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    Summary
    EudraCT Number:2012-001316-35
    Sponsor's Protocol Code Number:KF6005/07
    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:2012-11-12
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedSpain - AEMPS
    A.2EudraCT number2012-001316-35
    A.3Full title of the trial
    Efficacy, safety, and tolerability of oral GRT6005 versus morphine sulphate PR in subjects with chronic moderate to severe pain related to cancer.
    Eficacia, seguridad y tolerabilidad de GRT6005 oral frente a sulfato de morfina de acción prolongada en pacientes con dolor crónico moderado a severo, producido por cáncer
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Clinical Trial comparing the ability of pain reduction and side effects; like vomiting, nausea, ect.; of a new anti-pain medicament GRT6005 and morphine sulfate Prolonged Release (PR) in patients suffering from chronic cancer pain of moderate to severe strength.
    Ensayo clínico que compara la habilidad de reduccción del dolor y acontecimientos adversos, como nausea, vómitos de un nuevo medicamento analgésico (GRT6005) en comparación con el sulfato de morfina de acción prolongada en pacientes con dolor oncológico crónico moderado a severo.
    A.4.1Sponsor's protocol code numberKF6005/07
    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 SponsorGrünenthal GmbH
    B.1.3.4CountryGermany
    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 supportGrünenthal GmbH
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationGrünenthal GmbH
    B.5.2Functional name of contact pointGRT Trial Information Desk
    B.5.3 Address:
    B.5.3.1Street AddressZieglerstr. 6
    B.5.3.2Town/ cityAachen
    B.5.3.3Post code52078
    B.5.3.4CountryGermany
    B.5.4Telephone number+492415693223
    B.5.6E-mailclinical-trials@grunenthal.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 nameGRT6005 200 µg film-coated tablet
    D.3.2Product code GRT6005
    D.3.4Pharmaceutical form Film-coated 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 INNINN not available
    D.3.9.2Current sponsor codeGRT6005
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 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 nameGRT6005 400 µg film-coated tablet
    D.3.2Product code GRT6005
    D.3.4Pharmaceutical form Film-coated 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 INNINN not available
    D.3.9.2Current sponsor codeGRT6005
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number400
    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 nameGRT6005 600 µg film-coated tablet
    D.3.2Product code GRT6005
    D.3.4Pharmaceutical form Film-coated 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 INNINN not available
    D.3.9.2Current sponsor codeGRT6005
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number600
    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 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 MXL 30 mg prolonged-release capsule
    D.2.1.1.2Name of the Marketing Authorisation holderNapp Pharmaceuticals Limited
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Prolonged-release capsule
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNmorphine sulphate
    D.3.9.1CAS number 6211-15-0
    D.3.9.3Other descriptive nameMORPHINE SULFATE PENTAHYDRATE
    D.3.9.4EV Substance CodeSUB22187
    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.IMP: 5
    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 MXL 60 mg prolonged-release capsule
    D.2.1.1.2Name of the Marketing Authorisation holderNapp Pharmaceuticals Limited
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Prolonged-release capsule
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNmorphine sulphate
    D.3.9.1CAS number 6211-15-0
    D.3.9.3Other descriptive nameMORPHINE SULFATE PENTAHYDRATE
    D.3.9.4EV Substance CodeSUB22187
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    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 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: 6
    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 MXL 90 mg prolonged-release capsule
    D.2.1.1.2Name of the Marketing Authorisation holderNapp Pharmaceuticals Limited
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Prolonged-release capsule
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNmorphine sulphate
    D.3.9.1CAS number 6211-15-0
    D.3.9.3Other descriptive nameMORPHINE SULFATE PENTAHYDRATE
    D.3.9.4EV Substance CodeSUB22187
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number90
    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 placeboFilm-coated tablet
    D.8.4Route of administration of the placeboOral use
    D.8 Placebo: 2
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboCapsule, hard
    D.8.4Route of administration of the placeboOral use
    D.8 Placebo: 3
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboCapsule, hard
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    The trial population, comprising patients with cancer pain requiring WHO Step III analgesics, will represent the typical population suffering from cancer-related pain. Patient having various types of cancer will be included. The pain condition affecting cancer patients represents a mixed type of pain as it is composed of various pain components (i.e., visceral, neuropathic, and somatic) of different dominance depending on the type of cancer, its stage, localization, and previous treatments.
