| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
| Cushing’s syndrome is a condition caused by production of excess amounts of cortisol, a hormone produced by the adrenal glands in the body. |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Hormonal diseases [C19] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10035109 |
| E.1.2 | Term | Pituitary-dependent Cushing's syndrome |
| E.1.2 | System Organ Class | 10014698 - Endocrine disorders |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| 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 11β-hydroxysteroid dehydrogenase type 1 (HSD-1) ratio. |
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| E.2.2 | Secondary objectives of the trial |
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. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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%, FBG > 100 to 125 mg/dL, or 2-hour OGTT 140 to 199 mg/dL. Insulin-resistance may also be defined by abnormal HOMA-IR >2.5 or by CGM data (e.g., mean glucose, glycemic variability, time in range, estimated HbA1c)²⁸
b. Diagnosis of dyslipidemia:
This is evidenced by history of total cholesterol level of ≥ 6.2 mmol/L (240 mg/dL) or triglycerides of ≥ 5.2 mmol/L (200 mg/dL) Current total cholesterol may be < 6.2 mmol/L, and current triglycerides may be < 5.2 mmol/L, if controlled with allowed lipid-lowering therapy.
c. Diagnosis of hypertension:
Incident hypertension should be brought under control and stabilized prior to randomization at Day 1. Subjects with hypertension which is reasonably, but sub-optimally managed by standard therapy at baseline (systolic blood pressure [SBP] >140 but < 180 or DBP > 90 but < 120 mmHg) qualify.
d. Diagnosis of osteoporosis or osteopenia: Osteopenia (T-score ≤ -1.0 or Z-score ≤ -2.0) or osteoporosis as determined previously, during by the site’s local Baseline DEXA reading or history or evidence of minimal-traumatic or osteoporotic fracture treated with lifestyle modification with mineral or vitamin supplementation or stable approved osteoporosis therapies. |
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| E.4 | Principal 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 within 3 years other than ectopic ACTH from an unidentified source, non-melanoma skin cancer, thyroid cancer, or early-stage prostate cancer. If stable and requiring hormone-suppressive therapy, subjects with prostate cancer may be included at Medical Monitor discretion, however their data may be excluded in assessment of SPI-62 effects on HPA and HPG axes).
20. Any major surgery, or significant post-operative sequelae, within 1 month prior to informed consent or planned during the trial.
21. Pregnant, lactating, or planning fertility in the next 6 months and unwilling to adhere to approved contraceptive use or abstinence.
22. Participation in any clinical trial within 1 month prior to informed consent (or longer for biologic and long-lasting experimental therapies).
23. Receipt of blood products within 2 months prior to Screening.
24. Donation of blood from 3 months prior to Screening, plasma from 2 weeks prior to Screening, or platelets from 6 weeks prior to Screening. Subjects are not to donate blood, plasma, or platelets during the study.
25. Poor peripheral venous access.
26. Any other current or prior medical condition expected to interfere with the conduct of the study or the evaluation of its results.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The urinary HSD-1 ratio ([tetrahydrocortisol + allotetrahydrocortisol]/tetrahydrocortisone) at Week 6 in subjects with Cushing’s disease. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | 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 Disorder Scale (SMDDS), Short Form Survey-36 version 2 (SF-36v2), Medical Outcomes Study Sleep Scale-Revised (MOS-Sleep-R), pain numeric rating scale (NRS), and Patient Global Impression of Severity(PGI-S)/Patient Global Impression of Change (PGI-C) at Week 6, as well as change from baseline during 6 and 12 weeks of SPI-62 administration, will be described.
- Proportions of subjects with urinary HSD-1 ratio ≤ 0.7 and ≤ 0.2 at Week 6 will be reported.
- Change from baseline during 6 and 12 weeks of SPI-62 administration on urinary HSD-1 ratio will be described.
- 24-hour UFC, and spot urine for the urinary ratio cortisone/cortisol at Week 6, as well as change from baseline during 6 and 12 weeks of SPI-62 administration, will be described.
- Changes in Cushing’s phenotypic features will be tabulated (Appendix 9).
- The predictive value of urinary HSD-1 ratio at Week 6 for clinical efficacy endpoints will be described.
- Efficacy analyses will be reported for all evaluable subjects, per-protocol subjects and for the subset of evaluable and per-protocol subjects with Cushing’s disease. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
For safety:
- at Week 6, as well as changes from baseline during 12 weeks of SPI-62 administration
For exploratory endpoints:
- at Week 6, as well as change from baseline during 6 and 12 weeks of SPI-62 administration
- at Week 6, as well as change from baseline during 6 and 12
weeks of SPI-62 administration
- at Week 6
- from baseline during 6 and 12 weeks of SPI-62 administration
- at Week 6, as well as change from baseline during 6
and 12 weeks of SPI-62 administration
- ratio at Week 6 |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
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| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
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| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 6 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| United States |
| Bulgaria |
| Romania |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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