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    Summary
    EudraCT Number:2011-002178-22
    Sponsor's Protocol Code Number:11-AVR-130
    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:2011-10-31
    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 number2011-002178-22
    A.3Full title of the trial
    A Phase 2, Double-blind, Randomized, Placebo-controlled, Four-arm, Multicenter, Dose-finding Study to Assess the Safety and Efficacy of Three Dose Levels of AVP-923 (Dextromethorphan/Quinidine) in the Treatment of Central Neuropathic Pain in Patients with Multiple Sclerosis
    Estudio fase 2, doble ciego, aleatorizado, controlado con placebo, en cuatro grupos, multicéntrico, de búsqueda de dosis para evaluar la seguridad y la eficacia de tres niveles de dosis de AVP-923 (dextrometorfano/quinidina) en el tratamiento del dolor neuropático central en pacientes con esclerosis múltiple.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase 2, Double-blind, Randomized, Placebo-controlled, Four-arm, Multicenter, Dose-finding Study to Assess the Safety and Efficacy of Three Dose Levels of AVP-923 (Dextromethorphan/Quinidine) in the Treatment of Central Neuropathic Pain in Patients with Multiple Sclerosis
    Estudio fase 2, doble ciego, aleatorizado, controlado con placebo, en cuatro grupos, multicéntrico, de búsqueda de dosis para evaluar la seguridad y la eficacia de tres niveles de dosis de AVP-923 (dextrometorfano/quinidina) en el tratamiento del dolor neuropático central en pacientes con esclerosis múltiple.
    A.4.1Sponsor's protocol code number11-AVR-130
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT01324232
    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 SponsorAvanir 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 supportAvanir Pharmaceuticals, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAvanir Pharmaceuticals, Inc.
    B.5.2Functional name of contact pointClinical Trial Information Desk
    B.5.3 Address:
    B.5.3.1Street Address20 Enterprise, Suite 200
    B.5.3.2Town/ cityAliso Viejo
    B.5.3.3Post codeCA 92656
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1 949-268-1167
    B.5.5Fax number+1 949-268-1168
    B.5.6E-mailstudy11AVR130@avanir.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 nameDextrometorfano/Quinidina
    D.3.2Product code AVP-923
    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 INNDEXTROMETORFANO HIDROBROMURO
    D.3.9.1CAS number 125-69-9
    D.3.9.2Current sponsor code11-AVR-130
    D.3.9.3Other descriptive nameN/A
    D.3.9.4EV Substance CodeSUB01645MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number45
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNQuinidina sulfato
    D.3.9.2Current sponsor code11-AVR-130
    D.3.9.3Other descriptive nameN/A
    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 nameDextrometorfano/Quinidina
    D.3.2Product code AVP-923
    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 INNDEXTROMETORFANO HiDROBROMURO
    D.3.9.1CAS number 125-69-9
    D.3.9.2Current sponsor code11-AVR-130
    D.3.9.3Other descriptive nameN/A
    D.3.9.4EV Substance CodeSUB01645MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number30
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNQuinidina sulfato
    D.3.9.2Current sponsor code11-AVR-130
    D.3.9.3Other descriptive nameN/A
    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: 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 nameDextrometorfano/Quinidina
    D.3.2Product code AVP-923
    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 INNDEXTROMETORFANO HIDROBROMURO
    D.3.9.1CAS number 125-69-9
    D.3.9.2Current sponsor code11-AVR-130
    D.3.9.3Other descriptive nameN/A
    D.3.9.4EV Substance CodeSUB01645MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNQuinidina sulfato
    D.3.9.2Current sponsor code11-AVR-130
    D.3.9.3Other descriptive nameN/A
    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.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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Central Neuropathic Pain in Multiple Sclerosis
    Dolor neuropático central en la esclerosis múltiple
    E.1.1.1Medical condition in easily understood language
    Central Neuropathic Pain in Multiple Sclerosis
    Dolor neuropático central en la esclerosis múltiple
    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 14.0
    E.1.2Level LLT
    E.1.2Classification code 10054095
    E.1.2Term Neuropathic pain
    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
    The objectives of the study are to evaluate the safety, tolerability, and efficacy of 3 doses of AVP-923 capsules containing either 45 mg DM and 10 mg Q (AVP-923-45) or 30 mg DM 10 mg Q (AVP-923-30) or 20 mg DM and 10 mg Q (AVP-923-20) compared to placebo, for the treatment of central neuropathic pain in a population of patients with multiple sclerosis (MS) over a 12-week period.
    Los objetivos del estudio son evaluar la seguridad, tolerabilidad y eficacia de 3 dosis diferentes de cápsulas de AVP-923 que contengan 45 mg de DM y 10 mg de Q (AVP-923-45), 30 mg de DM y 10 mg de Q (AVP-923-30), o bien, 20 mg de DM y 10 mg de Q (AVP-923-20) en comparación con el placebo, para el tratamiento del dolor neuropático central en una población de pacientes con EM, durante un período de 12 semanas.
