Hammersmith Functional Motor Scale Expanded

Instrument Name: Hammersmith Functional Motor Scale Expanded

Abbreviation: HFMSE

Points for Consideration:

More information needed

Description of Tool:

The HFMSE is a PerfO designed to assess gross motor function in Non-ambulant SMA populations.

Minimum Qualification Required by COA Administrator: MA or BA

Year: 2011

Objective of Development:

To assess high functioning SMA type II and III patients

Population of Development: Age range (therapeutic indication):

2 to 45 years in the development study
(Muscular Atrophy, Spinal)

Pediatric Population(s) in which COA has been used:

Congenital, Hereditary and neonatal diseases and Abnormalities; Nervous system disorders

COA type:

Number of Items 33 items

Mode of Administration:

Data Collection Mode:

Time for Completion: 12 minutes

Response Scales: 3-point verbal rating scale ranging from 0 "No response" to 2 "full response"

Summary of Scoring:

Available Scores:
Global Score ranging from 0 to 66

Weighting:
No

Score Interpretation:
Higher score = Better motor skills levels

Evidence of Literature Review: None identified

Evidence of Instrument Review: Yes

Evidence of Clinical or Expert Input: Yes

Evidence of concept elicitation in target patient population: Yes

Evidence of a Saturation Grid: None identified

Evidence for Selection of Data Collection Method: None identified

Recall/Observation Period:

Evidence for Selection of Reponse Options: Yes

Evidence of cognitive interviewing of draft instrument in target patient population: Yes

Evidence of Preliminary Scoring of Items and Domains: Yes

Evidence related to respondent and administrator burden: Yes

Evidence of a Conceptual Framework: None identified

Evidence of an item-tracking matrix: None identified

Evidence related to item selection: None identified

Evidence of re-testing the final version: Yes

Internal consistency (Cronbach's alpha): None Identified

Test-retest Reliability (ICC):

Kaufmann P (2011)
- Intraclass Correlation Coefficient (ICC): > 0.98 (exact value Not stated)
- Was a definition of stability applied to identify stable patients: No
- Time frame or interval between the two administrations: 2 months
- Population/Disease: Patients with SMA 2 (n= 35) or SMA 3 (n= 30) (mean age 11.2 ( SD 9.1))

Glanzmann A (2017)
- Intraclass Correlation Coefficient (ICC): r=0.959 (95%CI: 0.942–0.971)
- Was a definition of stability applied to identify stable patients: No
- Time frame or interval between the two administrations: Not stated (between the screening and baseline visits)
- Population/Disease: Patients from multicenter clinical trials in spinal muscular atrophy (SMA), n=125

Inter-rater/ inter-interviewer reliability (kappa):

Glanzmann A (2017)
- Intraclass Correlation Coefficient (ICC):Initial inter-rater reliability for all 3 assessments of total score and individual items was excellent (r = 0.867–0.994). Annual retraining reliability results were similar for the HFMSE (r=0.887–0.996) and RULM (r = 0.932–0.982) and slightly lower for CHOP INTEND (r = 0.817–0.889).
- Population/Disease: Patients from multicenter clinical trials in spinal muscular atrophy (SMA), n=125

Evidence of test-retest or inter-rater reliability: Yes

Concurrent validity (convergent, divergent):

O'Hagen JM (2007)

Correlation coefficient used: Spearman rank correlation coefficient
Measure: With the sum of the remaining 75 items of Gross Motor Function Measure (GMFM) and the full items of the GMFM.
Results:
The correlation between HFMSE and the GMFM-75 items was ρ=0.97, p: Not stated
The correlation between HFMSE and the Full GMFM was ρ=0.98, p: Not stated
Population/Disease: Patients with Spinal Muscular Atrophy (SMA) type II and type III; n= 38 ( Type II (n = 21), median age = 5.7 years,
range 2.3–32.5 years; Type III (n = 17) median age = 9.1 years, range 3.9–45.1 years)

Correlation coefficient used: Spearman rank correlation coefficient
Measure: A 10-functional rating scale of the severity of each patient ranging from 1 "inability to sit independently" to 10 "the ability to perform age appropriate moto skills".
Results: The correlation between HFMSE and the functional rating scale was ρ=0.90, p: Not stated
Population/Disease: Patients with Spinal Muscular Atrophy (SMA) type II and type III; n= 38 ( Type II (n = 21), median age = 5.7 years,
range 2.3–32.5 years; Type III (n = 17) median age = 9.1 years, range 3.9–45.1 years)

