Workshop on Clinical Outcome Measures and endpoints for efficacy assessment in spinal muscular atrop

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Workshop on Clinical Outcome Measures and
endpoints for efficacy assessment in spinal
muscular atrophy13th October European Medicines
Agency, London

• Scientific Consensus on Outcome Measures for
  Ambulatory SMA

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Ambulatory Individuals with SMA (Able to
walk 10 M with no assistive device)

• Experts convened to discuss outcome measures
  endpoints used in SMA.
• Initiated an evidence based literature review
  of outcome measures used in SMA.
• Results of above shared with working groups and
  recommendations offered.
• What is missing from the Evidence Based Medicine
  paradigm in this ambulatory or SMA III
  presentation is the consensus of patient opinion

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Suggestion for Primary Outcome Measure

• The Six Minute Walk Test (6MWT)
• The 6MWT has been used to assess function and
  endurance in a number of diseases and has
  recently been chosen as a primary outcome in
  therapeutic trials in several neuromuscular
  disorders.
• There is no literature on the use of the 6MWT in
  ambulatory individuals with SMA.
• Why recommend? Precedent in other disorders,
  including neuromuscular, and its acceptance by
  Regulatory as a primary outcome measure.

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Secondary Outcome Measures

• A comprehensive assessment including measures of
  function, strength, pulmonary function and
  electrophysiological studies.

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Secondary Outcome Recommendations

• Timed Functional Tests (10 M walk, up from floor,
  out of chair, climbing stairs)
• Functional Scale ( MFM, North Star, Expanded
  Hammersmith, MHFMS-EXTEND)
• Record of Falls
• Strength Hand-held myometry (age gt 5 years)
• Pulmonary Function Forced Vital Capacity (FVC)
  (age gt5 years)
• CMAP

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Evidence for 6MWT

• Cardiopulmonary literature
• Fibromyalgia, Poliomyelitis, Myotonic Dystrophy,
  Spinal Bulbar Muscular Atrophy, MPS 1,Late Onset
  Pompe disease
• Demonstrated to be a safe, easy, and inexpensive
  way to measure functional capacity/impairment in
  both children and adults

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Evidence for 6MWT continued

• Distance walked in the 6MWT has correlated
  significantly with the physiologic cost index,
  lower extremity strength, balance, pre-test pain,
  FVC, and with sub-scores (Physical Function and
  Physical Component Summary) of the SF-36
• There is normative data for both children and
  adults

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6MWT in Neuromuscular Disease

• CONCLUSION The 6MWT has been demonstrated
  reliable, valid and sensitive to change in
  distance walked in children and adults with
  various neuromuscular disorders. These finding
  support the use of the 6MWT as an outcome
  measure/endpoint for ambulatory individuals in
  clinical studies in neuromuscular disease.
• Further study is recommended to validate the use
  of the 6MWT in the ambulatory SMA population.

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Evidence Based Literature Review of Outcomes in
SMA III (ambulatory)

• Inclusion Criteria
• SMA 5q
• Patients (not animals or cells)
• Prospective studies
• Use of measure/scale/test as related to
  one or
• more of the following
• Survival Pulmonary/respiratory
  function
• Motor function strength
• Electrophysiological function
• Quality of life

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Evidence Based Literature Review cont.

• Exclusion Criteria
• No retrospective or single case studies
• No diagnostic studies with genetics or
  EMG
• No genetic studies
• No reviews or meeting reports
• No cognitive functional measures
• No surgical studies
• No sleep studies

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Reviewing the Outcomes Literature

• Committee chose a preliminary approach to get a
  handle on the data
• 1. Sorted data by outcome measure by
  report
• 2. Sorted outcome measures by ability
  of data on
• a given measure to contribute to
  clinical trial
• design

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Timed Functional Tests

• Time to walk/run 10 M
• Time to climb standard stairs
• Time to arise from floor
• The above timed tests had one paper with
  sufficient data to perform power calculations.
  Minimal information exists on reliability,
  validity, sensitivity, MCID (minimal clinically
  important difference), and natural history.
• Time to get up from chair had no information in
  the SMA population though has been used in
  Limb-Girdle Dystrophy natural history studies

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Functional Scales/Motor Function

• Of the functional scales recommended (MFM, North
  Star, Expanded Hammersmith, MHFMS-EXTEND) one
  publication on the Hammersmith in SMA III had
  sufficient data for power calculations

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Number of Falls

• No published information

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Strength/Force Production

• Hand held dynamometry/myometry (HHD)
• Seven publications have sufficient data for power
  calculations
• One of the seven documents reliability in their
  own cohort. Other papers reference a paper that
  documents the reliability of HHD in SMA II III
  while looking at the relationship between HHD
  measurements and function

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Pulmonary Function

• Forced Vital Capacity (FVC)
• Three publication had sufficient data to perform
  power calculations.
• One of the above publications documented
  reliability
• One paper looked at change over time documenting
  limited change over 2-6 years

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Electrophysiological Evaluation

• CMAP
• Two publications had sufficient data for power
  calculations
• An upcoming presentation will address
  electrophysiological studies in SMA

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Summary

• Both literature expert opinion support the use
  of recommended primary secondary outcome
  measures
• A Quality or Life Measure Patient consensus
  need to be incorporated into the oaradigm
• Presented outcomes have precedent as being used
  as primary secondary outcomes in presently
  ongoing therapeutic trials in other neuromuscular
  disorders
• Studies are ongoing that further investigate the
  use of presented outcomes in SMA in therapeutic
  trials