Trial Outcomes & Findings for Spinal Muscular Atrophy (SMA) Biomarkers Study in the Immediate Postnatal Period of Development (NCT NCT01736553)

NCT ID: NCT01736553

Last Updated: 2018-05-04

Results Overview

Describe \& compare the distribution of motor function assessments over the first two years of life in SMA vs. healthy control infants. The TIMPSI is used to assess the postural and selective control of movement typically used by infants younger than 5 months. The TIMPSI scores were related to an infant's ability to reach. The TIMPSI is a 29-item evaluation that contains 3 item sets: a Screening set, an Easy set, and a Hard set. The Screening set consists of 11 items from the TIMP, each with a 5- to 7-point rating scale; the Easy set has 6 items with 5- or 6-point rating scales and 4 dichotomously scored items; the Hard set has 8 items, 3 with 5-point rating scales and 5 items that are scored dichotomously. The Total score is derived from all subset scores and is the sum of those subset scores. The final score could range from 0 to 99 points. The higher the score the better the functional ability of the participant. Linear mixed effects models were used for analyses.

Recruitment status

COMPLETED

Target enrollment

53 participants

Primary outcome timeframe

Up to 24 months

Results posted on

2018-05-04

Participant Flow

12/2012 first subject enrolled, 9/2014 Enrollment Complete, 8/2015 Last Subject Visit

Subject's had staggered enrollment into the study based upon when identified with SMA. Participants could have visits at 0 and 3 months of age. We tried to enroll as early as possible, but only reported the data starting at 6months. 6 months was when the official visits began.

Participant milestones

Participant milestones
Measure
Infants With Spinal Muscular Atrophy
Infants diagnosed Spinal Muscular Atrophy
Healthy Controls
Healthy control infants
Overall Study
STARTED
26
27
Overall Study
COMPLETED
7
23
Overall Study
NOT COMPLETED
19
4

Reasons for withdrawal

Reasons for withdrawal
Measure
Infants With Spinal Muscular Atrophy
Infants diagnosed Spinal Muscular Atrophy
Healthy Controls
Healthy control infants
Overall Study
Death
12
0
Overall Study
Withdrawal by Subject
5
2
Overall Study
Lost to Follow-up
2
2

Baseline Characteristics

Spinal Muscular Atrophy (SMA) Biomarkers Study in the Immediate Postnatal Period of Development

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure
Infants With Spinal Muscular Atrophy
n=26 Participants
Infants diagnosed Spinal Muscular Atrophy
Healthy Controls
n=27 Participants
Healthy control infants
Total
n=53 Participants
Total of all reporting groups
Ethnicity (NIH/OMB)
Hispanic or Latino
6 Participants
n=5 Participants
3 Participants
n=7 Participants
9 Participants
n=5 Participants
Ethnicity (NIH/OMB)
Not Hispanic or Latino
20 Participants
n=5 Participants
24 Participants
n=7 Participants
44 Participants
n=5 Participants
Race (NIH/OMB)
Asian
0 Participants
n=5 Participants
1 Participants
n=7 Participants
1 Participants
n=5 Participants
Ethnicity (NIH/OMB)
Unknown or Not Reported
0 Participants
n=5 Participants
0 Participants
n=7 Participants
0 Participants
n=5 Participants
Race (NIH/OMB)
American Indian or Alaska Native
0 Participants
n=5 Participants
0 Participants
n=7 Participants
0 Participants
n=5 Participants
Age, Continuous
39 Weeks
STANDARD_DEVIATION 1.5 • n=5 Participants
39 Weeks
STANDARD_DEVIATION 1.4 • n=7 Participants
39 Weeks
STANDARD_DEVIATION 1.45 • n=5 Participants
Age, Customized
Age at Enrollment · 0-2 Months
4 Participants
n=5 Participants
10 Participants
n=7 Participants
14 Participants
n=5 Participants
Age, Customized
Age at Enrollment · 2-4 Months
16 Participants
n=5 Participants
9 Participants
n=7 Participants
25 Participants
n=5 Participants
Age, Customized
Age at Enrollment · 5-6 Months
6 Participants
n=5 Participants
8 Participants
n=7 Participants
14 Participants
n=5 Participants
Sex: Female, Male
Female
15 Participants
n=5 Participants
14 Participants
n=7 Participants
29 Participants
n=5 Participants
Sex: Female, Male
Male
11 Participants
n=5 Participants
13 Participants
n=7 Participants
24 Participants
n=5 Participants
Race (NIH/OMB)
Native Hawaiian or Other Pacific Islander
1 Participants
n=5 Participants
0 Participants
n=7 Participants
1 Participants
n=5 Participants
Race (NIH/OMB)
Black or African American
1 Participants
n=5 Participants
1 Participants
n=7 Participants
2 Participants
n=5 Participants
Race (NIH/OMB)
White
24 Participants
n=5 Participants
21 Participants
n=7 Participants
45 Participants
n=5 Participants
Race (NIH/OMB)
More than one race
0 Participants
n=5 Participants
3 Participants
n=7 Participants
3 Participants
n=5 Participants
Race (NIH/OMB)
Unknown or Not Reported
0 Participants
n=5 Participants
1 Participants
n=7 Participants
1 Participants
n=5 Participants
Region of Enrollment
United States
26 Participants
n=5 Participants
27 Participants
n=7 Participants
53 Participants
n=5 Participants
SMN2 Copy Number
1
0 Participants
n=5 Participants
12 Participants
n=7 Participants
12 Participants
n=5 Participants
SMN2 Copy Number
2
16 Participants
n=5 Participants
13 Participants
n=7 Participants
29 Participants
n=5 Participants
SMN2 Copy Number
3
5 Participants
n=5 Participants
1 Participants
n=7 Participants
6 Participants
n=5 Participants
SMN2 Copy Number
4
1 Participants
n=5 Participants
0 Participants
n=7 Participants
1 Participants
n=5 Participants
SMN2 Copy Number
Unknown
4 Participants
n=5 Participants
1 Participants
n=7 Participants
5 Participants
n=5 Participants
Birth Weight
7 lbs
STANDARD_DEVIATION 1.2 • n=5 Participants
7 lbs
STANDARD_DEVIATION 1.4 • n=7 Participants
7 lbs
STANDARD_DEVIATION 1.3 • n=5 Participants
Birth Length
20 inches
STANDARD_DEVIATION 1.2 • n=5 Participants
20 inches
STANDARD_DEVIATION 1.0 • n=7 Participants
20 inches
STANDARD_DEVIATION 1.1 • n=5 Participants

PRIMARY outcome

Timeframe: Up to 24 months

Population: The overall number of participants analyzed (19 and 26) differs from the total enrollment in each cohort reported in the participant flow (26 and 27, respectively) because of the staggered enrollment and significant mortality.

