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    Summary
    EudraCT Number:2014-000162-22
    Sponsor's Protocol Code Number:112025-002
    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:2015-01-16
    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 number2014-000162-22
    A.3Full title of the trial
    Prospective, single arm, open-label, multicenter, international study to assess the effects of metyrapone in patients with endogenous Cushing?s syndrome during a 12-week treatment period followed by an extension period of 24 weeks.
    Estudio internacional, prospectivo, de un solo grupo, sin enmascaramiento y multicéntrico para valorar los efectos de la metirapona en pacientes con síndrome de Cushing endógeno durante un período de tratamiento de 12 semanas seguido de un período de prolongación opcional de 24 semanas.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study to assess the effects of metyrapone in patients with Cushing?s syndrome during a 12-week treatment period
    Estudio para evaluar los efectos de la metirapona en pacientes con sindorme de Cushing durante un período de tratamiento 12 semanas.
    A.3.2Name or abbreviated title of the trial where available
    PROMPT
    A.4.1Sponsor's protocol code number112025-002
    A.5.4Other Identifiers
    Name:INDNumber:116160
    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 SponsorLaboratoire HRA Pharma
    B.1.3.4CountryFrance
    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 supportLaboratoire HRA Pharma
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationLaboratoire HRA Pharma
    B.5.2Functional name of contact pointOlga Kroselj
    B.5.3 Address:
    B.5.3.1Street Address15 rue b??ranger
    B.5.3.2Town/ cityParis
    B.5.3.3Post code75003
    B.5.3.4CountryFrance
    B.5.4Telephone number00330140336599
    B.5.5Fax number00330142771060
    B.5.6E-mailo.kroselj@hra-pharma.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 Metopirone 250 mg capsules
    D.2.1.1.2Name of the Marketing Authorisation holderLaboratoire HRA Pharma
    D.2.1.2Country which granted the Marketing AuthorisationIreland
    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 namemetyrapone
    D.3.4Pharmaceutical form Capsule, soft
    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 INNMETYRAPONE
    D.3.9.1CAS number 54-36-4
    D.3.9.4EV Substance CodeSUB08925MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number250
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Treatment of Cushing?s syndrome
    Tratmiento del Sindrome de Cushing
    E.1.1.1Medical condition in easily understood language
    Treatment of Cushing?s syndrome which is a rare disorders characterized by a chronic hypercortisolism.
    E.1.1.2Therapeutic area Diseases [C] - Hormonal diseases [C19]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 17.1
    E.1.2Level PT
    E.1.2Classification code 10011652
    E.1.2Term Cushing's syndrome
    E.1.2System Organ Class 10014698 - Endocrine 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 primary objective is to assess the efficacy of metyrapone (MTP) to normalize cortisol levels (Urinary Free Cortisol ? UFC) after 12 weeks of treatment in patients with endogenous Cushing?s syndrome (CS).
    El objetivo principal consiste en valorar la eficacia de la metirapona (MTP) para normalizar los niveles de cortisol (cortisol libre en orina, CLO) tras 12 semanas de tratamiento en pacientes con síndrome de Cushing (SC) endógeno.
    E.2.2Secondary objectives of the trial
    A)To assess the effects of metyrapone after 12 weeks of treatment on:
    1)Salivary and serum cortisol levels
    2)Hormonal and biochemical parameters that are associated with Cushing?s syndrome or represent safety measurements
    3)Clinical signs of Cushing?s syndrome
    4)Quality of life as judged by Cushing?s Quality of Life (CushingQoL) questionnaire and Tuebingen Cushing's disease quality of life inventory
    5)Safety and tolerability
    B)To identify factors that predict the success rate defined as eucortisolemia achievement at 12 weeks. Parameters for identifying these factors will include age, gender, mean baseline UFC and cause of CS.
    C) To assess the effects of long-term MTP treatment on efficacy and safety parameters (up to 36 weeks of treatment)
    A) Valorar los efectos de la metirapona tras 12 semanas de tratamiento sobre:
    1) Niveles de cortisol en saliva y suero
    2) Parámetros hormonales y bioquímicos que están asociados al síndrome de Cushing o representan medidas de seguridad
    3) Signos clínicos del síndrome de Cushing
    4) Calidad de vida, valorada según el cuestionario sobre calidad de vida de Cushing (Cushing QoL) y test de calidad de vida de la enfermedad de Cushing de Tuebingen
    5) Seguridad y tolerabilidad
    B) Identificar factores que predigan la tasa de éxito, definida como logro de eucortisolemia a las 12 semanas. Entre los parámetros para identificar estos factores se incluirán la edad, el sexo, el CLO medio inicial y la causa del SC.
    C) Valorar los efectos del tratamiento con MTP a largo plazo sobre los parámetros de eficacia y seguridad (hasta 36 semanas de tratamiento).
