endogenous Cushing’s syndrome MedDRA version: 20.0 Level: SOC Classification code 10014698 Term: Endocrine disorders System Organ Class: 10014698 - Endocrine disorders
Conditions
Interventions
Product Name: ATR-101
Pharmaceutical Form: Tablet
INN or Proposed INN: Nevanimibe hydrochloride
CAS Number: 133825-81-7
Current Sponsor
CI-984
Concentration unit: mg milligram(s)
Concentration type: range
Concentration number: 250-500
Pharmaceutical form of the placebo: T
Sponsors
Millendo Therapeutics, Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Provision of signed and dated informed consent prior to any study-specific procedures 2. Men and women 18-80 years of age (inclusive) at screening 3. Subjects must have a confirmed diagnosis of endogenous Cushing’s syndrome as evidenced by baseline UFC 1.3 to 10 × ULN (mean of all 24-hr UFC levels obtained during the screening period within 28 days of enrolment into the open-label dose-escalation period) AND documentation at any time of ONE of the following three criteria: • For subjects with a diagnosis of pituitary Cushing’s syndrome, either: - Magnetic resonance imaging (MRI) confirmation of pituitary adenoma (greater than or equal to 0.6 cm), OR - For subjects with a pituitary microadenoma less than 0.6 cm, bilateral inferior petrosal sinus sampling (BIPSS) showing an ACTH gradient > 2 before or > 3 after corticotropin-releasing hormone (CRH) or desmopressin (DDAVP) stimulation, OR - For subjects who have had prior pituitary surgery: histopathology confirming an ACTH-staining adenoma • For subjects with a diagnosis of adrenal Cushing’s syndrome: MRI or computed tomography (CT) of the adrenal glands showing an adrenal tumor • For subjects with a diagnosis of ectopic ACTH as the cause of their Cushing’s syndrome: ACTH-dependent Cushing’s syndrome and either: - MRI showing no pituitary adenoma, OR - MRI showing only a small pituitary adenoma ( 2 years OR must have been permanently surgically sterilized (bilateral salpingectomy or tubal occlusion) > 2 years OR male partner(s) has had a vasectomy > 2 years OR must consent to use two permitted medically-acceptable methods of contraception throughout the study during any sexual intercourse with a male partner. Permitted medically-acceptable methods of birth control for this study include oral contraceptives, contraceptive implants, Depo-Provera®, contraceptive patch, vaginal ring, male condom, female condom, spermicide, diaphragm with spermicide, cervical cap with spermicide, contraceptive sponge, or an intrauterine device (IUD) that does not contain steroid hormones; IUDs must have been in place for at least 28 days prior to first dose of study drug. 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 12 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 4
Exclusion criteria
Exclusion criteria: 1. Pseudo-Cushing’s syndrome, cyclic Cushing’s syndrome or current iatrogenic Cushing’s syndrome 2. Subjects who are considered candidates for surgical treatment of Cushing’s syndrome, unless it is clearly documented that the subject has refused such surgery or that surgery cannot be scheduled for at least the anticipated duration of the study 3. Normal late night salivary cortisol value during screening, unless the subject’s history clearly demonstrates that he or she does not have pseudo-Cushing’s or cyclic Cushing’s. If the subject has a normal late night salivary cortisol, and the PI feels the subject does not have pseudo-Cushing’s or cyclic Cushing’s, the subject may be enrolled with approval of the medical monitor 4. Normal 24-hr UFC during screening (this would be suggestive of cyclic Cushing’s) 5. Radiotherapy of the pituitary within 6 months prior to or during screening 6. For subjects with pituitary Cushing’s syndrome, any compression of the optic chiasm or the presence of a tumor within 2 mm of the optic chiasm on the most recent pituitary MRI prior to or during screening 7. Use of or medical requirement for any of the following medications within the timeframes specified below prior to collection of the first 24-hr UFC during Screening and throughout study participation: • Inhibitors of steroidogenesis (ketoconazole, metyrapone): 1 week • Pituitary-directed agents: Dopamine agonists (bromocriptine, cabergoline) and PPAR? agonists (rosiglitazone or pioglitazone): 4 weeks • Octreotide LAR, Lanreotide SR and Lanreotide autogel: 14 weeks • Octreotide (immediate release formulation): 1 week • Pasireotide: 4 weeks • Mitotane: 26 weeks • Mifepristone: 3 weeks 8. Uncontrolled diabetes mellitus, as evidenced by HbA1c > 9.0% at screening 9. Uncontrolled hypertension, defined as systolic blood pressure > 160 mmHg or diastolic blood pressure > 90 mmHg during screening. Note: if appropriate, subjects may have blood pressure medications adjusted and blood pressure reassessed at an unscheduled visit prior to Visit T1. 