    E.2.2Secondary objectives of the trial
    Not applicable.
    No aplicable.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1.Males and females 18 to 85 years of age, inclusive.
    2.The patient has a diagnosis of RRMS or SPMS (MS must be diagnosed according to the McDonald criteria).
    3.The patient has a clinical history and clinical relevant symptoms of central neuropathic pain (dysesthetic pain) secondary to MS for at least 30 days prior to screening and expected to remain otherwise stable during the study. Patients meeting the criterion for central neuropathic pain and experiencing concomitant non-central neuropathic pain are allowed to participate in the study.
    4.Mean PRS score at Baseline is more or equal to 4.
    5.The patient has not experienced an MS relapse within the previous 30 days.
    6.The patient has stable hematologic, hepatic, and renal function, with no clinically significant symptoms, and with clinical laboratory results (complete blood cell count [CBC], clinical chemistry, and urinalysis) up to 1-fold higher than the upper limit of the normal range.
    7.The patient has a resting respiratory rate between 12 and 20 breaths per minute.
    8.The patient has an ECG (obtained within 4 weeks prior to entry and evaluated by a certified cardiologist) with no evidence of clinically significant abnormality and with no evidence of: complete heart block, ventricular tachycardia, or frequent unifocal ventricular ectopic beats (>5 per minute).
    9.If female, must not be pregnant, breast-feeding, or planning a pregnancy during the course of the study, and must have a negative urine pregnancy test at Screening and at baseline.
    10.If female, must have been practicing a medically-acceptable method of birth control for at least 1 month prior to randomization (oral contraceptive tablets, hormonal implant device, hormone patch, intrauterine device, diaphragm and contraceptive cream or foam, condom with spermicide, tubal ligation, or abstinence) or be surgically sterile or post-menopausal.
    11.Patients currently receiving an MS disease-modifying therapy ([MS DMT] eg, interferon beta, glatiramer, natalizumab, fingolimod) are eligible provided they have been on a stable dose of these medications for at least 2 months prior to randomization.
    12.Patients currently receiving fampridine should be on a stable dose for at least 2 months prior to randomization.
    13.Patients currently taking SSRIs (selective serotonin reuptake inhibitors) for the treatment of major depression for at least 3 months on a stable dose prior to randomization are eligible, provided the SSRI dose remains unchanged during the study.
    14.Patient must not show current symptoms of a depressive disorder.
    15.Patient must have a score of ?19 in the BDI-II at screening and at baseline.
    16.Patient must be willing to not take any prohibited medications during the study.
    17.Patient or their legal guardian signed and received a copy of an informed consent form (ICF) after the nature and risks of study participation had been fully explained to them
    1.Hombres y mujeres de entre 18 y 85 años de edad, inclusive. 2.El paciente tiene un diagnóstico de EMRR o EMPS (la EM debe diagnosticarse de acuerdo con los criterios de McDonald, 2005).3. El paciente tiene antecedentes clínicos y síntomas relevantes de dolor neuropático central (dolor disestésico) secundario a la EM durante al menos 30 días antes de la selección y se espera que continúen estables durante el estudio. Se permitirá participar en el estudio a pacientes que cumplan con los criterios de dolor neuropático central y a los que experimenten dolor neuropático no central concomitante.4.La puntuación media de la PRS en el período basal es mayor o igual a 4. 5.El paciente no ha tenido una recaída de la EM durante los 30 días previos a la selección.6.Las funciones hematológica, hepática y renal del paciente son estables, no presenta síntomas clínicos significativos y los resultados del laboratorio clínico (hemograma completo, bioquímica clínica y análisis de orina) son hasta el doble del límite superior del rango normal. 7. El paciente tiene una frecuencia respiratoria en reposo de entre 12 y 20 respiraciones por minuto.8. El ECG del paciente (realizado en las 4 semanas previas a la aleatorización y evaluado por un cardiólogo certificado) no muestra evidencia de anomalías clínicas significativas, ni de bloqueo auriculoventricular total, taquicardia ventricular ni extrasístoles ventriculares unifocales frecuentes (>5 por minuto).
