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

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ClinicalTrials.gov Identifier: NCT01736553
Recruitment Status : Completed
First Posted : November 29, 2012
Results First Posted : May 4, 2018
Last Update Posted : May 4, 2018
Sponsor:
Collaborators:
National Institute of Neurological Disorders and Stroke (NINDS)
Cure SMA
Massachusetts General Hospital
University of Iowa
Information provided by (Responsible Party):
Stephen J. Kolb, Ohio State University

Study Type Observational
Study Design Observational Model: Cohort;   Time Perspective: Prospective
Condition Spinal Muscular Atrophy (SMA)
Enrollment 53
Recruitment Details 12/2012 first subject enrolled, 9/2014 Enrollment Complete, 8/2015 Last Subject Visit
Pre-assignment Details 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.
Arm/Group Title Infants With Spinal Muscular Atrophy Healthy Controls
Hide Arm/Group Description Infants diagnosed Spinal Muscular Atrophy Healthy control infants
Period Title: Overall Study
Started 26 27
Completed 7 23
Not Completed 19 4
Reason Not Completed
Death             12             0
Withdrawal by Subject             5             2
Lost to Follow-up             2             2
Arm/Group Title Infants With Spinal Muscular Atrophy Healthy Controls Total
Hide Arm/Group Description Infants diagnosed Spinal Muscular Atrophy Healthy control infants Total of all reporting groups
Overall Number of Baseline Participants 26 27 53
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous   [1] 
Mean (Standard Deviation)
Unit of measure:  Weeks
Number Analyzed 26 participants 27 participants 53 participants
39  (1.5) 39  (1.4) 39  (1.45)
[1]
Measure Description: Gestational age at birth is reported.
Age, Customized   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Age at Enrollment Number Analyzed 26 participants 27 participants 53 participants
0-2 Months
4
  15.4%
10
  37.0%
14
  26.4%
2-4 Months
16
  61.5%
9
  33.3%
25
  47.2%
5-6 Months
6
  23.1%
8
  29.6%
14
  26.4%
[1]
Measure Description: Age at Enrollment
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 26 participants 27 participants 53 participants
Female
15
  57.7%
14
  51.9%
29
  54.7%
Male
11
  42.3%
13
  48.1%
24
  45.3%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 26 participants 27 participants 53 participants
Hispanic or Latino
6
  23.1%
3
  11.1%
9
  17.0%
Not Hispanic or Latino
20
  76.9%
24
  88.9%
44
  83.0%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 26 participants 27 participants 53 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
0
   0.0%
Asian
0
   0.0%
1
   3.7%
1
   1.9%
Native Hawaiian or Other Pacific Islander
1
   3.8%
0
   0.0%
1
   1.9%
Black or African American
1
   3.8%
1
   3.7%
2
   3.8%
White
24
  92.3%
21
  77.8%
45
  84.9%
More than one race
0
   0.0%
3
  11.1%
3
   5.7%
Unknown or Not Reported
0
   0.0%
1
   3.7%
1
   1.9%
Region of Enrollment  
Measure Type: Count of Participants
Unit of measure:  Participants
United States Number Analyzed 26 participants 27 participants 53 participants
26
 100.0%
27
 100.0%
53
 100.0%
SMN2 Copy Number  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 26 participants 27 participants 53 participants
1
0
   0.0%
12
  44.4%
12
  22.6%
2
16
  61.5%
13
  48.1%
29
  54.7%
3
5
  19.2%
1
   3.7%
6
  11.3%
4
1
   3.8%
0
   0.0%
1
   1.9%
Unknown
4
  15.4%
1
   3.7%
5
   9.4%
Birth Weight  
Mean (Standard Deviation)
Unit of measure:  Lbs
Number Analyzed 26 participants 27 participants 53 participants
7  (1.2) 7  (1.4) 7  (1.3)
Birth Length  
Mean (Standard Deviation)
Unit of measure:  Inches
Number Analyzed 26 participants 27 participants 53 participants
20  (1.2) 20  (1.0) 20  (1.1)
1.Primary Outcome
Title Motor Function Assessments- Test for Infant Motor Performance Screening Items (TIMPSI)
Hide Description

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.