Describe \& compare the distribution of motor function assessments over the first two years of life in SMA vs. healthy control infants. The TIMPSI is used to assess the postural and selective control of movement typically used by infants younger than 5 months. The TIMPSI scores were related to an infant's ability to reach. The TIMPSI is a 29-item evaluation that contains 3 item sets: a Screening set, an Easy set, and a Hard set. The Screening set consists of 11 items from the TIMP, each with a 5- to 7-point rating scale; the Easy set has 6 items with 5- or 6-point rating scales and 4 dichotomously scored items; the Hard set has 8 items, 3 with 5-point rating scales and 5 items that are scored dichotomously. The Total score is derived from all subset scores and is the sum of those subset scores. The final score could range from 0 to 99 points. The higher the score the better the functional ability of the participant. Linear mixed effects models were used for analyses.

Outcome measures

Outcome measures
Measure
Infants With Spinal Muscular Atrophy
n=19 Participants
Infants diagnosed Spinal Muscular Atrophy
Healthy Controls
n=26 Participants
Healthy control infants
Motor Function Assessments- Test for Infant Motor Performance Screening Items (TIMPSI)
6 month
36.06 scores on a scale
Interval 27.2 to 44.91
88.47 scores on a scale
Interval 80.52 to 96.43
Motor Function Assessments- Test for Infant Motor Performance Screening Items (TIMPSI)
9 month
40.54 scores on a scale
Interval 29.91 to 51.18
89.44 scores on a scale
Interval 81.47 to 97.41
Motor Function Assessments- Test for Infant Motor Performance Screening Items (TIMPSI)
12 month
32.03 scores on a scale
Interval 21.39 to 42.68
85.39 scores on a scale
Interval 77.41 to 93.36
Motor Function Assessments- Test for Infant Motor Performance Screening Items (TIMPSI)
18 month
26.35 scores on a scale
Interval 10.87 to 41.83
87.35 scores on a scale
Interval 79.12 to 95.57
Motor Function Assessments- Test for Infant Motor Performance Screening Items (TIMPSI)
24 month
23.14 scores on a scale
Interval 10.04 to 36.23
88.65 scores on a scale
Interval 80.19 to 97.11

PRIMARY outcome

Timeframe: Up to 24 months

Population: Patients enrolled in the trial from birth. The overall number of participants analyzed (14 and 0) differs from the total enrollment in each cohort reported in the participant flow (26 and 27, respectively) because of the staggered enrollment, significant mortality, and protocol design of who was eligible for this second motor measure.

The TIMPSI motor function testing was done during all of the study visits knowing that the healthy controls would eventually ceiling out. The study design allowed for secondary motor function tests based on the score of the TIMPSI. If infants scored a 41 or above on the TIMPSI they would be tested with the AIMS. If they were below they were tested with the CHOP-INTEND. The CHOP-INTEND is a reliable and validated, comprehensive assessment of the postural and selective control of movement needed by infants. It is a clinician-rated questionnaire developed to assess motor skill in spinal muscular atrophy type I. The 16 items are scored from 0 to 4. The global score ranges from 0 to 64, a higher score indicating better motor skills.(Finkel, McDermott, 2014). All healthy controls based upon scores at 6 months moved on to the AIMS test, therefore no healthy controls completed the CHOP-INTEND. Linear mixed effects models were used for analyses of Motor function outcome data.

Outcome measures

Outcome measures
Measure
Infants With Spinal Muscular Atrophy
n=14 Participants
Infants diagnosed Spinal Muscular Atrophy
Healthy Controls
Healthy control infants
Motor Function Assessments- The Children's Hospital of Philadelphia Infant Test for Neuromuscular Disorders (CHOP-INTEND)
6 month
18.38 scores on a scale
Interval 15.02 to 21.75
Motor Function Assessments- The Children's Hospital of Philadelphia Infant Test for Neuromuscular Disorders (CHOP-INTEND)
9 month
13.18 scores on a scale
Interval 9.24 to 17.12
Motor Function Assessments- The Children's Hospital of Philadelphia Infant Test for Neuromuscular Disorders (CHOP-INTEND)
12 month
9.74 scores on a scale
Interval 5.01 to 14.46
Motor Function Assessments- The Children's Hospital of Philadelphia Infant Test for Neuromuscular Disorders (CHOP-INTEND)
18 month
7.52 scores on a scale
Interval 2.89 to 12.16
Motor Function Assessments- The Children's Hospital of Philadelphia Infant Test for Neuromuscular Disorders (CHOP-INTEND)
24 month
7.01 scores on a scale
Interval 6.82 to 7.19

PRIMARY outcome

Timeframe: Up to 24 months

Population: Patients enrolled in the trial from birth to 6 months of age. The overall number of participants analyzed (5 and 26) differs from the total enrollment in each cohort reported in the participant flow (26 and 27) because of the staggered enrollment, significant mortality and protocol design of who was eligible for this second motor measure.

Linear mixed effects models were used for analyses. The reason that the number of infants differ from those in participant flow is based upon the protocol. The selection of which secondary test to perform depended upon the score of the TIMPSI that was performed. TIMPSI \<41, do CHOP-NTEND. TIMPSI \> 41, do AIMS. The AIMS incorporates the neuromaturational concept and the dynamical systems theory and is used to measure gross motor maturation of infants from birth through the age of independent walking (Piper, Pinnell et al. 1992, Piper, Darrah et al 1994). In the AIMS, the impact of neurological components on motor development is reflected by a sequence of motor skills, which are used as the basis of assessment. The AIMS consists of 58 items, including 4 positions: prone (21 items), supine (9 items), sitting (12 items) \& standing(16 items). The highest score available is 58. The higher the score the better the functional ability of the participant.

