What is Meaningful Change in Spinal Muscular Atrophy?

What is Meaningful Change in Spinal Muscular Atrophy?

A tool that is commonly used to evaluate motor function in spinal muscular atrophy (SMA) patients is the Hammersmith Functional Motor Scale (HFMSE).1 Given the extensive use of this tool, particularly for clinical trial research that aims to identify and develop therapeutic interventions to help those with SMA,2–5 it is important that the HFMSE provides a comprehensive view of motor function in SMA patients and that there are no important aspects of motor function that are not captured through the tool. 

HFMSE consists of 33 items that relate to the following abilities: rolling, getting up from a lying position, sitting on a chair without the need for support, propping on arms, kneeling, standing, stepping, jumping, squatting, and walking up and down stairs.6 Given the growing recognition that the HFMSE may not encapsulate every meaningful aspect of motor function in SMA, researchers have begun to discuss how else motor function could be evaluated in SMA patients. 

A second tool, the Upper Limb Module (ULM), has thus been developed as an attempt to capture aspects of motor function that may not be captured by the HFMSE.7–9 This tool focuses on identifying changes in abilities related to daily activities in those with SMA who are unable to walk.10 Nonetheless, researchers now realize that patients and their loved ones and caregivers may be able to provide invaluable information on what defines meaningful change in SMA that can be incorporated into tools used to evaluate function and functional change.11,12 This notion is corroborated by the United States Food and Drug Administration (FDA), which has published guidance calling for more patient input related to outcomes.13,14

Recent research into what is considered meaningful change for those affected by SMA has provided some powerful insights.1 For one, what is important to SMA patients is not consistent from patient to patient. Common themes, however, have been identified. Two such themes are the fear associated with loss of functioning and the lack of expectation of functional improvement. Consistent with these themes, many patients with SMA view therapies that can stop the progression of SMA as beneficial, even if those therapies are not associated with improvements. 

SMA patients have also reported that they believe that the items covered in both the HFMSE and the ULM are important but that they worry that some functional changes that may not be identified through these tools could be meaningful to patients and should therefore be assessed.1 In addition, changes in motor function represent just one area of changes that SMA patients experience,15 and neither the HFMSE nor the ULM get at other aspects of the disease. Researchers suggest that clinical trials should include measures of some of these other elements of SMA, including, for instance, respiratory function, swallowing, fatigue, falls, and ability to perform daily activities.16 Going forward, input from those with SMA, as well as their loved ones and caretakers, will likely prove extremely helpful in identifying the outcomes that should be evaluated and in developing the appropriate tools to do so.

References

1. McGraw S, Qian Y, Henne J, Jarecki J, Hobby K, Yeh W-S. A qualitative study of perceptions of meaningful change in spinal muscular atrophy. BMC Neurol. 2017;17(1):68. doi:10.1186/s12883-017-0853-y

2. Kaufmann P, McDermott MP, Darras BT, et al. Prospective cohort study of spinal muscular atrophy types 2 and 3. Neurology. 2012;79(18):1889-1897. doi:10.1212/WNL.0b013e318271f7e4

3. Kirschner J, Schorling D, Hauschke D, et al. Somatropin treatment of spinal muscular atrophy: a placebo-controlled, double-blind crossover pilot study. Neuromuscul Disord. 2014;24(2):134-142. doi:10.1016/j.nmd.2013.10.011

4. Chen T-H, Chang J-G, Yang Y-H, et al. Randomized, double-blind, placebo-controlled trial of hydroxyurea in spinal muscular atrophy. Neurology. 2010;75(24):2190-2197. doi:10.1212/WNL.0b013e3182020332

5. Mazzone E, De Sanctis R, Fanelli L, et al. Hammersmith Functional Motor Scale and Motor Function Measure-20 in non ambulant  SMA patients. Neuromuscul Disord. 2014;24(4):347-352. doi:10.1016/j.nmd.2014.01.003

6. Glanzman AM, O’Hagen JM, McDermott MP, et al. Validation of the Expanded Hammersmith Functional Motor Scale in spinal muscular  atrophy type II and III. J Child Neurol. 2011;26(12):1499-1507. doi:10.1177/0883073811420294

7. Montes J, Glanzman AM, Mazzone ES, et al. Spinal muscular atrophy functional composite score: A functional measure in spinal muscular atrophy. Muscle Nerve. 2015;52(6):942-947. doi:10.1002/mus.24670

8. Sivo S, Mazzone E, Antonaci L, et al. Upper limb module in non-ambulant patients with spinal muscular atrophy: 12 month changes. Neuromuscul Disord. 2015;25(3):212-215. doi:10.1016/j.nmd.2014.11.008

9. Seferian AM, Moraux A, Canal A, et al. Upper limb evaluation and one-year follow up of non-ambulant patients with spinal muscular atrophy: an observational multicenter trial. PLoS One. 2015;10(4):e0121799. doi:10.1371/journal.pone.0121799

10. Mazzone E, Bianco F, Martinelli D, et al. Assessing upper limb function in nonambulant SMA patients: development of a new module. Neuromuscul Disord. 2011;21(6):406-412. doi:10.1016/j.nmd.2011.02.014

11. Peay HL, Hollin I, Fischer R, Bridges JFP. A community-engaged approach to quantifying caregiver preferences for the benefits and risks of emerging therapies for Duchenne muscular dystrophy. Clin Ther. 2014;36(5):624-637. doi:10.1016/j.clinthera.2014.04.011

12. Crosby RD, Kolotkin RL, Williams GR. Defining clinically meaningful change in health-related quality of life. J Clin Epidemiol. 2003;56(5):395-407.

13. Guidance for industry: patient-reported outcome measures: use in medical product  development to support labeling claims: draft guidance. Health Qual Life Outcomes. 2006;4:79. doi:10.1186/1477-7525-4-79

14. McLeod LD, Coon CD, Martin SA, Fehnel SE, Hays RD. Interpreting patient-reported outcome results: US FDA guidance and emerging methods. Expert Rev Pharmacoecon Outcomes Res. 2011;11(2):163-169. doi:10.1586/erp.11.12

15. Nurputra DK, Lai PS, Harahap NIF, et al. Spinal muscular atrophy: from gene discovery to clinical trials. Ann Hum Genet. 2013;77(5):435-463. doi:10.1111/ahg.12031

16. Iannaccone ST, Hynan LS, Morton A, Buchanan R, Limbers CA, Varni JW. The PedsQL in pediatric patients with Spinal Muscular Atrophy: feasibility, reliability, and validity of the Pediatric Quality of Life Inventory Generic Core Scales and Neuromuscular Module. Neuromuscul Disord. 2009;19(12):805-812. doi:10.1016/j.nmd.2009.09.009