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    Summary
    EudraCT Number:2013-000473-68
    Sponsor's Protocol Code Number:KF6005/08
    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:2013-06-26
    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 number2013-000473-68
    A.3Full title of the trial
    Efficacy, safety and tolerability of multiple doses of oral cebranopadol in subjects with moderate to severe chronic pain due to diabetic peripheral neuropathy
    Eficacia, seguridad y tolerabilidad de Cebranopadol, a múltiples dosis vía oral en pacientes con dolor crónico de moderado a severo debido a polineuropatía diabética periférica
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Clinical trials assessing efficacy, safety and tolerability of different doses of oral cebranopadol in patients with moderate to severe chronic pain due to diabetic peripheral neuropathy
    Ensayo clinico para evaluar la eficacia, seguridad y tolerabilidad de Cebranopadol, a diferentes dosis vía oral en pacientes con dolor crónico de moderado a severo debido a polineuropatía diabética periférica
    A.4.1Sponsor's protocol code numberKF6005/08
    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 nameCebranopadol 100 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 INNCebranopadol
    D.3.9.2Current sponsor codeGRT6005
    D.3.9.3Other descriptive nameGRT6005
    D.3.9.4EV Substance CodeSUB31708
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    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 nameCebranopadol 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 INNCebranopadol
    D.3.9.2Current sponsor codeGRT6005
    D.3.9.3Other descriptive nameGRT6005
    D.3.9.4EV Substance CodeSUB31708
    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: 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 nameCebranopadol 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 INNCebranopadol
    D.3.9.2Current sponsor codeGRT6005
    D.3.9.3Other descriptive nameGRT6005
    D.3.9.4EV Substance CodeSUB31708
    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: 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 Lyrica 75 mg hard capsules
    D.2.1.1.2Name of the Marketing Authorisation holderPfizer Limited
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Capsule, hard
    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 INNPregabalin
    D.3.9.1CAS number 148553-50-8
    D.3.9.3Other descriptive namePREGABALIN
    D.3.9.4EV Substance CodeSUB10023MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number75
    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 Lyrica 150 mg hard capsules
    D.2.1.1.2Name of the Marketing Authorisation holderPfizer Limited
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Capsule, hard
    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 INNPregabalin
    D.3.9.1CAS number 148553-50-8
    D.3.9.3Other descriptive namePREGABALIN
    D.3.9.4EV Substance CodeSUB10023MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number150
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboCapsule, hard
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Moderate to severe chronic pain due to diabetic peripheral neuropathy (DPN) requiring analgesia in subjects with well-controlled and stable type 1 or type 2 diabetes mellitus.
    Pacientes con dolor crónico de moderado a severo debido a polineuropatía diabética periférica, con Diabetes Mellitus tipo I o II bien controlada y estable, que requieran analgésia.
    E.1.1.1Medical condition in easily understood language
    Pain due to nerve damage caused by diabetes mellitus type 1 or type 2
    Dolor debido al daño de un nervio causado por con Diabetes Mellitus tipo I o II
    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 16.0
    E.1.2Level PT
    E.1.2Classification code 10012680
    E.1.2Term Diabetic neuropathy
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To assess the analgesic efficacy, safety, and tolerability of once daily orally administered cebranopadol in a total of 3 fixed doses (100 µg, 300 µg, and 600 µg cebranopadol) compared to placebo in subjects with moderate to severe chronic pain due to DPN.
    Evaluar la eficacia, la seguridad y la tolerabilidad de la administración de Cebranopadol oral una vez al día utilizando 3 dosis fijas (100 µg, 300 µg y 600 µg de Cebranopadol), en comparación con Placebo, en pacientes con dolor crónico de moderado a severo debido a polineuropatía diabética periférica.
    E.2.2Secondary objectives of the trial
    Not Applicable
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Informed consent signed (Visit 1).
    2. Male or female subjects aged 18 years to 80 years inclusive at the Enrollment Visit (Visit 1).
    3. All subjects must have type 1 or type 2 diabetes mellitus and must have a documented clinical diagnosis of painful DPN with symptoms and signs for at least 3 months and pain present at the Enrollment Visit (Visit 1).
    4. The investigator considers the subject?s blood glucose to be controlled by a diet, oral anti-hyperglycemic medication, and/or insulin for at least 3 months prior to Enrollment Visit. This control should be documented. Hemoglobin (HbA1C) should not be greater than 11% at the Enrollment Visit (Visit 1).
