The Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND)

Instrument Name: The Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND)

Abbreviation: CHOP-INTEND

Points for Consideration:

Has been used in EMA and FDA labels

Description of Tool:

The Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) is a 16 -item ClinRO used to assess motor skill in spinal muscular atrophy type I in ages 1-38 months. 3-, 4-, 5-point Likert Scale ranging from 0 to 4. Higher score = Better motor skills

Minimum Qualification Required by COA Administrator: PhD or MA

Year: 2010

Objective of Development:

To assess motor skill in spinal muscular atrophy type I

Population of Development: Age range (therapeutic indication):

1.4-37.9 months (Muscular Atrophy, Spinal)

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

Nervous System Diseases; Musculoskeletal Diseases; Nutritional and Metabolic Diseases; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

COA type:

Number of Items 16

Mode of Administration:

Data Collection Mode:

Time for Completion: Not reported

Response Scales: Varies by item: 3-, 4-, or 5-point categorical responses based on examination

Summary of Scoring:

Available scores: Global score ranging from 0 to 64

Weighting: No

Score Interpretation: Higher score = Better motor skills

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:

Evidence for Selection of Reponse Options: Yes

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

Evidence of Preliminary Scoring of Items and Domains: None identified

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: Yes

Evidence of re-testing the final version: None identified

Internal consistency (Cronbach's alpha): None Identified

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

Glanzmann (2010)
Intra-rater reliability
- Intraclass Correlation Coefficient (ICC): 0.96
- Was a definition of stability applied to identify stable patients: No
- Time frame or interval between the two administrations: 2 months
- Population/Disease: Infants with SMA-I (mean age 11.5 months; (age range 1.4–37.9 months); n= 9

Inter-rater reliability
1- Intraclass Correlation Coefficient (ICC): 0.98
- Population/Disease: Infants with a variety of neuromuscular diseases (age range Not stated); n= 10

2- Intraclass Correlation Coefficient (ICC): 0.93
- Population/Disease: Typically developing infants (age range 36 weeks to 8 months); n= 8

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

Concurrent validity (convergent, divergent):

AlfaNo L (2019)
- Correlation coefficient used: Not stated
- Measure: Neuromuscular gross motor outcome (GRO)
- Results: CHOP NTEND was significantly correlated with the GRO
- Population/Disease: Patients with SMA types 1 to 3; n= 41;mean age: 6.9 ± 6.1 years, range: 0.4 – 31.1

Known-group validity:

Glanzmann (2011)
1- Measure/Groups of patients: Age and months since symptom onset
- A priori hypotheses: Not stated
- Were hypotheses confirmed: Not applicable
- Results: Pearson correlation coefficient.
- There were significant correlations between CHOP-INTEND scores and age (r= -0.51; p= 0.0.007) and months since symptom onset (r= -0.49; p= 0.005)
- When patients were categorized by SMN2 copy number, the correlation between age and copy number was stronger. In patients with 2 copies of SMN2, r= 0.60 (n=16; p= 0.015), and in those with 3 copies, r= 0.83 (n= 9; p= 0.005)

KNown-groups validity
2- Measure/Groups of patients: Patients requiring bilevel positive airway pressure (BiPAP) (n= 15) vs patients Not requiring BiPAP (n= 12)
- A priori hypotheses: Not stated
- Were hypotheses confirmed: Not applicable
- Results: T-test; Pearson correlation coefficient.
- Patients who required BiPAP (mean= 15.2± 10.2) and those who did Not have a requirement for BiPAP (mean= 31.2±4.2) scored significantly differently on the CHOP INTEND (p< 0.0001) - The difference between patients requiring more than 8 hours of BiPAP and those needing less than 8 hours was also significant (n= 26, p< 0.0001). The duration of BiPAP required had a significant correlation with the CHOP INTEND score (r= 0.74; p< 0.0001) - Population/Disease: Subjects with SMA-I (age range 3 to 260 months; mean= 49, SD= 69); n= 27

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: None identified

Evidence of concurrent validity: Yes

Evidence of known-groups validity: Yes

Evidence of ability to detect change over time: None

Ability to detect change (Responsiveness):

None identified

Evidence of responder thresholds: None identified

Glanzman AM, Mazzone E, Main M, Pelliccioni M, Wood J, Swoboda KJ, Scott C, Pane M, Messina S, Bertini E, Mercuri E, Finkel RS. The Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND): test development and reliability. Neuromuscul Disord. 2010 Mar;20(3):155-61 (Full text article: https://www.ncbi.nlm.nih.gov/pubmed/20074952)

