Evaluation of Clofutriben (SPI-62) in the Management of ACTH-Dependent Cushing's Syndrome: A Clinical Trial
- Trial ID
- 2024-515913-17-00
- Protocol
- SPI-62-CL-2001
- Sponsor
- Sparrow Pharmaceuticals Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to characterize the **pharmacologic effect** of SPI-62 in subjects with adrenocorticotropic hormone (ACTH)-dependent **Cushing's syndrome**, including Cushing's disease, ectopic ACTH secretion, and ectopic corticotrophin-releasing hormone (CRH) secretion. This will be measured using the urinary 11β-hydroxysteroid dehydrogenase type 1 (HSD-1) ratio. Understanding the pharmacologic effect is clinically relevant as it may provide insights into the efficacy of SPI-62 in modulating the biochemical pathways involved in Cushing's syndrome, potentially leading to improved therapeutic strategies.
Secondary objectives include:
- Evaluating the safety of SPI-62 in subjects with ACTH-dependent Cushing's syndrome, focusing on changes in hypothalamic pituitary adrenal (HPA) and hypothalamic pituitary gonadal (HPG) axis biomarkers and associated adverse events (AEs). Long-term safety will be monitored through vital signs, AEs, and specific laboratory evaluations during an open-label extension phase.
- Estimating 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.
Participants
The clinical trial involves a total of **8 participants** diagnosed with **Cushing's Syndrome**, specifically focusing on ACTH-dependent forms such as Cushing's disease, ectopic ACTH secretion, and ectopic corticotrophin-releasing hormone (CRH) secretion. The study population includes both **male and female** subjects aged **18 years or older**. Participants were selected based on their ability to provide informed consent and the presence of active and consistent cortisol excess, as evidenced by specific diagnostic criteria. The trial includes individuals with documented diagnoses who may have declined surgery or have residual or recurrent disease post-surgery. Participants are required to comply with reproductive precautions and exhibit current evidence of Cushing's morbidities, such as hyperglycemia, dyslipidemia, hypertension, or osteopenia. The trial population is considered vulnerable, and lifestyle factors such as diet and physical activity are not specified in the available data.
Plans and Procedures
The clinical trial is designed to evaluate the pharmacologic effect of **SPI-62**, a novel inhibitor of 11β-hydroxysteroid dehydrogenase type 1, in subjects with adrenocorticotropic hormone (ACTH)-dependent **Cushing's Syndrome**. This is a randomized, double-blind, controlled trial with a primary objective to assess the urinary HSD-1 ratio at Week 6 in subjects with Cushing's disease. The trial is expected to commence recruitment on August 2, 2024, and conclude by December 31, 2029. The study will involve multiple visits, starting with a screening visit to confirm eligibility based on criteria such as age, ability to provide informed consent, and evidence of cortisol excess. Participants will be required to provide urine samples and undergo dexamethasone suppression testing as part of the inclusion criteria.
Following the screening, eligible participants will be randomized to receive either the investigational product or a control, with the treatment administered orally in the form of film-coated tablets. The maximum daily dose is set at 6 mg, with a treatment period not exceeding 41 days. Study visits will include baseline assessments, periodic follow-ups to monitor safety and efficacy, and an end-of-study visit to evaluate the primary and secondary endpoints. These endpoints include adverse events, changes in clinical laboratory evaluations, and assessments of glucose metabolism and bone health.
The expected duration of participant involvement is approximately 12 weeks, including the treatment and follow-up phases. Conditions that may lead to early termination from the study include significant adverse events, non-compliance with study procedures, or withdrawal of consent. The trial will adhere to rigorous safety monitoring protocols, with regular assessments of vital signs, ECGs, and laboratory parameters to ensure participant safety throughout the study duration.