Time Frame Up to 24 months
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Infants With Spinal Muscular Atrophy Healthy Controls
Hide Arm/Group Description:
Infants diagnosed Spinal Muscular Atrophy
Healthy control infants
Overall Number of Participants Analyzed 19 26
Mean (95% Confidence Interval)
Unit of Measure: scores on a scale
6 month Number Analyzed 19 participants 26 participants
36.06
(27.20 to 44.91)
88.47
(80.52 to 96.43)
9 month Number Analyzed 11 participants 26 participants
40.54
(29.91 to 51.18)
89.44
(81.47 to 97.41)
12 month Number Analyzed 12 participants 26 participants
32.03
(21.39 to 42.68)
85.39
(77.41 to 93.36)
18 month Number Analyzed 4 participants 23 participants
26.35
(10.87 to 41.83)
87.35
(79.12 to 95.57)
24 month Number Analyzed 7 participants 21 participants
23.14
(10.04 to 36.23)
88.65
(80.19 to 97.11)
2.Primary Outcome
Title Motor Function Assessments- The Children's Hospital of Philadelphia Infant Test for Neuromuscular Disorders (CHOP-INTEND)
Hide Description 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.
Time Frame Up to 24 months
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Infants With Spinal Muscular Atrophy
Hide Arm/Group Description:
Infants diagnosed Spinal Muscular Atrophy
Overall Number of Participants Analyzed 14
Mean (95% Confidence Interval)
Unit of Measure: scores on a scale
6 month Number Analyzed 14 participants
18.38
(15.02 to 21.75)
9 month Number Analyzed 6 participants
13.18
(9.24 to 17.12)
12 month Number Analyzed 7 participants
9.74
(5.01 to 14.46)
18 month Number Analyzed 2 participants
7.52
(2.89 to 12.16)
24 month Number Analyzed 3 participants
7.01
(6.82 to 7.19)
3.Primary Outcome
Title Motor Function Assessments-Alberta Infant Motor Scale (AIMS)
Hide Description

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.

Time Frame Up to 24 months
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Infants With Spinal Muscular Atrophy Healthy Controls
Hide Arm/Group Description:
Infants diagnosed Spinal Muscular Atrophy
Healthy control infants
Overall Number of Participants Analyzed 5 26
Mean (95% Confidence Interval)
Unit of Measure: Scores on a scale
6 month Number Analyzed 5 participants 25 participants
11.74
(3.91 to 19.58)
19.29
(16.4 to 22.19)
9 month Number Analyzed 4 participants 26 participants
15.58
(2.51 to 28.64)
34.10
(29.05 to 39.14)
12 month Number Analyzed 5 participants 25 participants
21.60
(6.66 to 36.53)
37.10
(30.52 to 43.68)
18 month Number Analyzed 3 participants 24 participants
19.18
(2.03 to 36.32)
38.62
(31.30 to 45.93)
24 month Number Analyzed 4 participants 22 participants
14.71
(2.17 to 27.25)
37.76
(29.81 to 45.71)
4.Primary Outcome
Title Putative Physiological Biomarker- Compound Motor Action Potential Testing (CMAP)
Hide Description

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.

Time Frame Up to 24 months
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Infants With Spinal Muscular Atrophy Healthy Controls
Hide Arm/Group Description:
Infants diagnosed Spinal Muscular Atrophy
Healthy control infants
Overall Number of Participants Analyzed 18 26
Mean (95% Confidence Interval)
Unit of Measure: mV
6 month Number Analyzed 18 participants 26 participants
1.07
(0.17 to 1.96)
6.00
(5.22 to 6.78)
12 month Number Analyzed 11 participants 25 participants
0.51
(-0.56 to 1.59)
5.95
(5.16 to 6.75)
18 month Number Analyzed 5 participants 24 participants
0.49
(-0.98 to 1.95)
6.55
(5.75 to 7.36)
24 month Number Analyzed 6 participants 21 participants
-0.02
(-1.46 to 1.42)
6.74
(5.91 to 7.58)
5.Primary Outcome
Title Molecular Biomarkers- mRNA
Hide Description

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.

