Cushing's disease in patients in whom pituitary surgery has not been curative or in situations where it is contraindicated or refused by patient. MedDRA version: 20.0 Level: LLT Classification code 10011651 Term: Cushing's disease System Organ Class: 100000004860
Conditions
Interventions
Trade Name: Dostinex
Product Name: Cabergolina
Product Code: [G02CB03]
Pharmaceutical Form: Tablet
INN or Proposed INN: CABERGOLINA
CAS Number: 81409-90-7
Current Sponsor code: OPR000000310
Other desc
Sponsors
Dipartimento di Medicina-DIMED, università di Padova
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Age> 18 years at the enrollment visit Diagnosis of Cushing's disease with at least one criterion between: · Immunohistochemistry positive for ACTH of the pituitary adenoma Center / periphery gradient> 3 for ACTH after CRH catheterization of the petrosal sinuses · At least two positive tests between CRH response (ACTH> 50% from baseline), suppression of cortisol after high doses of dexamethasone (> 80% from baseline), pituitary MRI with adenoma = 6mm; remission of hypercorticism after pituitary surgery . Biochemical hypercorticism before enrollment (mCLU> ULN) . Adequate performance status: ECOG = 2 . Verbal and written informed consent of the patient before any screening procedure · Patients who have already undergone transphenoidal surgery or patients who are not candidates for surgery . Failure of medical treatments currently available for Cushing's disease (failure to normalize urinary free cortisol values after at least 3 months of treatment with the maximum tolerated dose of the drug and / or persistence of signs and symptoms related to hypercortisolism) . Adequate contraception (see section 4.1.1) 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 60 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 8
Exclusion criteria
Exclusion criteria: - ACTH-independent Cushing's syndrome - Pituitary surgery in the last 2 months prior to enrollment - Radiotherapy in the previous 3 years - Genetic-related causes of Cushing's syndrome (Carney complex, McCune-Albright syndrome, MEN-1) - Major surgery in the month preceding the start of the study- Heart failure (NYHA class III or IV), unstable angina, severe arrhythmic syndrome, or clinically significant alteration of cardiovascular function - Heart failure (NYHA class III or IV), unstable angina, severe arrhythmic syndrome, or clinically significant alteration of cardiovascular function · Mitotane therapy in the year preceding the enrollment - Hepatopathy, such as cirrhosis, chronic active hepatitis or chronic hepatitis, or AST / ALT levels> 2 x ULN, creatininemia> 2 x ULN, bilirubinemia> 2 x ULN - White blood cell (WBCs) 470 mSec, hypokalemia, hypomagnesemia, family history of long QT syndrome) - Pregnancy or lactation period - Alcohol abuse or drug abuse - Any other recent or active neoplastic disease (with the exception of cutaneous basal cancer and in situ carcinoma of the cervix or other malignant neoplasms without evidence of disease in the last 3 years) - Acute infection or chronic uncontrolled infection - Ongoing therapy with antifibrinolytic agents, such as tranexamic acid, aminocaproic acid or aprotinin - Hypersensitivity to tretinoin or other retinoids, to cabergoline, ergot alkaloids, to soy, peanuts, fructose or to any of the excipients listed in section 6.1. of the RCP of the two IMPs - History of pulmonary, pericardial or retroperitoneal fibrosis, evidence of cardiac valvulopathy determined on the echocardiogram performed before treatment - Hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption - Raynaud's syndrome - History of peptic ulcer or previous gastrointestinal bleeding - History of serious mental disorders (especially if psychotic) - Patient judged to be potentially unreliable and/or uncooperative towards the procedures of the study or judged incapable of completing the entire study.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Evaluate the effectiveness of cabergoline (initial dosage of 1.5 mg/week) and retinoic acid (initial dosage of 20 mg/day) monotherapies after 3 months and their combination 6 months from baseline;Secondary Objective: 1. Evaluate the changes in urinary free cortisol with respect to baseline at each scheduled visit 2. Evaluate the effects on ACTH, serum cortisol and salivary in the two treatment groups compared to baseline 3. Assess the variation of continuous clinical variables in the two treatment arms compared to the baseline 4. To evaluate the effects on categorical clinical parameters in the two treatment groups at each visit 5. Evaluate the effects on quality of life in the two treatment groups 6. Evaluate the safety profile of each monotherapy treatment and their combination (CA + RA and RA + CA);Primary end point(s): Proportion of patients that urinary free cortisol values (mean of two values) evaluated after 3 months of treatment for monotherapy, and after 6 months of treatment for combined therapy.;Timepoint(s) of evaluation of this end point: after 3 and 6 months of treatment | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): 1. Absolute and percentage change in the mean CLU value with respect to baseline at each visit 2. Absolute and percentage changes in ACTH, serum cortisol and salivary at each visit compared to the baseline 3. Absolute and percentage variations of clinical (blood pressure, body mass index, waist circumference) and biochemical (total cholesterol, HDL, LDL, triglycerides, blood sugar, HbA1c, insulin) variables 4. Variation of clinical signs with respect to baseline: rubeosis, hirsutism, strie rubrae, muscle atrophy, supraclavicular fat 5. Change in Cushing QoL questionnaire score after 3 and 6 months of treatment 6. Toxicity will be assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE v.5) and by performing blood and instrumental tests (blood count, kidney and liver function, lipid and glycemic profile, echocardiogram);Timepoint(s) of evaluation of this end point: after 6 and 12 months of treatment | — |
Countries
Italy
Contacts
Public ContactSegreteria Dipartimento di Medicina
Dipartimento di Medicina-DIMED
Outcome results
None listed