Evaluation of 68Ga-NODAGA-Exendin PET/CT Imaging in Assessing Beta Cell Mass in Type 1 Diabetes Patients Treated with Exenatide and Verapamil

The primary objective of this study is to measure the pancreatic uptake of **68Ga-NODAGA-exendin** using PET/CT imaging. This aims to detect intra-individual differences in **beta cell mass** before and after treatment, as well as inter-individual differences between the treatment group and the placebo group. This is clinically relevant as it may provide insights into the effects of treatment on beta cell mass in individuals with **type 1 diabetes mellitus**, potentially informing therapeutic strategies.

Secondary objectives include:

• Comparing changes in pancreatic 68Ga-NODAGA-exendin uptake to changes in C-peptide and insulin/proinsulin measurements. This comparison could elucidate the relationship between imaging biomarkers and biochemical markers of beta cell function.
• Quantifying the differences in 68Ga-NODAGA-exendin uptake between individuals and between two time points of imaging intra-individually. This quantification is intended for future calculations of study group sizes, which is essential for designing adequately powered studies.

The clinical trial involves a total of **10 participants** diagnosed with **type 1 diabetes mellitus**. The study population includes both male and female subjects, aged 18 years and older, who have not yet started treatment or placebo in the VER-A-T1D trial and have provided written informed consent. Participants were selected based on their inclusion in the VER-A-T1D trial, ensuring they meet the age requirement and have consented to participate. The trial does not involve a vulnerable population, and no specific lifestyle considerations such as diet or physical activity are highlighted. The selection criteria ensure a focus on adult individuals with type 1 diabetes, allowing for the assessment of pancreatic uptake of 68Ga-NODAGA-exendin by PET/CT to detect differences in beta cell mass.

The clinical trial is designed to evaluate the effects of **exenatide** and **verapamil** on beta cell mass in individuals with **type 1 diabetes mellitus**. This is a randomized, double-blind, controlled trial with a primary objective to measure pancreatic uptake of 68Ga-NODAGA-exendin using PET/CT imaging. The trial aims to detect intra-individual differences in beta cell mass before and after treatment, as well as inter-individual differences between the treatment and placebo groups. The trial is expected to last until April 2025, with recruitment having started in January 2021.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as being part of the VER-A-T1D trial, having provided written informed consent, and being at least 18 years old. Following the screening, participants will be randomized to receive either the active treatment or placebo. The trial includes follow-up visits to monitor changes in pancreatic uptake of 68Ga-NODAGA-exendin, C-peptide, and proinsulin/preproinsulin levels. The end-of-study visit will assess the primary endpoint, which is the total pancreatic uptake of 68Ga-NODAGA-exendin for beta cell mass determination at inclusion and after 12 months.

Participant involvement is expected to last for the duration of the trial, with the maximum treatment period being 3 months for **verapamil** and 1 month for **exenatide**. Conditions that may lead to early termination from the study include withdrawal of consent or any adverse events that compromise participant safety. The trial is conducted in accordance with ethical standards and regulatory requirements, ensuring the integrity and reliability of the collected data.

The clinical trial involves the administration of **Exenatide**, a synthetic peptide analog of exendin-4, which is a **glucagon-like peptide-1 (GLP-1) receptor agonist**. The pharmaceutical form of Exenatide is denoted as PHF00231MIG. It is administered via an **intravenous bolus** route. The maximum daily dose is 100 MBq, with a total dose not exceeding 100 MBq over the treatment period. The treatment duration is limited to one day. Exenatide has undergone a C-terminal modification with Lys, and a chelator NODAGA is attached via an AHX spacer for labeling with Ga-68, which is crucial for the PET/CT imaging process in the study. Participant compliance with the dosing schedule is monitored through standard clinical trial procedures.

**Verapamil** is also utilized in this study as a non-experimental treatment. It is a **calcium-channel blocker** with the pharmaceutical form PHF00212MIG. Verapamil is administered orally, with a maximum daily dose of 360 mg and a total dose not exceeding 360 mg over a treatment period of three days. The use of Verapamil serves as a comparator treatment to evaluate its effects on beta cell mass in conjunction with Exenatide. Compliance with Verapamil administration is similarly monitored to ensure adherence to the dosing regimen.

Efficacy in this clinical trial will be assessed by evaluating the **total pancreatic uptake of 68Ga-NODAGA-exendin** using PET/CT imaging. This primary endpoint aims to determine the beta cell mass at the point of inclusion and after 12 months of treatment. The trial will also assess secondary endpoints, which include changes in 68Ga-NODAGA-exendin pancreas uptake in relation to changes in C-peptide and proinsulin/preproinsulin measurements. Additionally, differences in 68Ga-NODAGA-exendin uptake will be evaluated between individuals and between the two timepoints of imaging intra-individually.

The measurement of these endpoints will be conducted at specific timepoints, with the primary endpoint being assessed at the start of the trial and after 12 months. The secondary endpoints will involve analyzing changes in biomarker levels and imaging results over the course of the study. The use of PET/CT imaging provides a quantitative method to assess the uptake of the radiolabeled compound, allowing for precise evaluation of beta cell mass and function. The data collected will be analyzed to determine the efficacy of the treatment in altering pancreatic uptake and related biomarker levels.