10. Any history of gastric or small intestinal surgery or any current disease that causes malabsorption. Note: irritable bowel syndrome is acceptable for inclusion 11. Alcohol or substance abuse (cocaine, amphetamines and/or opioids) within the year prior to screening 12. Abnormal laboratory values as per the guidelines listed below or any other clinically significant, unexplained laboratory abnormality according to the Investigator: Serum ALT or AST > 3 × ULN • Serum total bilirubin > 1.5 × ULN • Serum creatinine > 1.5 × ULN • Glomerular filtration rate 470 msec on electrocardiogram at screening (subjects with a single QTc > 470 msec may have 2 additional ECGs taken during screening and the QTcs averaged; if the average QTc is > 470 msec then the subject is excluded) 15. Known
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To evaluate the efficacy and safety of orally-administered ATR-101 in adults with endogenous Cushing’s syndrome; Secondary Objective: • To evaluate the changes in adrenal steroids and adrenal steroid intermediates • To evaluate the change in adrenocorticotropic (ACTH) • To evaluate the change in metabolic syndrome-related parameters, including fasting glucose, insulin, lipid panel, blood pressure and body mass index (BMI) • To assess the safety and tolerability of ATR-101 • To determine the pharmacokinetics (PK) of ATR-101 and its major metabolites • To evaluate the PK/pharmacodynamic (PD) relationships of ATR-101 ;Primary end point(s): The proportion of subjects with either a normal 24-hr UFC or a reduction in 24-hr UFC of = 50% relative to their baseline value at the end of the double-blind randomized withdrawal period;Timepoint(s) of evaluation of this end point: Baseline to End of Treatment | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): • The proportion of subjects with a normal 24-hr UFC at the end of the double-blind randomized withdrawal period • The proportion of subjects with a reduction in 24-hr UFC of = 50% relative to their baseline value at the end of the double-blind randomized withdrawal period • The proportion of subjects with a normal 24-hr UFC at the end of the open-label dose-escalation period and at the end of the additional open-label dosing period • The proportion of subjects with a reduction in 24-hr UFC of = 50% relative to their baseline value at the end of the open-label dose-escalation period and at the end of the additional open-label dosing period • The change and percentage change in the 24-hr UFC from randomization at the end of the double-blind randomized withdrawal period • The change and percentage change in the 24-hr UFC from baseline at the end of the open-label dose-escalation period and at the end of the additional open-label dosing period • The proportion of subjects with a normal late night salivary cortisol at the end of the double-blind randomized withdrawal period • The proportion of subjects with a normal late night salivary cortisol at the end of the open-label dose-escalation period and at the end of the additional open-label dosing period • The change and percentage change in the late night salivary cortisol from randomization at the end of the double-blind randomized withdrawal period • The change and percentage change in the late night salivary cortisol from baseline at the end of the open-label dose-escalation period and at the end of the additional open-label dosing period • The change and percentage change from baseline in blood hormone levels, including 11-DOC, 17-OHP, A, A4, ACTH, cortisol, DHEA, DHEAS, free T, P, renin, SHBG and total T • Th | — |
Countries
United Kingdom, United States
Contacts
Public ContactClinical Trials Information
Medpace
Outcome results
None listed