Time Frame Up to 24 months
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Infants With Spinal Muscular Atrophy Healthy Controls
Hide Arm/Group Description:
Infants diagnosed Spinal Muscular Atrophy
Healthy control infants
Overall Number of Participants Analyzed 19 22
Mean (95% Confidence Interval)
Unit of Measure: SMN/HPRT Ratio
6 month Number Analyzed 19 participants 22 participants
0.55
(0.39 to 0.71)
1.29
(1.14 to 1.44)
12 month Number Analyzed 10 participants 21 participants
0.47
(0.26 to 0.69)
1.21
(1.06 to 1.37)
18 month Number Analyzed 5 participants 22 participants
0.50
(0.19 to 0.80)
1.11
(0.96 to 1.26)
24 month Number Analyzed 5 participants 17 participants
0.66
(0.35 to 0.97)
1.20
(1.03 to 1.37)
6.Primary Outcome
Title Molecular Biomarkers- SMN Protein Levels
Hide Description 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.
Time Frame Up to 24 months
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Infants With Spinal Muscular Atrophy Healthy Controls
Hide Arm/Group Description:
Infants diagnosed Spinal Muscular Atrophy
Healthy control infants
Overall Number of Participants Analyzed 15 18
Mean (95% Confidence Interval)
Unit of Measure: pg/10^7 PBMC
6 month Number Analyzed 15 participants 18 participants
4798.85
(2799.07 to 6798.63)
8325.96
(6435.08 to 10217)
12 month Number Analyzed 8 participants 17 participants
6719.63
(4404.92 to 9034.3)
10247
(8228.29 to 12265)
18 month Number Analyzed 5 participants 14 participants
3108.79
(476.39 to 5741.19)
6635.90
(4401.46 to 8870.34)
24 month Number Analyzed 3 participants 12 participants
8502.48
(5562.01 to 11443)
12030
(9552.13 to 14507)
7.Primary Outcome
Title Putative Physiological Biomarkers-Weight
Hide Description 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.
Time Frame Up to 24 months
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Infants With Spinal Muscular Atrophy Healthy Controls
Hide Arm/Group Description:
Infants diagnosed Spinal Muscular Atrophy
Healthy control infants
Overall Number of Participants Analyzed 19 26
Mean (95% Confidence Interval)
Unit of Measure: kg
6 month Number Analyzed 19 participants 25 participants
6.88
(6.46 to 7.31)
7.83
(7.43 to 8.23)
9 month Number Analyzed 11 participants 26 participants
7.92
(7.34 to 8.49)
8.94
(8.51 to 9.37)
12 month Number Analyzed 12 participants 26 participants
8.71
(8.10 to 9.33)
9.88
(9.41 to 10.36)
18 month Number Analyzed 5 participants 24 participants
9.95
(9.17 to 10.72)
11.40
(10.95 to 11.85)
24 month Number Analyzed 7 participants 22 participants
10.47
(9.71 to 11.23)
12.74
(12.25 to 13.23)
8.Primary Outcome
Title Correlation of Biomarkers With Motor Function Tests for SMA Subjects- CMAP
Hide Description 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.
Time Frame up to 24 months
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Correlation With TIMPSI Correlation With CHOP-INTEND
Hide Arm/Group Description:
[Not Specified]
[Not Specified]
Overall Number of Participants Analyzed 19 14
Mean (95% Confidence Interval)
Unit of Measure: mV/scale unit
6 month Number Analyzed 19 participants 14 participants
9.36
(5.59 to 13.13)
17.25
(-2.26 to 36.77)
12 month Number Analyzed 12 participants 7 participants
22.88
(16.24 to 29.52)
21.53
(-34.94 to 78.00)
18 month Number Analyzed 4 participants 0 participants
17.48
(9.07 to 25.89)
24 month Number Analyzed 7 participants 0 participants
18.57
(10.03 to 27.11)
9.Primary Outcome
Title Correlation of Biomarkers With Motor Function Tests for SMA Subjects- mRNA
Hide Description 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.
Time Frame up to 24 months
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Correlation With TIMPSI Correlation With CHOP-INTEND
Hide Arm/Group Description:
[Not Specified]
[Not Specified]
Overall Number of Participants Analyzed 26 26
Mean (95% Confidence Interval)
Unit of Measure: (SMN/HPRT ratio)/scale unit
6 month
53.60
(-0.04 to 107.24)
0.11
(-15.81 to 16.03)
12 month
125.52
(40.81 to 210.22)
0.11
(-15.81 to 16.03)
18 month
181.22
(3.65 to 358.78)
0.11
(-15.81 to 16.03)
24 month
46.43
(-12.65 to 105.51)
0.11
(-15.81 to 16.03)
10.Primary Outcome
Title Correlation of Biomarkers With Motor Function Tests for SMA Subjects- SMN Protein
Hide Description 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.
Time Frame up to 24 months
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Correlation With CHOP-INTEND Correlation With TIMPSI
Hide Arm/Group Description:
[Not Specified]
[Not Specified]
Overall Number of Participants Analyzed 14 19
