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    Summary
    EudraCT Number:2016-002259-11
    Sponsor's Protocol Code Number:GRT-ZVO-2016-01
    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:2016-07-15
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedSpain - AEMPS
    A.2EudraCT number2016-002259-11
    A.3Full title of the trial
    A multicenter, open-label, single-arm, Phase IIIb trial to evaluate the effectiveness, safety, tolerability, usability and health economics resource utilization of Zalviso® for management of acute moderate to severe postoperative pain.
    Estudio de fase IIIb, de un solo brazo, abierto y multicéntrico para evaluar la efectividad, la seguridad, la tolerabilidad, la facilidad de uso y la utilización de recursos de Zalviso® en el manejo del dolor agudo postoperatorio de moderado a intenso
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A multicenter, open-label, single-arm, Phase IIIb trial to evaluate the effectiveness, safety, tolerability, usability and health economics resource utilization of Zalviso® for management of acute moderate to severe postoperative pain.
    Estudio de fase IIIb, de un solo brazo, abierto y multicéntrico para evaluar la efectividad, la seguridad, la tolerabilidad, la facilidad de uso y la utilización de recursos de Zalviso® en el manejo del dolor agudo postoperatorio de moderado a intenso
    A.4.1Sponsor's protocol code numberGRT-ZVO-2016-01
    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 SponsorGRUNENTHAL PHARMA S.A.
    B.1.3.4CountrySpain
    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 supportGRUNENTHAL PHARMA.S.A
    B.4.2CountrySpain
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationGRUNENTHAL PHARMA S.A.
    B.5.2Functional name of contact pointAna Leal
    B.5.3 Address:
    B.5.3.1Street AddressDoctor Zamenhof 36
    B.5.3.2Town/ cityMadrid
    B.5.3.3Post code28027
    B.5.3.4CountrySpain
    B.5.4Telephone number34913017822
    B.5.6E-mailana.leal@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 Yes
    D.2.1.1.1Trade name Zalviso®
    D.2.1.1.2Name of the Marketing Authorisation holderGrünenthal GmBh
    D.2.1.2Country which granted the Marketing AuthorisationSpain
    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 Sublingual tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSublingual use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNSUFENTANIL CITRATE
    D.3.9.1CAS number 60561-17-3
    D.3.9.4EV Substance CodeSUB04616MIG
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number15
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Yes
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Acute moderate to severe postoperative pain
    Dolor agudo post-operatorio de moderado a severo.
    E.1.1.1Medical condition in easily understood language
    Acute moderate to severe postoperative pain
    Dolor agudo post-operatorio de moderado a severo.
    E.1.1.2Therapeutic area Diseases [C] - Symptoms and general pathology [C23]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Evaluate the effectiveness of Zalviso® for the management of acute postoperative pain by using a Patient Global Assessment (PGA) of the method of pain control.
    Evaluar la efectividad de Zalviso® en el manejo del dolor agudo postoperatorio utilizando una Evaluación Global del Paciente (PGA) del método de control del dolor
    E.2.2Secondary objectives of the trial
    •To evaluate the effectiveness of Zalviso® for the management of acute postoperative pain by using a Healthcare Professional Global Assessment of the method of pain control.
    •To assess the pain intensity during treatment with Zalviso® by using a 0-10 NRS
    •To assess the quality of sleep during treatment with Zalviso® by using a 0-10 NRS.
    •To evaluate the safety and tolerability of Zalviso®.
    •To assess the ease of use of the device by using the time and personnel required to train patients about its use and the Ease of Care questionnaire.
    •To obtain data about patients receiving patient controlled analgesia with Zalviso®, (demographics , details of the surgery and perioperative prescribed concomitant medication, patient mobilization/mobility after surgery, and quality of recovery after surgery, by using the Quality of Recovery-15 questionnaire
    •To obtain data on health care resource utilization by patients treated with Zalviso® over a period of up to 72 hours.
    •Evaluar la efectividad de Zalviso® en el manejo del dolor agudo postoperatorio utilizando una Evaluación Global del Profesional Sanitario
    •Evaluar la intensidad del dolor con Zalviso® utilizando una NRS de 0-10.