Glanzman AM, McDermott MP, Montes J, Martens WB, Flickinger J, Riley S, Quigley J, Dunaway S, O'Hagen J, Deng L, Chung WK, Tawil R, Darras BT, Yang M, Sproule D, De Vivo DC, Kaufmann P, Finkel RS; Pediatric Neuromuscular Clinical Research Network for Spinal Muscular Atrophy (PNCR); Muscle Study Group (MSG). Validation of the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND). Pediatr Phys Ther. 2011 Winter;23(4):322-6 (Full text article: https://journals.lww.com/pedpt/Fulltext/2011/23040/Validation_of_the_Children_s_Hospital_of.2.aspx)

Cech D, Biedry NL. Commentary on "Validation of the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND)". Pediatr Phys Ther. 2011 Winter;23(4):327 (Full text article: https://journals.lww.com/pedpt/Fulltext/2011/23040/Commentary_on__Validation_of_the_Children_s.3.aspx)

See (PubMed results: https://pubmed.ncbi.nlm.nih.gov/?term=%22CHOP%20INTEND%22&sort=date)

Glanzman AM, McDermott MP, Montes J, Martens WB, Flickinger J, Riley S, Quigley J, Dunaway S, O'Hagen J, Deng L, Chung WK, Tawil R, Darras BT, Yang M, Sproule D, De Vivo DC, Kaufmann P, Finkel RS; Pediatric Neuromuscular Clinical Research Network for Spinal Muscular Atrophy (PNCR); Muscle Study Group (MSG). Validation of the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND). Pediatr Phys Ther. 2011 Winter;23(4):322-6 [Full Text Article: https://journals.lww.com/pedpt/Fulltext/2011/23040/Validation_of_the_Children_s_Hospital_of.2.aspx]

