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    Summary
    EudraCT Number:2017-002780-17
    Sponsor's Protocol Code Number:ND0612-315
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2018-02-12
    Trial 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 ConcernedSpain - AEMPS
    A.2EudraCT number2017-002780-17
    A.3Full title of the trial
    A Pivotal, Open-Label, Randomized, Crossover, Four Sequences Study in Male and Female Patients with Advanced Parkinson’s Disease to Assess the Relative Bioavailability of Levodopa Administered as ND0612 Subcutaneous Infusion via a Pump System plus Additional Oral Administered Levodopa/Carbidopa versus Levodopa Administered as Carbidopa-Levodopa Enteral Suspension
    Estudio fundamental, abierto, cruzado y aleatorizado de cuatro secuencias en
    pacientes de ambos sexos con enfermedad de Parkinson avanzada para evaluar la
    biodisponibilidad relativa de levodopa administrada como perfusión subcutánea
    ND0612 mediante un sistema de bomba y de levodopa/carbidopa adicionales
    administradas por vía oral en comparación con levodopa administrada como
    suspensión enteral de carbidopa-levodopa
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study in Male and Female Patients with Advanced Parkinson’s Disease to Assess the blood levels of Levodopa Administered as ND0612 via a Pump System plus Additional Oral Administered Levodopa/Carbidopa versus Levodopa Administered as Duodopa.
    Estudio en pacientes de ambos sexos con enfermedad de Parkinson avanzada para evaluar los niveles sanguíneos de levodopa administrada como ND0612 mediante un sistema de bomba y de levodopa/carbidopa adicionales administradas por vía oral en comparación con levodopa administrada como Duodopa.
    A.4.1Sponsor's protocol code numberND0612-315
    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 SponsorNeuroDerm Ltd.
    B.1.3.4CountryIsrael
    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 supportNeuroDerm Ltd.
    B.4.2CountryIsrael
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNeuroDerm Ltd.
    B.5.2Functional name of contact pointOsnat Ehrman
    B.5.3 Address:
    B.5.3.1Street AddressRuhrberg Science building - Bell entrance - 5th floor - 3 Pekeris St.
    B.5.3.2Town/ cityRehovot
    B.5.3.3Post code7670212
    B.5.3.4CountryIsrael
    B.5.4Telephone number+1 703 864 8805
    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 nameND0612
    D.3.2Product code ND0612
    D.3.4Pharmaceutical form Solution for infusion in administration system
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNcarbidopa
    D.3.9.1CAS number 38821-49-7
    D.3.9.2Current sponsor code-
    D.3.9.3Other descriptive nameCARBIDOPA
    D.3.9.4EV Substance CodeSUB06126MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number7.5
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNlevodopa
    D.3.9.1CAS number 59-92-7
    D.3.9.2Current sponsor code-
    D.3.9.3Other descriptive nameLEVODOPA
    D.3.9.4EV Substance CodeSUB08468MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number60
    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 Yes
    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 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 Yes
    D.2.1.1.1Trade name SINEMET Plus
    D.2.1.1.2Name of the Marketing Authorisation holderMerck Sharp & Dohme Limited
    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 nameSINEMET
    D.3.4Pharmaceutical form Tablet
    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 INNlevodopa
    D.3.9.1CAS number 59-92-7
    D.3.9.3Other descriptive nameLEVODOPA
    D.3.9.4EV Substance CodeSUB08468MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNcarbidopa
    D.3.9.1CAS number 38821-49-7
    D.3.9.3Other descriptive nameCARBIDOPA
    D.3.9.4EV Substance CodeSUB06126MIG
    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: 3
    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 Duodopa LD/CD 20/5 mg/mL
    D.2.1.1.2Name of the Marketing Authorisation holderAbbVie Limited
    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 nameDuodopa LD/CD 20/5 mg/mL
    D.3.4Pharmaceutical form Intestinal gel
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntestinal use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNlevodopa
    D.3.9.1CAS number 59-92-7
    D.3.9.3Other descriptive nameLEVODOPA
    D.3.9.4EV Substance CodeSUB08468MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNcarbidopa
    D.3.9.1CAS number 38821-49-7
    D.3.9.3Other descriptive nameCARBIDOPA
    D.3.9.4EV Substance CodeSUB06126MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Parkinson’s Disease
    Enfermedad de Parkinson
    E.1.1.1Medical condition in easily understood language
    Parkinson's disease (PD) is a long-term degenerative disorder of the central nervous system that mainly affects the motor system.
