Cushing’s Syndrome MedDRA version: 20.1 Level: PT Classification code 10035109 Term: Pituitary-dependent Cushing's syndrome System Organ Class: 10014698 - Endocrine disorders
Conditions
Interventions
Product Name: SPI-62
Product Code: SPI-62
Pharmaceutical Form: Tablet
INN or Proposed INN: Not applicable
CAS Number: 1204178-50-6
Current Sponsor code: SPI-62
Other descriptive name: 11-ß-hydroxyster
Sponsors
Sparrow Pharmaceuticals, Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Male or female aged 18 years or older. 2. Able to provide written informed consent. 3. Active and consistent cortisol excess: This is defined as UFC > upper limit of normal (ULN) based on at least 2 valid (i.e., complete) 24-hour urine samples collected during Screening. The subject will be provided collection devices for three 24-hour collections to ensure 2 complete collections are received, particularly if a subject requires washout of other cortisol-suppressing agents. If more than 2 valid collections are received; the mean of all valid completed collections collected after completion of the washout period (if applicable), and available at Day 1 must be >ULN, as confirmed by the central laboratory. Should an additional, otherwise disqualifying, UFC value become available only after Day 1 randomization, the subject will be allowed to continue planned treatment and a sensitivity, per-protocol analysis will be conducted. 4. Documented diagnosis of ACTH-dependent Cushing’s syndrome: This includes Cushing’s disease, ectopic ACTH secretion, and ectopic CRH secretion. Subjects may include newly diagnosed subjects who have declined or are not considered candidates for surgery or subjects with residual or recurrent disease after surgery in whom surgery or radiation are not planned within the next 6 months. Previous medical records will be used to support the diagnosis. At least 1 of the following will be considered satisfactory to establish the diagnosis: a. History of positive ACTH-staining pathology. b. History of documented, transient, AI after tumor removal requiring glucocorticoid replacement. c. ACTH level > 20 pg/mL with positive ACTH or cortisol response to CRH or desmopressin (DDAVP) stimulation in the presence of hypercortisolemia. d. Inferior petrosal sinus sampling with ACTH central: plasma gradient = 2 before CRH or DDAVP or = 3 after CRH or DDAVP. e. Presumptive Cushing’s disease based on presence of a pituitary tumor = 6 mm along with positive ACTH or cortisol response to CRH or DDAVP stimulation or an overnight or high-dose (8 mg) dexamethasone suppression of cortisol, performed and interpreted according to locally recognized standards of diagnosis f. In the absence of any of the above, an individual might be eligible if ectopic ACTH-dependent Cushing’s syndrome was otherwise confirmed via adequate testing consistent with the local standards of care. Such cases must be discussed with and explicitly approved by the Medical Monitor and Sponsor, and the specific diagnostic criteria used to establish the diagnosis of ACTH-dependent Cushing’s syndrome must be documented. 5. Willing to comply with reproductive precautions: Females will not be pregnant or lactating, and females of childbearing potential and males will agree to use contraception as detailed in Appendix 4. 6. Current evidence of Cushing’s morbidities of hyperglycemia, dyslipidemia, hypertension, or osteopenia: Defined by having at least 1 of the below criteria, ideally including both or either of “a” and “b”, but including any of “a”, "b", "c" or "d". a. Diagnosis of insulin-resistance/pre-diabetes or type 2 diabetes: Including subjects on stable diabetic treatment, but excluding those ethically requiring further or frequent therapy adjustments. Type 2 diabetes is defined as a current HbA1c = 6.5% but = 9.5% (otherwise excluded), fasting blood glucose (FBG) > 126 mg/dL, or 2 hr OGTT = 200 mg/dL. Pre-diabetes is defined as current HbA1c 5.7%, F
Exclusion criteria
Exclusion criteria: 1. Recent or planned Cushing’s surgery: Surgery for Cushing’s within the past 6 weeks or planned within 24 weeks after randomization. 2. Use of medications for Cushing’s syndrome within the washout periods prior to randomization as described in Section 6.1. 3. Recent Cushing’s radiotherapy: Any fractionated radiation therapy for Cushing’s within the past 2 years, or conventional radiation therapy within 4 years. 4. History of bilateral adrenalectomy. 5. History of pseudo-Cushing’s syndrome. 6. History of cyclic Cushing’s syndrome. 7. Exogenous hypercortisolism or factitious Cushing’s syndrome. 8. History of non-ACTH-dependent hypercortisolism: This includes that caused by a known inherited syndrome (e.g., McCune Albright syndrome, Carney complex) but not including multiple endocrine neoplasia type 1 where diagnostic testing has led to a diagnosis of Cushing’s disease (79%) while excluding autonomous adrenal Cushing’s syndrome (21%). 