    •Evaluar la calidad del sueño con Zalviso® utilizando una NRS de 0-10.
    •Evaluar la seguridad y la tolerabilidad de Zalviso®
    •Evaluar la facilidad de uso del dispositivo utilizando el tiempo/personal necesario para entrenar a los pacientes en su utilización y cuestionario Ease of Care
    •Obtener datos sobre los pacientes que reciben analgesia controlada por el paciente con Zalviso®, (características demográficas, detalles de la cirugía y medicación concomitante perioperatoria prescrita, movilidad/movilización del paciente tras la cirugía y calidad de la recuperación tras la cirugía utilizando el cuestionario Quality of Recovery-15)
    •Obtener datos sobre utilización de recursos sanitarios por los pacientes tratados con Zalviso® en de hasta 72 horas
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1.The patient has provided written informed consent and signed the IRB approved consent form.
    2.The patient is an adult aged ≥ 18 years old.
    3.The patient is scheduled to undergo surgery, and is expected to remain hospitalized and have acute moderate to severe postoperative pain requiring parenteral opioids for at least 48 hours after surgery.
    4.The patient has visual and cognitive ability to use the Zalviso® administration device correctly.
    5.Treatment with Zalviso® according to the Summary of Product characteristics is appropriate for the patient.
    6.Female patients of childbearing potential must be using an effective method of birth control.

    Just before the start of treatment with Zalviso®, patients must fulfill all the following inclusion criteria to continue in the study:
    1.The patient has had a pain intensity < 5 in the NRS at any time after the surgery but he/she has acute moderate to severe postoperative pain at the time of starting treatment with Zalviso®, defined as a pain intensity ≥ 4 in the NRS.
    2.Treatment with Zalviso® starts before midnight on the day of the surgery.
    1.El paciente ha proporcionado su consentimiento informado por escrito y ha firmado el formulario de consentimiento aprobado por el CEIm.
    2.El paciente es un adulto ≥ 18 años de edad.
    3.El paciente tiene programada una cirugía y está previsto que permanezca hospitalizado y presente dolor agudo postoperatorio de moderado a intenso con necesidad de opioides parenterales durante por lo menos 48 horas tras la cirugía.
    4.El paciente tiene capacidad visual y cognitiva para utilizar correctamente el dispositivo de administración de Zalviso®.
    5.El tratamiento con Zalviso® de acuerdo con la ficha técnica es adecuado para el paciente.
    6.Las mujeres potencialmente fértiles deben estar utilizando un método anticonceptivo efectivo.

    Justo antes del inicio de tratamiento con Zalviso®, los pacientes deben cumplir todos los siguientes criterios de inclusión para continuar en el estudio:
    1.El paciente ha presentado una intensidad del dolor < 5 en la NRS en cualquier momento tras la cirugía, pero presenta dolor agudo postoperatorio de moderado a severo en el momento del inicio del tratamiento con Zalviso®, definido como una intensidad del dolor ≥ 4 en la NRS.
    2.El tratamiento con Zalviso® se inicia antes de las 12 de la noche del día de la cirugía.
    E.4Principal exclusion criteria
    1.The patient has hypersensitivity to the active substance or to any other ingredients of the sublingual tablet.
    2.The patient has significant respiratory depression, that is, an arterial oxygen saturation by pulse oximetry (SpO2) that cannot be maintained at 95% or greater with or without supplemental oxygen.
    3.The patient has current sleep apnea that has been documented by a sleep laboratory study or are on home continuous positive airway pressure.
    4.The patient has a medical condition that, in the Investigator’s opinion, could adversely impact the patient’s participation or safety, conduct of the study, or interfere with the pain assessments, including chronic pain or active infection.
    5.The patient is deemed by the Investigator to be unable to use the Zalviso® administration device correctly.
    6.The patient requires an additional scheduled surgical procedure within 72 hours of the surgery.
    7.The patient has received surgical premedication with long-acting opioid analgesics.
