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    Summary
    EudraCT Number:2016-000637-43
    Sponsor's Protocol Code Number:CTH-301
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2017-12-07
    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 number2016-000637-43
    A.3Full title of the trial
    An Open-Label, Phase 3 Study Examining the Long-Term Safety, Tolerability and Efficacy of APL-130277 in Levodopa Responsive Patients with Parkinson’s Disease Complicated by Motor Fluctuations (“OFF” Episodes).
    Estudio abierto de fase 3 que examina la seguridad, tolerabilidad y eficacia a largo plazo de APL-130277 en pacientes con respuesta a la levodopa con enfermedad de Parkinson complicada por fluctuaciones motoras (episodios “OFF”).
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Safety, tolerability and efficacy study to examine APL-130277 in patients with Parkinson’s Disease.
    Estudio de seguridad, tolerabilidad y eficacia para examinar APL-130277 en pacientes con enfermedad de Parkinson
    A.4.1Sponsor's protocol code numberCTH-301
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02542696
    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 SponsorSunovion Pharmaceuticals Inc.
    B.1.3.4CountryUnited States
    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 supportSunovion Inc
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationINC Research
    B.5.2Functional name of contact pointSusan Honn
    B.5.3 Address:
    B.5.3.1Street Address3201 Beechleaf Court, Suite 600
    B.5.3.2Town/ cityRaleigh
    B.5.3.3Post codeNC 27604-1547
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1919 8769300
    B.5.5Fax number+1919 8769360
    B.5.6E-mailSusan.Honn@INCResearch.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 nameApomorphine hydrochloride
    D.3.2Product code APL-130277
    D.3.4Pharmaceutical form Sublingual film
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSublingual use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNApomorphine hydrochloride
    D.3.9.1CAS number 41372-20-7
    D.3.9.2Current sponsor codeAPL-130277
    D.3.9.3Other descriptive nameAPOMORPHINE HYDROCHLORIDE
    D.3.9.4EV Substance CodeSUB12924MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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 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 nameApomorphine hydrochloride
    D.3.2Product code APL-130277
    D.3.4Pharmaceutical form Sublingual film
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSublingual use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNApomorphine hydrochloride
    D.3.9.1CAS number 41372-20-7
    D.3.9.2Current sponsor codeAPL-130277
    D.3.9.3Other descriptive nameAPOMORPHINE HYDROCHLORIDE
    D.3.9.4EV Substance CodeSUB12924MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number15
    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 nameApomorphine hydrochloride
    D.3.2Product code APL-130277
    D.3.4Pharmaceutical form Sublingual film
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSublingual use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNApomorphine hydrochloride
    D.3.9.1CAS number 41372-20-7
    D.3.9.2Current sponsor codeAPL-130277
    D.3.9.3Other descriptive nameAPOMORPHINE HYDROCHLORIDE
    D.3.9.4EV Substance CodeSUB12924MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    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 nameApomorphine hydrochloride
    D.3.2Product code APL-130277
    D.3.4Pharmaceutical form Sublingual film
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSublingual use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNApomorphine hydrochloride
    D.3.9.1CAS number 41372-20-7
    D.3.9.2Current sponsor codeAPL-130277
    D.3.9.3Other descriptive nameAPOMORPHINE HYDROCHLORIDE
    D.3.9.4EV Substance CodeSUB12924MIG
    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: 5
    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 nameApomorphine hydrochloride
    D.3.2Product code APL-130277
    D.3.4Pharmaceutical form Sublingual film
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSublingual use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNApomorphine hydrochloride
    D.3.9.1CAS number "41372-20-7
    D.3.9.2Current sponsor codeAPL-130277
    D.3.9.3Other descriptive nameAPOMORPHINE HYDROCHLORIDE
    D.3.9.4EV Substance CodeSUB12924MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number30
    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 placeboSublingual film
    D.8.4Route of administration of the placeboSublingual use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    "Levodopa Responsive Patients with Parkinson’s Disease complicated by Motor Fluctuations
    (“OFF” Episodes)"
    Pacientes con respuesta a la levodopa con enfermedad de Parkinson complicada por fluctuaciones motoras (episodios “OFF”)
    E.1.1.1Medical condition in easily understood language
    Central nervous system disease affecting the movement complicated by off symptoms.