Outcome measures

Outcome measures
Measure
Infants With Spinal Muscular Atrophy
n=5 Participants
Infants diagnosed Spinal Muscular Atrophy
Healthy Controls
n=26 Participants
Healthy control infants
Motor Function Assessments-Alberta Infant Motor Scale (AIMS)
6 month
11.74 Scores on a scale
Interval 3.91 to 19.58
19.29 Scores on a scale
Interval 16.4 to 22.19
Motor Function Assessments-Alberta Infant Motor Scale (AIMS)
9 month
15.58 Scores on a scale
Interval 2.51 to 28.64
34.10 Scores on a scale
Interval 29.05 to 39.14
Motor Function Assessments-Alberta Infant Motor Scale (AIMS)
12 month
21.60 Scores on a scale
Interval 6.66 to 36.53
37.10 Scores on a scale
Interval 30.52 to 43.68
Motor Function Assessments-Alberta Infant Motor Scale (AIMS)
18 month
19.18 Scores on a scale
Interval 2.03 to 36.32
38.62 Scores on a scale
Interval 31.3 to 45.93
Motor Function Assessments-Alberta Infant Motor Scale (AIMS)
24 month
14.71 Scores on a scale
Interval 2.17 to 27.25
37.76 Scores on a scale
Interval 29.81 to 45.71

PRIMARY outcome

Timeframe: Up to 24 months

Population: Patients enrolled in the trial from birth to 6 months. The overall number of participants analyzed (18/ and 26) differs from the total enrollment in the participant flow (26 and 27) because of the staggered enrollment, significant mortality and tolerance of procedure. Therefore not all infants enrolled were included in all longitudinal analyses.

Describe and compare the distribution of the putative physiological and molecular biomarkers over the first two years of life in SMA vs. healthy control infants. Maximum ulnar CMAP amplitude and area will be obtained by recording from the abductor digitiminimi muscle following ulnar nerve stimulation at the wrist. All electrophysiologic testing will be performed by certified electromyographers experienced in the assessment of pediatric patients. Maximum values for both negative peak (NP) amplitude and NP area will be obtained. No medications will be used. This test is done routinely in this population. Pediatric electrodes and each site's standard electromyograph devices will be utilized. The test, while not considered to be painful, may cause some discomfort similar to a static electric shock. Infants may whimper or cry due to the surprise of the shock. Each shock lasts approximately 0.1 millisecond. The testing duration is expected to be approximately 30 seconds.

Outcome measures

Outcome measures
Measure
Infants With Spinal Muscular Atrophy
n=18 Participants
Infants diagnosed Spinal Muscular Atrophy
Healthy Controls
n=26 Participants
Healthy control infants
Putative Physiological Biomarker- Compound Motor Action Potential Testing (CMAP)
6 month
1.07 mV
Interval 0.17 to 1.96
6.00 mV
Interval 5.22 to 6.78
Putative Physiological Biomarker- Compound Motor Action Potential Testing (CMAP)
12 month
0.51 mV
Interval -0.56 to 1.59
5.95 mV
Interval 5.16 to 6.75
Putative Physiological Biomarker- Compound Motor Action Potential Testing (CMAP)
18 month
0.49 mV
Interval -0.98 to 1.95
6.55 mV
Interval 5.75 to 7.36
Putative Physiological Biomarker- Compound Motor Action Potential Testing (CMAP)
24 month
-0.02 mV
Interval -1.46 to 1.42
6.74 mV
Interval 5.91 to 7.58

PRIMARY outcome

Timeframe: Up to 24 months

Population: Patients enrolled in the trial from birth to 6 months. The overall number of participants analyzed (19 and 22) differs from the total enrollment in the participant flow (26 and 27) because of the staggered enrollment, significant mortality, \& insufficient sample. Therefore not all infants enrolled were included in all longitudinal analyses.

Describe and compare the distribution of the putative physiological and molecular biomarkers over the first two years of life in SMA vs. healthy control infants. Results were measured in survival motor neurons (SMN), hypoxanthine phosphoribosyltransferase (HPRT) Ratio.

Outcome measures

Outcome measures
Measure
Infants With Spinal Muscular Atrophy
n=19 Participants
Infants diagnosed Spinal Muscular Atrophy
Healthy Controls
n=22 Participants
Healthy control infants
Molecular Biomarkers- mRNA
6 month
0.55 SMN/HPRT Ratio
Interval 0.39 to 0.71
1.29 SMN/HPRT Ratio
Interval 1.14 to 1.44
Molecular Biomarkers- mRNA
12 month
0.47 SMN/HPRT Ratio
Interval 0.26 to 0.69
1.21 SMN/HPRT Ratio
Interval 1.06 to 1.37
Molecular Biomarkers- mRNA
18 month
0.50 SMN/HPRT Ratio
Interval 0.19 to 0.8
1.11 SMN/HPRT Ratio
Interval 0.96 to 1.26
Molecular Biomarkers- mRNA
24 month
0.66 SMN/HPRT Ratio
Interval 0.35 to 0.97
1.20 SMN/HPRT Ratio
Interval 1.03 to 1.37

PRIMARY outcome

Timeframe: Up to 24 months

Population: Patients enrolled in the trial from birth to 6 months. The overall number of participants analyzed (15 and 18) differs from the total enrollment reported in the participant flow (26 and 27) because of the staggered enrollment, significant mortality, insufficient sample. Therefore not all infants enrolled were included in all longitudinal analyses.

Describe and compare the distribution of the putative physiological and molecular biomarkers over the first two years of life in SMA vs. healthy control infants.