    La enfermedad de Parkinson (EP) es un trastorno degenerativo a largo plazo del sistema nervioso central que afecta principalmente al sistema motor.
    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 20.0
    E.1.2Level HLT
    E.1.2Classification code 10034005
    E.1.2Term Parkinson's disease and parkinsonism
    E.1.2System Organ Class 100000004852
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To assess relative bioavailability of levodopa (LD) administered as ND0612,
    infused subcutaneously (s.c.), with orally co-administered LD/CD (Test)
    versus LD administered as carbidopa-levodopa enteral suspension (CLES),
    infused via a permanent percutaneous endoscopic gastrostomy with jejunal
    tube (PEG-J) or a naso-jejunal tube (Reference).
    Evaluar la biodisponibilidad relativa de levodopa (LD) administrada como ND0612, mediante perfusión subcutánea (s.c.) con LD/CD administradas conjuntamente por vía oral (Prueba) en comparación con LD administrada como suspensión enteral de carbidopa-levodopa (CLES), infundida mediante gastrostomía endoscópica percutánea con sonda yeyunal (PEG-J) o sonda nasoyeyunal (Referencia).
    E.2.2Secondary objectives of the trial
    • To assess the safety and tolerability of study treatments.
    • To assess the pharmacokinetics (PK) of LD and carbidopa (CD) derived from ND0612 plus oral LD/CD or from CLES.
    • Evaluar la seguridad y la tolerabilidad de los tratamientos del estudio. • Evaluar la farmacocinética (FC) de LD y carbidopa (CD) derivada de ND0612 más LD/CD orales o de CLES.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Male or non-pregnant, non-lactating female patient with idiopathic PD currently responding to LD therapy, aged ≥30 years.
    2. Female patients must have a negative pregnancy test at screening and at admission.
    3. Patients must have a body mass index (BMI) within the range of 18.5 – 35 kg/m2, where BMI = body weight (kg) / height (m2) at screening.
    4. Must be willing and able to communicate and participate in the whole study.
    5. Must provide written informed consent.
    6. Area of administration to be evaluable for local skin reaction (normal skin without skin burns, scars or large tattoos in the area of administration).
    7. Must agree to use an adequate method of contraception (per local independent ethics committee requirements).
    For Cohort 1 only:
    8. Currently treated with CLES via PEG-J at a dose of at least 800 mg LD/day and up to 2200 mg LD/day.
    For Cohort 2 only:
    8. Stable PD treatment for at least 30 days before screening with at least 4 doses/day of LD/DOPA-decarboxylase-inhibitor (or at least 3 doses/day of Rytary or Numient) or for whom the conversion to oral LD/CD IR tablets will lead to a LD dose between 800 and 2200 mg/day and according to Investigator judgment motor fluctuations cannot be further improved by adjusting oral LD medication.
    9. Must have a minimum of 2 hours of “OFF” time per day as estimated by the patient.
    1. Paciente de sexo masculino o femenino que no esté embarazada ni en periodo de lactancia con EP idiopática que responda actualmente al tratamiento con LD, de
    edad #30 años.
    2. Las pacientes de sexo femenino deben someterse a una prueba de embarazo con resultado negativo en la selección e ingreso.
    3. Los pacientes deben tener un índice de masa corporal (IMC) de 18,5-35 kg/m2 en la selección, siendo el IMC = peso corporal (kg)/altura (m2).
    4. Deben estar dispuestos a comunicarse y participar durante todo el estudio.
    5. Deben otorgar un consentimiento informado por escrito.
    6. Debe poder evaluarse una reacción cutánea local en el punto de administración (piel normal sin quemaduras, cicatrices ni tatuajes grandes en el punto de administración).
    7. Debe comprometerse a utilizar un método anticonceptivo adecuado (según lo exija el comité de ética de la investigación local).
    Solo para la Cohorte 1:
    8. Tratamiento actual con CLES vía PEG-J con una dosis de al menos 800 mg de LD/día y de hasta 2200 mg de LD/día.
    Solo para la Cohorte 2:
    8. Tratamiento de la EP estable durante al menos 30 días antes de la selección con al menos 4 dosis/día de un inhibidor de LD/DOPA descarboxilasa (o al menos 3 dosis/día de Rytary o Numient) o para quienes la conversión a comprimidos de LD/CD de LI supondrá una dosis de LD de entre 800 y 2200 mg/día y, según la opinión del investigador, las fluctuaciones motoras no
    puedan mejorarse al ajustar la medicación de LD oral. 9. Debe tener un mínimo de 2 horas en estado «OFF» al día según lo considere el paciente.
