Study of SPI-62 in Patients with Adrenocorticotropic Hormone-dependent Cushing’s Syndrome

Phase 1

• Conditions: Cushing’s Syndrome; MedDRA version: 20.1Level: PTClassification code 10035109Term: Pituitary-dependent Cushing's syndromeSystem Organ Class: 10014698 - Endocrine disorders; Therapeutic area: Diseases [C] - Hormonal diseases [C19]

• Registration Number: EUCTR2021-006184-19-BG
• Lead Sponsor: Sparrow Pharmaceuticals, Inc.

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2022-05-31
• Last Update Posted: 23 October 2023

Recruitment & Eligibility

• Status: Authorised-recruitment may be ongoing or finished
• Sex: All
• Target Recruitment: 26

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 < 6.5 but > 5.7%, F

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 (< 1 year) cerebro- or cardiovascular events, hypertriglyceridemia with pancreatitis), persistent uncontrolled hypertension (systolic blood
pressure > 180 mmHg or DBP > 120 mmHg), or recent (< 1 year) osteoporotic fracture ethically requiring additional medical intervention.
11. Use of drugs likely to interfere with study assessments:
These include chronic systemic corticosteroids, thiazolidinediones, 5-alpha-reductase inhibitors,
certain drugs that affect cognitive testing (e.g., oxybutynin or opioids) within 12 weeks prior to the first dose of study drug. See concomitant medications section for recommendations regarding use of certain other allowed medications.
12. Uncontrolled hypothyroidism or hyperthyroidism:
Free thyroxine should be in normal range and stable, whether endogenous or on levothyroxine replacement [> 8 weeks] and without elevated thyroid-stimulating hormone.
13. Moderate or severe renal impairment: Defined by an estimated glomerular filtration rate (GFR) repeatedly < 60 mL/min/1.73 m2 or confirmed by measured GFR < 60 mL/min/1.73 m2.
14. Medically significant liver disease Including cirrhosis, chronic active hepatitis, chronic persistent hepatitis, or subjects with serum total bilirubin > 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 (< 1 year) myocardial infarction or stroke, orthostatic or vasovagal syncope, QT interval corrected (QTc) intervals > 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

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified