Efficacy and Safety of Clostridium Botulinum Neurotoxin Type A in Pediatric Lower Limb Spasticity Due to Cerebral Palsy: A Randomized, Double-Blind, Placebo-Controlled Study

The primary objective of this study is to demonstrate the **efficacy** of NT 201 by showing its superiority compared to placebo in children and adolescents with lower limb spasticity caused by cerebral palsy, assessed at week 4 to week 6 following a single injection. This is clinically relevant as it aims to establish NT 201 as a more effective treatment option for managing spasticity in this patient population, potentially improving their quality of life and functional outcomes.

Secondary objectives include: - Demonstrating the relevance of the effect of NT 201 compared to placebo in terms of response rates in the derived Modified Ashworth Scale (MAS) score of plantar flexors at week 4 or week 6 after a single injection. - Assessing the effect of NT 201 compared to placebo using the Global Impression of Change of Plantar Flexor Spasticity Scale (GICSPF) at week 4 to week 6 after a single injection. - Evaluating the effect of NT 201 compared to placebo using the Goal Attainment Scale (GAS) at week 4 to week 6 after a single injection.

The clinical trial involves a total of **105 participants** diagnosed with **pediatric lower limb spasticity** caused by **cerebral palsy**. The study population includes both male and female subjects aged between 2 and 17 years. Participants were selected based on specific criteria, including the presence of bilateral, symmetrical pes equinus due to lower limb spasticity, with any Gross Motor Function Classification System level. The trial population is characterized by an identical Modified Ashworth Scale plantar flexor score of at least 2 for pes equinus clinical patterns in both legs at a neutral ankle position and knee at maximum extension. The study includes a vulnerable population, and lifestyle factors such as diet and physical activity were not specified. Key inclusion criteria for the Open-Label Extension Period require a Modified Ashworth Scale plantar flexor score of at least 1 in both pes equinus clinical patterns and agreement from the investigator, parents, and the subject, if applicable, to continue treatment.

The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled** study with a two-stage, multicenter approach, followed by an open-label extension period. The primary objective is to evaluate the efficacy and safety of NT 201 in treating lower limb spasticity in children and adolescents with **cerebral palsy**. The trial is expected to run from October 12, 2022, to March 4, 2025, with recruitment starting on November 15, 2022, and ending on August 27, 2024. Participants will be involved for a maximum treatment period of 32 weeks.

The study visits are structured to include an initial screening visit to assess eligibility based on criteria such as age (2 to 17 years), bilateral symmetrical pes equinus due to lower limb spasticity, and a modified Ashworth Scale (MAS) plantar flexor score of ≥2. Following the screening, participants will undergo a baseline visit where they will receive a single injection of either NT 201 or placebo. Control visits are scheduled at weeks 4 and 6 to evaluate the primary endpoint, which is the change in the derived MAS score of plantar flexors. Secondary endpoints include the response in the MAS score, GICS-PF score, and GAS T-score at these control visits.

The open-label extension period will allow participants who meet specific criteria, such as a MAS plantar flexor score of ≥1, to continue treatment. The end-of-study visit will conclude the participant's involvement, assessing long-term safety and efficacy outcomes. Participants may be withdrawn from the study early if they experience adverse events, fail to comply with the study protocol, or if the investigator deems it necessary for their safety. The trial is conducted under strict adherence to ethical guidelines and regulatory requirements to ensure the safety and well-being of all participants.

The clinical trial involves the administration of **XEOMIN**, a pharmaceutical product containing **Clostridium botulinum neurotoxin type A (150 kD), free of complexing proteins**. This experimental medication is provided in the form of a powder for the preparation of a solution for injection. The product is manufactured by Merz Pharmaceuticals GmbH and is identified by the marketing authorization number 16-0111 in Latvia and 23378 in Poland. The medication is administered via **intramuscular injection**. The maximum daily dose is 400 U units, with a total maximum dose of 400 U units over a treatment period of up to 32 weeks. The trial-specific labeling is applied to the investigational medicinal product (IMP). The active substance is classified under the ATC code M03AX01, which corresponds to botulinum toxin.

The study also includes a **placebo** comparator, referred to as "Placebo to NT201." The placebo is designed to match the experimental treatment in appearance but does not contain the 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 not associated with any specific pharmaceutical form or active substance, and it is not linked to any marketing authorization number or ATC classification.

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is the change in the derived modified Ashworth Scale (MAS) score of plantar flexors from baseline at control visits at week 4 and week 6. This scale is a widely used tool for measuring spasticity, which is a key symptom in patients with lower limb spasticity caused by cerebral palsy.

Secondary endpoints include the response in the derived MAS score of plantar flexors at control visits at week 4 or week 6, with a response defined as an improvement of at least 1 point on the derived MAS score compared to the study baseline. Additional secondary endpoints are the Global Impression of Change Scale for Plantar Flexors (GICS-PF) score and the Goal Attainment Scaling (GAS) T-score, both evaluated at control visits at week 4 and week 6. These measures provide a comprehensive assessment of the treatment's impact on the patient's condition.

The trial is designed as a prospective, randomized, double-blind, placebo-controlled, two-stage, multicenter study with an open-label extension period. The main objective is to demonstrate the efficacy of NT 201 by showing its superiority compared intra-individually to placebo in children and adolescents with lower limb spasticity due to cerebral palsy, specifically at week 4 to week 6 after a single injection. The trial will utilize validated scales and scores to ensure the reliability and accuracy of the efficacy assessments.