Evaluation of Endoscopic Endonasal Surgery Versus Cabergoline in Biochemical Remission of Microprolactinomas in Treatment-Naïve Patients

The primary objective of this study is to evaluate the **non-inferiority** of endoscopic endonasal surgery (EES) compared to cabergoline (CAB), the standard care, in achieving biochemical remission in patients with newly diagnosed, treatment-naïve **microprolactinomas**. Biochemical remission is defined as the normalization of prolactin levels in the absence of treatment, assessed at 6- and 12-month follow-ups. This objective is clinically relevant as it aims to establish whether surgical intervention can be as effective as pharmacological treatment, potentially offering an alternative therapeutic approach for patients.

Secondary objectives include:

• Determining the rate of drug resistance, defined as the failure to achieve normal prolactin levels and a reduction in adenoma size of less than 50% on maximally tolerated doses after at least 6 months of treatment with CAB. The study may also investigate potential predictors of drug resistance.
• Assessing the residual mass of microprolactinomas (m-PRL) via MRI with gadolinium contrast medium at 6 and 12 months following EES or the initiation of CAB treatment.
• Evaluating the type and rate of surgical complications, with an exploration of potential predictors of these complications.

The clinical trial focuses on individuals diagnosed with **microprolactinomas**, a condition characterized by small pituitary adenomas. The study population includes both male and female participants over the age of 18, with no upper age limit specified. Participants are required to have clinical manifestations suggestive of hyperprolactinemia, with prolactin levels confirmed through multiple determinations. The trial does not specify the total number of participants, as this information was not provided by the sponsor. The selection criteria ensure that participants have not undergone previous medical, surgical, or radiation treatment for hyperprolactinemia. The study population is selected based on their ability to understand the study's purpose, provide informed consent, and complete self-administered questionnaires. The trial includes a vulnerable population, indicating that additional ethical considerations are in place to protect these participants. Lifestyle factors such as diet and physical activity are not detailed in the available data.

The clinical trial is designed to evaluate the **non-inferiority** of endoscopic endonasal surgery (EES) compared to **cabergoline** (CAB), the standard care, in achieving biochemical remission in patients with newly diagnosed, treatment-naïve **microprolactinomas**. This study is structured as a randomized, controlled trial with a double-blind design to ensure unbiased results. The trial is expected to commence on September 2, 2024, and conclude by April 1, 2026, with a total duration of approximately 19 months.

Participants will undergo a series of study visits, beginning with an inclusion visit where eligibility is confirmed based on criteria such as age over 18 years, signed informed consent, and specific clinical manifestations. The inclusion visit will also involve baseline assessments, including MRI and prolactin level measurements. Follow-up visits are scheduled at 6 and 12 months post-treatment initiation to monitor prolactin levels and assess tumor size via MRI. The primary endpoint is the rate of biochemical remission, defined by prolactin normalization without treatment, evaluated at these follow-up visits. Secondary endpoints include the assessment of tumor remnants and drug resistance in CAB-treated patients.

The expected length of participant involvement is up to 12 months, with conditions for early termination including withdrawal of consent, adverse events, or non-compliance with the study protocol. Participants will be monitored closely throughout the trial to ensure safety and adherence to the study procedures. The end-of-study visit will involve final assessments to evaluate the long-term outcomes of the interventions. This trial aims to provide valuable insights into the efficacy of surgical versus medical treatment in managing microprolactinomas.

The clinical trial involves the use of **cabergoline**, marketed under the name **DOSTINEX 0.5 mg compresse**, as the experimental medication. **Cabergoline** is a chemical substance administered in the form of a **tablet**. The pharmaceutical form is specified as **COMPRESSE**, and the medication is intended for **oral use**. The maximum daily dose of **cabergoline** is 0.5 mg, with a total maximum dose of 3 mg over the course of the treatment. The treatment period is set for a maximum of 12 months. The medication is manufactured by Pfizer Italia S.R.L. and is not a pediatric formulation. The administration schedule and participant compliance will be monitored throughout the trial to ensure adherence to the dosing regimen.

In this study, **cabergoline** serves as the standard-of-care therapy for patients with microprolactinomas. The trial aims to compare the efficacy of surgical treatment versus medical treatment with **cabergoline**. No placebo or additional comparator treatments are utilized in this trial. The primary objective is to assess the non-inferiority of endoscopic endonasal surgery (EES) compared to **cabergoline** in achieving biochemical remission, defined as the normalization of prolactin levels without ongoing treatment, at 6- and 12-month follow-ups in newly diagnosed, treatment-naïve patients.

Efficacy in the clinical trial titled "Surgical versus Medical Treatment in Microprolactinomas (SUMET PRO)" will be assessed primarily through the measurement of **prolactin** levels. The primary endpoint is the rate of biochemical remission, defined as the normalization of prolactin levels in the absence of treatment, at 6- and 12-month follow-up intervals. Prolactin levels will be measured using single fasting venous sampling at these specified timepoints to evaluate the efficacy of endoscopic endonasal surgery (EES) compared to cabergoline (CAB), which is the standard care.

Secondary endpoints include the assessment of microprolactinoma (m-PRL) remnants via MRI with gadolinium contrast medium (g.c.m.) at baseline, 6 months, and 12 months. This will help determine the ability of EES and CAB to reduce tumor mass by evaluating m-PRL diameters. Additionally, the trial will assess the rate of drug resistance in patients treated with CAB, defined as the failure to achieve normal prolactin levels and a reduction of adenoma size by less than 50% on maximally tolerated doses after at least 6 months of treatment. This will be determined through prolactin level measurements at baseline and at the 6- and 12-month follow-up.