Mean (95% Confidence Interval)
Unit of Measure: (pg/10^7 PBMC)/scale unit
6 month Number Analyzed 14 participants 19 participants
-0.0011
(-0.0053 to 0.0032)
-0.0003
(-0.0033 to 0.0027)
12 month Number Analyzed 7 participants 12 participants
0.00066
(-0.0057 to 0.0071)
-0.0003
(-0.00033 to 0.0027)
18 month Number Analyzed 2 participants 4 participants
0.026
(-0.0093 to 0.061)
-0.0003
(-0.00033 to 0.0027)
24 month Number Analyzed 0 participants 7 participants
-0.0003
(-0.00033 to 0.0027)
11.Primary Outcome
Title Correlation of Biomarkers With Motor Function Tests for SMA Subjects- Weight
Hide Description 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.
Time Frame up to 24 months
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Correlation With TIMPSI Correlation With CHOP-INTEND
Hide Arm/Group Description:
[Not Specified]
[Not Specified]
Overall Number of Participants Analyzed 26 26
Mean (95% Confidence Interval)
Unit of Measure: kg/scale unit
2.27
(-3.34 to 7.87)
-2.39
(-4.13 to -0.65)
12.Primary Outcome
Title Correlation of Biomarkers With Motor Function Tests for Healthy Control Subjects- CMAP
Hide Description 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.
Time Frame up to 24 months
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Correlation With TIMPSI Correlation With AIMS
Hide Arm/Group Description:
Healthy Control Subjects Motor Test- TIMPSI correlated with the CMAP exam
Healthy Control Subjects Motor Test- AIMS correlated with the CMAP exam
Overall Number of Participants Analyzed 26 26
Mean (95% Confidence Interval)
Unit of Measure: mV/scale unit
6 month Number Analyzed 26 participants 25 participants
-0.23
(-2.88 to 2.43)
0.21
(-0.63 to 1.05)
12 month Number Analyzed 26 participants 25 participants
-4.52
(-7.53 to -1.51)
0.21
(-0.63 to 1.05)
18 month Number Analyzed 23 participants 24 participants
-0.58
(-3.07 to 1.92)
0.21
(-0.63 to 1.05)
24 month Number Analyzed 21 participants 22 participants
1.14
(-2.05 to 4.34)
0.21
(-0.63 to 1.05)
13.Primary Outcome
Title Correlation of Biomarkers With Motor Function Tests for Healthy Control Subjects- mRNA
Hide Description 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.
Time Frame up to 24 months
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Correlation With TIMPSI Correlation With AIMS
Hide Arm/Group Description:
Healthy Control Subjects Motor Test- TIMPSI correlated with the mRNA
Healthy Control Subjects Motor Test- AIMS correlated with the mRNA
Overall Number of Participants Analyzed 26 26
Mean (95% Confidence Interval)
Unit of Measure: (SMN/HPRT Ratio)/scale unit
9.52
(3.18 to 15.86)
-2.46
(-6.20 to 1.28)
14.Primary Outcome
Title Correlation of Biomarkers With Motor Function Tests for Healthy Control Subjects- Weight
Hide Description 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.
Time Frame up to 24 months
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Correlation With TIMPSI Correlation With AIMS
Hide Arm/Group Description:
Healthy Control Subjects Motor Test- TIMPSI correlated with weight
Healthy Control Subjects Motor Test- AIMS correlated with weight
Overall Number of Participants Analyzed 26 26
Mean (95% Confidence Interval)
Unit of Measure: kg/scale unit
6 month
0.60
(-1.71 to 2.90)
1.48
(-0.68 to 3.66)
9 month
0.60
(-1.71 to 2.90)
-0.72
(-4.06 to 2.62)
12 month
0.60
(-1.71 to 2.90)
1.14
(-2.12 to 4.39)
18 month
0.60
(-1.71 to 2.90)
-0.46
(-4.39 to 3.47)
24 month
0.60
(-1.71 to 2.90)
3.53
(-0.76 to 7.82)
15.Secondary Outcome
Title Biomarker Prediction of Risk of Death
Hide Description 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).
Time Frame Up to 24 months
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Hide Analysis Population Description
[Not Specified]
Arm/Group Title Estimated Hazard Ratio
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Proportional hazards regression models used to determine if motor function scores, mRNA, and protein levels predict death in SMA subjects
Overall Number of Participants Analyzed 26
Mean (95% Confidence Interval)
Unit of Measure: Hazard Ratio
TIMPSI (per 10 unit increase)
0.72
(0.50 to 1.04)
CHOP-INTEND (per 10 unit increase)
0.94
(0.59 to 1.51)
CMAP Peak Amplitude (per 1 unit increase)
0.37
(0.10 to 1.29)
mRNA (per 1 unit increase)
0.28
(0.0009 to 8.82)
Protein Level (per 1000 unit increase)
1.27
(0.98 to 1.65)
Weight (per 10kg increase)
0.02
(0.0004 to 1.28)
16.Secondary Outcome
Title Motor Function Assessments- Test for Infant Motor Performance Screening Items (TIMPSI) SMN Copy Number =2 Cohort
Hide Description

