Study to assess the effects of metyrapone in patients with Cushing’s syndrome during a 12-week treatment period

• Register: EUCTR
• Last refreshed on: 30 November 2020
• Main ID: EUCTR2014-000162-22-IT
• Date of registration: 25/11/2014
• Prospective Registration: Yes
• Primary sponsor: Laboratoire HRA Pharma
• Public title: Study to assess the effects of metyrapone in patients with Cushing’s syndrome during a 12-week treatment period
• Scientific title: 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. - PROMPT
• Date of first enrolment: 19/03/2015
• Target sample size: 70
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2014-000162-22
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no Randomised: no Open: yes Single blind: no Double blind: no Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: no Other: no Number of treatment arms in the trial: 1
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): yes

Countries of recruitment

Belgium, Germany, Hungary, Italy, Poland, Spain, Sweden, Switzerland, United States

Contacts

• Name: Olga Kroselj
• Affiliation: Laboratoire HRA Pharma

• Name: Olga Kroselj
• Affiliation: Laboratoire HRA Pharma

Key inclusion & exclusion criteria

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




Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 65
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 5

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


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Hormonal diseases [C19]

Treatment of Cushing’s syndrome
MedDRA version: 17.1 Level: PT Classification code 10011652 Term: Cushing's syndrome System Organ Class: 10014698 - Endocrine disorders

Intervention(s)

Trade Name: Metopirone 250 mg capsules/Cormeto
Product Name: metyrapone
Pharmaceutical Form: Capsule
INN or Proposed INN: METYRAPONE
CAS Number: 54-36-4
Concentration unit: mg milligram(s)
Concentration number: 250-

Primary Outcome(s)

Timepoint(s) of evaluation of this end point: after 12 weeks of treatment

Main Objective: 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).

Primary end point(s): mean 24-hour UFC

Secondary Objective: 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)

Secondary Outcome(s)

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.

Timepoint(s) of evaluation of this end point: after 36 weeks of treatment

Secondary ID(s)

116160

112025-002

2014-000162-22-DE

Source(s) of Monetary Support

Laboratoire HRA Pharma

Ethics review

Status: Approved
Approval date: 19/03/2015
Contact: