Effects of Metyrapone in Patients With Endogenous Cushing's Syndrome

Phase 3

Completed

• Conditions: Cushing's Syndrome
• Interventions: Drug: metyrapone

• Registration Number: NCT02297945
• Lead Sponsor: HRA Pharma

Brief Summary

The purpose of this prospective, international phase III/IV study is to assess the efficacy and safety of metyrapone in patients with endogenous Cushing's syndrome during up to 36 weeks of treatment. The ability of metyrapone (250 mg capsules) to normalize urinary free cortisol (UFC) levels will be assessed during up to 36 weeks (9 months) of treatment.

Detailed Description

This study will include Cushing disease patients with persistent or recurrent disease (after pituitary surgery) or who are newly diagnosed but are unsuitable for early surgery or wish to defer surgery. It will also include patients with ectopic ACTH syndrome (either occult, after surgery failure, or inoperable or metastatic) and patients with Cushing's syndrome from adrenal causes.

The ability of metyrapone to normalize urinary free cortisol levels will be assessed during up to 36 weeks (9 months) of treatment. Patients participating in this study and who are controlled or close to the target at the end of a 3-months period may continue with an optional extension period of 6 months in which the long-term efficacy and safety profiles of metyrapone will be assessed. This extension study is intended to provide new findings to consolidate existing efficacy and safety data on metyrapone in the treatment of Cushing's syndrome.

Study Timeline

• Study First Submitted: 2014-11-19
• Study First Submitted QC: 2014-11-19
• Study First Posted: 2014-11-21
• Study Start: 2015-04
• Primary Completion: 2019-11
• Study Completion: 2020-04-29
• Status Verified: 2020-09
• Last Update Submitted: 2020-09-24
• Last Update Posted: 2020-09-25

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 50

Inclusion Criteria

1. Patients with endogenous Cushing's syndrome:

• Cushing disease patients with persistent or recurrent disease (after pituitary surgery) or who are newly diagnosed but are unsuitable for early surgery or wish to defer surgery;
• Patients with ectopic ACTH syndrome (either occult, after surgery failure, or inoperable or metastatic);
• Patients with Cushing's syndrome from adrenal causes

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 x 109 /L; hemoglobin <10 g/dL; platelets <100 x 109 /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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Metyrapone	metyrapone	Metyrapone will be administered orally in an open-label fashion. Two possible initiation doses will be used depending on the severity of hypercortisolism, dose will then be adjusted (up or down-titrated) during the first month on an individual basis according to clinical tolerance and cortisol levels achieved.

Primary Outcome Measures

Name	Time	Method
Normalization of cortisol levels (urinary free cortisol)	3 months

Trial Locations

Locations (36)

CHU Erasme; 🇧🇪 Brussels, Belgium

Spitalul Universitar de Urgenta Militar Central 'Dr Carol Davila'; 🇷🇴 Bucharest, Romania

Spitalul Clinic Judetean de Urgenta Sibiu; 🇷🇴 Sibiu, Romania

Spitalul Clinic Judetean de Urgenta Cluj-Napoca; 🇷🇴 Cluj-Napoca, Romania

S.C Centrul Clinic Mediquest SRL; 🇷🇴 Sângeorgiu De Mureş, Romania

Spitalul Clinic Judetean Mures; 🇷🇴 Târgu-Mureş, Romania

Munich university; 🇩🇪 Munich, Germany

University hospital Wuerzburg; 🇩🇪 Wuerzburg, Germany

Charité Berlin; 🇩🇪 Berlin, Germany

University of Pecs; 🇭🇺 Pecs, Hungary

San Luigi Gonzaga Hospital, University of Turin; 🇮🇹 Orbassano, Turin, Italy

Ospedale San Luca IRCCS Istituto Auxologico Italiano; 🇮🇹 Milan, Italy

Ondokuz Mayıs University Medical Faculty; 🇹🇷 Samsun, Turkey

Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology; 🇵🇱 Gliwice, Poland

Institutul National de Endocrinologie 'C.I Parhon' - Endocrinologie VI; 🇷🇴 Bucharest, Romania

University hospital clinic of Barcelona; 🇪🇸 Barcelona, Spain

University of Padova; 🇮🇹 Padova, Italy

University Debrecen; 🇭🇺 Debrecen, Hungary

University of Turin; 🇮🇹 Turin, Italy

University of Szeged; 🇭🇺 Szeged, Hungary

Institutul National de Endocrinologie 'C.I Parhon' - Endocrinologie II; 🇷🇴 Bucharest, Romania

Federico II University; 🇮🇹 Naples, Italy

Dokuz Eylul UMF; 🇹🇷 Izmir, Turkey

Hospital Universitario La Ribera; 🇪🇸 Valencia, Spain

University Hospital; 🇵🇱 Krakow, Poland

University Clinical Hospital; 🇵🇱 Wrocław, Poland

Ankara Numune Training and Research Hospital; 🇹🇷 Ankara, Turkey

Karadeniz Teknik University; 🇹🇷 Trabzon, Turkey

University hospital Antwerp; 🇧🇪 Antwerp, Belgium

University hospital Saint Luc; 🇧🇪 Brussels, Belgium

CHU Liège; 🇧🇪 Liege, Belgium

Universitätsklinikum Essen; 🇩🇪 Essen, Germany

State health center; 🇭🇺 Budapest, Hungary

Semmelweis Egyetem II. Belgyógyászati Klinika; 🇭🇺 Budapest, Hungary

Grande Ospedale Metropolitano Niguarda; 🇮🇹 Milan, Italy

S. Giuseppe Hospital; 🇮🇹 Milan, Italy