    8.The patient is receiving or has received monoamine oxidase inhibitors within 14 days before the study entry.
    9.The patient has participated in a clinical trial of an investigational drug or device within 30 days of screening visit or is scheduled to receive an investigational product while participating in this study.
    10.The patient is pregnant.

    Just before the start of treatment with Zalviso®, patients must not meet any of the following exclusion criteria to continue in the study:
    1.The patient is not awake, not breathing spontaneously or has a respiratory rate that is less than 8 breaths per minute or greater than 24 breaths per minute.
    2.The patient is not able to answer questions and follow commands.
    3.The patient is vomiting and not responsive to standard treatment
    1.El paciente tiene hipersensibilidad al principio activo o a cualquier otro componente del comprimido sublingual.
    2.El paciente presenta depresión respiratoria significativa, es decir, una saturación arterial de oxígeno mediante oximetría de pulso (SpO2) que no puede mantenerse en valores del 95% o superiores con o sin suplementos de oxígeno.
    3.El paciente presenta actualmente apnea del sueño documentada mediante un estudio de laboratorio del sueño o está con presión positiva continua en la vía aérea domiciliaria.
    4.El paciente presenta un trastorno médico que, según la opinión del Investigador, podría afectar negativamente a la participación del paciente o a su seguridad, al desarrollo del estudio, o interferir con las evaluaciones del dolor, incluyendo dolor crónico o infección activa.
    5.El Investigador considera que el paciente no es capaz de utilizar correctamente el dispositivo de administración de Zalviso®.
    6.El paciente requiere un procedimiento quirúrgico programado adicional en las 72 horas siguientes a la cirugía.
    7.El paciente ha recibido premedicación quirúrgica con analgésicos opioides de acción prolongada.
    8.El paciente está recibiendo o ha recibido inhibidores de la monoamino oxidasa en los 14 días anteriores a la entrada en el estudio.
    9.El paciente ha participado en un ensayo clínico con un fármaco o un dispositivo en investigación en los 30 días anteriores a la visita de selección o tiene programado recibir un producto en investigación durante su participación en este estudio.
    10.La paciente está embarazada.

    Justo antes del inicio de tratamiento con Zalviso®, los pacientes no deben cumplir ninguno de los siguientes criterios de exclusión para continuar en el estudio:
    1.El paciente no está despierto, no respira espontáneamente o presenta una frecuencia respiratoria inferior a 8 respiraciones por minuto o mayor de 24 respiraciones por minuto.
    2.El paciente no es capaz de responder a preguntas ni seguir órdenes.
    3.El paciente está vomitando y no responde al tratamiento estándar
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is the success rate on the PGA, defined as the proportion of patients with a response of “good” or “excellent” in the PGA of the method of pain control, on the second postoperative day (the closest assessment to 48 hours after handing over the device to the patient).
    La variable principal es el nivel de éxito en la PGA, definida como la proporción de pacientes con una respuesta de “bueno” o “excelente” en la PGA del método de control del dolor, el segundo día postoperatorio (la evaluación más cercana a las 48 horas tras la entrega del dispositivo al paciente).
    E.5.1.1Timepoint(s) of evaluation of this end point
    the closest assessment to 48 hours after handing over the device to the patient
    la evaluación más cercana a las 48 horas tras la entrega del dispositivo al paciente
    E.5.2Secondary end point(s)
    •Success rate on the PGA, defined as the proportion of patients with a response of “good” or “excellent” in the PGA of the method of pain control, on the day of surgery and the first and third postoperative days.
    •Success rate on the HPGA, defined as the proportion of healthcare professionals with a response of “good” or “excellent” in the HPGA of the method of pain control, on the day of surgery and the first, second and third postoperative days.
    •Total score on the Ease of Care (EOC) questionnaire completed by the nurse and the patient at the end of treatment.
    •Pain intensity on a 0-10 Numerical Rating Scale (NRS) at several time points: when the device is handed over to the patient, 1, 2, 3, 4, 8, 12, 16, 20, 24 hours after handing over the device to the patient, twice a day in the first to (at most) third postoperative days and at the end of treatment.