Yes

Spinraza, Nusinersen (EMA, 2017)
Results:
Study 1: Published in the label/SPC: 30-May-2017. Major revision: 02-May-2019
At the final analysis, a statistically significant greater percentage of patients achieved the definition of a motor milestone responder in the Spinraza group (51%) compared to the sham-control group (0%) (p<0.0001). Statistically significant effects on event-free survival, overall survival, the proportion of patients achieving the definition of a motor milestone responder, and the percentage of patients with at least a 4-point improvement from baseline in Children’s Hospital of Philadelphia Infant Test for Neuromuscular Disease (CHOP INTEND) score were observed in patients in the Spinraza group compared to those in the sham-control group (Table 2). In the efficacy set, 18 patients (25%) in the Spinraza group and 12 patients (32%) in the sham-control group required permanent ventilation. Of these patients, 6 (33%) in the Spinraza group and 0 (0%) in the sham-control group met the protocol-defined criteria for a motor-milestone responder. The extent of improvement in CHOP INTEND is shown in Figure 1 (change from baseline score for each subject). New data 02/05/2019: Study CS11 (SHINE): Improvements in motor function were observed among patients continuing Spinraza from Study CS3B, as well as those who initiated Spinraza in Study CS11 (Figure 3), with the greatest benefit observed in those with earlier treatment initiation. Among patients without permanent ventilation at the baseline of Study CS11, a majority were alive and without permanent ventilation at the time of interim analysis. In patients randomized to Spinraza in Study CS3B and including the experience in Study CS11, the median time to death or permanent ventilation was 73 weeks. At the time of a Study CS11 interim analysis, 61 out of 65 patients (94%) were alive. Of the 45 patients who had Not met the definition of permanent ventilation in Study CS3B, 38 patients (84%) were alive without permanent ventilation in Study CS11 at the time of interim analysis. Further improvement in mean total motor milestone (HINE-Section 2) (2.1; SD 4.36; n=22) and CHOP INTEND (4.68; SD 3.993, n=22) scores were observed from baseline to Study Day 304 in Study CS11. Patients who first initiated Spinraza treatment in Study CS11 (n=24; sham control in Study CS3B) were of a median age of 17.8 months (range 10 - 23 months) and had a mean CHOP INTEND score of 17.25 (range 2.0 - 46.0) at baseline in Study CS11. At the time of interim analysis, 22 out of 24 patients (92%) were alive. Of the twelve patients (50%) who had Not met the definition of permanent ventilation in Study CS3B, 7 patients (58%) were alive without permanent ventilation in Study CS11. The median time to death or permanent ventilation was 50.9 weeks after initiation of Spinraza treatment in Study CS11. Improvement in mean total motor milestone (HINE-Section 2) (1.2; SD 1.8; n=12) and CHOP INTEND (3.58; SD 7.051, n=12) scores were observed from baseline to Study Day 304 in Study CS11. These results are supported by an open-label Phase 2 study in symptomatic patients diagNosed with SMA (CS3A). Median age of onset of clinical signs and symptoms was 56 days and patients had either 2 SMN2 gene copies (n=17) or 3 SMN2 gene copies (n=2) (SMN2 gene copy number unkNown for 1 patient). Patients in this study were deemed most likely to develop Type I SMA. The median age at first dose was 162 days. At the time of the planned interim analysis patients in the study had a median time on study of 670 days. At this time, 13 out of 20 patients (65%) had met the primary endpoint with a sustained improvement in mean motor milestone achievement over time. A sustained improvement in mean CHOP INTEND score was observed from baseline to day 694 (mean change 16.90). Overall, 11 out of 20 patients (55%) met the endpoint of an increase in total CHOP INTEND score of ≥4 points as of their last study visit prior to data cut-off. Study 3: Published in the label/SPC: 30-May-2017. Major revision: 02-May-2019 At the planned interim analysis, No patients had met the primary endpoint of death or respiratory intervention. Patients achieved milestones unexpected in Type I or II SMA and more consistent with Normal development. At the interim analysis, all 25 (100%) patients had achieved the WHO motor milestone of sitting without support, 22 (88%) patients were walking with assistance. Among patients older than the WHO defined window for expected age of achievement (95th percentile), 17 of 22 (77%) had achieved walking alone. The mean CHOP INTEND score at last assessment was 61.0 (46 - 64) amongst patients with 2 SMN2 copies and 62.6 (58 - 64) amongst those with 3 SMN2 copies. All patients had the ability to suck and swallow at last assessment, with 22 (88%) infants achieving a maximal score on the HINE Section 1. The proportion of patients developing clinically manifested SMA was assessed amongst patients who reached the Day 700 visit at the interim analysis (n=16). The protocol-defined criteria for clinically manifested SMA included age-adjusted weight below the fifth WHO percentile, a decrease of 2 or more major weight growth curve percentiles, the placement of a percutaneous gastric tube, and/or the inability to achieve expected age-appropriate WHO milestones (sitting without support, standing with assistance, hands-and-knees crawling, walking with assistance, standing alone and walking alone). At day 700, 7 out of 11 patients (64%) with 2 SMN2 gene copies and 0 out of 5 patients (0%) with 3 SMN2 copies, met the protocol-defined criteria of clinically manifested SMA, however, these patients were gaining weight and achieving WHO milestones, inconsistent with Type I SMA. [See Table 2 and Figure 1 in the sub worksheet "Spinraza_EMA_CHOP-INTEND"] Spinraza, Nusinersen (FDA, 2016) Results: Published in the label/SPC: 23-Dec-2016. Major revision: 14-May-2018 At the final analysis, the study also assessed treatment effects on the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND), which is an evaluation of motor skills in patients with infantile-onset SMA. The CHOP-INTEND results are displayed in Table 3. [See Table 3 in sub worksheet "Spinraza_FDA_CHOP-INTEND"] Zolgensma, OnasemNogene Abeparvovec-Xioi (FDA, 2019) Results: No results for the CHOP-INTEND presented in the label. Zolgensma, OnasemNogene Abeparvovec (EMA, 2020) Results: Published in the label/SPC: 18-May-2020: AVXS-101-CL-303 Phase 3 Study in Patients with Type 1 SMA Motor function improvements were also observed as measured by the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND), see Figure 2. Twenty-one patients (95.5%) achieved a CHOP-INTEND score ≥ 40, 14 (64%) had achieved a CHOP-INTEND score ≥ 50, and 5 patients (23%) had achieved a CHOP-INTEND score ≥ 60. Patients with untreated SMA Type 1 almost never achieve a CHOP-INTEND score ≥ 40. Motor milestone achievement was observed in some patients despite plateauing of CHOP-INTEND. No clear correlation was observed between CHOP-INTEND scores and motor milestone achievement. AVXS-101-CL-304 Phase 3 study in patients with pre-symptomatic SMA: Four patients achieved the milestone of walking alone (28.6%). Twelve patients (85.7%) have achieved CHOP-INTEND scores ≥ 60 as of the 31 December 2019 data cut-off. https://www.ema.europa.eu/en/medicines/human/EPAR/spinraza; Published in the label/SPC: 17-May-2020: https://www.ema.europa.eu/en/medicines/human/EPAR/zolgensma; https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/209531s007s008lbl.pdf; https://www.ema.europa.eu/en/medicines/human/EPAR/evrysdi

Original: English for the USA

Translations:
None identified

N/A

Author:
Allan M. Glanzman
The Children’s Hospital of Philadelphia
3401 Civic Center Blvd.
Philadelphia, PA 10104
USA
E-mail: glanzmana@email.chop.edu

Contact:
Cassie Tran
Senior Licensing Associate
Office of TechNology Transfer
The Children’s Hospital of Philadelphia
USA
E-mail: trancm@chop.edu

Copyright:
© 2010 The Children’s Hospital of Philadelphia, All Rights Reserved.

CoU:
*With fees for commercial/pharmaceutical companies
*With the signature of a contract/agreement
*Other: For further information please contact directly Cassie Tran

Not reported

Review copy available in Table 1 in Glanzmann AM, 2010: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3260046/