Glanzman AM (2011)

Correlation coefficient used: Spearman rank correlation coefficient
Measure: With the sum of the remaining 75 items of Gross Motor Function Measure (GMFM) and the full items of the GMFM and clinical presentation (functional rating scale)
Results:
Significant correlation between HFMSE and the GMFM-75 items was found: r=0.98, p<0.0001 Significant correlation between HFMSE and the Full GMFM was found r=0.99, p<0.0001 Population/Disease: Patients with Spinal Muscular Atrophy (SMA) type II and type III ; n= 38 (mean age 11.2 ( SD 9.1) Correlation coefficient used: Spearman rank correlation coefficient Measure: A 10-functional rating scale of the severity of each patient Results: Significant correlation between HFMSE and the functional rating scale was found: ρ=0.92, p<0.0001 Population/Disease: Patients with Spinal Muscular Atrophy (SMA) type II and type III ; n= 38 (mean age 11.2 ( SD 9.1) Dunaway S (2014) Correlation coefficient used: Pearson's correlation coefficient Measure: Timed Up & Go Test (TUG) Results: There was significant correlation between the HFMSE and the TUG (r= -0.717; p= 0.003) Population/Disease: Patients with SMA (mean age 28.7 years, range 10–49 years); n= 15

Known-group validity:

Glanzman AM (2011)

