CAT-Trial: CGRP monoclonal Antibody for Treatment of painful diabetic neuropathy: a double-blind, multicenter, placebo-controlled, international phase II clinical trial

The primary objective of this clinical trial is to evaluate the **efficacy** of eptinezumab in reducing pain intensity in patients with painful diabetic polyneuropathy. This is measured by the change in weekly self-reported mean pain intensity using the numerical rating scale (NRS) from baseline over a 24-week period following the first administration. This objective is clinically relevant as it aims to determine the potential of eptinezumab as a therapeutic option for managing pain in this patient population, which could significantly impact their quality of life.

Secondary objectives include:

• Assessing the efficacy of eptinezumab on neuropathic pain severity, as measured by the total score of the Neuropathic Pain Scale (NPS) at baseline, week 12, and week 24.
• Evaluating pain relief categorized as complete, good, moderate, mild, none, or worse at weeks 12 and 24.

The clinical trial involves a total of **30 participants** diagnosed with **painful diabetic polyneuropathy**. The study population includes both male and female subjects, aged between **18 and 75 years**. Participants were selected based on specific criteria, including a confirmed diagnosis of probable diabetic polyneuropathy, as defined by the Toronto consensus criteria, and a **Toronto Clinical Neuropathy Score (TCNS)** greater than 5, or abnormal results from DPNCheck or nerve conduction studies (NCS). Additionally, participants must have experienced probable neuropathic pain, as per the NeuPSIG guidelines, with symmetric distal pain more severe in the distal lower extremities for more than six months. An average pain score of 4 or higher on a numerical rating scale during the baseline week was also required. The trial does not include a vulnerable population, and no specific lifestyle considerations such as diet or physical activity were highlighted in the selection process.

The clinical trial is designed to evaluate the efficacy of **eptinezumab** in the treatment of **painful diabetic polyneuropathy**. This is a randomized, double-blind, placebo-controlled, international phase II trial. The study aims to assess the change in weekly self-reported mean pain intensity using the numerical rating scale (NRS) from baseline over a period of 24 weeks following the first administration of the investigational product. The trial is expected to conclude by July 31, 2025, with recruitment having commenced on January 30, 2023.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (18-75 years), a confirmed diagnosis of probable diabetic polyneuropathy, and an average pain score of ≥4 on the NRS during the baseline week. Following randomization, participants will receive either the investigational product, **VYEPTI 100 mg concentrate for solution for infusion**, or a placebo, administered via intravenous infusion. The maximum treatment period for the investigational product is 48 weeks, while the placebo is administered for up to 24 weeks.

Study visits will occur at baseline, and at weeks 12 and 24, to evaluate primary and secondary endpoints. The primary endpoint is the difference in self-reported average pain intensity between the eptinezumab-treated group and the placebo group. Secondary endpoints include differences in neuropathic pain severity and pain relief at specified intervals. The end-of-study visit will mark the conclusion of the participant's involvement, which is expected to last up to 24 weeks from the first administration.

Participants may be withdrawn from the study early if they experience adverse events, fail to comply with study procedures, or if the investigator deems it necessary for their safety. The trial is conducted in accordance with ethical guidelines and regulatory requirements to ensure the safety and well-being of all participants.

The clinical trial involves the administration of **VYEPTI**, a 100 mg concentrate for solution for infusion, containing the active substance **eptinezumab**. Eptinezumab is a monoclonal antibody classified under the ATC code N02CD05. The pharmaceutical form of VYEPTI is a solution for infusion, and it is administered via **intravenous administration**. The maximum daily dose is 3.57 mg, with a total maximum dose of 300 mg over a treatment period of up to 48 weeks. The administration schedule is designed to ensure optimal efficacy while monitoring participant compliance through regular assessments.

In addition to the experimental treatment, a **Saline Nebuliser Solution** containing **sodium chloride** 0.9% w/v is used as a comparator treatment. This solution is also administered via intravenous infusion. The maximum daily dose for the saline solution is 1.19 ml, with a total maximum dose of 100 ml over a treatment period of up to 24 weeks. The saline solution serves as a placebo to evaluate the efficacy of the experimental treatment in a double-blind, placebo-controlled setting. Compliance with the dosing schedule is monitored to ensure the integrity of the trial results.

The efficacy of eptinezumab in the treatment of painful diabetic neuropathy will be assessed through a double-blind, multicenter, placebo-controlled, international phase II clinical trial. The primary endpoint for evaluating efficacy is the difference in self-reported average pain intensity between the eptinezumab-treated group and the placebo-treated group. This will be measured using the average numerical rating scale (NRS) (0-10) with a modified version of the Brief Pain Inventory (BPI) from baseline, which is one week before randomization, over a period of 24 weeks following the first administration.

Secondary endpoints include the difference between groups in neuropathic pain severity as measured by the Neuropathic Pain Scale (NPS) at baseline, week 12, and week 24. Additionally, the difference in pain relief, categorized as complete, good, moderate, mild, none, or worse, will be assessed at weeks 12 and 24. The primary and secondary endpoints will be collected and analyzed at specified time points to determine the efficacy of the treatment.