Clinical Trials

Inclusion Criteria:

Subjects must satisfy all following criteria at the Screening visit unless otherwise stated:

• Male or female aged 18 years or older.
• Able to provide written informed consent.
• Active and consistent cortisol excess:
  This is defined as having a consistently elevated UFC in patients newly diagnosed
  with Cushing’s or in patients with recurrent or refractory Cushing’s disease having
  high-normal UFCs or both of the other guideline-recommended tests (overnight
  dexamethasone suppression or late-night/bedtime salivary cortisol) being consistent
  with cortisol excess:
  • Urinary free cortisol (UFC) > upper limit of normal (ULN) based on at least 2
    valid (i.e., complete) 24-hour urine samples collected during Screening. The subjects 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.
• Overnight dexamethasone suppression testing to minimally include a non-suppressed morning serum cortisol ≥ 1.8 mcg/dL (50 nmol/L) after 1 mg ONDST within the last year. Testing should be confirmed by concurrent dexamethasone level adequate to provide suppression. Individuals using estrogen should meet further criteria accounting for potential increased
  corticosteroid binding globulin (CBG); e.g., free cortisol > 80 ng/dL (2.2 nmol/L), total serum cortisol ≥ 5 mcg/dL (138 nmol/L), or correction based on CBG measurement. If ONDST dates or results are not available for
  tests performed within the past year, ONDST with dexamethasone level should be repeated to confirm eligibility and should use local laboratory results.
• Late-night/bedtime salivary cortisol above ULN based on at least 2 adequate samples collected during Screening using local laboratory results.
• 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:
  • History of positive ACTH-staining pathology;
  • History of documented, transient, AI after tumor removal requiring
    glucocorticoid replacement;
  • ACTH level > 20 pg/mL with positive ACTH or cortisol response to CRH or desmopressin (DDAVP) stimulation in the presence of hypercortisolemia;
  • Inferior petrosal sinus sampling with ACTH central: plasma gradient ≥ 2 before CRH or DDAVP or ≥ 3 after CRH or DDAVP;
  • 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;
  • 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. 
• 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.
• Current evidence of Cushing’s comorbidities 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”;
  • 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-hour 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).
  • 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;
  • 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;
  • Diagnosis of osteoporosis or osteopenia:
  • Osteopenia (T-score ≤ -1.0 or Z-score ≤ -2.0) or osteoporosis as determined previously, during 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. 

Exclusion Criteria:

Subjects will be excluded from the study if they satisfy any of the following criteria at the Screening visit unless otherwise stated:

• Recent or planned Cushing’s surgery:
• Surgery for Cushing’s within the past 6 weeks or planned within 6 months after randomization.
• Use of medications for Cushing’s syndrome within the washout periods prior to randomization.
• Recent Cushing’s radiotherapy:
• A history of radiation therapy for Cushing’s within a period prior to plateau of efficacy (typically within the past 2 years of intensive targeted therapy [e.g., stereotactic radiation] or within 4 years of more conventional radiation therapy).
• History of bilateral adrenalectomy.
• History of pseudo-Cushing’s syndrome.
• History of cyclic Cushing’s syndrome.
• Exogenous hypercortisolism or factitious Cushing’s syndrome.
• History of non-ACTH-dependent hypercortisolism:
• This includes disease 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%).
• 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 impingement on vital structures. For example, tumor showing aggressive growth abutting or compressing the optic chiasm or with evidence of blood-vessel encroachment, encirclement, invasion, or compression.
• Uncontrolled Cushing’s comorbidities 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- orcardiova scular 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.
• Use of drugs likely to interfere with study assessments:
• These include chronic systemic corticosteroids, thiazolidinediones, drugs that may alter the metabolism and clearance of corticosteroids (e.g., 5-alpha-reductase inhibitors), supplements or traditional medicines that contain a HSD-1 inhibitor, within 12 weeks prior to the first dose of study drug. 
• Uncontrolled hypothyroidism or hyperthyroidism:
• For patients with a history of, or treatment for, abnormal thyroid function, free thyroxine (T4) should be in normal range and stable, whether endogenous or on levothyroxine replacement [> 8 weeks]. Thyroid-stimulating hormone (TSH) will often not be reliable in post-operative patients, but if measured, should not be significantly elevated. Locally obtained recent, (within 3 months of screening) T4 and TSH results may be used for screening evaluation. If central laboratory data are not available, or delayed, these labs may be obtained locally during the screening period.
• Moderate or severe renal impairment:
• Defined by an estimated glomerular filtration rate (GFR) repeatedly < 60 mL/min/1.73 m^2  or confirmed by measured GFR < 60 mL/min/1.73 m^2.
• In the long-term phase of study, patients having function decline to < 45 mL/min/1.73 m^2 should be withdrawn from the study unless formal renal-impairment studies support safe continuation.
• 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.
• 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 msec, or evidence of significant, life-threatening arrhythmia or bradycardia (HR < 45 bpm).
• History of idiopathic thrombocytopenic purpura.
• History of adrenal carcinoma.
• 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.
• History of cancer within 3 years other than ectopic ACTH from an unidentified source, with plans for therapy, intervention (e.g., biopsy), or likelihood for recurrence is likely to interfere with or confound the results of this trial. If stable and requiring hormone-suppressive therapy, subjects with breast, prostate, bone, or other endocrine cancer may be included at Medical Monitor discretion, however their data may be excluded in assessment of SPI-62 effects on HPA and HPG axis biomarkers).
• Any major surgery, or significant post-operative sequelae, within 1 month prior to informed consent or planned during the trial.
• Pregnant, lactating, or planning fertility in the next 6 months and unwilling to adhere to approved contraceptive use or abstinence.
• Participation in any clinical trial within 30 days or 5 half-lives, whichever is longer, prior to informed consent (or longer for biologic and long-lasting experimental therapies).
• Receipt of blood products within 2 months prior to Screening.
• 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.
• Poor peripheral venous access.
• Any other current or prior medical condition expected to interfere with the conduct of the study or the evaluation of its results. 

Note: Other protocol defined Inclusion/Exclusion Criteria may apply.

Eligibility last updated 8/28/23. Questions regarding updates should be directed to the study team contact.