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.

Inclusion Criteria:

- Male or female patients with clinically definite MS, either RRMS or a progressive
form (SPMS, PPSM, PRMS)

- Ages 18-65 years.

- Patients must be in a stable state, with no clinical relapses or methylprednisolone
treatments in the last 30 days, or have slowly progressive MS, with an EDSS score of
2.0-6.5.

- Patients must have functionally significant spasticity in predominantly one lower
extremity as determined by a score of >2 on the Modified Ashworth Scale at screen

Exclusion Criteria:

- Unstable medical or neurological disease

- Known sensitivity to Xeomin

- Prior injection with any botulinum toxin within 6 months

- EDSS score of 7.0 or greater

- Exacerbation of MS within the past 30 days

- Significant cognitive impairment or psychiatric disease

- Advanced arthritis or any other cause of clinically significant limitation of passive
range of motion around any of the joints being assessed in the study.

- Concomitant neurologic conditions causing spasticity or rigidity.

- Has had major surgery within 3 months prior to Screening visit that may affect
spasticity assessments such as back, lower leg or knee surgeries.

- Use of medications that could influence muscle tone or any anti-spasticity
medications must be stable >90 days prior to screening visit and must remain stable
throughout study period.