Treatment
The clinical trial involves the administration of **SPI-62_DF2**, an experimental medication developed by Sparrow Pharmaceuticals, Inc. The active substance in SPI-62_DF2 is **clofutriben**, a chemical compound known for its potent and selective inhibition of 11β-hydroxysteroid dehydrogenase type 1 (HSD-1). The pharmaceutical form of SPI-62_DF2 is a film-coated tablet, designed for oral use. The maximum daily dose is 6 mg, with the same amount being the maximum total dose allowed per day. The treatment period for participants is capped at 41 days. The primary objective of the trial is to evaluate 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.
In addition to the experimental treatment, the study may include non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments, although specific details are not provided in the source data. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the prescribed regimen. The trial does not involve a pediatric formulation, and SPI-62_DF2 is not classified as an orphan drug. The study aims to measure the effect of the treatment using the urinary 11β-hydroxysteroid dehydrogenase type 1 (HSD-1) ratio as a biomarker.
Efficacy
Efficacy in the clinical trial of SPI-62 for the treatment of **Adrenocorticotropic Hormone (ACTH)-dependent Cushing's Syndrome** will be assessed using several primary and secondary endpoints. The primary endpoint is the urinary 11β-hydroxysteroid dehydrogenase type 1 (HSD-1) ratio, specifically the ratio of [tetrahydrocortisol + allotetrahydrocortisol] to tetrahydrocortisone, measured at Week 6 in subjects with Cushing's disease. This endpoint will provide a quantitative measure of the pharmacologic effect of SPI-62 on the HSD-1 enzyme activity.
Secondary endpoints include a range of clinical and laboratory evaluations. These encompass adverse events, changes in clinical laboratory evaluations, ECG intervals, pulse, temperature, and biomarkers of the hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-gonadal (HPG) axes at Week 6, as well as changes from baseline during 12 weeks of SPI-62 administration. Additional assessments involve glucose area under the curve (AUC) during oral glucose tolerance tests, continuous glucose monitoring parameters, HbA1c, insulin levels, fasting plasma glucose, body weight, body mass index, and dual-energy x-ray absorptiometry (DEXA) scan results. Muscle strength performance and scores on various patient-reported outcome measures, such as the Symptoms of Major Depressive Disorder Scale and the Short Form Survey-36 version 2, will also be evaluated.
The trial will further report the proportions of subjects achieving specific urinary HSD-1 ratio thresholds at Week 6 and describe changes from baseline in urinary HSD-1 ratio over 6 and 12 weeks of treatment. The predictive value of the urinary HSD-1 ratio at Week 6 for clinical efficacy endpoints will be analyzed, and efficacy analyses will be conducted for all evaluable subjects, including those with Cushing's disease. These comprehensive assessments will be conducted at specified timepoints to ensure a robust evaluation of SPI-62's efficacy in the target population.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Male or female aged 18 years or older.
- Able to provide written informed consent.
- Active and consistent cortisol excess: a. 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 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. b. 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. c. Late-night/bedtime salivary cortisol above ULN.
- 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.
- 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.
- 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 minimaltraumatic or osteoporotic fracture treated with lifestyle modification with mineral or vitamin supplementation or stable approved osteoporosis therapies.
Exclusion Criteria
- Recent or planned Cushing's surgery: Surgery for Cushing's within the past 6 months or planned within 24 weeks after randomization.
- Use of medications for Cushing's syndrome within the washout periods prior to randomization as described in Section 6.1.
- 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 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.
- 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. See Section 6.1 Concomitant Medications for recommendations regarding use of certain other allowed medications
- Uncontrolled hypothyroidism or hyperthyroidism.
- 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.In the long-term phase of study, patients having function decline to < 45 mL/min/1.73 m2 should be withdrawn from the study unless formal renal-impairment
- 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 ms, 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, non-melanoma skin cancer, thyroid cancer, or earlystage 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).
- 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 1 month 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.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Bulgaria | Not Recruiting | 02 Aug 2024 | 5 |
 Romania | Not Recruiting | 02 Aug 2024 | 4 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
SPI-62_DF2 | Test | FILM COATED TABLET | ORAL USE | 6 | 41 | PRD10172793 |