Revised Upper Limb Module

Instrument Name: Revised Upper Limb Module

Abbreviation: RULM

Points for Consideration:

Can be difficult to score in contracted patients. Psychometrics have been evaluated.

Description of Tool:

The Revised Upper Limb Module is a ClinRO which includes 20 tasks. Tasks are rated as can/canNot complete or on a 3-point verbal response scale from "(0) unable," to "(2) Able, No difficulty". Higher scores represent better physical functioning.

Minimum Qualification Required by COA Administrator: PhD or MA

Year: 2017

Objective of Development:

To assess motor performance in the upper limbs for individuals with Spinal Muscular Atrophy (SMA)

Population of Development: Age range (therapeutic indication):

3-71 years (Spinal Muscular Atrophy)

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

Nervous System Diseases

COA type: ClinRO

Number of Items 20

Mode of Administration: Interviewer-administered

Data Collection Mode: Paper and pen

Time for Completion: 5 to 20 minutes

Response Scales: Varies by item: Dichotomous: Can or Can Not 3-point verbal rating scale ranging from 0:

Summary of Scoring:

Available Scores:
Global score ranging from 0 to 37

Weighting:
No

Score Interpretation:
Higher score = Better physical functioning

Evidence of Literature Review: Yes

Evidence of Instrument Review: Yes

Evidence of Clinical or Expert Input: Yes

Evidence of concept elicitation in target patient population: None identified

Evidence of a Saturation Grid: None identified

Evidence for Selection of Data Collection Method: None identified

Recall/Observation Period: Present time

Evidence for Selection of Reponse Options: None identified

Evidence of cognitive interviewing of draft instrument in target patient population: None identified

Evidence of Preliminary Scoring of Items and Domains: Yes

Evidence related to respondent and administrator burden: None identified

Evidence of a Conceptual Framework: Yes

Evidence of an item-tracking matrix: None identified

Evidence related to item selection: Yes

Evidence of re-testing the final version: Yes

Internal consistency (Cronbach's alpha): None identified

Evidence of internal consistency:

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

Mazzone (2016) Intraclass Correlation Coefficient (ICC) The all 17 physical therapists: 0.928 UK: 0.933 US: 0.920 Italy: 0.947 - Population/Disease: Physical therapists; n= 3 (UK), 11 (US), 3 (Italy), age Not stated 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

Known-group validity:

Pera (2019)
KNown-groups validity:
- Measure/Groups of patients: Ambulant and Non-ambulant type 3 SMA patients (n= 32 and 22 respectively) and type 2 patients (n= 60) with different ages (<5 years, 5-9 years, 10-14 years and ≥ 15 years)
- A priori hypotheses: Not stated
- Were hypotheses confirmed: Not applicable
- Results: ANOVA, p<0.0001 for all results
The mean values were significantly different between type 2 patients (14.8±6.6), Non-ambulant type 3 patients (27.4±6.9) and ambulant type 3 patients (34.2±3.7), p<0.0001 for all results
A significant interaction between the 3 SMA groups and age was found (p= 0.011)
- Population/Disease: Patients with Ambulant and Non-ambulant type 2 and 3; n= 114, aged from 2.7 to 49.7, mean 13.3±10.1

AlfaNo LN (2020)
- Measure/Groups of patients: Correlation with the Ability Captured Through Interactive Video Evaluation
- A priori hypotheses: Not stated
- Were hypotheses confirmed: Not applicable
- Results: Spearman correlation coefficient
Significant correlation was found between the RULM and the ACTIVE (rho= 0.92; p<0.001)
- Population/Disease: Patients with SMA 2 (n= 27, mean age 11 years and 5 months) or with SMA 3 (n=10, mean age 12 years)

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: None identified

Evidence of known-groups validity: Yes

Ability to detect change (Responsiveness):

None identified

Responder Thresholds:

Stolte B (2020)
- Population/Disease: Patients with SMA type 2 (n= 15, mean range age 31.4 (18-52) or with SMA type 3 (n= 36, mean age range age 37.6 (18-74 years) and classified according to their ambulatory status (44% of the SMA type 3 patients were able to walk; None of the SMA type 2 patients were ambulatory
-Methods used: Distributions based
-Results:
Three different MCIR valued SEm, 1/2 SD and 1/3 SD were calculated with the overall cohort and by subgroups
Overall cohort: SEm= 2.9 ; 1/2 SD = 6.4 and 1/3 SD= 4.3
Non-ambulatory group: SEm= 2.0 ; 1/2 SD = 4.4 and 1/3 SD= 2.9
Ambulatory group: SEm= 0.4 ; 1/2 SD = 0.8 and 1/3 SD= 0.6
SMA type 2 group: SEm= 1.2 ; 1/2 SD = 2.7 and 1/3 SD= 1.8
SMA type 3 group: SEm= 2.7; 1/2 SD = 5.9 and 1/3 SD = 3.9

