Efficacy and Safety Assessment of VX-993 in Patients with Painful Diabetic Peripheral Neuropathy: A Phase 2 Randomized, Double-Blind, Active-Controlled Study

The primary objectives of this Phase 2, randomized, double-blind, active-controlled, dose-ranging, parallel-design study are to evaluate the **efficacy** and **safety** of oral VX-993 in subjects with pain associated with **diabetic peripheral neuropathy** (DPN). The study aims to assess the effectiveness of different doses of VX-993 in alleviating pain symptoms in this patient population, which is clinically relevant as DPN is a common and debilitating complication of diabetes, often leading to significant discomfort and reduced quality of life. Additionally, the study will evaluate the safety and tolerability of VX-993, ensuring that the treatment does not pose undue risks to patients. No secondary objectives are specified for this study.

The clinical trial involves a total of **240 participants** who are being evaluated for the efficacy and safety of VX-993 in treating **pain associated with diabetic peripheral neuropathy**. The study population includes both male and female subjects, with an age range that corresponds to adults and older adults. Participants were selected based on a diagnosis of **diabetes mellitus type 1 or type 2**, with a glycosylated hemoglobin A1c (HbA1c) of 9% or less, and optimized glycemic control as determined by the investigator. Additionally, subjects have been stable on anti-diabetic medication or dietary treatment for at least three months prior to the screening visit. The trial specifically targets individuals experiencing bilateral pain in the lower extremities due to diabetic peripheral neuropathy for a minimum duration of one year. The study does not include a vulnerable population, and lifestyle factors such as diet and physical activity are considered in the context of maintaining stable glycemic control. The selection criteria ensure a focus on individuals with a well-defined medical condition and treatment history, providing a robust basis for evaluating the investigational treatment's impact.

The clinical trial is a **Phase 2**, randomized, double-blind, active-controlled, dose-ranging, parallel-design study aimed at evaluating the efficacy and safety of oral VX-993 in subjects with **painful diabetic peripheral neuropathy**. The trial is designed to assess the change from baseline in the weekly average of daily pain intensity on the numeric pain rating scale (NPRS) at Week 12 as the primary endpoint. Secondary endpoints include the proportions of subjects achieving significant reductions in pain intensity and the safety and tolerability of VX-993, as determined by adverse events, laboratory test results, vital signs, and ECGs.

The trial will involve a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a diagnosis of diabetes mellitus type 1 or type 2, optimized glycemic control, and the presence of bilateral pain in the lower extremities due to diabetic peripheral neuropathy for at least one year. Following the screening, participants will be randomized to receive either VX-993, pregabalin, or their respective placebos, administered orally. The trial will include regular follow-up visits to monitor efficacy and safety parameters, with the end-of-study visit marking the conclusion of the participant's involvement.

The overall trial duration is estimated to be approximately 12 months, with participant involvement expected to last up to 13 weeks, depending on the treatment arm. Conditions that may lead to early termination from the study include significant adverse events, non-compliance with study procedures, or withdrawal of consent by the participant. The trial is not categorized as low intervention, and it is conducted under the regulatory framework for clinical trials, ensuring adherence to ethical and scientific standards.

The clinical trial involves the administration of **VX-993 tablet**, an experimental medication developed by Vertex Pharmaceuticals, Incorporated. VX-993 is a small molecule that functions as a voltage-gated sodium channel 1.8 (NaV1.8) inhibitor. The pharmaceutical form of VX-993 is a tablet, and it is administered orally. The dosing schedule for VX-993 is not specified in terms of milligrams per day, as the maximum daily dose amount is recorded as 0.0 mg. The treatment period for VX-993 is set for a maximum of 12 weeks. Participant compliance with the dosing regimen will be monitored throughout the study.

**Pregabalin** is used as an active comparator in this study. It is a calcium channel (alpha2-delta site) inhibitor, encapsulated to maintain the blinding of the study. Pregabalin is administered in capsule form, taken orally. Similar to VX-993, the specific dosage in milligrams per day is not detailed, with the maximum daily dose amount also recorded as 0 mg. The treatment period for Pregabalin is set for a maximum of 13 weeks. Compliance with the administration schedule will be closely monitored.

The study also includes a **Pregabalin placebo**, which serves as a control to the active comparator. This placebo is designed to mimic the appearance of the Pregabalin capsules but does not contain any active substance. The placebo is administered orally, and the treatment period is aligned with that of the active comparator, lasting up to 12 weeks. Monitoring of participant adherence to the placebo regimen will be conducted to ensure the integrity of the study results.

Additionally, a **VX-993 placebo** is utilized in the trial. This placebo is intended to match the VX-993 tablet in appearance but lacks any active pharmaceutical ingredient. The VX-993 placebo is administered orally, and the treatment duration is consistent with the VX-993 tablet, extending up to 12 weeks. Participant compliance with the placebo administration will be tracked to maintain the study's validity.

The efficacy of the investigational product VX-993 in treating subjects with painful diabetic peripheral neuropathy will be assessed using specific endpoints. The primary endpoint is the change from baseline in the weekly average of daily pain intensity, measured on the numeric pain rating scale (NPRS) at Week 12. Secondary endpoints include the proportions of subjects achieving ≥30%, ≥50%, and ≥70% reductions from baseline in the weekly average of daily pain intensity on the NPRS at Week 12. Additionally, safety and tolerability will be evaluated based on adverse events, laboratory test results, vital signs, and ECGs.