Measure/Groups of patients: Correlation between HFMSE and forces vital capacity (FCV)
A priori hypotheses: The relationship would be demonstrated
Were hypotheses confirmed: Yes
Results: Spearman rank correlation coefficients
Significant correlation was found between HFMSE and FCV (r= 0.87, p<0.0001) Population/Disease: Patients with SMA II or III; n= 56 (mean age 11.2 ( SD 9.1) Measure/Groups of patients: Correlation between HFMSE and knee extension strength (n= 56), elbow flexion strength (n= 61) and knee flexion strength (n=58) A priori hypotheses: The relationship would be demonstrated Were hypotheses confirmed: Yes Results: Spearman rank correlation coefficients; p< 0.0001 for all results Significant correlation between HFMSE and knee extension strength was found: r= 0.74 Significant correlation between HFMSE and elbow flexion strength was found: r= 0.77 Significant correlation between HFMSE and knee flexion strength was found: r= 0.74 Population/Disease: Patients with SMA II or SMA III; n= 56 to 61 (mean age 11.2 ( SD 9.1) KNown-groups validity: Measure/Groups of patients: Comparison of in HFMSE scores between patients with 2 SMN2 copies (n=3), 3 SMN2 copies (n= 47) or 4 SMN2 copies (n= 14) A priori hypotheses: Differences between each group will be found Were hypotheses confirmed: Yes Results: Kruskal-Wallis test: data Not shown A significant (p=0.0007) association between HFMSE and SMN2 copy number was found: 2 SMS2 copies (median= 3.0, IQR= 2-6); 3 SMN2 (median= 16.0, IQR= 3-34), and 4 SMN2 copies (median 51.0, IQR= 27-55) Population/Disease: Patients with different numbers of SMN 2 copies; n= 64 (mean age 11.2 ( SD 9.1) Measure/Groups of patients: Comparison of HFMSE scores between patients who needed less than 8 hours of bi-level airway pressure per day (n= 58) than those who needed at least 8 hours of bi-level positive airway pressure per day (n= 12) A priori hypotheses: HFMSE will be able to discriminate groups Were hypotheses confirmed: Yes Results: Wilcoxon rank sum tests: data Not shown A significant (p< 0.0001) difference was found between the subjects who needed less than 8 hours of bi-level positive airway pressure per day (median= 23.0 IQR= 9-50) than those who needed at least 8 hours of bi-level positive airway pressure per day (median= 3.0, IQR 0-7.5). Population/Disease: Patients with SMA II or III and who needed airway pressure ; n= 70 (mean age 11.2 ( SD 9.1) Measure/Groups of patients: Comparison of HFMSE scores between ambulatory patients (n= 25) and Non-ambulatory patients (n= 44) A priori hypotheses: HFMSE will be able to discriminate groups Were hypotheses confirmed: Yes Results: Wilcoxon rank sum tests: data Not shown A significant (p<0.0001) difference was found between ambulatory patients (median= 52, IQR= 48-57) and Non-ambulatory patients (media= 8, IQR= 2-18.5) Population/Disease: Ambulatory or Non-ambulatory patients with SMA II or III; n= 69 (mean age 11.2 ( SD 9.1) Measure/Groups of patients: Comparison of HFMSE scores between SMA type III patients (n= 33) and SMA type II patients (n= 37) A priori hypotheses: HFMSE will be able to discriminate groups Were hypotheses confirmed: Yes Results: Wilcoxon rank sum tests: data Not shown A significant difference was found between SMA type III patients (median) 49, IQR 29-55) and SMA type II (median= 8, IQR 2-17) Population/Disease: Patients with SMA II or SMA III; n= 70 (mean age 11.2 ( SD 9.1) Wijngaarde CA (2020) Measure/Groups of patients: Correlation with Medical Research Council (%MRC) scores Results: %MRC and HFMSE correlated strongly (τ = 0.80, 95% CI 0.77–0.82, n = 319 paired observations), except for patients with very low HFMSE scores. Population/Disease: 426 HFMSE measurements from 249 patients with SMA types 1c through , including 252 (59%) measurements during adulthood. Median age at inclusion was 19.7 years (IQR 7.5–38.5 years) [Please see Table 2 in the sub worksheet "Wijngaarde CA 2020"] Measure/Groups of patients: 6 groups according to the SMA types Results: Linear analyses stratified for SMA type revealed significant differences at baseline. Population/Disease: 426 HFMSE measurements from 249 patients with SMA types 1c through , including 252 (59%) measurements during adulthood (Table 2) Median age at inclusion was 19.7 years (IQR 7.5–38.5 years) Kaufmann P (2011) KNown-groups validity: Measure/Groups of patients: Mean change of annual HFMSE score in ambulatory participants (n= 22) vs Nonambulatory participants (n= 43) A priori hypotheses: Not stated Were hypotheses confirmed: Not applicable Results: ANCOVA. There was significant association between ambulatory status at baseline and mean annual rate of change in HFMSE score with a significant increase in function over time in ambulatory participants compared with a slight decline in function over time in Nonambulatory participants. The mean rate of change was 1.62 (95% CI, 0.14 to 3.10) in ambulatory participants and −0.47 (95% CI, −1.66 to 0.72) in Nonambulatory participants (p= 0.03) Population/Disease: Patients with SMA II or SMA III (mean age 11.2 ( SD 9.1)); n= 65 Montes J (2009) Measure/Groups of patients: Correlation with 6 minutes Walking Test (6MWT) Results: The 6MWT distance was significantly associated with HFMSE score (r = 0.563, p = 0.028) Population/Disease: Thirteen patients with SMA, median age 11 years (range 4 - 47) Dunaway S (2015) Measure/Groups of patients: Correlation with 6 minutes Walking Test (6MWT) Results: The 6MWT distance was significantly associated with HFMSE score (r=0.755, p<0.001) Population/Disease: Thirty ambulatory SMA, age Not stated

Evidence of Translatability Assessment: None identified

Evidence related to missing data: None identified

Evidence for Selection of Recall Period: None identified

Evidence of Administration Instructions and Training Provided: Yes

Evidence of concurrent validity: Yes

Evidence of known-groups validity: Yes

Evidence of ability to detect change over time: Yes

Ability to detect change (Responsiveness):

Young SD (2016)
Methods:
- Population/Disease: Patients with SMA II (n= 13) or SMA III (n= 5) who received scoliosis surgery
- Time horizon: at least 3 months post-operatively
- Group definition: Not stated
- Statistics used: Independent t-tests
- Results: There were significant differences in change scores between the stable and progressive groups (p< 0.001) - Group size: - Stable patients: n= 4 - Deteriorated patients: n= 14 - Magnitude of change for each group: - Stable patients: Minimal HFSME changes between -2 and +2 points (mean values: age= 8.6 years, SD= 3.3; baseline score= 6.8; change= -0.25, SD= 2.1) - Deteriorated patients: Loss of >3 points on the HFMSE, representing a clinically meaningful change (mean values: age= 10.0 years, SD= 3.9; baseline score= 19.4; change= -11.9, SD= 9.0)

Responder Thresholds:

Williams V (2019)
- Population/Disease: Patients with later-onset SMA; n= Not stated, age Not stated
-Methods used: Anchor-based
-Results:
MCID 3.82 based on the caregiver CGIC and 3.46 using the clinician CGIC at day 456; half-SD=4.1 and SEM=2.6

ROC curve analyses supported a smaller MCID of 2 HFMSE points of improvement as
meaningful to caregivers and clinicians

Provisional MCID and responder definition in was approximately 3-4 points of improvement on the 0 to 66 HFMSE scale.