    •Worst pain intensity on the day of surgery and the first to (at most) third postoperative days.
    •Percentage of time with severe pain (pain intensity ≥7) on the day of surgery and the first to (at most) third postoperative days.
    •Time-weighed summed pain intensity difference over the first 24 hours (SPID24) after handing over the device to the patient.
    •Quality of sleep on a 0-10 NRS in the first to (at most) third postoperative days.
    •Patient mobility/mobilization after surgery on the day of surgery and the first to (at most) third postoperative days.
    •QoR-15 score at the end of treatment.
    •Resource utilization.
    •Adverse events and incidents with the device
    •Nivel de éxito en la PGA, definida como la proporción de pacientes con una respuesta de “bueno” o “excelente” en la PGA del método de control del dolor, el día de la cirugía y el primer y el tercer día postoperatorio.
    •Nivel de éxito en la HPGA, definida como la proporción de profesionales sanitarios con una respuesta de “bueno” o “excelente” en la HPGA del método de control del dolor, el día de la cirugía y el primer, el segundo y el tercer día postoperatorio.
    •Puntuación total del cuestionario Ease of Care (EOC) cumplimentado por personal de enfermería y por el paciente al final del tratamiento.
    •Intensidad del dolor en una escala categórica numérica (NRS) de 0-10 en varios momentos: a la entrega del dispositivo al paciente, 1, 2, 3, 4, 8, 12, 16, 20, 24 horas tras la entrega del dispositivo al paciente, dos veces al día desde el primer a (como máximo) tercer día postoperatorio y al final del tratamiento.
    •Peor intensidad de dolor el día de la cirugía y desde el primer a (como máximo) tercer día postoperatorio.
    •Porcentaje de tiempo con dolor intenso (intensidad del dolor ≥7) el día de la cirugía y desde el primer a (como máximo) tercer día postoperatorio.
    •Diferencia en la intensidad del dolor sumada y ponderada por el tiempo durante las primeras 24 horas (SPID24) tras la entrega del dispositivo al paciente.
    •Calidad del sueño en una NRS de 0-10 desde el primer a (como máximo) tercer día postoperatorio.
    •Movilidad/movilización del paciente tras la cirugía el día de la cirugía y desde el primer a (como máximo) tercer día postoperatorio.
    •Puntuación del QoR-15 al final del tratamiento.
    •Utilización de recursos.
    •Acontecimientos adversos y problemas con el dispositivo médico
    E.5.2.1Timepoint(s) of evaluation of this end point
    24, 48 and 72 hours after handing over the device to the patient
    24, 48 y 72 horas tras la entrega del dispositivo al paciente
    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 No
    E.6.5Efficacy No
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Effectiveness and resources utilization
    Efectividad y utilización de recursos
    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) Yes
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.3 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 No
    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
    Patients who complete all the assessments and questionnaires on the day of surgery and the first to three postoperative days will be considered as completer.
    A patient may terminate participation in the trial without providing a reason and without personal disadvantage. The Investigator can stop the participation of a patient after consideration of the benefit/risk ratio.
    Reasons:
    •Safety reasons
    •Adverse events/incidents with medical device
    •Withdrawal of consent
    •Lack of efficacy
    Pacientes que completan valoraciones y cuestionarios el día de la cirugía y del 1er al 3er día postoperatorio, se considerarán como finalizados.
    Cualquier paciente podrá finalizar su participación en el ensayo sin motivo alguno y sin desventajas personales. El investigador podrá finalizar la participación de un paciente tras valorar el balance beneficio/riesgo.
    Razones:
    •Motivos de seguridad
    •Acontecimientos adversos/incidentes del dispositivo
    •Retirada de consentimiento
    •Falta de eficacia
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years0
    E.8.9.1In the Member State concerned months7
    E.8.9.1In the Member State concerned 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: 160
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 40
    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 No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    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 state200
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    None
    Ninguno
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2016-10-10
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-09-13
    P. End of Trial
    P.End of Trial StatusCompleted
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