Evaluation of Silibinin Efficacy and Safety in Active Cushing's Disease: A Multicenter, Open-Label, Dose-Titration Study

The primary objective of this study is to evaluate the **efficacy** of Silycus® in decreasing and/or normalizing excess cortisol secretion in patients with active **Cushing's disease**. This will be assessed through measurements of 24-hour urinary free cortisol, midnight salivary cortisol, or suppression by low-dose dexamethasone. The clinical relevance of this objective lies in addressing the hypercortisolism characteristic of Cushing's disease, which can lead to significant morbidity if not effectively managed.

Secondary objectives include: - Evaluating the effect of Silycus® on the signs and symptoms of hypercortisolism. - Assessing the safety and tolerability of Silycus® in patients with Cushing’s disease. - Evaluating the pharmacokinetic (PK) profile of **silibinin** in these patients. These secondary objectives aim to provide a comprehensive understanding of the therapeutic profile of Silycus®, ensuring both its efficacy and safety in the target population.

The clinical trial focuses on evaluating the efficacy of Silycus® in patients with active **Cushing's disease**. The study population includes both male and female adults aged 18 years and older. Participants are selected based on their diagnosis of Cushing's disease, which is confirmed through established guidelines. The trial includes individuals with either newly diagnosed or persistent/recurrent disease. Participants must have a mean value of 24-hour urinary free cortisol at least 1.5 times above the upper limit of normal, along with elevated late-night salivary cortisol or unsuppressed cortisol after dexamethasone administration. The trial population comprises individuals who are either not surgical candidates or have delayed surgery, and those on inadequate or poorly tolerated medical treatments. Participants are required to provide written informed consent and adhere to protocol requirements. The sponsor has not provided information regarding the total number of participants in the study.

The clinical trial is designed to evaluate the **efficacy** and safety of Silycus® in patients with **Cushing's disease**. This is a multicenter, single-arm, open-label, dose-titration, proof-of-concept study. The trial will assess the ability of Silycus® to decrease and/or normalize excess cortisol secretion, with efficacy measured by 24-hour urinary free cortisol, midnight salivary cortisol, or suppression by low-dose dexamethasone. The study is expected to run until December 31, 2026, with recruitment having started on October 15, 2021. Participants will be involved for a maximum treatment period of 3 months, with the primary endpoint assessed after 12 weeks of administration.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (≥18 years), diagnosis of active Cushing's disease, and willingness to provide informed consent. The trial will include follow-up visits to monitor the efficacy and safety of the treatment, with assessments of clinical signs and symptoms, adverse events, and pharmacokinetic profiles. The end-of-study visit will conclude the participant's involvement, with final evaluations of the primary and secondary endpoints.

Participants may be withdrawn from the study if they experience significant adverse events, fail to adhere to the protocol, or if the investigator deems it necessary for their safety. The trial is not a low-intervention study and is categorized as a Phase II clinical trial. The investigational product, Silycus®, is administered orally in the form of granules in a sachet, with a maximum daily dose of 600 mg. The study aims to provide valuable insights into the treatment of Cushing's disease, focusing on both efficacy and safety outcomes.

The clinical trial involves the administration of **Silycus®**, an experimental medication formulated as **granules in sachet**. The active substance in Silycus® is **silibinin**, a purified standardized extract derived from milk thistle fruit. The pharmaceutical form is designed for **oral use**, ensuring ease of administration. Participants in the trial will receive a maximum daily dose of 600 mg, with the total dose not exceeding 600 mg per day. The treatment period is limited to a maximum of 3 months. The study aims to evaluate the efficacy of Silycus® in reducing or normalizing excess cortisol secretion in patients with active **Cushing's disease**. The efficacy will be assessed through measurements of 24-hour urinary free cortisol, midnight salivary cortisol, or suppression by low-dose dexamethasone.

In this trial, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The study is structured as a multicenter, single-arm, open-label, dose-titration, proof-of-concept study. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the prescribed regimen. The trial does not include any pediatric formulations, and Silycus® is not classified as an orphan drug. The study is conducted under the sponsorship of IBI G. LORENZINI SPA, with the product identified by the sponsor product code 2020-005605-93.

The efficacy of Silycus® in the treatment of Cushing's disease will be assessed through a composite primary endpoint. This endpoint includes the evaluation of **urinary free cortisol (UFC)**, late night salivary cortisol levels, and cortisol suppression with low dose dexamethasone. Specifically, the efficacy will be determined by the percentage of patients in whom UFC normalized or decreased by at least 50% compared to pretreatment values, the percentage of patients with elevated late night salivary cortisol at baseline in whom salivary cortisol normalized, and the percentage of patients who failed to suppress after low dose dexamethasone at baseline in whom normal suppression was restored. These assessments will be conducted after 12 weeks of administration.

Secondary endpoints will focus on the effect of Silycus® on clinical signs and symptoms of Cushing's disease, including changes in body weight, blood pressure, glucose control, electrolyte derangements, and leukocytosis. These parameters will also be evaluated after 12 weeks of treatment. Additionally, the safety of Silycus® will be analyzed based on the frequency and severity of adverse events, and the pharmacokinetic profile of **silibinin** will be evaluated in patients with Cushing's disease following the first dose, during uptitration, and at steady state.