Evidence of responder thresholds: Yes

Pera, M. C., Coratti, G., Forcina, N., Mazzone, E. S., Scoto, M., Montes, J., Pasternak, A., Mayhew, A., Messina, S., Sframeli, M., Main, M., Lofra, R. M., Duong, T., Ramsey, D., Dunaway, S., Salazar, R., Fanelli, L., Civitello, M., de Sanctis, R., Antonaci, L., … Mercuri, E. (2017). Content validity and clinical meaningfulness of the HFMSE in spinal muscular atrophy. BMC neurology, 17(1), 39. https://doi.org/10.1186/s12883-017-0790-9

Main, M., Kairon, H., Mercuri, E., & Muntoni, F. (2003). The Hammersmith functional motor scale for children with spinal muscular atrophy: a scale to test ability and monitor progress in children with limited ambulation. European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society, 7(4), 155–159. https://doi.org/10.1016/s1090-3798(03)00060-6

Conference Abstract] Burbridge C, Kelly K, Garcia L., et al. Mapping a qualitative exploration of meaningful change in later-onset (type II or III) spinal muscular atrophy to the Hammersmith Functional Motor Scale expanded (HFMSE). Value in Health. Conference: ISPOR 2019: Rapid. Disruptive. InNovative: A New Era in HEOR. United States. 22 (Supplement 2) (pp S284), 2019. Date of Publication: May 2019. (https://www.valueinhealthjournal.com/article/S1098-3015(19)31539-6/fulltext?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS1098301519315396%3Fshowall%3Dtrue)

[Conference Abstract] Dunaway S, Montes J, Kramer S, et al. Six-minute walk test is reliable and valid in spinal muscular atrophy. Neurology. Conference: 67th American Academy of Neurology Annual Meeting, AAN 2015. Washington, DC United States. Conference Publication: (var.pagings). 84 (SUPPL. 14) (No pagination), 2015. Date of Publication: 06 Apr 2015

Dunaway S., Montes J., Garber C.E., et al Performance of the timed "up & go" test in spinal muscular atrophy. Muscle Nerve. 2014;50(2):273-277 (https://onlinelibrary.wiley.com/doi/full/10.1002/mus.24153)

Glanzman AM, O'Hagen JM, McDermott MP. Validation of the Expanded Hammersmith Functional Motor Scale in spinal muscular atrophy type II and III. J Child Neurol. 2011 Dec;26(12):1499-507

Kaufmann P, McDermott MP, Darras BT, et al. Observational Study of Spinal Muscular Atrophy Type 2 and 3: Functional Outcomes Over 1 Year. Arch Neurol. 2011;68(6):779–786 (https://jamanetwork.com/journals/jamaneurology/fullarticle/503374)

McGraw S, Qian Y, Henne J, Jarecki J, Hobby K, Yeh WS. A qualitative study of perceptions of meaningful change in spinal muscular atrophy. BMC Neurol. 2017 Apr 4;17(1):68 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5381033/)

Montes J, Dunaway S, Glanzman A, et al. The 6-minute walk test in ambulatory subjects with SMA. Journal of Clinical Neuromuscular Disease. Conference: 31st Annual Carrell-Krusen Symposium. Dallas, TX United States. Conference Publication: (var.pagings). 10 (3) (pp 156), 2009. Date of Publication: March 2009.

O'Hagen JM, Glanzman AM, McDermott MP. An expanded version of the Hammersmith Functional Motor Scale for SMA II and III patients. Neuromuscular Disord. 2007 Oct;17(9-10):693-7

Pera MC, Coratti G, Forcina N, et al. Content validity and clinical meaningfulness of the HFMSE in spinal muscular atrophy. BMC Neurol. 2017 Feb 23;17(1):39 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5324197/)

Tillmann RP, Ramsey D, Main M, et al. Revised hammersmith scale (RHS) and hammersmith functional motor scale extended (HFMSE) for spinal muscular atrophy (SMA), a longitudinal comparison of captured disease progression. Developmental Medicine and Child Neurology. Conference: 44th Annual Conference of the British Paediatric Neurology Association, BPNA 2018. United Kingdom. 59 (Supplement 4) (pp 43), 2017. Date of Publication: December 2017. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5319655/)

Wijngaarde, Camiel A., et al. "Muscle strength and motor function in adolescents and adults with spinal muscular atrophy." Neurology 95.14 (2020): e1988-e1998.