Evidence of responder thresholds: Yes

Mazzone ES, Mayhew A, Montes J, Ramsey D, Fanelli L, Young SD, Salazar R, De Sanctis R, Pasternak A, Glanzman A, Coratti G, Civitello M, Forcina N, Gee R, Duong T, Pane M, Scoto M, Pera MC, Messina S, Tennekoon G, Day JW, Darras BT, De Vivo DC, Finkel R, Muntoni F, Mercuri E. Revised upper limb module for spinal muscular atrophy: Development of a new module. Muscle Nerve. 2017 Jun;55(6):869-874
PubMed Abstract: https://pubmed.ncbi.nlm.nih.gov/27701745/

Pera MC, Coratti G, Mazzone ES, Montes J, Scoto M, De Sanctis R, Main M, Mayhew A, Muni Lofra R, Dunaway Young S, Glanzman AM, Duong T, Pasternak A, Ramsey D, Darras B, Day JW, Finkel RS, De Vivo DC, Sormani MP, Bovis F, Straub V, Muntoni F, Pane M, Mercuri E; iSMAC Consortium Group. Revised upper limb module for spinal muscular atrophy: 12 month changes. Muscle Nerve. 2019 Apr;59(4):426-430
PubMed Abstract: https://pubmed.ncbi.nlm.nih.gov/30677148/

Stolte B, Bois JM, Bolz S. Minimal clinically important differences in functional motor scores in adults with spinal muscular atrophy. Eur J Neurol. 2020 Dec;27(12):2586-2594.
(https://onlinelibrary.wiley.com/doi/10.1111/ene.14472)

AlfaNo LN, Miller NF, IammariNo MA. ACTIVE (Ability Captured Through Interactive Video Evaluation) workspace volume video game to quantify meaningful change in spinal muscular atrophy. Dev Med Child Neurol. 2020 Mar;62(3):303-309.
(https://pubmed.ncbi.nlm.nih.gov/30963554/)

[Conference Abstract] Glanzman A, Mazzone E, Young SD. Reliability of functional outcome measures in spinal muscular atrophy: Results from multi-centered, global, phase 3 clinical trials (S13.004). Neurology Apr 2017, 88 (16 Supplement) S13.00
(https://n.neurology.org/content/88/16_Supplement/S13.004)

Yes

Evrysdi, Risdiplam (FDA, 2020)
Results:
The primary analysis on the change from baseline in MFM32 total score at Month 12 showed a clinically meaningful and statistically significant difference between patients treated with EVRYSDI and placebo. The results of the primary analysis and key secondary endpoints are shown in Table 3 and Figure 1.

[Please seeTable 3 in the sub worksheet "Evrysdi_FDA_RULM"]

Spinraza, Nusinersen (EMA, 2017)
Results:
Major revision: 02-May-2019: An interim analysis was conducted when all patients had completed their month 6 assessment and at least 39 patients had completed their Month 15 assessment, see Table 3. 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 2, 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. In patients with Type II SMA the Upper Limb Module test was conducted with mean improvement of 1.9 (SD 2.68, n=11) at Day 253 and 3.5 (SD 3.32, n=9) at Day 1050. The mean total score was13.8 (SD 3.09) at Day 253 and 15.7 (SD 1.92) at Day 1050 The 6MWT (six-minute walk test) was conducted for ambulatory patients only. In these patients, a mean improvement of 96.7 metres (SD 42.36, n=6), with a mean 6MWT distance of 278.2 metres (SD 157.58) was observed after 1050 days. Two previously Non-independent ambulatory patients (Type III) achieved independent walking, and one Non-ambulatory patient (Type II) achieved independent walking.
New data: 02/05/2019: CS7 (EMBRACE): All patients who received Spinraza were alive as of the early termination of Part 1, however, one patient in the control arm died at Study Day 289. In addition, No patients in the Spinraza or shamcontrol group required the use of permanent ventilation. Of the 13 patients with infantile-onset SMA, 7 of out 9 patients (78%; 95%CI: 45, 94) in the Spinraza group and 0 out of 4 patients (0%; 95%CI: 0, 60) in the sham group met the criteria for motor milestone response (according to HINE section 2: ≥2 point increase [or maximal score] in ability to kick OR ≥1 point increase in the motor milestones of head control, rolling, sitting, crawling, standing or walking and improvement in more categories of motor milestones than worsening) . Of the 8 patients with later-onset SMA, 4 out of 5 patients (80%; 95% CI: 38, 96) in the Spinraza group and 2 out of 3 (67%; 95% CI: 21, 94) in the sham-control group met this definition of response.
https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/213535s001lbl.pdf; https://www.ema.europa.eu/en/medicines/human/EPAR/spinraza

Yes

Original languages:
English for the UK
English for the USA
Italian for Italy

None identified

Author:
Eugenio Mercuri, MD
Paediatric Neurology
Catholic University
Rome
Italy
E-mail: eugeniomaria.mercuri@unicatt.it

Not reported

Not reported

Available in RULM manual