    E.4Principal exclusion criteria
    1. Previously unable to tolerate ND0612 and/or have experienced intolerable adverse drug reactions associated with its use or serious adverse reaction.
    2. Atypical or secondary parkinsonism.
    3. Acute psychosis or hallucinations within the past 6 months prior to screening.
    4. Any relevant medical, surgical, or psychiatric condition, laboratory value, or concomitant medication which, in the opinion of the Investigator, makes the patient unsuitable for study entry or potentially unable to complete all aspects of the study.
    5. Any malignancy in the 5 years prior to randomization (excluding basal cell carcinoma of the skin, transitional cell carcinoma in situ or cervical carcinoma in situ that have been successfully treated).
    6. Positive serum serology for Hepatitis B Virus (HBV), Hepatitis C Virus (HCV) or Human Immunodeficiency Virus (HIV) at the screening visit.
    7. Patients with a history of drug abuse or alcoholism within the past 12 months prior to screening or positive drugs of abuse or alcohol test result at the screening visit and/or on admission.
    8. Routine alcohol consumption in males >21 units per week and females >14 units per week (1 unit = ½ pint beer, 25 mL of 40% spirit or a 125-mL glass of wine).
    9. Clinically significant electrocardiogram (ECG) rhythm abnormalities.
    10.Renal or liver dysfunction that may alter drug metabolism including: serum creatinine >1.5 mg/dL, serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2 x upper limit of normal (ULN), total serum bilirubin >2.5 mg/dL.
    11. Patients who have previously been enrolled in this study.
    12. Patients who do not have suitable veins for multiple venipunctures / cannulation as assessed by the Investigator at the screening visit.
    13. Psychiatric, neurological or behavioral disorders that may interfere with the conduct or interpretation of the study, including dementia, or patients who are considered to be violent or at suicidal risk by the Investigator.
    14. Presence or history of clinically significant allergy requiring treatment, as judged by the Investigator or serious hypersensitivity to any drug or the formulation excipients. Hay fever is allowed unless it is active.
    15.Blood loss of greater than 500 mL within the previous 3 months prior to first dosing.
    16. Current use of the dopamine agonist pramipexole within 1 month before Day 1.
    17. Intake of domperidone within 2 days before Day 1 or planned to be taken before last PK sampling.
    18. Intake of
    - Catechol-O-methyltransferase (COMT) inhibitors as entacapone, opicapone or agents including them (i.e. Stalevo)
    - DDCI other than CD (i.e. beserazide, methyldopa [Aldomet, Aldoril, Dopamet, Dopegyt], DL-x-Difluoromethyl DOPA (DFMD), 3',4',5,7- Tetrahydroxy-8-methoxyisoflavone)
    - Rytary or Numient within 2 days prior randomization. Patients who are taking any of these medications at screening should be converted to an equivalent dose of oral LD/CD IR tablets as detailed in Table 4).
    19. Intake of donepezil (Aricept) within 14 days before Day 1.
    20. Intake of trihexylphenidyl (benzhexole) within 2 days before Day 1.
    21. Intake of multivitamins with iron (e.g. Pimavanserin) within 8 hours prior to start of study treatment on Day 1
    22. Intake of calcium carbonate, sodium carbonate, aluminum hydroxide, aluminum carbonate, magnesium hydroxide or magnesium oxide within 8 hours prior to start of study treatment on Day 1
    23.Current participation in a clinical study with an investigational compound or past participation within the last 30 days or within less than 5 times the half-life of the investigational product administered in the clinical research study, whichever is longer.
    24.Any PD-related feature or symptom that could interfere with the study conduct and results as assessed by the Investigator.
    25.History or presence of narrow-angle glaucoma.
    26.Any history or presence of prolactin-releasing pituitary tumor (prolactinoma).
    27. Patients who are not willing to adhere to the protocol-prescribed study
    restrictions.
    28. Patients who are employees of a study site or Sponsor, or immediate family members thereof.
    29. The patient is a vulnerable patient, e.g., kept in detention, protected adults under guardianship, trusteeship, or committed to an institution by governmental or juridical order.