Outcome measures

Outcome measures
Measure
Infants With Spinal Muscular Atrophy
n=15 Participants
Infants diagnosed Spinal Muscular Atrophy
Healthy Controls
n=18 Participants
Healthy control infants
Molecular Biomarkers- SMN Protein Levels
6 month
4798.85 pg/10^7 PBMC
Interval 2799.07 to 6798.63
8325.96 pg/10^7 PBMC
Interval 6435.08 to 10217.0
Molecular Biomarkers- SMN Protein Levels
12 month
6719.63 pg/10^7 PBMC
Interval 4404.92 to 9034.3
10247 pg/10^7 PBMC
Interval 8228.29 to 12265.0
Molecular Biomarkers- SMN Protein Levels
18 month
3108.79 pg/10^7 PBMC
Interval 476.39 to 5741.19
6635.90 pg/10^7 PBMC
Interval 4401.46 to 8870.34
Molecular Biomarkers- SMN Protein Levels
24 month
8502.48 pg/10^7 PBMC
Interval 5562.01 to 11443.0
12030 pg/10^7 PBMC
Interval 9552.13 to 14507.0

PRIMARY outcome

Timeframe: Up to 24 months

Population: Subjects enrolled from birth to 6 months. The overall number of participants analyzed (19 and 26) differs from the total enrollment reported in the participant flow (26 and 27) because of the staggered enrollment \& significant mortality. Therefore not all infants enrolled were included in all longitudinal analyses.

Describe and compare the distribution of the putative physiological and molecular biomarkers over the first two years of life in SMA vs. healthy control infants.

Outcome measures

Outcome measures
Measure
Infants With Spinal Muscular Atrophy
n=19 Participants
Infants diagnosed Spinal Muscular Atrophy
Healthy Controls
n=26 Participants
Healthy control infants
Putative Physiological Biomarkers-Weight
6 month
6.88 kg
Interval 6.46 to 7.31
7.83 kg
Interval 7.43 to 8.23
Putative Physiological Biomarkers-Weight
9 month
7.92 kg
Interval 7.34 to 8.49
8.94 kg
Interval 8.51 to 9.37
Putative Physiological Biomarkers-Weight
12 month
8.71 kg
Interval 8.1 to 9.33
9.88 kg
Interval 9.41 to 10.36
Putative Physiological Biomarkers-Weight
18 month
9.95 kg
Interval 9.17 to 10.72
11.40 kg
Interval 10.95 to 11.85
Putative Physiological Biomarkers-Weight
24 month
10.47 kg
Interval 9.71 to 11.23
12.74 kg
Interval 12.25 to 13.23

PRIMARY outcome

Timeframe: up to 24 months

Population: The overall number of participants analyzed (19 and 14) differs from the total enrollment reported in the participant flow (26) because of the staggered enrollment and significant mortality. Therefore not all infants enrolled were included in all longitudinal analyses.

In these analyses motor function score was the outcome measure. Correlation was defined as the estimated mean increase per a one unit increase in the biomarker under consideration. A linear mixed effects model was used to estimate the correlation between the biomarker and motor function score. Separate models were used for the TIMPSI and CHOP-INTEND. In the CHOP-INTEND analyses, correlations were not estimable for the 18 and 24 month visits.

Outcome measures

Outcome measures
Measure
Infants With Spinal Muscular Atrophy
n=19 Participants
Infants diagnosed Spinal Muscular Atrophy
Healthy Controls
n=14 Participants
Healthy control infants
Correlation of Biomarkers With Motor Function Tests for SMA Subjects- CMAP
6 month
9.36 mV/scale unit
Interval 5.59 to 13.13
17.25 mV/scale unit
Interval -2.26 to 36.77
Correlation of Biomarkers With Motor Function Tests for SMA Subjects- CMAP
12 month
22.88 mV/scale unit
Interval 16.24 to 29.52
21.53 mV/scale unit
Interval -34.94 to 78.0
Correlation of Biomarkers With Motor Function Tests for SMA Subjects- CMAP
18 month
17.48 mV/scale unit
Interval 9.07 to 25.89
Correlation of Biomarkers With Motor Function Tests for SMA Subjects- CMAP
24 month
18.57 mV/scale unit
Interval 10.03 to 27.11

PRIMARY outcome

Timeframe: up to 24 months

In these analyses motor function score was the outcome measure. Correlation was defined as the estimated mean increase per a one unit increase in the biomarker under consideration. A linear mixed effects model was used to estimate the correlation between the biomarker and motor function score. Separate models were used for the TIMPSI and CHOP-INTEND.

Outcome measures

Outcome measures
Measure
Infants With Spinal Muscular Atrophy
n=26 Participants
Infants diagnosed Spinal Muscular Atrophy
Healthy Controls
n=26 Participants
Healthy control infants
Correlation of Biomarkers With Motor Function Tests for SMA Subjects- mRNA
6 month
53.60 (SMN/HPRT ratio)/scale unit
Interval -0.04 to 107.24
0.11 (SMN/HPRT ratio)/scale unit
Interval -15.81 to 16.03
Correlation of Biomarkers With Motor Function Tests for SMA Subjects- mRNA
12 month
125.52 (SMN/HPRT ratio)/scale unit
Interval 40.81 to 210.22
0.11 (SMN/HPRT ratio)/scale unit
Interval -15.81 to 16.03
Correlation of Biomarkers With Motor Function Tests for SMA Subjects- mRNA
18 month
181.22 (SMN/HPRT ratio)/scale unit
Interval 3.65 to 358.78
0.11 (SMN/HPRT ratio)/scale unit
Interval -15.81 to 16.03
Correlation of Biomarkers With Motor Function Tests for SMA Subjects- mRNA
24 month
46.43 (SMN/HPRT ratio)/scale unit
Interval -12.65 to 105.51
0.11 (SMN/HPRT ratio)/scale unit
Interval -15.81 to 16.03

PRIMARY outcome

Timeframe: up to 24 months

Population: The overall number of participants analyzed (14 and 19) differs from the total enrollment reported in the participant flow (26) because of the staggered enrollment and significant mortality. Therefore not all infants enrolled were included in all longitudinal analyses.

In these analyses motor function score was the outcome measure. Correlation was defined as the estimated mean increase per a one unit increase in the biomarker under consideration. A linear mixed effects model was used to estimate the correlation between the biomarker and motor function score. Separate models were used for the TIMPSI and CHOP-INTEND. In the CHOP-INTEND analyses, the correlation at the 24 month visit was not estimable.

