A parallel-group treatment, proof-of-concept Phase 2, multicenter, double-blind, randomized 2 arm clinical trial to investigate the efficacy and safety of subcutaneous NT 201 injections compared with placebo injections in decreasing pain intensity in male and female participants aged 18 years and older with moderate or severe chronic neuropathic pain due to postherpetic neuralgia or peripheral nerve injury.

The primary objective of this clinical trial is to establish evidence of the **efficacy** of NT 201 in the treatment of moderate to severe chronic peripheral neuropathic pain (PNP) in patients with postherpetic neuralgia or chronic neuropathic pain after peripheral nerve injury. This will be achieved by demonstrating the superiority of NT 201 compared to placebo in reducing Average Daily Pain (ADP) intensity. Clinically, this is significant as it addresses the need for effective pain management strategies in patients suffering from chronic neuropathic pain, which can significantly impact quality of life.

Secondary objectives include:

• Estimating the effect size of NT 201 in reducing the Neuropathic Pain Symptom Inventory (NPSI) total score in patients with moderate to severe chronic PNP due to postherpetic neuralgia or peripheral nerve injury, compared to placebo.
• Demonstrating the safety and tolerability of NT 201 compared to placebo in participants with postherpetic neuralgia or chronic neuropathic pain after peripheral nerve injury.

The clinical trial focuses on individuals experiencing **moderate to severe chronic peripheral neuropathic pain** due to postherpetic neuralgia or peripheral nerve injury. The study population includes both male and female participants, with an age range encompassing adults and older adults. The trial does not specify the total number of participants, as this information was not provided by the sponsor. Participants were selected based on the presence of chronic peripheral neuropathic pain persisting for at least six months, plausibly related to an episode of herpes zoster or a peripheral nerve injury. The trial includes individuals with a documented diagnosis of chronic neuropathic pain after peripheral nerve injury or postherpetic neuralgia, with a probable level of certainty according to the NeuPSIG/IASP grading system. Additionally, participants must have a score of at least 4 out of 10 on the Neuropathic Pain 4 Questions (DN4) questionnaire. The trial population includes vulnerable groups, although specific lifestyle considerations such as diet or physical activity are not detailed in the available data.

The clinical trial is designed as a **randomized**, **double-blind**, controlled study to evaluate the efficacy and safety of subcutaneous NT 201 injections compared to placebo in reducing pain intensity in participants with moderate to severe chronic neuropathic pain due to postherpetic neuralgia or peripheral nerve injury. The trial will involve male and female participants aged 18 years and older. The study is structured into two arms, with participants randomly assigned to receive either the active treatment or placebo. The trial is expected to last approximately 20 weeks, with recruitment starting on January 29, 2024, and ending on February 3, 2025.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as chronic peripheral neuropathic pain persisting for at least six months and a documented diagnosis of postherpetic neuralgia or neuropathic pain after peripheral nerve injury. The screening will also include a score of at least 4 on the Neuropathic Pain 4 Questions (DN4) questionnaire. Following the screening, participants will attend regular follow-up visits to monitor changes in pain intensity and assess any treatment-emergent adverse events. The primary endpoint is the weekly average change in Average Daily Pain (ADP) intensity from baseline at Weeks 2 to 12. Secondary endpoints include changes in the NPSI total score and the incidence of adverse events.

The expected length of participant involvement is approximately 20 weeks, with the possibility of early termination if significant adverse events occur or if the participant withdraws consent. The trial will conclude with an end-of-study visit to evaluate the overall outcomes and safety of the treatment. Participants' involvement may be terminated early if they experience severe adverse reactions or if they choose to withdraw from the study. The trial aims to provide evidence of the efficacy of NT 201 in reducing pain intensity compared to placebo, contributing valuable data to the treatment of chronic neuropathic pain.

The clinical trial involves the administration of **XEOMIN**, a pharmaceutical product containing **Clostridium botulinum neurotoxin type A (150kD), free of complexing proteins**. This experimental medication is provided in the form of a powder for solution for injection. The product is administered via **subcutaneous injection**. The maximum daily dose is 300 U units, with a total maximum dose of 300 U units over a treatment period of up to 20 days. The product is specifically labeled for clinical trial use and is manufactured by Merz Pharmaceuticals GmbH. Participant compliance with the dosing schedule will be monitored throughout the trial.

The study also includes a **placebo** comparator, referred to as "Placebo to NT 201". This placebo is designed to match the experimental treatment in appearance but contains no active substance. The placebo is used to maintain the double-blind nature of the trial, ensuring that neither the participants nor the investigators know which treatment is being administered. The placebo is administered in the same manner as the experimental treatment, via subcutaneous injection, to ensure consistency in the administration process.

Additionally, **paracetamol** is included as a non-experimental treatment in the study. Paracetamol is provided in tablet form and serves as an analgesic and antipyretic. It is administered orally, with a maximum daily dose of 4000 mg and a total maximum dose of 560 g over the course of the trial. This medication is used to manage any pain or fever that may arise during the study, ensuring participant comfort and safety. Compliance with the paracetamol dosing schedule will also be monitored to ensure adherence to the study protocol.

The efficacy of the clinical trial will be assessed by evaluating the primary and secondary endpoints. The primary endpoint is the weekly averages of changes from baseline in Average Daily Pain (ADP) intensity at Weeks 2 to 12. This will be measured to determine the effectiveness of **NT 201** in reducing pain intensity compared to placebo in participants with moderate to severe chronic neuropathic pain due to postherpetic neuralgia or peripheral nerve injury.

Secondary endpoints include changes from baseline in the Neuropathic Pain Symptom Inventory (NPSI) total score at Weeks 2 to 12, and the incidence of treatment-emergent adverse events (TEAEs) related to the study intervention, as assessed by the investigator from intervention to the end of the study. These assessments will provide additional insights into the efficacy and safety profile of the treatment. The trial is designed as a multicenter, double-blind, randomized, parallel-group study, ensuring rigorous evaluation of the treatment's efficacy.