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.

Time Frame Up to 24 months
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Hide Analysis Population Description
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.
Arm/Group Title Infants With Spinal Muscular Atrophy (SMN=2) Healthy Controls
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Infants diagnosed Spinal Muscular Atrophy (SMN=2)
Healthy control infants
Overall Number of Participants Analyzed 14 26
Mean (95% Confidence Interval)
Unit of Measure: Scores on a scale
6 month Number Analyzed 14 participants 26 participants
24.53
(17.89 to 31.17)
88.25
(83.34 to 93.15)
9 month Number Analyzed 6 participants 26 participants
20.08
(10.11 to 30.05)
89.20
(84.29 to 94.11)
12 month Number Analyzed 7 participants 26 participants
13.82
(4.40 to 23.24)
85.15
(80.24 to 90.06)
18 month Number Analyzed 2 participants 23 participants
8.82
(-8.24 to 25.89)
87.36
(82.16 to 92.56)
24 month Number Analyzed 3 participants 21 participants
7.51
(-6.83 to 22.03)
88.92
(83.49 to 94.36)
17.Secondary Outcome
Title Motor Function Assessments- The Children's Hospital of Philadelphia Infant Test for Neuromuscular Disorders (CHOP-INTEND) SMN Copy Number =2 Cohort
Hide Description

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).