9. High risk of acute morbidity from corticotroph adenoma growth: (similar to that which occurs with Nelson’s syndrome) defined as: Current evidence of macroadenoma with, or at risk of, optic nerve or vital structure compression, e.g., tumor showing aggressive growth within 2 mm of optic chiasm or with evidence of blood-vessel encroachment. 10. Uncontrolled Cushing’s morbidities of hyperglycemia, dyslipidemia, hypertension, or osteopenia: Including evidence of chronic, poor glycemic control (HbA1c > 9.5%), symptomatic dyslipidemia (e.g., hypercholesterolemia with recent ( 180 mmHg or DBP > 120 mmHg), or recent ( 8 weeks] and without elevated thyroid-stimulating hormone. 13. Moderate or severe renal impairment: Defined by an estimated glomerular filtration rate (GFR) repeatedly 1.5 × ULN (unless previously diagnosed with benign Gilbert’s disease) or serum ALT or AST >3 × ULN. 15. Medically significant cardiovascular or ECG abnormalities: This includes subjects with recent ( 500 ms, or evidence of significant, life-threatening arrhythmia or bradycardia (HR < 45 bpm). 16. History of idiopathic thrombocytopenic purpura. 17. History of adrenal carcinoma. 18. Recent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection: Positive test for infection within the past 4 weeks or hospitalization for coronavirus disease 2019 (COVID-19) within the past 6 months. 19. History of cancer wi
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To characterize the pharmacologic effect of SPI-62 in subjects with ACTH-dependent Cushing’s syndrome including Cushing’s disease, ectopic ACTH secretion, and ectopic corticotrophin-releasing hormone (CRH) secretion, as measured using the urinary 11ß-hydroxysteroid dehydrogenase type 1 (HSD-1) ratio.;Secondary Objective: Secondary objectives of this study are: • To evaluate the safety of SPI-62 in subjects with ACTH-dependent Cushing’s syndrome, including changes on hypothalamic pituitary adrenal (HPA) and hypothalamic pituitary gonadal (HPG) axis biomarkers and associated adverse events (AEs). Exploratory objectives of this study are: • To estimate SPI-62’s effect on clinical parameters across Cushing’s features including: hyperglycemia, dyslipidemia, adiposity, hepatic steatosis, hypertension, glaucoma, mood, cognition, osteopenia, and muscle strength.;Primary end point(s): The urinary HSD-1 ratio ([tetrahydrocortisol + allotetrahydrocortisol]/tetrahydrocortisone) at Week 6 in subjects with Cushing’s disease.;Timepoint(s) of evaluation of this end point: - at Week 6 | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Safety - Adverse events, including clinically significant abnormal values on clinical laboratory evaluations (clinical chemistry, hematology, and urinalysis), continuous glucose monitoring (CGM), 12-lead ECGs, vital signs measurements (including orthostatic vital sign measurements), physical examinations, and clinically significant changes from baseline for HPA and HPG axis biomarkers (ACTH, serum cortisol, free cortisol, cortisone, arginine vasopressin [AVP], testosterone, estradiol, dehydroepiandrosterone [DHEA], DHEA sulfate [DHEA-S], androstenedione, aldosterone, renin, follicle-stimulating hormone [FSH], luteinizing hormone [LH], sex hormone binding globulin [SHBG], progesterone) or HSD-2 ratio will be reported. - Clinical laboratory evaluations, ECG intervals, pulse, temperature, and HPA and HPG axis biomarkers at Week 6, as well as changes from baseline during 12 weeks of SPI-62 administration, will be described. Exploratory endpoints - Glucose AUC during oral glucose tolerance test (OGTT) and OGTTCGM, average glucose, time > 140 and > 200 mg/dL by CGM, HbA1c, insulin, fasting plasma glucose, body weight, body mass index, dual energy x-ray absorptiometry (DEXA) scan results (body fat and muscle content [including total body, trunk, abdominal, head/neck and hepatic fat content], bone-mineral density [T- and Z-scores] and trabecular bone score), bone markers [osteocalcin, procollagen I N-terminal peptide (PINP)], systolic and diastolic blood pressure [DBP], intraocular pressure (IOP), total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglycerides, and coagulation parameters (prothrombin time ([PT]and activated partial thromboplastin time [aPTT]) at Week 6, as well as change from baseline during 6 and 12 weeks of SPI-62 administration, will be described. - Performance on muscle strength (Timed Up and Go-Chair Stand [TUG-CS], hand grip strength [HGS] tests), and scores on Symptoms of Major Depressive Disord | — |
Countries
Bulgaria, Romania, United States
Contacts
Public ContactFrank Czerwiec
Sparrow Pharmaceuticals, Inc.
Outcome results
None listed