    Enfermedad de Sistema Nervioso Central complicada por afectar al movimiento debido a síntomas off.
    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 LLT
    E.1.2Classification code 10034006
    E.1.2Term Parkinson's disease aggravated
    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 evaluate the long-term safety and tolerability of APL-130277 in patients with Parkinson’s disease (PD).
    Evaluar la seguridad y tolerabilidad a largo plazo de APL 130277 en pacientes con enfermedad de Parkinson (EP).
    E.2.2Secondary objectives of the trial
    "Not applicable"
    "No applicable"
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    De Novo Patients – patients who have not previously participated in a study with APL-130277.
    1. Male or female ≥ 18 years of age.
    2. Clinical diagnosis of Idiopathic PD, consistent with UK Brain Bank Criteria (excluding the "more than one affected relative" criterion.).
    3. Clinically meaningful response to Levodopa (L-Dopa) as determined by the Investigator.
    4. Receiving stable doses of L-Dopa/carbidopa and/or L-Dopa/benserazide (immediate or chronic release [CR]) administered at least 4 times per day OR Rytary™ administered at least 3 times per day, for at least 4 weeks before the initial Screening Visit (SV1). Adjunctive PD medication regimens must be maintained at a stable dose for at least 4 weeks prior to the initial Screening Visit (SV1) with the exception that MAO-B inhibitors must be maintained at a stable level for at least 8 weeks prior to the initial Screening Visit (SV1).
    5. No planned medication change(s) or surgical intervention anticipated during the course of study.
    6. Patients must experience at least one well defined "OFF" episode per day with a total daily "OFF" time duration of ≥ 2 hours during the waking day, based on patient self-assessment.
    7. Patient and/or caregiver must be trained in performing home dosing diary assessments of the motor state and must be able to recognize "ON" and "OFF" states.
    8. Stage III or less on the modified Hoehn and Yahr scale in the "ON" state.
    9. Mini–Mental State Examination (MMSE) score > 25.
    10. If female and of childbearing potential, must agree to be sexually abstinent or use one of the following highly effective methods of birth control:
    • Hormonal contraceptives (eg, combined oral contraceptives, patch, vaginal ring, injectables, and implants);
    • Intrauterine contraceptive system;
    • Surgical sterilization or partner sterile (must have documented proof);
    AND
    One of the following effective methods of birth control:
    • Male/female condom;
    • Cervical cap with spermicide;
    • Diaphragm with spermicide;
    • Contraceptive sponge.
    11. Male patients must be either surgically sterile, agree to be sexually inactive or use a double-barrier method of birth control (eg, condom and diaphragm with spermicide, condom with cervical cap and spermicide) from first study drug administration until 90 days after final drug administration.
    12. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study-related procedures.
    13. Able to understand the consent form, and to provide written informed consent.

    Rollover Patients
    1. Completion of any of the following studies: CTH-201, CTH-203, CTH-300, or CTH-302 and, in the opinion of the Investigator, would benefit from continued treatment with APL-130277.
    2. No major increases in concomitant PD medications since completion of any of the following studies: CTH-201, CTH-203, CTH-300, or CTH-302. Any change in PD medications since the previous study should be discussed with the Medical Monitor to determine patient eligibility in the current study.
    3. If female and of childbearing potential, must agree to be sexually abstinent or use one of the following highly effective methods of birth control:
    • Hormonal contraceptives (eg, combined oral contraceptives, patch, vaginal ring, injectables, and implants);
    • Intrauterine contraceptive system;
    • Surgical sterilization or partner sterile (must have documented proof);
    AND
    One of the following effective methods of birth control:
    • Male/female condom;
    • Cervical cap with spermicide;
    • Diaphragm with spermicide;
    • Contraceptive sponge.
    4. Male patients must be either surgically sterile, agree to be sexually inactive or use a double-barrier method of birth control (eg, condom and diaphragm with spermicide, condom with cervical cap and spermicide) from first study drug administration until 90 days after final drug administration.
    5. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study-related procedures.