Time Frame Up to 24 months
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Hide Analysis Population Description
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.
Arm/Group Title Infants With Spinal Muscular Atrophy (SMN=2)
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Infants diagnosed Spinal Muscular Atrophy (SMN=2)
Overall Number of Participants Analyzed 14
Mean (95% Confidence Interval)
Unit of Measure: Scores on a scale
6 month Number Analyzed 14 participants
18.05
(14.86 to 21.25)
9 month Number Analyzed 6 participants
12.87
(8.93 to 16.81)
12 month Number Analyzed 7 participants
9.38
(4.61 to 14.12)
18 month Number Analyzed 2 participants
7.33
(2.39 to 12.26)
24 month Number Analyzed 3 participants
7.00
(6.72 to 7.28)
18.Secondary Outcome
Title Putative Physiological Biomarker- Compound Motor Action Potential Testing (CMAP) SMN Copy Number = 2 Cohort
Hide Description

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.

Time Frame Up to 24 months
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Infants With Spinal Muscular Atrophy (SMN=2) Healthy Controls
Hide Arm/Group Description:
Infants diagnosed Spinal Muscular Atrophy (SMN=2)
Healthy control infants
Overall Number of Participants Analyzed 13 26
Mean (95% Confidence Interval)
Unit of Measure: mV
6 month Number Analyzed 13 participants 26 participants
0.36
(-0.04 to 1.84)
5.95
(5.30 to 6.60)
12 month Number Analyzed 7 participants 25 participants
0.33
(-0.54 to 1.19)
5.92
(5.25 to 6.58)
18 month Number Analyzed 2 participants 24 participants
0.90
(-0.04 to 1.84)
6.49
(5.80 to 7.19)
24 month Number Analyzed 0 participants 21 participants
6.63
(5.92 to 7.36)
19.Secondary Outcome
Title Molecular Biomarkers- mRNA SMA Copy Number = 2 Cohort
Hide Description 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.
Time Frame Up to 24 months
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Infants With Spinal Muscular Atrophy (SMN=2) Healthy Controls
Hide Arm/Group Description:
Infants diagnosed Spinal Muscular Atrophy (SMN=2)
Healthy control infants
Overall Number of Participants Analyzed 14 22
Mean (95% Confidence Interval)
Unit of Measure: SMN/HPRT Ratio
6 month Number Analyzed 14 participants 22 participants
0.46
(0.31 to 0.62)
1.29
(1.16 to 1.43)
12 month Number Analyzed 6 participants 21 participants
0.38
(0.31 to 0.45)
1.21
(1.07 to 1.35)
18 month Number Analyzed 2 participants 22 participants
0.29
(0.08 to 0.49)
1.12
(0.97 to 1.26)
24 month Number Analyzed 3 participants 22 participants
0.40
(0.19 to 0.61)
1.23
(1.07 to 1.39)
20.Secondary Outcome
Title Molecular Biomarkers- SMN Protein Levels SMA Copy Number = 2
Hide Description 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.
Time Frame Up to 24 months
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Infants With Spinal Muscular Atrophy (SMN=2) Healthy Controls
Hide Arm/Group Description:
Infants diagnosed Spinal Muscular Atrophy (SMN=2)
Healthy control infants
Overall Number of Participants Analyzed 10 18
Mean (95% Confidence Interval)
Unit of Measure: pg/10^7 PBMC
6 month Number Analyzed 10 participants 18 participants
3785.02
(1245.92 to 6324.12)
8598.73
(6472.81 to 10725)
12 month Number Analyzed 4 participants 17 participants
5800.63
(2828.39 to 8772.87)
10614
(8341.73 to 12887)
18 month Number Analyzed 2 participants 14 participants
1612.35
(-1753.19 to 4977.90)
6426.06
(3892.03 to 8960.09)
24 month Number Analyzed 1 participants 12 participants
