DOPA/DDCI ir kitų priešparkinsoninių vaistų režimas mažiausiai 4 savaites prieš atranką.
    8. “Nusidėvėjimo“ fenomeno ženklai (trumpesnis ir silpnesnis vaisto poveikis pavartojus įprastą dozę) mažiausiai 4 savaites prieš atrankos vizitą, kai nepaisant optimalios priešparkinsoninės terapijos (tyrėjo sprendimu) su vidutine paros doze pabudus mažiausiai 1,5 valandos IŠSIJUNGIA, neskaitant ankstyvo ryto prieš pirmą dozę IŠSIJUNGIMO.
    9. Sugebantis įskaitomai žymėti motorines fluktuacijas dienyne (savarankiškai arba su šeimos/globėjo(s) pagalba).
    10. Neturinti mėnesinių mažiausiai 1 metus arba chirurgiškai sterili mažiausiai 6 mėnesius prieš atranką. Vaisingo amžiaus moterys turi naudoti efektyvius nehormoninius kontracepcijos metodus.
    V2 (Randomizacija, Diena 0)
    11. Vadovaujantis dienyno pildymo instrukcijomis užpildytos savęs vertinimo dienyno dalys ir padarytos ≤3 klaidos per dieną.
    12. Mažiausiai 1,5 valandos IŠSIJUNGIA per diena, neskaitant ankstyvo ryto prieš pirmą dozę IŠSIJUNGIMO periodo (tai yra laikotarpis tarp pabudimo ir atsako į pirmą L DOPA/DDCI dozę), kaip ir nurodyta savęs vertinimo dienyne bent 2 iš 3-jų dienų prieš V2.
    13. Atrankos metu laboratorijos tyrimų rezultatai tyrėjo įvertinti tinkamais (tai yra, kliniškai nereikšmingi tiriamojo sveikatai arba tyrimo tikslui).
    E.4Principal 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 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.
    V1 (Atranka, iki 14 dienų prieš V2)
    1. Ne idiopatinė PL (atipinis parkinsonizmas, antrinis [įgytas ar simptomatinis] parkinsonizmas, parkinsonizmo plius sindromas).
    2. Diskinezijos negalios balas >3 pagal Unifikuotą Parkinsono ligos įvertinimo skalę (UPDRS) poskyrio IV A punktą 33.
    3. Sunkūs ir/ arba nenuspėjami IŠSIJUNGIMO periodai.
    4. Gydymas draudžiamais vaistais: tolcapone, neuroleptikais, venlafaxine, monoaminooksidazės inhibitoriais (išskyrus selegiline iki 10 mg per parą vartojant per burną arba 1,25 mg per parą žando absorbcijos formuluotėje arba rasagiline iki 1 mg per parą), arba antiemetikais su antidopaminerginiu veikimu (išskyrus domperidone) vieno mėnesio laikotarpyje prieš atranką.
    5. Ankstesnis entakapone vartojimas.
    6. Gydymas apomorphine, alpha-methyldopa arba reserpine vieno mėnesio laikotarpyje prieš atranką arba jei tikėtina, kad šie vaistai bus reikalingi bet kuriuo dalyvavimo tyrime metu.
    7. Anksčiau vartotų priešparkinsoninių vaistų dozės pakeitimas 4 savaičių laikotarpyje prieš atranką.
    8. Ankstesnis arba planuojamas (viso tyrimo metu, įskaitant AP periodą) gilus smegenų stimuliavimas.
    9. Ankstesnė stereotaksinė PL chirurgija (pvz. palidotomija, talamotomija) arba planuojama stereotaksinė chirurgija dalyvavimo tyrime metu.
    10. Bet koks TVP 3-jų mėnesių laikotarpiu prieš atranką (arba 5-ių produkto skilimo pusperiodžių laikotarpiu, pasirenkant ilgesnįjį laikotarpį) vartojimas.
