Title: Workshop on Clinical Outcome Measures and endpoints for efficacy assessment in spinal muscular atrop
1Workshop 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
2Ambulatory 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
3Suggestion 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.
4Secondary Outcome Measures
- A comprehensive assessment including measures of
function, strength, pulmonary function and
electrophysiological studies.
5Secondary 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
6 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
7Evidence 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
86MWT 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.
9Evidence 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
-
10Evidence 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
11Reviewing 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
12Timed 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
13Functional 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
14Number of Falls
15Strength/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
16Pulmonary 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
17Electrophysiological Evaluation
- CMAP
- Two publications had sufficient data for power
calculations - An upcoming presentation will address
electrophysiological studies in SMA
18Summary
- 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