    La población de estudio incluye pacientes con dolor oncológico que requieren analgésicos de escalón III (OMS), y es representativa de la población afecta de dolor oncológico. Se incluirán pacientes afectos de varios tipos de cáncer. El dolor que afecta a pacientes de cáncer representa un tipo mixto de dolor pues se compone de varios componentes de dolor (visceral, neuropático y somático) de dominio diferente dependiendo del tipo de cáncer, su fase, la localización,y los anteriores tratamientos.
    E.1.1.1Medical condition in easily understood language
    In this clinical trial patients with chronic, cancer related pain will be recruited. Chronic pain is among the most important of symptoms associated with the course of cancer disease.
    En este ensayo clínico se incluirá a pacientes con dolor oncológico crónico. El dolor crónico es uno de los síntomas más importantes asociados con la enfermedad oncoloógica.
    E.1.1.2Therapeutic area Diseases [C] - Symptoms and general pathology [C23]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level PT
    E.1.2Classification code 10058019
    E.1.2Term Cancer pain
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective is to evaluate the efficacy of orally administered GRT6005 in comparison with morphine sulfate PR in subjects suffering from chronic moderate to severe pain related to cancer.
    El objetivo principal es evaluar la eficacia de GRT6005 oral en comparación con el sulfato de morfina de acción prolongada en pacientes con dolor oncológico crónico moderado a severo.
    E.2.2Secondary objectives of the trial
    The secondary objective is to compare the safety and tolerability of GRT6005 and morphine sulfate PR.
    El objetivo secundario es comparar la seguridad y la tolerabilidad de GRT6005 y del sulfato de morfina de AP
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Subjects must have signed an informed consent form (ICF) indicating that they understand the purpose of and procedures required for the trial and are willing to participate in the trial.
    2. Subjects must be at least 18 years of age at the Enrollment Visit (Visit 1).
    3. Subjects willing to use medically acceptable and highly effective
    methods of birth control.
    For women of childbearing potential a medically acceptable and
    highly effective method of birth control is defined as any form of
    contraception with a low failure rate defined as <1% per year. For
    example:
    ? Hormonal contraceptives for at least 2 months prior to the
    Enrollment Visit (Visit 1) and until at least 4 weeks after the End
    of Treatment Visit (Visit 11).
    ? An intra-uterine device.
    Additional barrier contraception must be used by the partner for the duration of the trial, defined as from the time of the Enrollment Visit until 4 weeks after the End of Treatment Visit. Women of non-childbearing potential may be included if post-menopausal for at least 2 years and ?55 years old.
    For men:
    Men have to use barrier contraception (condom) during sexual
    intercourse from the first administration of IMP until 4 weeks after the End of Treatment Visit. The male subject has to take care that the female sexual partner uses at least 1 additional method of contraception with a low failure rate defined as <1% per year (e.g.,oral contraceptives for at least 2 months prior to the Enrollment Visit) during this time frame. A double-barrier method should be supplemented by the use of spermicidal agents.
    4. Subjects
    ? Requiring daily basic pain analgesia diagnosed with active cancer
    including hematological malignant diseases.
    ? Opioid-naïve or receiving daily opioid treatment in doses not
    higher than 90 mg morphine taken orally or its equivalent
    (including World Health Organization [WHO] Step II analgesics).
    ? Suffering from cancer-related but not cancer therapy-related
    chronic pain for a period of ?4 weeks prior to Visit 1.
    5. Performance Status: Eastern Cooperation Oncology Group
    (ECOG) ?2.