    9. Si el paciente es mujer, no debe estar embarazada, en periodo de lactancia, ni planear quedarse embarazada durante el transcurso del estudio, y el resultado de la prueba de embarazo en orina realizada durante la selección y la visita basal debe ser negativo.10. Si el paciente es mujer, debe haber usado un método de control anticonceptivo aceptable desde el punto de vista médico durante al menos 1 mes, antes de la aleatorización (anticonceptivos orales, implante hormonal, parche hormonal, dispositivo intrauterino, diafragma y crema o espuma anticonceptiva, condón con espermicida, ligadura de trompas o abstinencia), o ser estéril mediante cirugía o estar en etapa posmenopáusica.11.Los pacientes que actualmente están recibiendo terapia modificadora de la EM ([TME-EM] p. ej., interferón Beta, glatirámero, natalizumab, fingolimod, mitoxantrona) son elegibles, siempre y cuando hayan estado recibiendo una dosis estable de estos medicamentos, durante al menos 2 meses antes de la aleatorización.12. Los pacientes que actualmente toman fampridina/dalfampridina, deben estar con una dosis estable desde al menos 2 meses, antes de la aleatorización.13. Los pacientes que actualmente tomen ISRS (inhibidores selectivos de la recaptación de serotonina) en dosis estables para el tratamiento de la depresión mayor, durante al menos 3 meses antes de la aleatorización son elegibles, siempre y cuando la dosis de ISRS sea la misma durante el estudio.14. El paciente no debe presentar actualmente síntomas de trastornos depresivos.15. El paciente debe obtener una puntuación <=19 en el BDI-II durante la selección y la visita basal.16. El paciente debe estar de acuerdo en no tomar ningún medicamento no permitido durante el estudio.17.El paciente o su tutor legal firmaran y recibieran una copia del formulario de consentimiento informado, tras recibir las explicaciones pertinentes y detalladas sobre la naturaleza y los riesgos de la participación en el estudio.
    E.4Principal exclusion criteria
    1.Patient (or caregiver) is unwilling or unable, in the opinion of the investigator, to comply with study instructions.
    2.The patient has other types of non-central neuropathic pain (e.g., back pain, headache, painful tonic spasms) without having clinical symptoms of central neuropathic pain.
    3.Patients with myasthenia gravis.
    4.Any personal history of complete heart block, QTc prolongation, or torsades de pointes.
    5.Any family history of congenital QT interval prolongation syndrome.
    6.Patients with known sensitivity to DM, Q, or opiate drugs (codeine, etc.).
    7.Patients with known sensitivity to acetaminophen (also known as paracetamol).
    8.Patients experiencing an MS relapse within the previous 30 days.
    9.Patients who have been taking disallowed concomitant medications within 2 weeks prior to Baseline (Day 1).
    10.Patients currently using, or have been using marijuana or dronabinol within 2 weeks prior to Baseline (Day 1).
    11.Patients with a current or prior history of major psychiatric disorder. Exclusionary psychiatric diagnoses, to be determined by chart review and patient interview, include the following Axis I disorders (according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition [DSM-IV] criteria): (i) current symptoms of major depression; (ii) bipolar disorder; (iii) schizophrenia or other psychotic disorder; (iv) somatoform disorders; and the Axis II disorder of borderline personality.
    12.Patients that have a score of ?20 in the BDI-II.
    13.Patients with co-existent major systemic diseases that would interfere with interpretation of the results of the study (eg, malignancy [except skin basal-cell carcinoma], poorly controlled diabetes, poorly controlled hypertension, ischemic cardiac disease, dilated cardiomyopathy, or valvular heart disease).
    14.Patients who are currently participating in, or who have participated in other clinical study within the past 30 days.
    15.Patients with severe and/or unstable pulmonary disease.
    16.Patients with resting respiratory rate <12 breaths per minute or >20 breaths per minute.
    17.Patients who have received DM co-administered with Q within the previous 3 months.
    18.Patients with hypotension (systolic blood pressure [BP] <100 mm Hg), history of postural syncope, or any history of unexplained syncope (evaluated on a case by case basis).
    19.Patients with a history of substance and/or alcohol abuse within the past 2 years.
    20.Women who are pregnant or likely to become pregnant during the course of the study.
    1. Según el punto de vista del investigador, el paciente (o persona a cargo de su cuidado) no está dispuesto o no es capaz de cumplir con las instrucciones del estudio. 2. El paciente presenta otros tipos de dolor neuropático no central (p. ej., lumbalgia, cefalea, dolor visceral crónico, dolor musculoesquelético postural) sin síntomas clínicos de dolor neuropático central. 3. Pacientes con miastenia grave.4.Cualquier antecedente personal de bloqueo auriculoventricular total, prolongación del QTc o taquicardia ventricular polimorfa (torsades de pointes).5. Cualquier antecedente familiar de síndrome congénito de intervalo de QTc prolongado.6.Los pacientes con sensibilidad conocida al DM, la Q o fármacos opiáceos (codeína, etc.).