    11. Bet kokia sveikatos būklė, kuri galėtų padidinti pavojų arba trukdyti vertinimui.
    12. Ankstesni (per pastaruosius metus) arba dabartiniai įrašai apie suicidines mintis ar bandymus nusižudyti.
    13. Dabartiniu metu arba anksčiau (per pastaruosius metus) nustatyti reikšmingi depresiniai sutrikimai; manija, bipolinis sutrikimas, psichozė, distimija, generalizuotas nerimo sutrikimas, piktnaudžiavimas alkoholiu ar medžiagomis, išskyrus kofeiną ar nikotiną, impulsų kontroliavimo sutrikimas (pvz. patologinis lošimas), demencijos ar valgymo sutrikimai pagal Psichikos sutrikimų diagnostikos ir statistikos vadovą, IV-asis leidimas, tekstas peržiūrėtas (DSM-IV) Amerikos Psichiatrų Asociacijos, 2000 kriterijų, tyrėjui nusprendus.
    14. Kliniškai reikšmingi elektrokardiogramos (EKG) pakitimai (jei reikalinga, reikšmingumas turėtų būti įvertintas ir kardiologo).
    15. Neseniai pasireiškusi nestabili širdies ir kraujagyslių liga, įskaitant, bet neapsiribojant, nekontroliuojama hipertenzija, miokardo infarktu su reikšmingomis sistolinėm ar diastolinėmis disfunkcijomis, nestabilia angina, staziniu širdies nepakankamumu (Niujorko Širdies asociacija, funkcinė klasė ≥III), ir kliniškai reikšminga širdies aritmija (Mobitzo II 2-o ar 3-io laipsnio AV blokada ar bet kokia kita aritmija, kuri sukeltų hemodinamines apkrovas, tokias kaip simptominė bradikardiją ar alpimas).
    16. Ankstesnė inkstų transplantacija arba šiuo metu taikoma inkstų dializė.
    17. Feochromocitoma, paraganglioma ar kita katecholaminų sekrecijos neoplazija
    18. Žinomas padidintas jautrumas TVP sudėtinėms dalims.
    19. Anamnezėje buvęs neuroleptinis maligninis sindromas (NMS) ar į NMS panašūs sindromai, arba netrauminė rabdomiolizė.
    20. Anamnezėje arba dabar sergantis vėžiu, dėl kurio, tyrėjo nuomone, tiriamasis turi būti pašalintas iš tyrimo (pvz. melanoma, prostatos vėžys).
    21. Nestabili aktyvi uždaro kampo arba nestabili atviro kampo glaukoma.
    22. Anamnezėje ar dabartiniu metu nustatytas šio tyrimo kontekste reikšmingas susirgimas, tai yra, susijęs su tiriamojo saugumu ar tyrimo sąlygomis, pvz. kurios gali įtakoti TVP absorbciją ar metabolizmą (pvz. reikšminga kepenų liga).
    23. Nėštumas arba maitinimas krūtimi.
    V2 (Randomizacija, Diena 0)
    24. Bet kokie kepenų fermentų (alanino aminotransferazės ir/arba aspartato aminotransferazės) pakitimai >2 kartus viršijantys viršutinę normos ribą laboratorinių tyrimų rezultatuose atrankos metu.
    25. Natrio koncentracija kraujo plazmoje <130 mmol/L, leukocitų skaičius <3000 ląstelių/mm3 ar bet kokie kiti reikšmingi laboratoriniai pakitimai nustatyti laboratorinių tyrimų rezultatuose atrankos metu, kurie tyrėjo nuomone, gali kelti pavojų paciento saugumui.
    26. Netinkamas lydimųjų L-DOPA/DDCI ir kitų priešparkinsoninių vaistų vartojimas atrankos periodo laikotarpiu.
    E.5 End points
    E.5.1Primary 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 highdensity
    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).
    E.5.1.1Timepoint(s) of evaluation of this end point
    After unblinding of the study data
    E.5.2Secondary 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).
    E.5.2.1Timepoint(s) of evaluation of this end point
    After unblinding of the study data.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    double-blind period followed by open label period
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial5
    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.8.4.1Number of sites anticipated in Member State concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA100
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If 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
    E.8.7Trial 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
    provided in the protocol
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 30
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 20
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state50
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 400
    F.4.2.2In the whole clinical trial 550
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    not different from the expected normal treatment of that condition
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2010-11-30
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2010-10-22
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2014-12-17
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