Evaluation of SPI-62 for the Management of Hypercortisolism Associated with Benign Adrenal Tumors

The primary objective of this study is to evaluate the **benefit-risk** profile of SPI-62 in patients experiencing complications due to **hypercortisolism** related to autonomous cortisol secretion (ACS) from a benign adrenal tumor, while being managed under standard care. This is clinically relevant as it aims to determine the therapeutic potential and safety of SPI-62 in addressing the complications associated with hypercortisolism, which can significantly impact patient health and quality of life.

Secondary objectives include: - Assessing the short-term progression, persistence, improvement, or resolution of clinical signs and symptoms of hypercortisolism, such as **hyperglycemia**, dyslipidemia, osteopenia, and hypertension. - Evaluating the long-term safety of SPI-62 concerning serious morbidity and mortality. - Investigating the efficacy of SPI-62 in reducing morbidity and mortality related to hypercortisolism.

The clinical trial involves a total of **23 participants** diagnosed with **hypercortisolism related to benign adrenal tumour**. The study population includes both male and female adults, with an age range spanning from 18 to 64 years. Participants were selected based on their ability to provide informed consent and their willingness to adhere to necessary reproductive precautions. The trial specifically targets individuals with benign adrenal lesions and proven autonomous cortisol secretion (ACS), who have documented treatment for or evidence of ongoing metabolic consequences such as hyperglycemia, hypertension, hyperlipidemia, or osteopenia attributable to clinically significant hypercortisolism. Surgery as a first-line therapy must have been discussed with all eligible participants, who are included only if they have failed or rejected available surgical or medical therapies approved in their region of residence. The trial population includes a vulnerable group, and lifestyle considerations such as diet and physical activity are not specified in the available data.

The clinical trial is designed to evaluate the **benefit-risk** profile of SPI-62 in participants with **hypercortisolism** related to a benign adrenal tumor. This study is a Phase 4, randomized, double-blind, controlled trial. The trial is expected to run from January 25, 2023, to December 1, 2029. Participants will be administered SPI-62 in the form of a film-coated tablet, with a maximum daily dose of 2 mg and a total dose not exceeding 6 mg over a treatment period of up to 78 weeks. The trial will include several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor progress and safety, and a final end-of-study visit to assess outcomes.

Participants will be involved in the study for a maximum of 78 weeks, during which they will undergo regular assessments to evaluate the progression, persistence, improvement, or resolution of clinical signs and symptoms associated with hypercortisolism, such as hyperglycemia, dyslipidemia, osteopenia, and hypertension. The primary endpoint will focus on the evaluation of the benefit-risk profile of SPI-62, including laboratory data and the incidence of treatment-emergent adverse events. Secondary endpoints will assess both short-term and long-term safety and efficacy outcomes.

Inclusion criteria require adult participants with proven autonomous cortisol secretion and documented metabolic consequences of hypercortisolism. Participants must have discussed surgical options and either failed or rejected available therapies. Conditions for early termination from the study include the occurrence of serious adverse events or non-compliance with study protocols. The trial aims to provide comprehensive data on the safety and efficacy of SPI-62 in managing complications due to hypercortisolism in a controlled clinical setting.

The clinical trial involves the administration of the experimental medication **SPI-62**, which is being evaluated for its efficacy in treating **hypercortisolism** related to a benign adrenal tumor. The active substance in SPI-62 is **4-{5-[2-(4-chloro-2,6-difluorophenoxy)propan-2-yl]-4-methyl-4H-1,2,4-triazol-3-yl}-3-fluorobenzamide**, a chemical compound. The pharmaceutical form of SPI-62 is a film-coated tablet, designed for oral administration. The dosing regimen for SPI-62 involves a maximum daily dose of 2 mg, with a total maximum dose of 6 mg over the course of the treatment period. The maximum treatment duration is set at 78 weeks. The medication is not formulated for pediatric use and is not classified as an orphan drug.

In addition to the experimental treatment, participants in the study will continue to receive standard-of-care therapy as part of their management for hypercortisolism. This standard-of-care therapy serves as a non-experimental treatment and is intended to provide a baseline for evaluating the benefit-risk profile of SPI-62. The study does not include a placebo or comparator treatment. Compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the prescribed regimen. Participants' response to the treatment will be assessed in the context of their ongoing standard-of-care management.

Efficacy in the clinical trial of SPI-62 for the treatment of **hypercortisolism** related to a benign adrenal tumor will be assessed through a combination of primary and secondary endpoints. The primary endpoint involves an evaluation of the benefit-risk profile of SPI-62, which includes laboratory data, the incidence of treatment-emergent adverse events (TEAEs), and the progression or regression of the underlying disease or its complications. Secondary endpoints focus on the short-term progression, persistence, improvement, or resolution of clinical signs, markers, and symptoms of hypercortisolism, such as hyperglycemia, dyslipidemia, osteopenia, and hypertension, as well as other features associated with endogenous hypercortisolism. Additionally, long-term safety concerning serious morbidity or mortality will be monitored.