Safety of Xeomin for Lower Limb Spasticity in Multiple Sclerosis Patients

Overall Design: Thirty patients with MS, male or female, ages 18-70, either relapsing or progressive types, are to be evaluated in a prospective treatment trial comparing gait before and after injections of Xeomin.

Patient Population: The patients included are to have functionally significant equinovarus spasticity in primarily one lower extremity; functionally significant spasticity is defined as spasticity impairing gait during observation of during a 25 foot walk, causing falls, or leading to secondary orthopedic complications such as genu recurvatum or pain in the low back or hip. The patients are to be ambulatory, with stable disease.

Dose Selection: A dose of 200 units to 400 units of Xeomin will be injected by EMG-guided technique into the appropriate muscles in the effected leg. These muscles may include gastrocnemius and soleus, tibialis posterior or other muscles as determined by the examiner. The dose administered will be determined by the blinded injector based on determination of muscle bulk and the degree of spasticity Blinding: Investigators will be blinded to medication used throughout study. Site will randomize subjects in a 1:1 fashion by using an unblinded site delegate.

Compliance with Laws and Regulations: This study will be conducted in accordance with the U.S. Food and Drug Administration (FDA) regulations, the International Conference on Harmonisation (ICH) E6 Guideline for Good Clinical Practice (GCP), and applicable local, state, and federal laws.

Study Assessments: After informed consent is obtained and screening measurements are completed, the patients will return at 4 weeks for injection for primary and secondary efficacy evaluations. Additional evaluations at 6 and 12 weeks will be made in order to determine the duration of effect of Xeomin for secondary efficacy evaluations.

Concomitant therapy includes any prescription or over the counter preparations being taken by the patient at any time from screening through the last study visit. All concomitant medications should be reported to the investigator and recorded.

Patients enrolled in the study will be permitted to take all medication with the exception of the following

• Methylprednisolone within 30 days prior to screening
• Injection of any botulinum toxin within the past 6 months (180days)

During the study patients will be permitted to receive any treatment deemed necessary by the investigator for the management of disease. However patients requiring commencement of excluded therapies will be discontinued from the study and the data will not be used for statistical purposes.

Study Assessments:

Patients must sign informed consent form before any screening evaluations or measurements are performed. Patients must satisfy all of the inclusion criteria and none of the exclusion criteria to be randomized. Information regarding consented patients who are not subsequently randomized will be keep in the regulatory binder.

SAFETY MEASURES

Safety assessments will consist of monitoring and recording adverse events (AE's) and serious adverse events (SAE's). All SAE's will be reported to the FDA Med Watch within 48 business hrs of site notification of such SAE. For this protocol a serious SAE will be defined as any AE that is meets any of the following criteria:

• Fatal (i.e. the AE actually causes or leads to death)
• Life threatening (i.e. the AE in the view of the investigator, placing the patient at immediate risk of death)
• Requires or prolongs hospitalization
• Results in persistent or significant disability/incapacity (i.e. the AE results in substantial disruption to the patients ability to conduct normal life functions)
• A congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the investigational product
• Considered a significant medical event by the investigator (e.g, may jeopardize the patient or may require medical/surgical intervention to prevent one of the outcomes listed above)

The FDA Adverse Event Reporting System Med Watch is a Reporting system for Health Professionals

STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE A detailed description of the statistical methodology will be provided in the statistical analysis plan (SAP) which may deviate from the analysis outlined in the protocol; however, any substantial deviations from the protocol will be detailed in a protocol amendment.

Description of Endpoints

• Primary Endpoint Mean change from injection visit to week 6 in the Modified Ashworth score between Xeomin vs placebo group
• Secondary Endpoints
• Mean change from injection visit to week 6 in Multiple Sclerosis Impact Scale (MSIS-29) Physical and psychological scores between Xeomin vs placebo group
• Mean change from injection visit to week 6 in T25FW between Xeomin vs Placebo group.
• Patient global impression of change (PGIC) between Xeomin vs placebo group
• Clinical Global Impression of change between Xeomin vs placebo group
• Mean change from injection visit to week 6 in Likert pain scale between Xeomin vs placebo group
• Mean change from injection visit to week 6 in MSWS-12 between Xeomin vs placebo group.

Demography and Baseline Disease Characteristics

• Demographic and baseline characteristics will be presented descriptively (i.e., mean, standard deviation, median, range) and analyzed with appropriate statistical methods given the distribution and type of data.

Efficacy

• Analysis Population The Intent-to-Treat population is defined as all subjects who receive at least 1 dose of study treatment and who provide efficacy assessment.
• General Methods of Analysis Descriptive statistics will be provided for all efficacy endpoints. A two-sided test, p-value and confidence interval will be presented for analysis in general.
• Primary Endpoint Analysis The primary endpoint is the mean change from injection visit to week 6 in Modified Ashworth score . A two sample T-test will be used to compare the treatment difference between Xeomin and placebo group. If the data is not normally distributed, Wilcoxon's rank sum test will be used for the analysis.
• Secondary Endpoints Analysis Percent change from injection visit to week 6 will be calculated for the primary endpoint. It will be analyzed similarly as that for the primary endpoint. For secondary endpoints MSIS 29, T25FW, Likert pain scale and MSWS-12 a similar statistical approach as outlined for the primary endpoint will be used to assess the mean changes from injection visit to week 6 in each of the scales between treatment groups.

Patient global impression of change (PGIC) and clinical global Impression of change will be analyzed using the Wilcoxon's rank sum test.

Safety

• Analysis Population The safety population is defined as all subjects who receive at least 1 dose of study treatment.

Adverse events will be listed. Serious AE will be listed as well.

Sample Size Considerations Based on observational study, patients using Xeomin had an improvement of 50% on the Ashworth scale. A sample size of 15 patients per group will provide 80% power to detect a treatment difference of 50% with a 0.05 two-sided significance level using a chi-square test.