    Additional inclusion criteria at Visit 2
    1. Subjects with a mean score of ?5 points (11-point NRS) for the ?average pain intensity over the last 24 hours? calculated from the pain assessments recorded during the last 3 days prior to Visit 2.
    2. Compliance with the use of the e-diary defined as 100% of all NRS entries available during the 3 days prior to Visit 2 and at least 75% of all NRS entries available between Visit 1 and Visit 2 (as assessed at Visit 2).
    1. Los sujetos deberán haber firmado un formulario de consentimiento informado (FCI) en el que se indique que entienden el propósito y los procedimientos necesarios para realizar el estudio y en el que afirmen que desean participar en el estudio.
    2. Los sujetos deben tener al menos 18 años en la visita de inclusión (visita 1).
    3. Los sujetos están dispuestos a utilizar métodos anticonceptivos médicamente aceptables y muy eficaces.
    En el caso de las mujeres potencialmente fértiles, un método anticonceptivo médicamente aceptable y muy eficaz es aquel con una tasa de ineficacia baja, es decir, <1 % al año. Por ejemplo:
    ? anticonceptivos hormonales desde al menos 2 meses antes de la visita de inclusión (visita 1) y hasta al menos 4 semanas después de la visita de finalización del tratamiento (visita 11).
    ? Un dispositivo intrauterino.
    La pareja de estas mujeres deberá utilizar un anticonceptivo de barrera adicional mientras dure el estudio, que se define como el tiempo transcurrido entre la visita de inclusión y hasta 4 semanas después de la visita de finalización del estudio. Se considerará que las mujeres ya no son potencialmente fértiles si llevan siendo posmenopáusicas al menos 2 años y tienen ?55 años.
    En el caso de los hombres:
    A los hombres se les exigirá el uso de un anticonceptivo de barrera (preservativo) durante el coito a partir del momento de la primera administración del PEI y hasta 4 semanas después de la visita de finalización del tratamiento. El sujeto tendrá que encargarse de que su pareja utilice al menos 1 anticonceptivo adicional con una tasa de ineficacia <1 % al año (ej., anticonceptivos orales durante al menos los 2 meses previos a la visita de inclusión) mientras dure el estudio. El método de doble barrera debe complementarse con el uso de agentes espermicidas.
    4. Sujetos:
    ? Que necesiten a diario una analgesia básica para el dolor y hayan sido diagnosticados con un cáncer activo, incluidas las neoplasias hemáticas malignas.
    ? Sin tratamiento previo con opioides o que reciban a diario un tratamiento con opioides en dosis que no superen los 90 mg de morfina por vía oral o su equivalente (incluidos los analgésicos del escalón II de la Organización Mundial de la Salud ?OMS?).
    ? Que padezcan un dolor oncológico crónico pero no un dolor crónico relacionado con el tratamiento antineoplásico durante un período de ? 4 semanas antes de la visita 1.
    5. Grado de actividad: Grupo Cooperativo de Oncólogos del Este (ECOG)? 2.
    Criterios de inclusión adicionales en la visita 2
    1.Sujetos con una puntuación media ?5 puntos (NRS de 11 puntos) para la «intensidad media del dolor durante las últimas 24 horas» calculada a partir de las evaluaciones del dolor registradas durante los 3 días previos a la visita 2.
    2. Cumplimiento con el uso del diario electrónico, definido como incluir el 100 % de las entradas de la NRS durante los 3 días previos a la visita 2 y al menos el 75 % de todas esas entradas entre las visitas 1 y 2 (según se evalúe en la visita 2).
    E.4Principal exclusion criteria
    1. Evidence of ongoing alcohol/drug abuse or history of alcohol/drug abuse within the last 2 years in the investigator?s judgment, based on patient history and physical examination.
    2. The subject has a clinically significant disease other than cancer which in the investigator's opinion may affect efficacy or safety assessments e.g., significant unstable cardiac, vascular, pulmonary, gastrointestinal, endocrine, neurological, infectious disease, psychiatric (resulting in disorientation, memory impairment or inability to report accurately) or
    metabolic disorders.