    5. Subject must require analgesic medication (non-opioids or opioids up to an equivalent dose of 160 mg oral morphine/day) for the treatment of pain due to DPN for at least 3 months prior to Visit 1 and must be dissatisfied with the current analgesic treatment (in terms of efficacy and/or tolerability). Analgesic medication should be required on at least 4 of 7 consecutive days.
    6. Subjects must be using medically acceptable and highly effective methods of birth control (and willing to use them during the trial):
    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 and until at least 4 weeks after Visit 7.
    ? An intra-uterine device.
    Additional barrier contraception must be used by the partner for the duration of the trial. A double-barrier method should be supplemented by the use of spermicidal agents.
    Women of non-childbearing potential may be included if surgically sterile (i.e., after hysterectomy) or post-menopausal for at least 2 years.
    For men: Men have to use barrier contraception (condom) during sexual intercourse for the duration of the trial. 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) during this time frame.
    7. Women of childbearing potential must have a negative urine ? human chorionic gonadotropin (?-hCG) pregnancy test at the Enrollment Visit (Visit 1) and at the Baseline Visit (Visit 3).
    8. A baseline pain intensity score ?5 on the 11-point NRS without intake of any analgesic (including rescue medication) at Visit 3. For each of the last 3 days prior to Visit 3, a 24 hour NRS score ?4 is required.
    The baseline pain will be calculated as the average over the three 24-hour pain assessments of the last 3 days prior to the Baseline Visit (Visit 3).
    1. Consentimiento informado firmado (visita 1).
    2. Hombres o mujeres de edades comprendidas entre ?18 y ?80 años en el momento de la visita de inclusión (visita 1).
    3. Todos los pacientes deberán presentar diabetes mellitus tipo 1 o 2 y tener un diagnóstico clínico documentado de neuropatía diabética periférica dolorosa con síntomas y signos durante al menos 3 meses y con dolor presente en la visita de inclusión (visita 1).
    4. El investigador considera que la glucemia del paciente está controlada mediante una dieta, fármacos hipoglucemiantes orales y/o insulina durante al menos 3 meses antes de la visita de inclusión. Dicho control deberá estar documentado. La hemoglobina glucosilada (HbA1C) no deberá ser superior al 11 % en la visita de inclusión (visita 1).
    5. El paciente deberá haber necesitado medicación analgésica (fármacos no opioides, o bien opioides hasta una dosis equivalente a 160 mg/día de morfina oral) para tratar el dolor debido a la neuropatía diabética periférica durante al menos 3 meses antes de la visita 1. y no debe estar satisfecho con su tratamiento analgésico actual (en términos de eficacia y/o tolerabilidad). Medicación analgésica debe ser demandada al menos 4 días en un período de 7 días consecutivos.
    6. Los pacientes deberán estar utilizando métodos anticonceptivos altamente eficaces y clínicamente aceptables (y deberán estar dispuestos a utilizarlos durante su participación en el ensayo clínico):
    En el caso de las mujeres en edad fértil, un método anticonceptivo altamente eficaz y clínicamente aceptable se define como cualquier forma de anticoncepción que presente una tasa de fracaso baja (definida como <1 % anual). Por ejemplo:
    ? Anticonceptivos hormonales tomados desde 2 meses antes de la visita de inclusión, como mínimo, y hasta 4 semanas después de la visita 7, como mínimo.
    ? Un dispositivo intrauterino.


    El compañero deberá utilizar un método anticonceptivo de barrera adicional mientras dure el ensayo clínico. Un método de doble barrera deberá añadirse, mediante el uso de productos espermicidas.

    Se considerarán mujeres sin posibilidad de quedarse embarazadas aquellas que hayan sido sometidas a alguna cirugía de esterilización (por ejemplo, tras una histerectomía) o las que lleven al menos 2 años en estado posmenopáusico.
    En el caso de los varones: los hombres deberán utilizar un anticonceptivo de barrera (preservativo) cuando mantengan relaciones sexuales mientras dure el ensayo clínico. Los hombres participantes deberán asegurarse de que su pareja sexual femenina utilice durante este periodo al menos 1 método anticonceptivo adicional que presente una tasa de fracaso baja (definida como <1 % anual), por ejemplo, anticonceptivos orales.
    7. Las mujeres en edad fértil deberán tener una prueba negativa de embarazo de gonadotropina coriónica humana ? (?-hCG) en orina en la visita de inclusión (visita 1) y en la visita basal (visita 3).