    Cohort 2 only:
    30.Contraindications for insertion of a naso-jenunal tube, e.g. recent nasal surgery, nasal fractures, upper gastrointestinal obstruction, esophageal atresia/stenosis, history of significant upper gastrointestinal bleeding,
    esophageal varices or coagulation abnormalities..
    1.Anteriormente, no han conseguido tolerarND0612 o han sufrido una reacción adversa al fármaco intolerable asociada a su uso o una reacción adversa grave.
    2.Parkinsonismo atípico o secundario.
    3.Psicosis o alucinaciones agudas en los 6meses anteriores a la selección.
    4.Cualquier afección médica, quirúrgica o psiquiátrica relevante, valor analítico o medicación concomitante que, según la opinión del investigador, haga que el paciente no sea apto para participar en el estudio o que pueda ser incapaz de cumplir con todos los aspectos del estudio.
    5.Cualquier neoplasia maligna en los 5 años anteriores a la aleatorización(excluidos el carcinoma basocelular de la piel,el carcinoma de células de transición localizado
    o el carcinoma cervical localizado tratados con éxito).
    6.Prueba sérica positiva para el virus de la hepatitis B(VHB),el virus de la hepatitis C(VHC)o el virus de la inmunodeficiencia humana(VIH)en la visita de selección.
    7.Pacientes con antecedentes de drogadicción o alcoholismo en los 12meses anteriores a la selección o con un resultado positivo en la prueba de presencia de drogas o alcohol
    en la visita de selección o ingreso.
    8.Consumo rutinario de alcohol en varones >21unidades/semana y en mujeres >14unidades/semana(1unidad= ½pinta de cerveza,25 ml de licor de40 % o una copa de vino de 125 ml).
    9.Anomalías del ritmo de electrocardiograma ECG) clínicamente significativas.
    10.Disfunción renal o hepática que pueda alterar el metabolismo del fármaco incluidas: creatinina sérica>1,5 mg/dl, aspartato aminotransferasa AST) o alanina aminotransferasa(ALT) >2veces el límite superior de la normalidad(LSN), bilirrubina sérica total>2,5mg/dl.
    11.Pacientes que han participado anteriormente en este estudio.
    12.Pacientes que no tengan venas aptas para varias venopunciones/canulaciones, según valore el investigador en la visita de selección.
    13.Trastornos psiquiátricos, eurológicos o de conducta que puedan interferir con la conducta o interpretación del estudio, incluida la demencia,o pacientes que el investigador considere violentos o con riesgo de suicidio.
    14.Presencia o antecedentes de alergia clínicamente significativa que necesitara tratamiento,según la opinión del investigador,o hipersensibilidad grave a cualquier fármaco o excipientes de las formulaciones. Se permite la rinitis si no está activa.
    15.Pérdida de sangre superior a 500ml en los 3meses anteriores a la primera administración.
    16.Uso actual del agonista de la dopamina pramipexol en el mes anterior al Día 1.
    17.Toma de domperidona en los 2 días anteriores al Día 1 o previsión de tomarla antes de la recogida de muestras de FC.
    18.Toma de -inhibidores de la catecol O-metiltransferasa (COMT) como la entacapona, opicapona o agentes que los incluyan (por ej., Stalevo) -DDCI distinto a CD (es decir, beserazida, metildopa [Aldomet, Aldoril, Dopamet, Dopegyt], DL-x-difluorometil DOPA [DFMD],3',4',5,7-tetrahidroxi-8-metoxiisoflavona) -Rytary o Numient en los 2 días anteriores a la aleatorización. Para los pacientes que estén tomando cualquiera de estos medicamentos en la selección, deberá realizarse una conversión a una dosis equivalente de comprimidos orales de LD/CD de LI como se indica en la Tabla4).
    19.Toma de donepezilo (Aricept) en los 14días anteriores al Día1.
    20.Toma de trihexifenidilo(Aricept)en los 2días anteriores al Día1.
    21.Toma de multivitaminas con hierro(por ej.Pimavanserin)en las 8horas anteriores al comienzo del tratamiento del estudio el Día1
    22.Toma de carbonato cálcico, carbonato sódico,hidróxido de aluminio, carbonato de aluminio, hidróxido de magnesio u óxido de magnesio en las 8 horas anteriores al comienzo del tratamiento del estudio el Día1
    23.Estar participando en un estudio clínico con un compuesto en investigación o haber participado en los últimos 30días o menos de 5veces la semivida del producto en investigación administrado en el estudio de investigación clínica, lo que sea más largo.