    3. Subjects with any gastrointestinal disorder that could, in the
    investigator?s opinion, limit the intake and/or elimination of IMP.
    4. Any pre-scheduled major surgery requiring general anesthesia during the trial.
    5. Known to or suspected of not being able to comply with the trial protocol and the use of IMP.
    6. History of seizure disorder and/or epilepsy or any condition associated with a significant risk of seizure or epilepsy.
    7. Known history and/or presence of symptomatic cerebral tumor or cerebral metastases.
    8. Subjects with impaired hepatic functionality or cellular integrity
    determined by a bilirubin value greater than 2 x the upper limit of
    normal, international normalized ratio (INR) >1.7, or aspartate
    transaminase (AST) or alanine transaminase (ALT) greater than
    3 x the upper limit of normal (ULN) at the Enrollment Visit (Visit 1).
    9. Inadequate baseline bone marrow reserve with a white blood cell count <2000/?L, a platelet count ?100 000/?L, and a hemoglobin level <8 g/dL at the Enrollment Visit (Visit 1).
    10. Subjects with impaired renal function. Creatinine clearance less than 60 mL per minute at the Enrollment Visit (Visit 1) (calculated from the Cockcroft-Gault formula).
    11. Subjects taking any forbidden concomitant medications at enrollment the trial.
    12. Uncontrolled hypertension (repeated measurements of systolic blood pressure >160 mmHg or diastolic blood pressure >95 mmHg).
    13. Clinically relevant history of hypersensitivity, allergy or
    contraindications to opioid medication or any of the excipients of
    morphine sulfate (PR or IR), or GRT6005 film-coated tablets.
    14. Chronic hepatitis B or C, or human immunodeficiency virus (HIV) known by history, or presence of active hepatitis B or C within the 3 months before the Enrollment Visit.
    15. History of torsade de pointes and/or presence of risk factors for torsade de pointes (e.g., heart failure, hypokalemia, or bradycardia).
    16. Marked prolongation of QTc (>450 ms for men, >470 ms for women) at the Enrollment Visit (Visit 1) confirmed by repeated measurement.
    17. Employees of the sponsor, investigator, or trial site or family members of the employees, sponsor, or investigator.
    18. Concurrent participation in another trial or planning to be enrolled in another clinical trial during the course of this trial.
    19. Previous participation in this or other trials with GRT6005.
    20. Have received an experimental drug or used an experimental medical device within 30 days before the planned start of treatment.
    1.Pruebas de alcoholismo / drogodependencia en curso o antecedentes de alcoholismo / drogodependencia en los últimos 2 años en opinión del investigador, basándose en la historia del paciente y en la exploración física.
    2. El sujeto sufre, además del cáncer, otra afección clínicamente relevante que, en opinión del investigador, podría afectar a las evaluaciones de la eficacia o la seguridad, por ejemplo, una afección cardíaca, vascular, pulmonar, gastrointestinal, endocrina, neurológica o infecciosa inestable e importante o un trastorno psiquiátrico (que conlleve desorientación, pérdidas de memoria o incapacidad para informar de manera precisa) o metabólico.
    3. Sujetos con un trastorno gastrointestinal que pudiera, en opinión del investigador, limitar la administración y/o la eliminación del PEI.
    4.Cualquier cirugía mayor programada previamente que obligue a usar anestesia general durante el estudio.
    5.Se sabe o se sospecha que no va a ser capaz de cumplir con el protocolo del estudio ni con el uso del PEI.
    6. Antecedentes de convulsiones y/o epilepsia o de cualquier afección asociada con un riesgo importante de convulsiones o epilepsia.
    7.Antecedentes conocidos y/o presencia de tumor cerebral sintomático o metástasis cerebrales.
