E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Treatment of Cushing?s syndrome |
Tratmiento del Sindrome de Cushing |
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E.1.1.1 | Medical condition in easily understood language |
Treatment of Cushing?s syndrome which is a rare disorders characterized by a chronic hypercortisolism. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Hormonal diseases [C19] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 17.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10011652 |
E.1.2 | Term | Cushing's syndrome |
E.1.2 | System Organ Class | 10014698 - Endocrine disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main 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. |
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E.2.2 | Secondary 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). |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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. |
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E.4 | Principal 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) |
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E.5 End points |
E.5.1 | Primary end point(s) |
mean 24-hour UFC |
Cortisol Libre en Orina (CLO) medio en 24 horas |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
after 12 weeks of treatment |
después de 12 semanas de tratamiento |
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E.5.2 | Secondary 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. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
after 36 weeks of treatment |
después de 36 semanas de tratamiento |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
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.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 27 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If 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 |
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E.8.7 | Trial 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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 3 |