E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Treatment of Cushing’s syndrome |
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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 | 20.0 |
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). |
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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)
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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 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
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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 count <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 with mitotane (Lysodren®) 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 |
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E.5 End points |
E.5.1 | Primary end point(s) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
after 12 weeks of treatment |
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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. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
after 36 weeks of treatment |
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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) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 40 |
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 |
Hungary |
Italy |
Poland |
Romania |
Spain |
Turkey |
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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 | 2 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 3 |
E.8.9.2 | In all countries concerned by the trial days | 0 |