Outcome measures

Outcome measures
Measure
Infants With Spinal Muscular Atrophy
n=14 Participants
Infants diagnosed Spinal Muscular Atrophy
Healthy Controls
n=19 Participants
Healthy control infants
Correlation of Biomarkers With Motor Function Tests for SMA Subjects- SMN Protein
6 month
-0.0011 (pg/10^7 PBMC)/scale unit
Interval -0.0053 to 0.0032
-0.0003 (pg/10^7 PBMC)/scale unit
Interval -0.0033 to 0.0027
Correlation of Biomarkers With Motor Function Tests for SMA Subjects- SMN Protein
12 month
0.00066 (pg/10^7 PBMC)/scale unit
Interval -0.0057 to 0.0071
-0.0003 (pg/10^7 PBMC)/scale unit
Interval -0.00033 to 0.0027
Correlation of Biomarkers With Motor Function Tests for SMA Subjects- SMN Protein
18 month
0.026 (pg/10^7 PBMC)/scale unit
Interval -0.0093 to 0.061
-0.0003 (pg/10^7 PBMC)/scale unit
Interval -0.00033 to 0.0027
Correlation of Biomarkers With Motor Function Tests for SMA Subjects- SMN Protein
24 month
-0.0003 (pg/10^7 PBMC)/scale unit
Interval -0.00033 to 0.0027

PRIMARY outcome

Timeframe: up to 24 months

In these analyses motor function score was the outcome measure. Correlation was defined as the estimated mean increase per a one unit increase in the biomarker under consideration. A linear mixed effects model was used to estimate the correlation between the biomarker and motor function score. Separate models were used for the TIMPSI and CHOP-INTEND.

Outcome measures

Outcome measures
Measure
Infants With Spinal Muscular Atrophy
n=26 Participants
Infants diagnosed Spinal Muscular Atrophy
Healthy Controls
n=26 Participants
Healthy control infants
Correlation of Biomarkers With Motor Function Tests for SMA Subjects- Weight
2.27 kg/scale unit
Interval -3.34 to 7.87
-2.39 kg/scale unit
Interval -4.13 to -0.65

PRIMARY outcome

Timeframe: up to 24 months

Population: The overall number of participants analyzed (26 and 26) differs from the total enrollment reported in the participant flow at each visit (27) because of the staggered enrollment, significant mortality and tolerance of testing.

In these analyses motor function score was the outcome measure. Correlation was defined as the estimated mean increase per a one unit increase in the biomarker under consideration. A linear mixed effects model was used to estimate the correlation between the biomarker and motor function score. Separate models were used for the TIMPSI and AIMS.

Outcome measures

Outcome measures
Measure
Infants With Spinal Muscular Atrophy
n=26 Participants
Infants diagnosed Spinal Muscular Atrophy
Healthy Controls
n=26 Participants
Healthy control infants
Correlation of Biomarkers With Motor Function Tests for Healthy Control Subjects- CMAP
6 month
-0.23 mV/scale unit
Interval -2.88 to 2.43
0.21 mV/scale unit
Interval -0.63 to 1.05
Correlation of Biomarkers With Motor Function Tests for Healthy Control Subjects- CMAP
12 month
-4.52 mV/scale unit
Interval -7.53 to -1.51
0.21 mV/scale unit
Interval -0.63 to 1.05
Correlation of Biomarkers With Motor Function Tests for Healthy Control Subjects- CMAP
18 month
-0.58 mV/scale unit
Interval -3.07 to 1.92
0.21 mV/scale unit
Interval -0.63 to 1.05
Correlation of Biomarkers With Motor Function Tests for Healthy Control Subjects- CMAP
24 month
1.14 mV/scale unit
Interval -2.05 to 4.34
0.21 mV/scale unit
Interval -0.63 to 1.05

PRIMARY outcome

Timeframe: up to 24 months

Population: Labs were not obtainable for all subjects. The overall number of participants analyzed (26 and 26) differs from the total enrollment reported in the participant flow (27) because of the staggered enrollment, significant mortality and protocol design.

In these analyses motor function score was the outcome measure. Correlation was defined as the estimated mean increase per a one unit increase in the biomarker under consideration. A linear mixed effects model was used to estimate the correlation between the biomarker and motor function score. Separate models were used for the TIMPSI and AIMS.

Outcome measures

Outcome measures
Measure
Infants With Spinal Muscular Atrophy
n=26 Participants
Infants diagnosed Spinal Muscular Atrophy
Healthy Controls
n=26 Participants
Healthy control infants
Correlation of Biomarkers With Motor Function Tests for Healthy Control Subjects- mRNA
9.52 (SMN/HPRT Ratio)/scale unit
Interval 3.18 to 15.86
-2.46 (SMN/HPRT Ratio)/scale unit
Interval -6.2 to 1.28

PRIMARY outcome

Timeframe: up to 24 months

Population: The overall number of participants analyzed (26 and 26) differs from the total enrollment reported in the participant flow (27) because of the staggered enrollment and significant mortality.

In these analyses motor function score was the outcome measure. Correlation was defined as the estimated mean increase per a one unit increase in the biomarker under consideration. A linear mixed effects model was used to estimate the correlation between the biomarker and motor function score. Separate models were used for the TIMPSI and AIMS.