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Any men and women ? 18 years
    2.Patients with endogenous Cushing?s syndrome for whom the following criteria apply:
    ?Newly diagnosed Cushing?s disease patients who are unsuitable for early surgery or wish to defer surgery;
    ?Or recurrent or persistent Cushing?s disease after pituitary surgery;
    ?Or patients with ectopic ACTH syndrome either occult or after surgery failure or inoperable or metastatic;
    ?Or patients with Cushing?s syndrome from adrenal causes who are unsuitable for early surgery or wish to defer surgery;
    3.For patients receiving previous medical therapy, the following wash-out periods should be completed:
    ?Steroidogenesis inhibitors excluding mitotane (e.g. ketoconazole), 1 week
    ?Dopamine agonists (bromocriptine, cabergoline), 4 weeks
    ?Pasireotide S/C, 1 week
    ?Pasireotide LAR (formulated for once-monthly dosing), 12 weeks
    ?Mifepristone, 4 weeks
    4.UFC ? 1.5-fold ULN on each of the three 24-hour urinary sampling measurements (after previous treatment withdrawal if applicable or in non-treated patients) provided that the diagnosis of Cushing?s syndrome has been confirmed. Urine collections for UFC measurements will be done within 2 to 5 weeks of the baseline visit.
    5.Female patients should not be at risk of pregnancy (could be included if sterilized, post-menopausal, sexually inactive or using methods of contraception throughout the study)
    6.Able and willing to give voluntary, written informed consent to participate in the study
    7.Agree to observe all study requirements and be available for all planned study visits
    1. Cualquier hombre y mujer ? 18 años
    2. Pacientes con síndrome de Cushing endógeno que cumplan alguno de los siguientes criterios:
    ? Pacientes con diagnóstico reciente de enfermedad de Cushing que no puedan someterse a cirugía temprana o prefieran evitarla
    ? Enfermedad de Cushing recidiva o persistente tras cirugía de hipófisis
    ? Pacientes con síndrome de ACTH ectópico inadvertido, en los que la cirugía no haya funcionado, que no se puedan operar o que sufran metástasis
    ? Pacientes con síndrome de Cushing debido a causas suprarrenales que no puedan someterse a cirugía temprana o prefieran evitarla
    3. En el caso de los pacientes que estén recibiendo un tratamiento médico anterior, deberán respetarse los siguientes períodos de reposo farmacológico:
    ? Inhibidores de la esteroidogénesis, con la excepción de mitotano (por ejemplo, ketoconazol), 1 semana
    ? Agonistas de la dopamina (bromocriptina, cabergolina), 4 semanas
    ? Pasireotida SC, 1 semana
    ? Pasireotida de acción prolongada (formulada para una dosis mensual), 12 semanas
    ? Mifepristona, 4 semanas
    4. CLO ? 1,5 veces el LSN en cada una de las medidas de las tres muestras de orina de 24 horas (tras retirada del tratamiento anterior si procede o en pacientes no tratados), siempre que se haya confirmado el diagnóstico de síndrome de Cushing. La toma de muestras de orina para medir el CLO se llevará a cabo entre 2 y 5 semanas después de la visita inicial.
    5. Las pacientes no deben estar en riesgo de embarazo (pueden incluirse si están esterilizadas, ya han pasado la menopausia, son sexualmente inactivas o usan métodos anticonceptivos durante todo el estudio).
    6. Capaces y dispuestos a dar su consentimiento informado voluntario y por escrito para participar en el estudio.
    7. Dispuestos a cumplir todos los requisitos del estudio y disponibles para todas las visitas del estudio previstas.
    E.4Principal exclusion criteria
    1.Pseudo Cushing?s syndrome
    2.Cyclic Cushing?s syndrome defined by at least one normal UFC value among at least three 24-hour urinary sampling measurements over the previous 2 months
    3.Advanced adrenocortical carcinoma or ectopic ACTH secretion (EAS) secondary to a small cell lung carcinoma
    4. Life expectancy less than 3 months
    5. Pituitary or adrenal surgery or pituitary irradiation or surgery of the ACTH-secreting ectopic tumor or bilateral adrenalectomy planned before the week 12 visit
    6.Pituitary irradiation within the previous 5 years (for Cushing?s disease patients)
    7. Enlarged pituitary adenoma (greater than 1 cm in vertical diameter and leaving less than 2 mm from the chiasma) or compression of the optic chiasma on the pituitary MRI for patients with Cushing?s disease
    8. Severe uncontrolled hypertension (>180/110 mmHg) despite anti-hypertensive therapy (for otherwise eligible patients, blood pressure medication may be adjusted to meet this criterion)
    9. Severe hypokalemia (< 2.5 mmol/L) despite corrective measures
    10. White blood cell counts <3 milliard /L; hemoglobin <10 g/dL; platelets <100 milliard/L
    11. Any other severe acute or chronic medical or psychiatric condition, or laboratory abnormality that in the judgment of the investigator, would present excess risk associated with study participation or study drug administration, or which, in the judgment of the investigator, would make the patient inappropriate for entry into this study.