    6. Able to understand the consent form, and to provide written informed consent.

    CTH-301 Completer Patients

    1. Completion of the CTH-301 study, and in the opinion of the Investigator, would benefit from continued treatment with APL-130277.
    other inclusion criteria for completers patients are the same as points 3, 4, 5 and 6 listed above for rollover patients.
    Pacientes de novo
    1.Hombre o mujer con una edad ≥ 18 años.
    2.Diagnóstico clínico de EP idiopática, conforme a los criterios del Banco de Cerebros del Reino Unido (excluyendo el criterio de “más de un familiar afectado”).
    3.Respuesta clínicamente significativa a la levodopa (L-Dopa) según lo determinado por el investigador.
    4.Administración de dosis estables de L-Dopa/carbidopa y/o L-Dopa/benserazida (liberación inmediata o crónica (LC)) al menos 4 veces al día O administración de Rytary™ al menos 3 veces al día, durante al menos 4 semanas antes de la visita de selección inicial (VS1). Las pautas terapéuticas complementarias para la EP deben mantenerse en una dosis estable durante al menos 4 semanas antes de la visita de selección inicial (VS1), con la excepción de que los inhibidores de MAO-B deben mantenerse en un nivel estable durante al menos 8 semanas antes de la visita de selección inicial (VS1).
    5.No se prevé ningún cambio de medicación o intervención quirúrgica durante el estudio.
    6.Los pacientes deben experimentar al menos un episodio “OFF” bien definido por día con una duración total del estado “OFF” diaria ≥ 2 horas durante las horas que está despierto, según la autoevaluación del paciente.
    7.El paciente y/o el cuidador deben tener formación sobre la realización de evaluaciones de diario de administración en el domicilio del estado motor, y deben ser capaces de reconocer los estados “ON” y “OFF”.
    8.Fase III o inferior de la escala de Hoehn y Yahr modificada en estado “ON”.
    9.Puntuación según el miniexamen cognoscitivo (MMSE) > 25.
    10.Si el sujeto es femenino y fértil, debe aceptar practicar la abstinencia sexual o utilizar uno de los siguientes métodos altamente eficaces de control de la natalidad:
    •anticonceptivos hormonales (p. ej., anticonceptivos orales combinados, parches, anillo vaginal, inyectables e implantes);
    •sistema anticonceptivo intrauterino;
    •esterilización quirúrgica o pareja estéril (debe tener prueba documentada);
    Y
    uno de los siguientes métodos eficaces de control de la natalidad:
    •preservativo masculino/femenino;
    •capuchón cervical con espermicida;
    •diafragma con espermicida;
    •esponja anticonceptiva.
    11.Los pacientes masculinos deben ser quirúrgicamente estériles, aceptar ser sexualmente inactivos o utilizar un método anticonceptivo de doble barrera (por ejemplo, preservativo y diafragma con espermicida, preservativo con capuchón cervical y espermicida) a partir de la primera administración del fármaco en estudio hasta 90 días después de la administración final del fármaco.
    12.Que desee y sea capaz de cumplir con las visitas programadas, el plan de tratamiento, las pruebas de lab. y otros procedimientos relacionados con el estudio.
    13.Que sea capaz de comprender el formulario de consentimiento, así como de proporcionar el consentimiento informado por escrito.
    Pacientes de repetición
    1.Finalización de la participación en cualquiera de los siguientes estudios: CTH-201, CTH-203, CTH-300 o CTH-302 y, en opinión del investigador, se beneficiarían de la continuidad del tratamiento con APL 130277.
    2.No ha habido aumentos importantes en la medicac. concomitante para la EP desde la finalización de cualquiera de los siguientes estudios: CTH-201, CTH-203, CTH-300 o CTH-302. Cualquier cambio de medicac. para la EP a partir del estudio anterior debe notificarse al monitor médico para que determine si el paciente es apto o no para el estudio actual.