    8. Sujetos con insuficiencia hepática o una alteración de la integridad celular determinada por un valor de la bilirrubina que sea más del doble del límite superior de la normalidad, un cociente internacional normalizado (CIN) >1,7 o la aspartato transaminasa (AST) o la alanina transaminasa (ALT) con valores que tripliquen el límite superior de la normalidad (LSN) en la visita de inclusión (visita 1).
    9. Una reserva inadecuada de médula ósea al inicio con un recuento leucocitario <2000/µl, un recuento plaquetario ?100.000/µl y un nivel de hemoglobina <8 g/dl en la visita de inclusión (visita 1).
    10. Sujetos con insuficiencia renal. Un aclaramiento de creatinina inferior a 60 ml por minuto en la visita de inclusión (visita 1) (calculado a partir de la fórmula de Cockcroft-Gault).
    11. Sujetos a los que se administren medicamentos concomitantes prohibidos en el momento de la inclusión en el estudio (sección 10.5.3).
    12. Hipertensión descontrolada (mediciones repetidas de una tensión arterial sistólica >160 mmHg o de una tensión arterial diastólica >95 mmHg).
    13. Antecedentes clínicamente relevantes de hipersensibilidad, alergia o contraindicaciones a los opioides o a cualquiera de los excipientes del sulfato de morfina (AP o LI) o a los comprimidos recubiertos con película de GRT6005.
    14. Hepatitis B o C crónica o virus de la inmunodeficiencia humana (VIH) conocido por historia clínica o por la presencia de la hepatitis B o C activa en los 3 meses previos a la visita de inclusión.
    15. Antecedentes de taquicardia ventricular en entorchado y/o presencia de factores de riesgo de taquicardia ventricular en entorchado (ej., insuficiencia cardíaca, hipopotasemia o bradicardia).
    16. Prolongación marcada del intervalo QT corregido (>450 ms en los hombres, >470 ms en las mujeres) en la visita de inclusión (visita 1) confirmada mediante la repetición de la medición.
    17. Empleados del promotor, el investigador o el centro del estudio o familiares de los empleados, el promotor o el investigador.
    18. Participación simultánea en otro estudio o previsión de que vaya a participar en otro ensayo clínico mientras dure este estudio.
    19.Participación previa en este o en otros estudios con GRT6005.
    20.Haber recibido un fármaco experimental o haber utilizado un dispositivo médico experimental en los 30 días previos al inicio previsto del tratamiento.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is the proportion of subjects with clinically relevant pain reduction at the end of the treatment.
    El criterio de valoración principal es la proporción de sujetos con una reducción del dolor clínicamente relevante al final del tratamiento
    E.5.1.1Timepoint(s) of evaluation of this end point
    the end of treatment
    al final del tratamiento
    E.5.2Secondary end point(s)
    The secondary endpoint is the frequency of treatment emergent adverse events (TEAEs) with particular focus on nausea, vomiting, somnolence, and dizziness.
    El criterio de valoración secundario es la frecuencia de los acontecimientos adversos surgidos durante el tratamiento (AAST), prestando especial atención a las náuseas, los vómitos, la somnolencia y los mareos.
    E.5.2.1Timepoint(s) of evaluation of this end point
    the end of treatment
    al final del tratamiento
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic Yes
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    double-dummy
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    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 concerned8
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA82
    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
    Argentina
    Australia
    Austria
    Belgium
    Brazil
    Bulgaria
    Chile
    Croatia
    Denmark
    France
    Germany
    Hungary
    Mexico
    Netherlands
    Norway
    Peru
    Poland
    Romania
    Slovakia
    Spain
    Sweden
    Switzerland
    United Kingdom
    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
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months3
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months3
    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: 652
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 652
    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 Yes
    F.3.3.7.1Details of other specific vulnerable populations
    subjects suffering cancer disease
    F.4 Planned number of subjects to be included
    F.4.1In the member state55
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 308
    F.4.2.2In the whole clinical trial 652
    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)
    Subjects will not receive IMP but any adequate analgesic of investigators? choice.
    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 Decision2012-12-14
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-12-07
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2015-10-16
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