    8. Puntuación basal de intensidad del dolor ?5 en la ECN de 11 puntos, sin ingesta de analgésicos (incluida la medicación de rescate), en la visita 3. Para cada uno de los 3 días previos a la visita 3 se requiere una puntuación ECN de 24 horas ?4.
    El dolor al inicio del estudio (basal) se calculará como la media de las tres valoraciones de 24 horas registradas en los últimos 3 días previos a la visita basal (visita 3).
    E.4Principal exclusion criteria
    1. Presence of other pain that could confound the assessment of, or contribute to, painful DPN. Such pain could include, but is not limited to, pain due to nerve entrapment (e.g., tarsal tunnel syndrome, osteoarthritis of the knee), peripheral vascular disease, radiculopathy, plantar fasciitis, tendonitis, mononeuritis multiplex, postherpetic neuralgia, complex regional pain syndrome, or fibromyalgia.
    2. Neuropathy due to etiologies other than diabetes. These neuropathies include, but are not limited to, those associated with autoimmune disorders, inflammatory neuropathies (e.g., chronic inflammatory demyelinating polyneuropathy), thyroid disease or endocrine disorders (other than diabetes), heavy metal or toxic neuropathy, nutritional deficiency, metabolic disorders, vasculitis, infections, injury, or paraneoplastic syndromes.
    3. Severe or extensive diabetic ulcers or amputations of the limbs (i.e., more than 2 toes) or Charcot?s joints due to diabetes. Subjects who have had an amputation for a reason other than diabetes (e.g., injury) may be eligible for this trial.
    4. Any clinically significant disease or laboratory findings that in the investigator?s opinion may affect efficacy or safety assessments or may compromise the subject?s safety during trial participation, e.g., significant unstable cardiac, vascular, pulmonary, gastrointestinal, endocrine, metabolic, neurological, or psychiatric disorders.
    5. Any medical or other reason (e.g., known or suspected inability of the subject to comply with the protocol and with the use of the IMP) that, in the investigator?s opinion, might indicate that the subject is unsuitable for the trial.
    6. Conditions that require treatment with forbidden medication (see Forbidden concomitant treatments).
    7. Use of forbidden concomitant medication as specified in Forbidden concomitant treatments.
    8. Previous or current alcohol or drug abuse or opioid dependency, according to the investigator?s judgment, based on the subject's history, examination, and the result of the drugs of abuse test. Subjects with positive urine drug test explained by a medically indicated treatment are allowed to participate in the trial as long as not specified otherwise in Forbidden concomitant treatments.
    9. Subjects with severe functional hepatic impairment corresponding to Child-Pugh classification C. Subjects with impaired hepatic cellular integrity indicated by aspartate transaminase (AST) or alanine transaminase (ALT) greater than 3 x the upper limit of normal (ULN).
    10. History of acute hepatitis within 3 months of Visit 1 or chronic hepatitis or a positive result on anti-hepatitis A IgM antibody within the past 6 months, hepatitis B surface antigen, or anti?hepatitis C antibody.
    11. Subjects with impaired renal function with a creatinine clearance less than 60 mL/min at the Enrollment Visit (Visit 1) (calculated from the Cockcroft-Gault [1976] formula).
    12. History of any major gastrointestinal prior procedures (e.g., gastric bypass) or gastrointestinal conditions (e.g., acute diarrhea, blind loop syndrome, gastric dumping syndrome, Whipple?s disease) that might affect the absorption or metabolism of cebranopadol.
    13. Presence of risk factors for (e.g., heart failure, hypokalemia, or bradycardia) or history of torsade de pointes and/or marked prolongation of the corrected QT (Fridericia) (QTcF >450 ms).
    14. History of seizure disorder and/or epilepsy or any condition associated with a significant risk for seizure disorder or epilepsy at the discretion of the investigator.
    1. Presencia de otro dolor que pudiese falsear o contribuir a falsear la evaluación de la neuropatía diabética periférica dolorosa. Dicho dolor podría ser, entre otros, un dolor debido a atrapamiento nervioso (por ejemplo, síndrome del túnel tarsiano, artrosis de la rodilla), vasculopatía periférica, radiculopatía, fascitis plantar, tendinitis, mononeuritis múltiple, neuralgia posherpética, síndrome de dolor regional complejo o fibromialgia.