    12. Pregnant or positive pregnancy test at entrance or breast-feeding women
    13. Current alcohol or drug abuse
    14. Acute or chronic severe uncontrolled infections
    15. Known hypersensitivity to metyrapone or to any of its excipients namely glycerol, disodium edentate, sodium hydroxide and phosphoric acid
    16.Patients who received mitotane (Lysodren??) at any time during the last 6 months or with mitotane plasma concentration > 3 mg/L
    17.Participation in another treatment study or receiving any investigational treatment (drug, biological agent or device) within 30 days
    18.Prohibited treatments
    1. Pseudosíndrome de Cushing
    2. Síndrome de Cushing cíclico, definido por al menos un valor de CLO normal entre, como mínimo, tres medidas de muestras de orina de 24 horas a lo largo de los 2 meses anteriores
    3. Carcinoma adrenocortical avanzado o secreción ectópica de ACTH (SEA) secundaria a un carcinoma de pulmón de células pequeñas
    4. Expectativa de vida inferior a 3 meses
    5. Cirugía hipofisaria o suprarrenal, radiación hipofisaria, cirugía del tumor ectópico que secreta ACTH o extirpación bilateral de la glándula suprarrenal previstas para antes de la visita de la semana 12
    6. Radiación de la hipófisis en los 5 años anteriores (para pacientes con enfermedad de Cushing)
    7. Adenoma de hipófisis agrandado (mayor que 1 cm de diámetro vertical y con menos de 2 mm desde el quiasma) o compresión del quiasma óptico en RMN de hipófisis para pacientes con enfermedad de Cushing
    8. Hipertensión incontrolada grave (>180/110 mmHg) a pesar del tratamiento antihipertensivo (para pacientes que sean aptos según el resto de criterios, puede ajustarse la medicación para la tensión arterial a fin de satisfacer este)
    9. Hipocaliemia grave (< 2,5 mmol/l) a pesar de las medidas correctivas
    10. Recuento de leucocitos < 3 x 109/l; hemoglobina < 10 g/dl; plaquetas < 100 x 109/l
    11. Cualquier otra afección médica o psiquiátrica aguda o crónica o anomalía clínica que, a juicio del investigador, supondría un riesgo excesivo asociado a la participación en el estudio o a la administración del fármaco en estudio o que, a juicio del investigador, haría que la participación del paciente en el estudio resultara inapropiada
    12. Mujeres embarazadas, con prueba de embarazo positiva en el momento de la incorporación, o lactantes
    13. Abuso actual de alcohol o drogas
    14. Infecciones graves sin controlar agudas o crónicas
    15. Hipersensibilidad conocida a la metirapona o a cualquiera de sus excipientes, a saber: glicerol, edetato disódico, hidróxido de sodio y ácido fosfórico
    16. Pacientes que hayan recibido mitotano (Lysodren®) en cualquier momento durante los últimos 6 meses o con una concentración en plasma de mitotano > 3 mg/l
    17. Participación en otro estudio de tratamiento o recepción de un tratamiento en fase de investigación (fármaco, agente biológico o dispositivo) en los 30 días anteriores
    18. Tratamientos prohibidos (véase la sección 6.2.1 Tratamientos prohibidos)
    E.5 End points
    E.5.1Primary end point(s)
    mean 24-hour UFC
    Cortisol Libre en Orina (CLO) medio en 24 horas
    E.5.1.1Timepoint(s) of evaluation of this end point
    after 12 weeks of treatment
    después de 12 semanas de tratamiento
    E.5.2Secondary end point(s)
    Morning serum cortisol (except for women taking an estrogen-containing oral contraceptive), salivary cortisol day curve, laboratory tests (fasting glucose, fasting insulin levels, Oral Glucose Tolerance Test (OGTT), Insulin Sensitivity Index (ISI), HbA1c, lipids, blood pressure, clinical signs of Cushing?s syndrome and the results of the quality of life questionnaires. The dosage of treatments for hypertension, diabetes and hypokalemia will be recorded and assessed for efficacy evaluation.
    El cortisol en suero matinal (excepto en el caso de mujeres que estén tomando un anticonceptivo oral que contenga estrógenos), curva diaria de cortisol en saliva, pruebas de laboratorio (glucosa en ayunas, niveles de insulina en ayunas, prueba de tolerancia a la glucosa oral [PTGO], índice de sensibilidad a la insulina [ISI], Hbg A1C, lípidos), tensión arterial, signos clínicos del síndrome de Cushing y resultados de los cuestionarios sobre calidad de vida. La dosificación de tratamientos para la hipertensión, diabetes e hipocaliemia se registrará y valorará para evaluar su eficacia.
    E.5.2.1Timepoint(s) of evaluation of this end point
    after 36 weeks of treatment
    después de 36 semanas de 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 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 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 No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial1
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA27
    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
    Belgium
    Germany
    Italy
    Poland
    Spain
    Sweden
    Switzerland
    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
    LVLS: Q1 2018
    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: 65
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 5
    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 state8
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 42
    F.4.2.2In the whole clinical trial 70
    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)
    At the end of the treatment period, the investigator will assess the patient?s state of health and propose the subsequent optimal patient? management.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2015-02-23
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-02-18
    P. End of Trial
    P.End of Trial StatusCompleted
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