Outcome measures

Outcome measures
Measure
Infants With Spinal Muscular Atrophy
n=26 Participants
Infants diagnosed Spinal Muscular Atrophy
Healthy Controls
n=26 Participants
Healthy control infants
Correlation of Biomarkers With Motor Function Tests for Healthy Control Subjects- Weight
24 month
0.60 kg/scale unit
Interval -1.71 to 2.9
3.53 kg/scale unit
Interval -0.76 to 7.82
Correlation of Biomarkers With Motor Function Tests for Healthy Control Subjects- Weight
6 month
0.60 kg/scale unit
Interval -1.71 to 2.9
1.48 kg/scale unit
Interval -0.68 to 3.66
Correlation of Biomarkers With Motor Function Tests for Healthy Control Subjects- Weight
9 month
0.60 kg/scale unit
Interval -1.71 to 2.9
-0.72 kg/scale unit
Interval -4.06 to 2.62
Correlation of Biomarkers With Motor Function Tests for Healthy Control Subjects- Weight
12 month
0.60 kg/scale unit
Interval -1.71 to 2.9
1.14 kg/scale unit
Interval -2.12 to 4.39
Correlation of Biomarkers With Motor Function Tests for Healthy Control Subjects- Weight
18 month
0.60 kg/scale unit
Interval -1.71 to 2.9
-0.46 kg/scale unit
Interval -4.39 to 3.47

SECONDARY outcome

Timeframe: Up to 24 months

Examine whether any of the motor function assessments, putative physiological, or molecular biomarkers predict risk of death in the SMA cohort. Proportional hazards regression models used to determine if motor function scores, mRNA, and protein levels predict death in SMA subjects. Considered each predictor separately modeled as a time-varying covariate (predictor values were allowed to vary as time to death was assessed).

Outcome measures

Outcome measures
Measure
Infants With Spinal Muscular Atrophy
n=26 Participants
Infants diagnosed Spinal Muscular Atrophy
Healthy Controls
Healthy control infants
Biomarker Prediction of Risk of Death
TIMPSI (per 10 unit increase)
0.72 Hazard Ratio
Interval 0.5 to 1.04
Biomarker Prediction of Risk of Death
CHOP-INTEND (per 10 unit increase)
0.94 Hazard Ratio
Interval 0.59 to 1.51
Biomarker Prediction of Risk of Death
CMAP Peak Amplitude (per 1 unit increase)
0.37 Hazard Ratio
Interval 0.1 to 1.29
Biomarker Prediction of Risk of Death
mRNA (per 1 unit increase)
0.28 Hazard Ratio
Interval 0.0009 to 8.82
Biomarker Prediction of Risk of Death
Protein Level (per 1000 unit increase)
1.27 Hazard Ratio
Interval 0.98 to 1.65
Biomarker Prediction of Risk of Death
Weight (per 10kg increase)
0.02 Hazard Ratio
Interval 0.0004 to 1.28

SECONDARY outcome

Timeframe: Up to 24 months

Population: The overall number of participants analyzed (14 and 26) differs from the total enrollment reported in the participant flow (26 and 27 respectively) because of the staggered enrollment, subset of infants with SMN2 \& significant mortality.

Describe and compare the distribution of motor function assessments over the first two years of life in SMA subjects with SMN copy number = 2 versus healthy control infants. The TIMPSI is used to assess the postural and selective control of movement typically used by infants younger than 5 months. The TIMPSI scores were related to an infant's ability to reach. The TIMPSI is a 29-item evaluation that contains 3 item sets: a Screening set, an Easy set, and a Hard set. The Screening set consists of 11 items from the TIMP, each with a 5- to 7-point rating scale; the Easy set has 6 items with 5- or 6-point rating scales and 4 dichotomously scored items; the Hard set has 8 items, 3 with 5-point rating scales and 5 items that are scored dichotomously. The Total score is derived from all subset scores and is the sum of those subset scores. The final score could range from 0 to 99 points. The higher the score the better the functional ability of the participant.

Outcome measures

Outcome measures
Measure
Infants With Spinal Muscular Atrophy
n=14 Participants
Infants diagnosed Spinal Muscular Atrophy
Healthy Controls
n=26 Participants
Healthy control infants
Motor Function Assessments- Test for Infant Motor Performance Screening Items (TIMPSI) SMN Copy Number =2 Cohort
6 month
24.53 Scores on a scale
Interval 17.89 to 31.17
88.25 Scores on a scale
Interval 83.34 to 93.15
Motor Function Assessments- Test for Infant Motor Performance Screening Items (TIMPSI) SMN Copy Number =2 Cohort
9 month
20.08 Scores on a scale
Interval 10.11 to 30.05
89.20 Scores on a scale
Interval 84.29 to 94.11
Motor Function Assessments- Test for Infant Motor Performance Screening Items (TIMPSI) SMN Copy Number =2 Cohort
12 month
13.82 Scores on a scale
Interval 4.4 to 23.24
85.15 Scores on a scale
Interval 80.24 to 90.06
Motor Function Assessments- Test for Infant Motor Performance Screening Items (TIMPSI) SMN Copy Number =2 Cohort
18 month
8.82 Scores on a scale
Interval -8.24 to 25.89
87.36 Scores on a scale
Interval 82.16 to 92.56
Motor Function Assessments- Test for Infant Motor Performance Screening Items (TIMPSI) SMN Copy Number =2 Cohort
24 month
7.51 Scores on a scale
Interval -6.83 to 22.03
88.92 Scores on a scale
Interval 83.49 to 94.36

SECONDARY outcome

Timeframe: Up to 24 months

Population: The overall number of participants analyzed (14) differs from the total enrollment reported in the participant flow (26) because of the staggered enrollment, subset of infants with SMN2 , and significant mortality. Healthy controls did not complete this visit due to the protocol.

Describe and compare the distribution of motor function assessments over the first two years of life in SMA subjects with SMN copy number = 2 versus healthy control infants. The CHOP-INTEND is a reliable and validated, comprehensive assessment of the postural and selective control of movement needed by infants. It is a clinician-rated questionnaire developed to assess motor skill in spinal muscular atrophy type I. The 16 items are scored from 0 to 4. The global score ranges from 0 to 64, a higher score indicating better motor skills.(Finkel, McDermott, 2014).