    2. Neuropatía debida a otras etiologías diferentes a la diabetes. Dichas neuropatías pueden ser, por ejemplo, las asociadas a trastornos autoinmunes, neuropatías inflamatorias (por ejemplo, polineuropatía desmielinizante inflamatoria crónica), trastornos tiroideos o endocrinos (diferentes a la diabetes), neuropatía tóxica o por metales pesados, deficiencia nutricional, trastornos metabólicos, vasculitis, infecciones, lesión o síndromes paraneoplásicos.
    3. Úlceras diabéticas severas o extensas, o amputación de miembros (es decir, más de 2 dedos del pie) o articulaciones de Charcot debido a la diabetes. Podrán ser aptos para este ensayo clínico los pacientes que hayan sufrido una amputación por algún motivo diferente a la diabetes (por ejemplo, por una lesión).
    4. Cualquier enfermedad clínicamente significativa o cualquier resultado de laboratorio que, en opinión del investigador, pudiese afectar a las valoraciones de eficacia o seguridad o pudiesen comprometer la seguridad del paciente durante su participación en el ensayo clínico (por ejemplo, trastornos importantes de inestabilidad cardiaca, vasculares, pulmonares, gastrointestinales, endocrinos, metabólicos, neurológicos o psiquiátricos).
    5. Cualquier enfermedad u otro motivo (por ejemplo, sospecha o confirmación de incapacidad del paciente para cumplir con el protocolo y con el uso del FI) que, en opinión del investigador, pudiese indicar que el paciente no es adecuado para este ensayo clínico.
    6. Enfermedades que requieran tratamiento con medicación prohibida
    7. Uso de la medicación prohibida
    8. Abuso previo o actual de drogas o de alcohol, o bien dependencia de opioides, basándose en el juicio del investigador y en el historial del paciente, su exploración y el resultado de la prueba de abuso de drogas. Los pacientes con un resultado positivo de la prueba de abuso de drogas en orina, que pueda explicarse por un tratamiento indicado por un médico.
    9. Pacientes con alteración hepática funcional severa, correspondiente a una clase C de Child-Pugh. Pacientes con alteración de la integridad de las células hepáticas, reflejada por niveles de ASAT o ALAT más de 3 x LSN.
    10. Historial de hepatitis aguda en los 3 meses previos a la visita 1 o hepatitis crónica o un resultado positivo en los análisis de anticuerpos IgM anti-hepatitis A en los últimos 6 meses, antígeno de superficie de la hepatitis B o anticuerpos anti?hepatitis C.
    11. Pacientes con alteración de la función renal con un aclaramiento de creatinina menor que 60 mL/min en la visita de inclusión (visita 1) (calculado mediante la fórmula de Cockcroft-Gault [1976]).
    12. Historial de cualquier cirugía mayor gastrointestinal previa (por ejemplo, derivación gástrica) o problemas gastrointestinales (por ejemplo, diarrea aguda, síndrome de asa ciega, síndrome de dumping, enfermedad de Whipple) que pudiesen afectar a la absorción o el metabolismo de Cebranopadol.
    13. Presencia de factores de riesgo (por ejemplo, insuficiencia cardiaca, hipopotasemia o bradicardia) o historial de torsade de pointes y/o prolongación importante del intervalo QT corregido (Fridericia) (QTcF > 450 mseg).
    14. Historial de trastornos convulsivos y/o epilepsia, o cualquier enfermedad asociada a un riesgo importante de trastornos convulsivos o epilepsia, determinado a juicio del investigador.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint will be the change from baseline pain to the average 24 hour pain during Week 6 of the Maintenance Phase. The 24 hour pain will be assessed once daily (evening) using an 11 point numeric rating scale (NRS) and a 24 hour recall period
    El criterio principal de valoración será el cambio respecto al inicio del estudio en el promedio del dolor de 24 horas durante las 6 semanas de la fase de mantenimiento.
    El dolor de 24 horas se evaluará una vez al día (por la noche) utilizando una ECN de 11 puntos y abarcando un periodo de 24 horas.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Week 6 of the maintenance phase
    6 semanas de fase de mantenimiento
    E.5.2Secondary end point(s)
    n.a.
    E.5.2.1Timepoint(s) of evaluation of this end point
    n.a.
    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 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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    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 No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial5
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned8
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA70
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    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
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months3
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months3
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 300
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 50
    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 state40
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 540
    F.4.2.2In the whole clinical trial 540
    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)
    Subject will return to normal treatment after the end of the trial.
    El paciente volverá a su tratamiento habitual al finalizar el estudio
    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 Decision2013-07-17
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-07-04
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2015-01-28
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
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