    3.Si el sujeto es femenino y fértil, debe aceptar practicar la abstinencia sexual o utilizar uno de los siguientes métodos altamente eficaces de control de la natalidad:
    •anticonceptivos hormonales (p. ej., anticonceptivos orales combinados, parches, anillo vaginal, inyectables e implantes);
    •sistema anticonceptivo intrauterino;
    •esterilización quirúrgica o pareja estéril (debe tener prueba documentada);
    Y
    uno de los siguientes métodos eficaces de control de la natalidad:
    •preservativo masculino/femenino;
    •capuchón cervical con espermicida;
    •diafragma con espermicida;
    •esponja anticonceptiva.
    4.Los pacientes masculinos deben ser quirúrgicamente estériles, aceptar ser sexualmente inactivos o utilizar un método anticonceptivo de doble barrera (por ej., preservativo y diafragma con espermicida, preservativo con capuchón cervical y espermicida) a partir de la primera administración del fármaco en estudio hasta 90 días después de la administrac. final del fármaco.
    5.Que desee y sea capaz de cumplir con las visitas programadas, el plan de tto, las pruebas de lab. y otros procedimientos relacionados con el estudio.
    6.Que sea capaz de comprender el formulario de consentimiento, así como de proporcionar el consentimiento informado por escrito.
    Pacientes que han completado el estudio de CTH-301
    1.Finalización de la participación en el estudio de CTH-301 y, en opinión del invest., se beneficiarían de la continuidad del tratamiento con APL 130277. Resto de criterios ver puntos 3,4,5 y 6 de pacientes de repetición.
    E.4Principal exclusion criteria
    "De Novo Patients – patients who have not previously participated in a study with APL-130277.
    1. Atypical or secondary parkinsonism.
    2. Previous treatment with any of the following: a neurosurgical procedure for PD; continuous subcutaneous (s.c.) apomorphine infusion; Duodopa/Duopa; or APL-130277.
    3. Treatment with any form of s.c. apomorphine within 7 days prior to the second Screening Visit (SV2). Patients that stopped s.c. apomorphine for any reason other than systemic safety concerns
    or lack of efficacy may be considered.
    4. Contraindications to APOKYN®, or hypersensitivity to apomorphine hydrochloride or any of the ingredients of APOKYN® (notably sodium metabisulfite).
    5. Female who is pregnant or lactating.
    6. Participation in a clinical trial within 30 days prior to the initial Screening Visit (SV1).
    7. Receipt of any investigational (ie, unapproved) medication within 30 days prior to the initial Screening Visit (SV1).
    8. Currently taking selective 5HT3 antagonists (ie, ondansetron, granisetron, dolasetron, palonosetron, alosetron), dopamine antagonists (excluding quetiapine and clozapine) or dopamine
    depleting agents.
    9. Drug or alcohol dependency in the past 12 months.
    10. Subject has a history of malignancy within 5 years prior to the Screening visit, except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer. Pituitary
    tumors of any duration are excluded.
    11. Clinically significant medical, surgical, or laboratory abnormality in the opinion of the Investigator.
    12. Major psychiatric disorder including, but not limited to, dementia, bipolar disorder, psychosis, or any disorder that, in the opinion of the Investigator, requires ongoing treatment that would make study participation unsafe or make treatment compliance difficult.
    13. History of clinically significant hallucinations during the past 6 months.
    14. History of clinically significant impulse control disorder(s).
    15. Dementia that precludes providing informed consent or would interfere with participation in the study.
    16. Current suicidal ideation within one year prior to the second Screening Visit (SV2) as evidenced by answering "yes" to Questions 4 or 5 on the suicidal ideation portion of the Columbia-
    Suicide Severity Rating Scale (C-SSRS) or attempted suicide within the last 5 years.
    17. Donation of blood or plasma in the 30 days prior to first dosing.
    18. Presence of canker or mouth sores within 30 days prior to the initial Screening Visit (SV1), or other clinically significant oral pathology in the opinion of the Investigator. The Investigator should followup
    with an appropriate specialist on any finding, if indicated, before enrolling a patient into the study.

    Rollover Patients and 301 Completers Patients

    1. Female who is pregnant or lactating.
    2. Presence of any major psychiatric disorder including, but not limited to, dementia, bipolar disorder, psychosis (including clinically significant hallucinations during the past 6 months) or any
    disorder that, in the opinion of the Investigator, requires ongoing treatment that would make study participation unsafe or make treatment compliance difficult.