Outcome measures

Outcome measures
Measure
Infants With Spinal Muscular Atrophy
n=14 Participants
Infants diagnosed Spinal Muscular Atrophy
Healthy Controls
Healthy control infants
Motor Function Assessments- The Children's Hospital of Philadelphia Infant Test for Neuromuscular Disorders (CHOP-INTEND) SMN Copy Number =2 Cohort
18 month
7.33 Scores on a scale
Interval 2.39 to 12.26
Motor Function Assessments- The Children's Hospital of Philadelphia Infant Test for Neuromuscular Disorders (CHOP-INTEND) SMN Copy Number =2 Cohort
24 month
7.00 Scores on a scale
Interval 6.72 to 7.28
Motor Function Assessments- The Children's Hospital of Philadelphia Infant Test for Neuromuscular Disorders (CHOP-INTEND) SMN Copy Number =2 Cohort
6 month
18.05 Scores on a scale
Interval 14.86 to 21.25
Motor Function Assessments- The Children's Hospital of Philadelphia Infant Test for Neuromuscular Disorders (CHOP-INTEND) SMN Copy Number =2 Cohort
9 month
12.87 Scores on a scale
Interval 8.93 to 16.81
Motor Function Assessments- The Children's Hospital of Philadelphia Infant Test for Neuromuscular Disorders (CHOP-INTEND) SMN Copy Number =2 Cohort
12 month
9.38 Scores on a scale
Interval 4.61 to 14.12

SECONDARY outcome

Timeframe: Up to 24 months

Population: The overall number of participants analyzed (13 and 26) differs from the total enrollment in the participant flow (26 and 27) because of the staggered enrollment, subset of patients with SMA, significant mortality, and tolerance of procedure.

Describe and compare the distribution of the putative physiological and molecular biomarkers over the first two years of life in SMA2 vs. healthy control infants. Maximum ulnar CMAP amplitude and area will be obtained by recording from the abductor digitiminimi muscle following ulnar nerve stimulation at the wrist. All electrophysiologic testing will be performed by certified electromyographers experienced in the assessment of pediatric patients. Maximum values for both negative peak (NP) amplitude and NP area will be obtained. No medications will be used. This test is done routinely in this population. Pediatric electrodes and each site's standard electromyograph devices will be utilized. The test, while not considered to be painful, may cause some discomfort similar to a static electric shock. Infants may whimper or cry due to the surprise of the shock. Each shock lasts approximately 0.1 millisecond. The testing duration is expected to be approximately 30 seconds.

Outcome measures

Outcome measures
Measure
Infants With Spinal Muscular Atrophy
n=13 Participants
Infants diagnosed Spinal Muscular Atrophy
Healthy Controls
n=26 Participants
Healthy control infants
Putative Physiological Biomarker- Compound Motor Action Potential Testing (CMAP) SMN Copy Number = 2 Cohort
6 month
0.36 mV
Interval -0.04 to 1.84
5.95 mV
Interval 5.3 to 6.6
Putative Physiological Biomarker- Compound Motor Action Potential Testing (CMAP) SMN Copy Number = 2 Cohort
12 month
0.33 mV
Interval -0.54 to 1.19
5.92 mV
Interval 5.25 to 6.58
Putative Physiological Biomarker- Compound Motor Action Potential Testing (CMAP) SMN Copy Number = 2 Cohort
18 month
0.90 mV
Interval -0.04 to 1.84
6.49 mV
Interval 5.8 to 7.19
Putative Physiological Biomarker- Compound Motor Action Potential Testing (CMAP) SMN Copy Number = 2 Cohort
24 month
6.63 mV
Interval 5.92 to 7.36

SECONDARY outcome

Timeframe: Up to 24 months

Population: The overall number of participants analyzed (14 and 22) differs from the total enrollment in the participant flow (26 and 27) because of the staggered enrollment, subset of patients with SMA, significant mortality, and insufficient sample.

Describe and compare the distribution of the putative physiological and molecular biomarkers over the first two years of life in SMA vs. healthy control infants.

Outcome measures

Outcome measures
Measure
Infants With Spinal Muscular Atrophy
n=14 Participants
Infants diagnosed Spinal Muscular Atrophy
Healthy Controls
n=22 Participants
Healthy control infants
Molecular Biomarkers- mRNA SMA Copy Number = 2 Cohort
6 month
0.46 SMN/HPRT Ratio
Interval 0.31 to 0.62
1.29 SMN/HPRT Ratio
Interval 1.16 to 1.43
Molecular Biomarkers- mRNA SMA Copy Number = 2 Cohort
12 month
0.38 SMN/HPRT Ratio
Interval 0.31 to 0.45
1.21 SMN/HPRT Ratio
Interval 1.07 to 1.35
Molecular Biomarkers- mRNA SMA Copy Number = 2 Cohort
18 month
0.29 SMN/HPRT Ratio
Interval 0.08 to 0.49
1.12 SMN/HPRT Ratio
Interval 0.97 to 1.26
Molecular Biomarkers- mRNA SMA Copy Number = 2 Cohort
24 month
0.40 SMN/HPRT Ratio
Interval 0.19 to 0.61
1.23 SMN/HPRT Ratio
Interval 1.07 to 1.39

SECONDARY outcome

Timeframe: Up to 24 months

Population: Patients enrolled in the trial at birth. The overall number of participants analyzed (10 and 18) differs from the total enrollment reported in the participant flow (26 and 27) because of the staggered enrollment, significant mortality, subset of SMA subjects, and insufficient sample.

Describe and compare the distribution of the putative physiological and molecular biomarkers over the first two years of life in SMA2 vs. healthy control infants.

Outcome measures

Outcome measures
Measure
Infants With Spinal Muscular Atrophy
n=10 Participants
Infants diagnosed Spinal Muscular Atrophy
Healthy Controls
n=18 Participants
Healthy control infants
Molecular Biomarkers- SMN Protein Levels SMA Copy Number = 2
24 month
6912.88 pg/10^7 PBMC
Interval 3225.48 to 10600.0
11727 pg/10^7 PBMC
Interval 8930.09 to 14523.0
Molecular Biomarkers- SMN Protein Levels SMA Copy Number = 2
6 month
3785.02 pg/10^7 PBMC
Interval 1245.92 to 6324.12
8598.73 pg/10^7 PBMC
Interval 6472.81 to 10725.0
Molecular Biomarkers- SMN Protein Levels SMA Copy Number = 2
12 month
5800.63 pg/10^7 PBMC
Interval 2828.39 to 8772.87
10614 pg/10^7 PBMC
Interval 8341.73 to 12887.0
Molecular Biomarkers- SMN Protein Levels SMA Copy Number = 2
18 month
1612.35 pg/10^7 PBMC
Interval -1753.19 to 4977.9
6426.06 pg/10^7 PBMC
Interval 3892.03 to 8960.09

SECONDARY outcome

Timeframe: Up to 24 months

Population: The overall number of participants analyzed (14 and 26) differs from the total enrollment reported in the participant flow (26 and 27) because of the staggered enrollment, subset of SMA subjects, and significant mortality. Therefore not all infants enrolled were included in all longitudinal analyses.