    24.Cualquier característica o síntoma relacionado con la EP que pudiera interferir con la realización del estudio y sus resultados, según valore el investigador.
    25.Antecedentes o presencia de glaucoma de ángulo agudo.
    26.Cualquier antecedente o presencia de tumor hipofisario liberador de prolactina(prolactinoma).
    27.Pacientes que no estén dispuestos a adherirse a las restricciones del estudio dispuestas en el protocolo.
    28.Pacientes que trabajen para un centro del estudio o para el Promotor, bien familiares cercanos de estos.
    29.Si el paciente es un paciente vulnerable,por ej.está detenido,es un adulto protegido bajo potestad,tutela o internado en una institución por orden gubernamental o judicial.
    Cohorte 2:
    30.Contraindicaciones para la inserción de la sonda nasoyeyunal, por ej.cirugía nasal reciente,fracturas nasales,obstrucción del tránsito gastroduodenal,atresia esofágica/estenosis,antecedentes de hemorragia gastroduodenal significativa,varices esofágicas o anomalías de coagulación.
    E.5 End points
    E.5.1Primary end point(s)
    For LD:
    • Cmax and AUC24 the concentrations measured with the following 24-hours periods will be included into the calculation of AUC24:
    for ND0612 16-hours regimen (Test 1): from start of dosing until 24 hours post start of dosing (06:00 to 06:00);
    for ND0612 24-hours regimen (Test 2): from start of second low rate period until end of third high rate period (20:00 to 20:00);
    for CLES regimen: from start of dosing until 24 hours post start of dosing (06:00 to 06:00)
    Para LD: •Cmáx y ABC24 Las concentraciones medidas con los periodos de 24 horas siguientes se incluirán en el cálculo del ABC24: para el régimen de 16 horas de ND0612 (Prueba 1): desde el comienzo de la administración hasta 24 horas después del comienzo de la administración (06:00 a 06:00); para el régimen de 24 horas de ND0612 (Prueba 2): desde el comienzo del segundo periodo de velocidad baja hasta el final del tercer periodo de velocidad alta (20:00 a 20:00); para el régimen de CLES: desde el comienzo de la administración hasta 24 horas después del comienzo de la administración (06:00 a 06:00)
    E.5.1.1Timepoint(s) of evaluation of this end point
    For LD:
    • Cmax and AUC24 the concentrations measured with the following 24-hours periods will be included into the calculation of AUC24:
    for ND0612 16-hours regimen (Test 1): from start of dosing until 24 hours post start of dosing (06:00 to 06:00);
    for ND0612 24-hours regimen (Test 2): from start of second low rate period until end of third high rate period (20:00 to 20:00);
    for CLES regimen: from start of dosing until 24 hours post start of dosing (06:00 to 06:00)
    Para LD: •Cmáx y ABC24 Las concentraciones medidas con los periodos de 24 horas siguientes se incluirán en el cálculo del ABC24: para el régimen de 16 horas de ND0612 (Prueba 1): desde el comienzo de la administración hasta 24 horas después del comienzo de la administración (06:00 a 06:00); para el régimen de 24 horas de ND0612 (Prueba 2): desde el comienzo del segundo periodo de velocidad baja hasta el final del tercer periodo de velocidad alta (20:00 a 20:00); para el régimen de CLES: desde el comienzo de la administración hasta 24 horas después del comienzo de la administración (06:00 a 06:00)
    E.5.2Secondary end point(s)
    For LD:
    • AUC16 (i.e. 6:00-22:00 for CLES and ND0612 16-hours and 6:00-22:00 last day of administration for ND0612 24-hours)
    • Cavg, (AUCt/t represents the mean concentration within the dosing period)
    • End points assessing the variability of the concentrations: these endpoints will be assessed both during the expected stable phase as defined in the SAP. For the piecewise approach, the end points are calculated separately for the 2 or 3 hour periods, as defined in the SAP.
