Efficacy and Safety of NT 201 in Treating Lower Limb Spasticity Post-Stroke or Traumatic Brain Injury in Adults: A Randomized, Double-Blind, Placebo-Controlled Study

The primary objective of this study is to evaluate the **efficacy** and **safety** of 400 Units [U] of NT 201 in the treatment of adult lower limb **spasticity** involving the ankle plantar flexors. This is clinically relevant as it aims to address the functional impairments and improve the quality of life in patients suffering from spasticity due to stroke or traumatic brain injury. The secondary objective is to assess the long-term safety of NT 201 in the treatment of spasticity with total body doses up to 800 U. This evaluation is crucial for understanding the extended safety profile of NT 201, ensuring its safe application in clinical practice for managing spasticity over prolonged periods.

The clinical trial involves a total of **257 participants** diagnosed with **lower limb spasticity**, specifically targeting the ankle plantar flexors. The study population includes both **female and male subjects** aged between 18 and 85 years. Participants were selected based on specific criteria, including a diagnosis of lower limb spasticity, with or without upper limb spasticity on the same body side, caused by stroke or traumatic brain injury. The trial focuses on individuals with disabling ankle flexor spasticity, presenting as pes equinus or pes equinovarus, and a Modified Ashworth Scale-Bohannon score of 2 or 3 points in the ankle plantar flexor of the target lower limb. Participants must have a minimum passive range of motion in the ankle of the target lower limb, with at least 10° dorsiflexion and 20° plantarflexion. Additionally, subjects must have had at least four months since their last botulinum neurotoxin injection for spasticity or any other condition. The trial includes individuals on anticoagulation therapy, provided they meet specific coagulation parameters. The study population is not limited by gender, and it includes a vulnerable population, ensuring a comprehensive evaluation of the treatment's efficacy and safety.

The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled** study to evaluate the efficacy and safety of NT 201 in treating **lower limb spasticity** caused by stroke or traumatic brain injury in adults. The trial will be conducted in multiple centers and will include an open-label extension phase, with or without combined upper limb treatment. The primary objective is to assess the efficacy and safety of 400 Units of NT 201 in treating adult lower limb spasticity involving the ankle plantar flexors. The trial is expected to conclude by March 2, 2026, with recruitment having started on September 2, 2019.

Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on specific inclusion criteria, such as age between 18 and 85 years, diagnosis of lower limb spasticity, and a Modified Ashworth Scale-Bohannon score of 2 or 3 points in the ankle plantar flexor. The study will include follow-up visits at Weeks 4 and 6 to assess changes from baseline in the derived MAS ankle score and other secondary endpoints. The end-of-study visit will mark the completion of the trial for each participant.

The expected duration of participant involvement is up to 92 days, corresponding to the maximum treatment period. Conditions that may lead to early termination from the study include the occurrence of treatment-emergent adverse events or failure to adhere to the study protocol. The trial will utilize **intramuscular injection** as the route of administration for the investigational product, NT 201, and its placebo counterpart. The study aims to provide valuable insights into the treatment of lower limb spasticity, contributing to the understanding of NT 201's therapeutic potential.

The clinical trial involves the administration of **XEOMIN**, a pharmaceutical product containing **Clostridium botulinum neurotoxin type A (150kD), free of complexing proteins**. XEOMIN is provided in the form of a powder for solution for injection. The product is manufactured by Merz Pharmaceuticals GmbH and is authorized for use in several countries under various marketing authorization numbers. The active substance is classified under the ATC code M03AX01, indicating its categorization as a botulinum toxin. The maximum daily dose is 800 U units, with a total maximum dose of 800 U units over a treatment period of up to 92 days. The administration route is via intramuscular injection, specifically targeting the treatment of lower limb spasticity in adult subjects. The dosing schedule is determined based on the specific needs of the trial and is monitored for compliance.

In addition to the experimental treatment, a **placebo** is utilized in the study to serve as a comparator. The placebo is designed to mimic the appearance and administration method of XEOMIN but does not contain the active neurotoxin. This placebo is used to maintain the double-blind nature of the trial, ensuring that neither the participants nor the investigators are aware of the treatment assignments. The placebo is administered following the same intramuscular injection route and dosing schedule as the active treatment, allowing for a controlled comparison of efficacy and safety outcomes.

The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary efficacy endpoint is the change from baseline in the derived Modified Ashworth Scale (MAS) ankle score, with the knee extended, at Weeks 4 to 6. This will be evaluated using a value modelled from the actual values measured at Week 4 (V3) and Week 6 (V4). Additionally, the Global Impression of Change Scale (GICS) assessed by the physician at Week 4 to 6 will serve as a co-primary endpoint for the US regulatory authority, and as a secondary endpoint otherwise. The primary safety variable will be the occurrence of treatment-emergent adverse events (TEAEs) during the main period.

Secondary efficacy endpoints include the change from study baseline in the Goal Attainment Scale (GAS) at Week 6 (V4), and the GICS assessed by the subject and caregiver from Week 4 (V3) to Week 6 (V4). These assessments will provide a comprehensive evaluation of the treatment's impact on lower limb spasticity in adult subjects. The trial is designed to ensure rigorous data collection and analysis, adhering to the standards expected in a phase 3 clinical trial.