[Conference Abstract] Williams V, Stull D, Houghton K., et al. Minimal clinically important differences of the expanded hammersmith functional motor scale in later-onset spinal muscular atrophy: results from the Phase 3 CHERISH trial. Poster presented at the 2019 AMCP Managed Care & Specialty Pharmacy Annual Meeting; March 25, 2019. San Diego, CA. [abstract] J Manag Care Spec Pharm. 2019 Mar; 25(3-a Suppl):S54

[Conference Abstract] Young S.D., Montes J., Salazar R., et al. Should motor function determine the timing of scoliosis surgery in spinal muscular atrophy (SMA)?. Neurology. 2016;86(16 SUPPL. 1):No pagination

Spinraza (EMA, 2017)
Results: At the final analysis, a statistically significant improvement in HFMSE score from baseline to Month 15 was seen in the Spinraza group compared to the sham-control group (Table 3, Figure 2). The analysis was conducted in the ITT population (Spinraza: n=84; sham-control: n=42), and post-baseline HFMSE data for patients without a Month 15 visit were imputed using the multiple imputation method. An analysis of the subset of patients in the ITT population who had observed values at Month 15 demonstrated consistent, statistically significant results. Of those with observed values at Month 15, a higher proportion of Spinraza treated subjects had improvement (73% vs 41%, respectively) and a lower proportion of Spinraza treated subjects had worsening (23% vs 44%, respectively) in total HFMSE score compared to sham-control. Secondary endpoints including functional measures and WHO motor milestone achievement were formally statistically tested and are described in Table 3. Initiation of treatment sooner after symptom onset resulted in earlier and greater improvement in motor function than those with delayed treatment initiation; however, both groups experienced benefit compared to sham-control.

New data: 02/05/2019: CS11 (SHINE): A majority of Spinraza treated patients experienced stabilization or improvement in motor function, with the greatest benefit observed in those with earlier treatment initiation. Of patients who initiated Spinraza treatment in Study CS4 (n=39), stabilization or additional improvements in mean HFMSE (0.2; SD 3.06) and RULM (0.7; SD 2.69) scores were observed from baseline to Study Day 265 in Study CS11. Patients who initiated Spinraza treatment in Study CS11 (n=20) had a median age of 4.0 years (range 3 - 8 years). Of these patients, stabilization or improvement in mean HFMSE (1.4; SD 4.02) and RULM (2.1; SD 2.56) scores were observed from baseline to Study Day 265 in Study CS11. These results are supported by 2 open label studies (study CS2 and study CS12). Patients were assessed over a 3 year treatment period. A sustained improvement was seen in patients with Type II, with a mean improvement from baseline HFSME score of 12.3 (SD 5.46, n=6), with a mean total score of 35.3 (SD 12.58) after 1050 days of treatment, No plateau was observed. Patients with Type III SMA demonstrated a mean improvement from baseline HFSME score of 1.6 (SD 3.91, n=7), with a mean total score of 53.0 (SD 9.22) after 1050 days.

[Please see Table 3 and Figure 2 in the sub worksheet "Spinraza_EMA_HFMSE"]

Spinraza (FDA, 2016)
Results: At the final analysis, a statistically significant improvement in HFMSE scores from baseline to Month 15 was observed in the SPINRAZA-treated group compared to the sham-control group (Table 5) (see also Figure 3).

[Please see Table 5 and Figure 3 in the sub worksheet "Spinraza_FDA_HFMSE"]

None identified

Original Language: English for the USA

Translations:
French for France

O'Hagen JM , Darras BT , Oskoui M , Tawil R , Annis C , Martens WB , Irvine C , Sanborn E , Riley S , Quigley J , Flickinger J , Ryan PA , McDermott MP , De Vivo DC , Glanzman AM , Finkel RS

Dr. Alan Glanzman
E-mail: GLANZMANA@email.chop.edu

Free access

The HFMSE is in the public domain

Review copy available online: http://www.columbiasma.org/docs/HFMSE_2019_Proforma.pdf?_sm_nck=1

None identified