Safety of Xeomin for Lower Limb Spasticity in Multiple Sclerosis Patients
Condition: Muscle Spasticity; Multiple Sclerosis
MeSH terms: Muscle Spasticity; Multiple Sclerosis; Sclerosis
Study type: Interventional
Phase: Phase 4

Summary: 
      The purpose of this study is to determine if Xeomin® will prove effective for significantly
      improving lower extremity spasticity and will be well tolerated by the majority of MS
      patients.
    

Detailed description: 
      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.
    

Intervention name(s): incabotulinumtoxinA; Placebo
Intervention type(s): Biological; Biological
Intervention description(s): 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 at injection visit; Saline injection on the day of injection visit
Other intervention name(s): Xeomin®
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: spasticity; lower limb; multiple sclerosis; toxin