Evaluation of the Safety and Efficacy of AbobotulinumtoxinA Versus OnabotulinumtoxinA in Adult Upper Limb Spasticity: A Randomized, Double-Blind, Crossover Study

The primary objective of this study is to demonstrate the **non-inferiority** of AbobotulinumtoxinA (Dysport®) compared to OnabotulinumtoxinA (Botox®) in terms of safety, as assessed by the rate of all treatment-emergent adverse events (TEAEs) from injection to 12 weeks. This is clinically relevant as it aims to establish that Dysport® is at least as safe as Botox® for treating adults with **upper limb spasticity**, which can significantly impact patient quality of life and functional ability.

Secondary objectives include:

• To evaluate clinical safety, providing further insights into the safety profile of the treatments.
• To assess efficacy, which will help determine the therapeutic effectiveness of Dysport® compared to Botox® in managing upper limb spasticity.

The clinical trial involves a total of **414 participants** who are being studied for **upper limb spasticity** (ULS) of any etiology in the US and France, or post-stroke ULS in Canada. The study population includes both male and female participants, aged between **18 to 80 years**. Participants are required to have stable ULS for at least three months, with treatment necessary for only one upper limb during the study. The trial includes individuals who are either naïve to or have been previously treated with BoNT-A for ULS. Participants must have a Modified Ashworth Scale (MAS) score of at least 2 in two muscle groups and a Disability Assessment Scale (DAS) score of at least 2 on the Principal Target of Treatment (PTT). The trial population was selected based on their ability to provide informed consent and their stability in terms of oral antispasticity, anticoagulant, and/or anticholinergic medication for at least three months prior to study entry. Both male and female participants are required to use effective contraception if there is a risk of pregnancy. The study does not exclude vulnerable populations, and participants must not be pregnant or breastfeeding. The trial aims to assess the safety of treatments over a 12-week period.

The clinical trial is designed as a **randomized**, **double-blind**, crossover study to evaluate the clinical safety and efficacy of AbobotulinumtoxinA (Dysport®) compared to OnabotulinumtoxinA (Botox®) in adults with **upper limb spasticity**. The trial is classified as a Phase IV low interventional study, adhering to the Clinical Trials Regulation (EU) No 536/2014. The primary objective is to demonstrate non-inferiority in terms of safety, assessed by the rate of treatment-emergent adverse events (TEAEs) from injection to 12 weeks. Secondary endpoints include the rate of adverse drug reactions (ADRs), serious adverse events (SAEs), and adverse events of special interest (AESIs), as well as assessments of muscle tone, perceived function, pain, and quality of life over a period of up to 24 weeks.

The trial is expected to last until September 2025, with recruitment having started in January 2022. Participants will be involved for a maximum treatment period of 51 weeks. The study includes several key visits: an initial screening visit to confirm eligibility, regular follow-up visits at weeks 1, 4, 10, 12, 16, 20, and 24 to monitor safety and efficacy, and an end-of-study visit to conclude participation. The inclusion criteria require participants to be between 18 and 80 years old, with stable upper limb spasticity for at least three months, and either naïve to or previously treated with botulinum toxin type A for upper limb spasticity. Participants must also meet specific muscle tone and functional criteria and be stable on any concurrent medications for at least three months prior to the study.

Participant involvement may be terminated early if they experience significant adverse events, fail to comply with study protocols, or if the investigator deems it clinically necessary. The study aims to ensure minimal risk to participants, with all procedures aligned with the Summary of Product Characteristics (SmPC) for the medicinal products involved. The trial's design and methodology are structured to provide robust data on the comparative safety and efficacy of the two treatments, contributing valuable insights into the management of upper limb spasticity.

The clinical trial involves the administration of two experimental medications, both of which are **botulinum toxin type A** formulations. The first medication is **BOTOX 200 UNITÉS ALLERGAN**, a **poudre pour solution injectable**. This pharmaceutical form is prepared as a **solution for injection** and is administered via the **intramuscular** route. The active substance in this formulation is **botulinum toxin type A**, a protein of biological origin. The maximum daily dose for this medication is 360 U units, with a total maximum dose of 360 U units over a treatment period of up to 51 weeks. The medication is manufactured by **ABBVIE** and is not a paediatric formulation. Participant compliance with the dosing schedule will be monitored throughout the study.

The second experimental medication is **DYSPORT 500 UNITES SPEYWOOD**, also a **poudre pour solution injectable**. Similar to the first medication, it is prepared as a **solution for injection** and administered **intramuscularly**. The active substance in this formulation is **botulinum toxin type A - haemagglutinin complex**, also a protein of biological origin. The maximum daily dose for this medication is 900 U units, with a total maximum dose of 900 U units over a treatment period of up to 51 weeks. This medication is produced by **IPSEN PHARMA** and is also not a paediatric formulation. Compliance with the dosing schedule will be closely monitored to ensure adherence to the study protocol.

Both medications are of biological/biotechnological origin and are not classified as Advanced Therapy Investigational Medicinal Products (ATIMP). The trial is designed to evaluate the clinical safety and efficacy of these formulations in treating adults with upper limb spasticity, with a focus on demonstrating non-inferiority in terms of safety based on the rate of treatment-emergent adverse events (TEAEs) from injection to 12 weeks. No non-experimental treatments, such as standard-of-care therapy or placebo, are used in this study.

The clinical trial aims to evaluate the efficacy of **AbobotulinumtoxinA** (Dysport®) in comparison with **OnabotulinumtoxinA** (Botox®) for treating adults with upper limb spasticity. Efficacy will be assessed through several primary and secondary endpoints. The primary endpoint is the rate of treatment-emergent adverse events (TEAEs) from injection to 12 weeks. Secondary endpoints include the rate of adverse drug reactions (ADRs), serious adverse events (SAEs), and adverse events of special interest (AESIs) within the same timeframe.

Additional secondary endpoints involve the duration of response based on retreatment criteria, muscle tone assessment using the Modified Ashworth Scale (MAS) for finger, wrist, and elbow flexors at specified intervals (1, 4, 10, 12 ± 16, 20, 24 weeks), and perceived function and pain evaluated by the Disability Assessment Scale (DAS) at the same timepoints. The Patient Global Assessment (PGA) of treatment response will also be measured at these intervals. Quality of life will be assessed using the SF-12 perceived health score and the SQoL-6D at 4 weeks, 12 weeks, and at the end of each treatment cycle.