    o Fluctuation Index (FI; ([Cmax-Cmin])/[Cavg])
    o Peak to Trough (PtT = Cmax/Cmin)
    o Swing ([Cmax-Cmin]/[Cmin])
    • t1/2 (if data permit)
    • lambda z (if data permit)
    • tmax
    • Ctrough (last planned PK sample in a period)
    For CD:
    • Cmax
    • AUC24
    • Ctrough (last planned PK sample in a period)
    For 3-OMD:
    • Cmax
    • AUC24
    • Ctrough (last planned PK sample in a period)
    Para LD: • ABC16 (es decir, 6:00-22:00 para 16 horas de CLES y ND0612 y 6:00-22:00 el último día de administración para 24 horas de ND0612) • Cprom,(ABCt/t representa la concentración media en el periodo de administración) •Criterios de valoración para evaluar la variabilidad de las concentraciones: estos criterios de valoración se evaluarán durante la fase estable prevista, tal y como se define en el PAE. Para el método por partes, los criterios de valoración se calcularán por separado para los periodos de 2 o 3 horas, tal y como se define en el PAE. o Índice de fluctuación (FI; [Cmáx-Cmím]/[Cprom]) o Pico a mínimo (PtT=Cmáx/Cmím) o Oscilación ([Cmáx-Cmím]/[Cmím]) • t1/2 (si lo permiten los datos) •lambda z (si lo permiten los datos) • tmáx • Cmím (última muestra FC planificada en un periodo) Para CD: • Cmáx • ABC24 • Cmím (última muestra FC planificada en un periodo) Para 3-OMD: • Cmáx • ABC24 • Cmím (última muestra FC planificada en un periodo)
    E.5.2.1Timepoint(s) of evaluation of this end point
    For LD:
    • AUC16 (i.e. 6:00-22:00 for CLES and ND0612 16-hours and 6:00-22:00 last day of administration for ND0612 24-hours)
    • Cavg, (AUCt/t within the dosing period)
    • End points assessing the variability of the concentrations: these endpoints will be assessed both during the expected stable phase as defined in the SAP. For the piecewise approach, the end points are calculated separately for the 2 or 3 hour periods, as defined in the SAP.
    • Ctrough (last planned PK sample in a period)
    For CD:
    • Cmax
    • AUC24
    • Ctrough (last planned PK sample in a period)
    For 3-OMD:
    • Cmax
    • AUC24
    • Ctrough (last planned PK sample in a period)
    Para LD: •ABC16 (es decir, 6:00-22:00 para 16 horas de CLES y ND0612 y 6:00-22:00 el último día de administración para 24 horas de ND0612) •Cprom, (ABCt/t representa la concentración media en el periodo de administración)•Criterios de valoración para evaluar la variabilidad de las concentraciones: estos criterios de valoración se evaluarán durante la fase estable prevista, tal y como se define en el PAE. Para el método por partes, los criterios de valoración se calcularán por separado para los periodos de 2 o 3 horas, tal y como se define en el PAE. •Cmím (última muestra FC planificada en un periodo) Para CD: •Cmáx •ABC24 •Cmím (última muestra FC planificada en un periodo) Para 3-OMD: •Cmáx •ABC24 •Cmím (última muestra FC planificada en un periodo)
    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 No
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    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 Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over Yes
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Duopa, Duodopa
    E.8.2.4Number of treatment arms in the trial4
    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 concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA10
    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
    France
    Italy
    Netherlands
    Spain
    United States
    E.8.7Trial has a data monitoring committee No
    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
    LVLS, completion of the last patient’s 4-weeks’ return
    visit (follow-up visit)
    Última visita del ultimo paciente, finalización de la visita de seguimiento tras 4 semanas del último paciente.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months4
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial months11
    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: 5
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 45
    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 state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 26
    F.4.2.2In the whole clinical trial 50
    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)
    Patients who complete the treatment periods will be offered to be enrolled to a separate study provided they are assessed by the Investigator as suitable candidates for the study who are capable of following study procedures independently or with the assistance of a study partner. In the follow-on study, they will be treated with open-label ND0612 for up to 48 weeks.
    Los pacientes que finalicen los periodos de tratamiento tendrán la posibilidad de participar en un estudio aparte siempre que el investigador considere que son candidatos aptos para el estudio y que son capaces de seguir los procedimientos del estudio de forma independiente o con la ayuda de un compañero del estudio. En el estudio subsiguiente, recibirán tratamiento con ND0612 de forma abierta durante un máximo de 48 semanas.
    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 Decision2018-05-21
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-03-01
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2018-10-15
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