ECE2018 Poster Presentations: Pituitary and Neuroendocrinology Pituitary - Clinical (101 abstracts)
PROMPT: a prospective study to assess efficacy and safety of metyrapone in endogenous Cushing’s syndrome
Lynnette Nieman 1 , Baris Akinci 2 , Albert Beckers 3 , Marek Bolanowski 4 , Felicia Alexandra Hanzu 5 , Emese Mezösi 6 , Anke Tönjes 7 , Martine Bostnavaron 8 , Amélie Jaspart 8 , Pascale Borensztein 8 , Marco Boscaro 9 & Carla Scaroni 9
1NICHD, Bethesda, MD, USA; 2Dokuz Eylul University Medical Faculty, Izmir, Turkey; 3CHU of Liége, Liége, Belgium; 4Samodzielny publiczny hospital and clinic, Wrocław, Poland; 5Hospital clinic, Barcelona, Spain; 6University of Pecs, Pecs, Hungary; 7Universitätsklinikum Leipzig, Leipzig, Georgia; 8HRA-Pharma, Paris, France; 9University of Padova, Padova, Italy.
Introduction: Metyrapone blocks cortisol production by inhibiting 11ß-hydroxylation of 11-deoxycortisol, the last step of cortisol synthesis. Based on observational retrospective studies published over more than 50 years metyrapone is approved for the treatment of endogenous Cushing’s syndrome (CS) in 14 European countries. PROMPT is the first prospective study to document the safety and efficacy of metyrapone using modern assay techniques.
Design and inclusion criteria: This is a single arm, open-label, multicenter, international trial. Adult patients with a new diagnosis of endogenous CS of any etiology (except advanced adrenal carcinoma) or recurrent or persistent Cushing’s disease (CD) after transsphenoidal surgery (TSS), are eligible if three baseline 24 h Urinary Free Cortisol (UFC) values are at least 50% above the upper limit of normal (ULN=165 nmol/24 h). Metyrapone given three or four times daily is titrated over 12 weeks to achieve normal urine and serum cortisol levels. After 12 weeks, patients whose mean value of 3 UFCs (mUFC) is less than 2-fold the ULN, may continue to receive metyrapone for another 24 weeks. Cortisol is measured in a central laboratory by LC-MS/MS.
Objectives: The primary objective is to assess the efficacy of metyrapone to normalise mUFC after 12 weeks of treatment. Secondary objectives are: assessment of the efficacy of metyrapone to normalise serum and salivary cortisol after 12 weeks and UFC after 24 weeks; assessment of changes in clinical symptoms of CS, blood pressure, quality of life (CushingQoL and Tuebingen CD QoL inventory); assessment of tolerance including adverse events and Ferriman-Gallwey score of hirsutism in women. The impact of metyrapone blockade on circulating lipids, glucose, ACTH, 11-deoxycortisol, deoxycorticosterone, renin/renin activity, androstenedione, DHEA-S and total testosterone levels is assessed. Time to 50% reduction of UFC, eucortisolemia, clinical and biochemical improvements, will be estimated. Exploratory objectives include factors predicting success and response relationships.
Status: The study started in 2015 and is ongoing in Belgium, Germany, Spain, Italy, Hungary, Poland and Turkey. To date 32 patients were included: 22 women and 10 men, with a mean age of 45 years old [21–73]; 29 have Cushing’s disease (20 had previous TSS, range [1–3]). Fifteen completed the 9 months therapy period. Nine patients stopped study at/or after the primary objective endpoint: 2 for inefficacy, 1 because mUFC was >2xULN despite improvement by 70%, 1 for hirsutism, 1 for SAE (severe hypotension, cellulitis, venous thrombosis, and renal insufficiency) and 4 underwent TSS.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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