    7.Los pacientes con sensibilidad conocida al acetaminofeno (también conocido como paracetamol).8. Los pacientes que presentan una recaída de la EM durante los 30 días previos a la selección.9.Los pacientes que hayan estado tomando medicamentos concomitantes no permitidos durante las 2 semanas previas a la visita basal (Día 1).10. Los pacientes que actualmente consuman o hayan consumido marihuana o dronabinol durante las 2 semanas previas a la visita basal (Día 1).11. Los pacientes con síntomas actuales o antecedentes previos de trastorno psiquiátrico mayor. Los diagnósticos psiquiátricos de exclusión, los cuales serán determinados mediante la revisión de la historia clínica y la entrevista con el paciente, incluyen los siguientes trastornos del eje 1 (según los criterios del Manual diagnóstico y estadístico de los trastornos mentales, cuarta edición [Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, DSM-IV]): (i) síntomas actuales de depresión mayor; (ii) síntomas actuales o antecedentes previos de trastorno bipolar; (iii) síntomas actuales o antecedentes previos de esquizofrenia u otro tipo de trastorno psicótico; (iv) síntomas actuales o antecedentes previos de trastornos somatomorfos y el trastorno límite de la personalidad del eje 2. 12. Los pacientes que obtengan una puntuación >=20 en el BDI-II.
    13.Los pacientes con enfermedades generalizadas coexistentes importantes que interferirían con la interpretación de los resultados del estudio (p. ej., tumores malignos [salvo el carcinoma basocelular cutáneo], diabetes no controlada adecuadamente, hipertensión arterial no controlada adecuadamente, cardiopatía isquémica, miocardiopatía dilatada o valvulopatía). 14. Los pacientes que actualmente participen o hayan participado en otros ensayos clínicos durante los últimos 30 días. 15. Los pacientes con enfermedad pulmonar grave o inestable. 16. Los pacientes con una frecuencia respiratoria en reposo de <12 o > 20 respiraciones por minuto.17.Los pacientes a quienes se les hayan administrado DM junto con Q, durante los 3 meses previos.18.Los pacientes con hipotensión arterial (tensión arterial [TA] sistólica <100 mm Hg), antecedentes de síncope postural o cualquier antecedente de síncope de causa indeterminada (evaluados caso por caso).19.Los pacientes con antecedentes de abuso de sustancias o alcoholismo durante los últimos 2 años. 20.Las mujeres que estén embarazadas o que probablemente se queden embarazadas durante el transcurso del estudio.
    E.5 End points
    E.5.1Primary end point(s)
    The primary efficacy endpoint is the 11 point (0-10) PRS obtained from daily patient diaries.
    El principal criterio de valoración de la eficacia son los 11 puntos (0-10) de la PRS obtenidos diariamente de los diarios de los pacientes.
    E.5.1.1Timepoint(s) of evaluation of this end point
    The primary analysis of the primary endpoint will be a comparison of the average PRS scores on Days 57-84 to the average PRS scores during the 7-day baseline recording period prior to randomization, using a mixed-effects regression model that accounts for within-patient correlation.
    El análisis primario del criterio de valoración principal será una comparación de las puntuaciones promedio de la PRS de los Días 57 al 84 con las puntuaciones promedio de la PRS durante el período de registro inicial de 7 días previo a la aleatorización, mediante el uso de un modelo de regresión de efectos mixtos que representa la correlación intra-paciente.
    E.5.2Secondary end point(s)
    Secondary efficacy endpoints include the FSS, MSIS-29, PSQI, MSNQ, and BDI-II.
    Los criterios de valoración de la eficacia secundarios incluyen la FSS, la MSIS-29, el PSQI, el MSNQ, la SDMT y el BDI-II.
    E.5.2.1Timepoint(s) of evaluation of this end point
    A secondary analysis will be a baseline-adjusted comparison of the area under the PRS curve over the on-treatment period using a parametric mixed-effects model.
    El análisis secundario será una comparación, adaptada según los valores iniciales, del área debajo de la curva de la PRS con el período de tratamiento activo, mediante el uso de un modelo paramétrico de efectos mixtos.
    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 Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    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 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) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial4
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned6
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA25
    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
    Bulgaria
    Czech Republic
    Poland
    Spain
    United States
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    End of the trial is LVLS
    El final del estudio es la última visita del último paciente.
    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 months5
    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 months5
    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.1.1Number of subjects for this age range: 0
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) No
    F.1.1.6.1Number of subjects for this age range: 0
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 400
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 400
    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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    All participants or their legal guardian must provide a signed informed consent form for the procedures in this study protocol
    Todos los participantes o sus tutores deben proporcinar un consentimiento informado firmado para los procedimientos de este estudio.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state90
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 140
    F.4.2.2In the whole clinical trial 400
    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)
    After the patient has completed his/her participation in the study, the treating physician will prescribe the appropriate available therapy to continue treatment
    Después de que el paciente complete su participación en el estudio, el médico prescribirá el tratamiento adecuado disponible para continuar el tratamiento.
    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 Decision2011-12-26
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2011-12-16
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2013-09-26
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