    3. Presence of any clinically significant medical (including CNS or CV events), surgical, or laboratory abnormality that would make study participation unsafe or make treatment compliance difficult.
    Clinical significance to be determined by the Investigator.
    4. Receipt of any investigational (ie, unapproved) medication or participation in any clinical trial since completing a previous study using APL-130277/ the CTH-301 study.
    5. Development of canker or mouth sores since completing a previous clinical study using APL-130277/the CTH- 301 study. For other clinically significant oral pathology, the Investigator should follow-up with an appropriate specialist on any finding, if indicated, before enrolling such a patient into the study. Clinical significance to be determined by the Investigator.
    6. Current suicidal ideation as evidenced by answering "yes" to Question 4 or 5 on the suicidal ideation portion of the C-SSRS at the Screening Visit (SV1)/ Phase 2 (SVP2).
    Pacientes de novo
    1.Parkinsonismo atípico o secundario.
    2.Tratamiento previo con cualquiera de los siguientes procedimientos: un procedimiento neuroquirúrgico para la EP; infusión continua de apomorfina subcutánea; Duodopa/Duopa; o APL 130277.
    3.Tratamiento con cualquier forma de apomorfina subcutánea durante los 7 días anteriores a la segunda visita de selección (VS2). Se pueden considerar pacientes que hayan interrumpido el tratamiento con apomorfina subcutánea por cualquier motivo, excepto por problemas de seguridad sistémica o falta de eficacia.
    4.Contraindicaciones de APOKYN® o hipersensibilidad al hidrocloruro de apomorfina o a cualquiera de los componentes de APOKYN® (especialmente metabisulfito sódico).
    5.Mujer embarazada o en período de lactancia.
    6.Participación en un ensayo clínico en los 30 días anteriores a la visita de selección inicial (VS1).
    7.Recepción de cualquier medicamento en investigación (no aprobado) en los 30 días previos a la visita de selección inicial (VS1).
    8.Que esté tomando antagonistas selectivos del 5HT3 (es decir, ondansetrón, granisetrón, dolasetrón, palonosetrón, alosetrón), antagonistas de dopamina (excluyendo la quetiapina y la clozapina) o agentes reductores de dopamina.
    9.Drogodependencia o alcoholismo durante los últimos 12 meses.
    10.El sujeto tiene antecedentes de neoplasia maligna en los 5 años anteriores a la visita de selección, excepto en el caso de cáncer de piel de células basales o escamocelular tratado correctamente o de cáncer cervical in situ. Se excluyen los tumores pituitarios de cualquier duración.
    11.Anomalías médicas, quirúrgicas o de laboratorio con importancia clínica, en opinión del investigador.
    12.Trastorno psiquiátrico importante incluidos, entre otros, demencia, trastorno bipolar, psicosis o cualquier trastorno que, en opinión del investigador, requiera un tratamiento continuo que dificulte la participación en el estudio o el cumplimiento del tratamiento.
    13.Historial de alucinaciones con importancia clínica durante los últimos 6 meses.
    14.Antecedentes de trastornos de control de impulso con importancia clínica.
    15.Demencia que impide la firma del consentimiento informado o dificultaría la participación en el estudio.
    16.Conducta suicida actual durante el año anterior a la segunda visita de selección (VS2), demostrada al responder “sí” a las preguntas 4 o 5 en la parte de conductas suicidas de la escala de Columbia para evaluar el riesgo de suicidio (C-SSRS), o intento de suicidio en los últimos 5 años.
    17.Donación de sangre o plasma en los 30 días anteriores a la primera administración.
    18.Presencia de úlceras o llagas orales en los 30 días anteriores a la visita de selección inicial (VS1) u otra patología oral clínicamente significativa, en opinión del investigador. El investigador debe consultar con un especialista adecuado cualquier hallazgo, si está indicado, antes de incluir a un paciente en el estudio.

    Pacientes de repetición y que hayan completado el studio de CTH-301:
    1.Mujer embarazada o en período de lactancia.