Describe and compare the distribution of motor function assessments over the first two years of life in SMA subjects with SMN copy number = 2 versus healthy control infants

Outcome measures

Outcome measures
Measure
Infants With Spinal Muscular Atrophy
n=14 Participants
Infants diagnosed Spinal Muscular Atrophy
Healthy Controls
n=26 Participants
Healthy control infants
Putative Physiological Biomarkers-Weight SMN Copy Number =2 Cohort
6 month
6.63 kg
Interval 6.14 to 7.13
7.83 kg
Interval 7.43 to 8.23
Putative Physiological Biomarkers-Weight SMN Copy Number =2 Cohort
9 month
7.70 kg
Interval 7.0 to 8.39
8.93 kg
Interval 8.5 to 9.36
Putative Physiological Biomarkers-Weight SMN Copy Number =2 Cohort
12 month
8.51 kg
Interval 7.7 to 9.32
9.88 kg
Interval 9.4 to 10.37
Putative Physiological Biomarkers-Weight SMN Copy Number =2 Cohort
18 month
9.65 kg
Interval 8.47 to 10.84
11.40 kg
Interval 10.93 to 11.87
Putative Physiological Biomarkers-Weight SMN Copy Number =2 Cohort
24 month
9.77 kg
Interval 8.57 to 10.98
12.72 kg
Interval 12.23 to 13.22

SECONDARY outcome

Timeframe: up to 24 months

Population: The overall number of participants with SMA analyzed (14/14) differs from the total enrollment reported in the participant flow (26) because of the staggered enrollment, subset of subjects with SMA and significant mortality.

Examine the correlation between each of the putative physiological and molecular biomarkers with the TIMPSI and CHOP-INTEND over the first two years of life in SMA (SMN = 2). All estimated correlations are the same at each study visit.

Outcome measures

Outcome measures
Measure
Infants With Spinal Muscular Atrophy
n=14 Participants
Infants diagnosed Spinal Muscular Atrophy
Healthy Controls
n=14 Participants
Healthy control infants
Correlation of CMAP Biomarker With Motor Function Tests for SMA Subjects SMN Copy Number =2 Cohort
5.10 mV/scores on a scale
Interval 0.095 to 10.11
3.71 mV/scores on a scale
Interval -0.21 to 7.62

SECONDARY outcome

Timeframe: up to 24 months

Population: The overall number of participants with SMA analyzed (14 and 14) differs from the total enrollment reported in the participant flow (26) because of the staggered enrollment, subset of subjects with SMA and significant mortality.

Examine the correlation between each of the putative physiological and molecular biomarkers with the TIMPSI and CHOP-INTEND over the first two years of life in SMA (SMN = 2). All estimated correlations are the same at each study visit.

Outcome measures

Outcome measures
Measure
Infants With Spinal Muscular Atrophy
n=14 Participants
Infants diagnosed Spinal Muscular Atrophy
Healthy Controls
n=14 Participants
Healthy control infants
Correlation of mRNA Biomarkers With Motor Function Tests for SMA Subjects SMN Copy Number =2 Cohort
-6.39 (SMN/HPRT)/scores on a scale
Interval -28.59 to 15.8
0.097 (SMN/HPRT)/scores on a scale
Interval -16.08 to 16.27

SECONDARY outcome

Timeframe: up to 24 months

Population: The overall number of participants with SMA analyzed (10/10) differs from the total enrollment reported in the participant flow (26) because of the staggered enrollment, insufficient sample, subset of subjects with SMA and significant mortality.

Examine the correlation between each of the putative physiological and molecular biomarkers with the TIMPSI and CHOP-INTEND over the first two years of life in SMA (SMN = 2). All estimated correlations are the same at each study visit.

Outcome measures

Outcome measures
Measure
Infants With Spinal Muscular Atrophy
n=10 Participants
Infants diagnosed Spinal Muscular Atrophy
Healthy Controls
n=10 Participants
Healthy control infants
Correlation of Protein Level Biomarkers With Motor Function Tests for SMA Subjects SMN Copy Number =2 Cohort
0.000063 (pg/10^7 PBMC0/scores on a scale
Interval -0.0012 to 0.0013
0.00048 (pg/10^7 PBMC0/scores on a scale
Interval -0.00077 to 0.0017

SECONDARY outcome

Timeframe: up to 24 months

Population: The overall number of participants with SMA analyzed (14/14) differs from the total enrollment reported in the participant flow (26) because of the staggered enrollment, subset of subjects with SMA and significant mortality.

Examine the correlation between each of the putative physiological and molecular biomarkers with the TIMPSI and CHOP-INTEND over the first two years of life in SMA (SMN = 2). All estimated correlations are the same at each study visit.

Outcome measures

Outcome measures
Measure
Infants With Spinal Muscular Atrophy
n=14 Participants
Infants diagnosed Spinal Muscular Atrophy
Healthy Controls
n=14 Participants
Healthy control infants
Correlation of Biomarkers (Weight) With Motor Function Tests for SMA Subjects SMN Copy Number =2 Cohort
-2.50 kg/scores on a scale
Interval -4.78 to -0.23
-2.43 kg/scores on a scale
Interval -4.19 to -0.67

Adverse Events

Infants With Spinal Muscular Atrophy

Serious events: 0 serious events
Other events: 0 other events
Deaths: 12 deaths

Healthy Controls

Serious events: 0 serious events
Other events: 0 other events
Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Adverse event data not reported

Additional Information

Dr. Stephen Kolb

The Ohio State Unviersity Wexner Medical Center

Phone: 614-366-9050

Results disclosure agreements

  • Principal investigator is a sponsor employee
  • Publication restrictions are in place