Evaluation of [18F]Fluoroethyltyrosine PET-MRI for Differentiating Cushing's Disease from Ectopic Cushing's Syndrome in ACTH-Dependent Hypercortisolism

The primary objective of this study is to compare the proportion of patients with **ACTH-dependent hypercortisolism** in whom Cushing's disease (CD) is correctly differentiated from ectopic Cushing's syndrome (CS) using **[18F]FET PET-MRI** compared to inferior petrosal sinus sampling (IPSS). This is clinically relevant as accurate differentiation between CD and ectopic CS is crucial for determining the appropriate therapeutic approach and improving patient outcomes.

Secondary objectives include:

• Analysis of the diagnostic accuracy of **[18F]FET-PET-MRI**, IPSS, and structural MRI for the exact localization of small functional pituitary neuroendocrine tumors (PitNETs) in patients with CD.
• Assessment of postoperative CD outcomes.
• Evaluation of copeptin as a diagnostic marker in the evaluation of CD.

The clinical trial involves a total of **13 participants** diagnosed with **ACTH-dependent hypercortisolism**. The study population includes both male and female subjects, aged 18 years and older, who are not considered part of a vulnerable population. Participants were selected based on specific inclusion criteria, including biochemically confirmed ACTH-dependent hypercortisolism and the presence of a pituitary microadenoma or negative/inconclusive findings on standard MRI of the pituitary sella-region. The trial does not specify any particular lifestyle considerations such as diet or physical activity. The selection process ensures that participants have an indication for further evaluation with IPSS, aligning with the study's objective to differentiate Cushing's disease from ectopic Cushing's syndrome using [18F]FET PET-MRI.

The clinical trial is designed to evaluate the efficacy of **[18F]FET PET-MRI** in distinguishing Cushing's disease from ectopic Cushing's syndrome in patients with **ACTH-dependent hypercortisolism**. This is a Phase III, randomized, double-blind, controlled trial. The trial will commence on June 2, 2025, and is estimated to conclude by January 2, 2029. Participants will be involved in the study for a maximum treatment period of one day, with the primary endpoint being the difference in the proportion of patients correctly diagnosed using the new imaging technique compared to the current standard, IPSS.

Study visits will follow a structured sequence, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (≥18 years) and biochemically confirmed ACTH-dependent hypercortisolism. Participants will then undergo the investigational procedure, **[18F]FET PET-MRI**, administered via intravenous injection. Follow-up visits will be scheduled to monitor the outcomes and any adverse events. The end-of-study visit will assess the primary and secondary endpoints, including the sensitivity and specificity of the imaging techniques.

Participant involvement is expected to be brief, with the main procedures occurring within a single day. However, follow-up visits may extend the total duration of involvement. Conditions that may lead to early termination from the study include withdrawal of consent, significant protocol deviations, or adverse events that compromise participant safety. The trial aims to provide robust data on the non-inferiority of **[18F]FET PET-MRI** compared to IPSS, with secondary endpoints evaluating the diagnostic accuracy and predictive values of the imaging modalities.

The clinical trial involves the use of the experimental medication **fluoroethyltyrosine F-18** (FET), which is administered as a **solution for injection**. This radiopharmaceutical is designed for intravenous injection and is utilized to enhance the detection of pituitary adenomas in patients with Cushing's disease. The maximum daily dose of FET is 0.01 Sv sievert, with a total maximum dose of 0.02 Sv sievert over the course of the treatment period, which is limited to one day. The administration of FET is conducted under controlled conditions to ensure precise dosing and participant safety.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are employed. The focus is solely on the efficacy of FET in improving diagnostic accuracy when used in conjunction with PET-MRI imaging. Participant compliance with the dosing schedule is monitored through direct supervision during the administration of the intravenous injection, ensuring adherence to the protocol and accurate data collection.

Efficacy in this clinical trial will be assessed by evaluating the ability of **[18F]FET PET-MRI** to correctly differentiate Cushing's disease (CD) from ectopic Cushing's syndrome (CS) in patients with ACTH-dependent hypercortisolism. The primary endpoint is the difference in the proportion of patients in whom CD is correctly distinguished from ectopic CS using **[18F]FET PET-MRI** compared to the current standard, inferior petrosal sinus sampling (IPSS). This comparison will focus on establishing the non-inferiority of **[18F]FET PET-MRI** relative to IPSS.

Secondary endpoints will include the sensitivity, specificity, positive and negative predictive values of both **[18F]FET PET-MRI** and IPSS for the precise localization of ACTH-secreting pituitary neuroendocrine tumors (PitNETs). These assessments will be based on post-operative neurosurgery and pathology reports, as well as biochemical remission as reference standards. Additionally, the area under the curve (AUC) for both techniques will be calculated from the receiver operating characteristic (ROC) curve to further evaluate their diagnostic performance.