    2.Presencia de cualquier trastorno psiquiátrico importante incluidos, entre otros, demencia, trastorno bipolar, psicosis (incluidas alucinaciones con importancia clínica durante los últimos 6 meses) o cualquier trastorno que, en opinión del investigador, requiera un tratamiento continuo que dificulte la participación en el estudio o el cumplimiento del tratamiento.
    3.Presencia de cualquier anomalía médica, quirúrgica o de laboratorio con importancia clínica (incluidos eventos del SNC o CV) que pueda dificultar la participación en el estudio o el cumplimiento del tratamiento. La importancia clínica debe determinarla el investigador.
    4.Recepción de cualquier medicamento en investigación (no aprobado) o participación en cualquier ensayo clínico desde la finalización de un estudio previo en el que se utilizó APL-130277.
    5.Desarrollo de úlceras o llagas orales desde la finalización de un estudio clínico previo en el que se utilizó APL-130277. Para otras patologías orales con importancia clínica, el investigador debe consultar con un especialista adecuado cualquier hallazgo, si se indica, antes de incluir a dicho paciente en el estudio. La importancia clínica debe determinarla el investigador.
    6.Conducta suicida actual demostrada al responder “sí” a las preguntas 4 o 5 en la parte de conductas suicidas de la escala C-SSRS en la visita de selección (VS1).
    E.5 End points
    E.5.1Primary end point(s)
    Evaluation of safety and tolerability data collected, including 12-lead ECGs, orthostatic hypotension OH, oropharyngeal and dopaminergic AEs, Columbia-Suicide Severity Rating Scale (C-SSRS), Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease Rating Scale (QUIP-RS), and the Epworth Sleepiness Scale (ESS) assessments.
    Evaluación de los datos de seguridad y tolerabilidad recopilados, incluidos los ECG de 12 derivaciones, la hipotensión ortostática (HO), los AA orofaríngeos y dopaminérgicos, la C SSRS, la escala de valoración del cuestionario de conductas impulsivas y compulsivas en la enfermedad de Parkinson (QUIP-RS) y las evaluaciones según la escala de somnolencia de Epworth (ESS).
    E.5.1.1Timepoint(s) of evaluation of this end point
    AEs and SAEs: Continous monitoring from Screening visit(-28 to -3) till end if study visit (Day203)
    ECG, Vital signs, C-SSRS: Screening visit 1 (SV 1) ( Study visit 2; Day -28 to -3) for De nevo and Study visit 1 (Day -28 to -3)for Roll over, Titration Visit (TV)1, TV2, TV3, TV4, TV5, TV6, Day 28, Day 56, Day 112, Day 196, Day 203(End of study).
    QUIP-RS and ESS assessments : SV 2 (de novo), SV1 (Roll-over), Day 28, Day 196 and Day 203."
    AEs y SAEs: monitorización contínua desde visita Screening (-28 a -3) hasta visita final de studio (Día203)
    ECG, signos vitals, C-SSRS: visita Screening 1 (SV 1) ( visita studio 2; Día -28 a -3) para De nevo y visita de estudio 1 (Día -28 a -3) para Roll over, Titration Visit (TV)1, TV2, TV3, TV4, TV5, TV6, Día 28, Día 56, Día 112, Día 196, Día 203 (final de estudio).
    QUIP-RS yd ESS assessments : SV 2 (de novo), SV1 (Roll-over), Día 28, Día 196 y Día 203."
    E.5.2Secondary end point(s)
    1. Mean change from pre-dose in MDS-UPDRS Part III Motor Examination (MDS-UPDRS MOTOR) score at 15, 30 and 60 minutes after dosing at Week 24, Week 36, and Week 48 visits (LTS V4, V5, and V6) of the LTS Phase.
    2. Percentage of patients with a patient-rated full "ON" response within 30 minutes at Week 24, Week 36, and Week 48 visits (LTS V4, V5, and V6) of the LTS Phase.
    3. The percentage of instances where a full "ON" response was achieved within 30 minutes after self-administration of study medication at Week 24, Week 36, and Week 48 visits (LTS V4, V5, and V6) of the LTS Phase based on the home dosing diary entries.
