| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated | |
| 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. |
| Levodopa (L-DOPA)/DDCI papildymas Parkinsono liga (PL) sergantiems pacientams, patiriantiems dozės pabaigos motorines fluktuacijas |
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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 | 16.1 |
| 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 |
|
| 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. |
| 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.2.2 | 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). |
| Ištirti kombinuoto vartojimo (L DOPA/DDCI plius BIA 9-1067, entacapone, arba placebas) saugumą ir toleravimą. |
|
| 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 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).
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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).
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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.
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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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.
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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.
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.5.1.1 | Timepoint(s) of evaluation of this end point |
| After unblinding of the study data |
|
| E.5.2 | 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). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| After unblinding of the study data. |
|
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| double-blind period followed by open label period |
|
| 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 | 4 |
| 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 |
| Bulgaria |
| France |
| Italy |
| Austria |
| Croatia |
| Netherlands |
| Portugal |
| Romania |
| Slovakia |
| Bosnia and Herzegovina |
| Montenegro |
| Czech Republic |
| Germany |
| Hungary |
| Latvia |
| Lithuania |
| Spain |
| Poland |
| Russian Federation |
| Serbia |
| Ukraine |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| 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 | 4 |
| 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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