    4. CGI-I post dosing.
    5. PGI-I post dosing.
    6. PDQ-39.
    7. MDS-UPDRS – Part II: Motor Aspects of Experiences of Daily Living.

    Other Patient-Reported Secondary Endpoints
    1. European Quality of Life – 5 Dimensions (EQ-5D)."
    1.Cambio medio desde la dosis previa en la parte III, exploración motora, de la MDS-UPDRS (MDS-UPDRS MOTOR) registrado tras 15, 30 y 60 minutos después de la administración en las visitas de las semanas 24, 36 y 48 (SLP V4, V5 y V6) de la fase de SLP.
    2.Porcentaje de pacientes con una respuesta de “ON” completo evaluada por el paciente en un plazo de 30 minutos en las visitas de las semanas 24, 36 y 48 (SLP V4, V5 y V6) de la fase de SLP.
    3.Porcentaje de casos en los que una respuesta de “ON” completo se alcanzó en un plazo de 30 minutos tras la autoadministración del medicamento en estudio en las visitas de las semanas 24, 36 y 48 (SLP V4, V5, y V6) de la fase de SLP en las entradas del diario de administración en el domicilio.
    4.Impresión clínica global de mejora (CGI-I) tras la administración.
    5.Impresión global de mejora del paciente (PGI-I) tras la administración.
    6.Cuestionario para la enfermedad de Parkinson 39 (PDQ-39).
    7.MDS-UPDRS, parte II: aspectos motores de las experiencias de la vida diaria.

    Otros criterios secundarios de valoración indicados por el paciente:
    1.Cuestionario europeo de calidad de vida: 5 dimensiones (EQ-5D).
    E.5.2.1Timepoint(s) of evaluation of this end point
    1. Mean change from pre-dose in MDS-UPDRS Part III Motor Examination (MDS-UPDRS MOTOR) score at 15, 30 and 60 minutes after dosing at Week 24, Week 36, and Week 48 visits (LTS V4, V5, and V6) of the LTS Phase.
    2. Percentage of patients with a patient-rated full "ON" response within 30 minutes at Week 24, Week 36, and Week 48 visits (LTS V4, V5, and V6) of the LTS Phase.
    3. The percentage of instances where a full "ON" response was achieved within 30 minutes after self-administration of study medication at Week 24, Week 36, and Week 48 visits (LTS V4, V5, and V6) of the LTS Phase based on the home dosing diary entries.
    4. CGI-I post dosing.
    5. PGI-I post dosing.
    6. PDQ-39.
    1.Cambio medio desde la dosis previa en la parte III, exploración motora, de la MDS-UPDRS (MDS-UPDRS MOTOR) registrado tras 15, 30 y 60 min. después de la administración en las visitas de las semanas 24, 36 y 48 (SLP V4, V5 y V6) de la fase de SLP
    2.Porcentaje de pacientes con una respuesta de “ON” completo evaluada por el paciente en un plazo de 30 min. en las visitas de las semanas 24, 36 y 48 (SLP V4, V5 y V6)de la fase de SLP
    3.Porcentaje de casos en los que una respuesta de “ON” completo se alcanzó en un plazo de 30 min. tras la autoadministración del medicamento en estudio en las visitas de las semanas 24, 36 y 48 (SLP V4, V5, y V6)de la fase de SLP en las entradas del diario de administración en el domicilio
    4.CGI-I tras la administración
    5.PGI-I tras la administración
    6.PDQ-39
    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 No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Tolerability
    Tolerabilidad
    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 No
    E.8.1.1Randomised No
    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 No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial1
    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 EEA35
    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
    Canada
    France
    Germany
    Italy
    Spain
    United Kingdom
    United States
    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
    LVLS
    UVUS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years6
    E.8.9.1In the Member State concerned months9
    E.8.9.1In the Member State concerned days1
    E.8.9.2In all countries concerned by the trial years6
    E.8.9.2In all countries concerned by the trial months9
    E.8.9.2In all countries concerned by the trial days1
    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: 207
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 243
    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 state22
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 160
    F.4.2.2In the whole clinical trial 450
    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)
    None.
    Ninguno
    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 Decision2018-02-06
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-01-24
    P. End of Trial
    P.End of Trial StatusOngoing
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