6912.88
(3225.48 to 10600)
11727
(8930.09 to 14523)
21.Secondary Outcome
Title Putative Physiological Biomarkers-Weight SMN Copy Number =2 Cohort
Hide Description 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
Time Frame Up to 24 months
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Infants With Spinal Muscular Atrophy (SMN=2) Healthy Controls
Hide Arm/Group Description:
Infants diagnosed Spinal Muscular Atrophy (SMN=2)
Healthy control infants
Overall Number of Participants Analyzed 14 26
Mean (95% Confidence Interval)
Unit of Measure: kg
6 month Number Analyzed 14 participants 25 participants
6.63
(6.14 to 7.13)
7.83
(7.43 to 8.23)
9 month Number Analyzed 6 participants 26 participants
7.70
(7.00 to 8.39)
8.93
(8.50 to 9.36)
12 month Number Analyzed 7 participants 26 participants
8.51
(7.70 to 9.32)
9.88
(9.40 to 10.37)
18 month Number Analyzed 2 participants 24 participants
9.65
(8.47 to 10.84)
11.40
(10.93 to 11.87)
24 month Number Analyzed 3 participants 22 participants
9.77
(8.57 to 10.98)
12.72
(12.23 to 13.22)
22.Secondary Outcome
Title Correlation of CMAP Biomarker With Motor Function Tests for SMA Subjects SMN Copy Number =2 Cohort
Hide Description 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.
Time Frame up to 24 months
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Correlation With TIMPSI Correlation With CHOP-INTEND
Hide Arm/Group Description:
Infants Diagnosed with SMN=2
Infants Diagnosed with SMN=2
Overall Number of Participants Analyzed 14 14
Mean (95% Confidence Interval)
Unit of Measure: mV/scores on a scale
5.10
(0.095 to 10.11)
3.71
(-0.21 to 7.62)
23.Secondary Outcome
Title Correlation of mRNA Biomarkers With Motor Function Tests for SMA Subjects SMN Copy Number =2 Cohort
Hide Description 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.
Time Frame up to 24 months
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Correlation With TIMPSI Correlation With CHOP-INTEND
Hide Arm/Group Description:
Infants diagnosed Spinal Muscular Atrophy (SMN=2)
Infants diagnosed Spinal Muscular Atrophy (SMN=2)
Overall Number of Participants Analyzed 14 14
Mean (95% Confidence Interval)
Unit of Measure: (SMN/HPRT)/scores on a scale
-6.39
(-28.59 to 15.80)
0.097
(-16.08 to 16.27)
24.Secondary Outcome
Title Correlation of Protein Level Biomarkers With Motor Function Tests for SMA Subjects SMN Copy Number =2 Cohort
Hide Description 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.
Time Frame up to 24 months
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Correlation With TIMPSI Correlation With CHOP-INTEND
Hide Arm/Group Description:
Infants diagnosed with SMA (SMN=2)
Infants diagnosed with SMA (SMN=2)
Overall Number of Participants Analyzed 10 10
Mean (95% Confidence Interval)
Unit of Measure: (pg/10^7 PBMC0/scores on a scale
0.000063
(-0.0012 to 0.0013)
0.00048
(-0.00077 to 0.0017)
25.Secondary Outcome
Title Correlation of Biomarkers (Weight) With Motor Function Tests for SMA Subjects SMN Copy Number =2 Cohort
Hide Description 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.
Time Frame up to 24 months
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Correlation With TIMPSI Correlation With CHOP-INTEND
Hide Arm/Group Description:
Infants diagnosed with SMA (SMN=2)
Infants diagnosed with SMA (SMN=2)
Overall Number of Participants Analyzed 14 14
Mean (95% Confidence Interval)
Unit of Measure: kg/scores on a scale
-2.50
(-4.78 to -.23)
-2.43
(-4.19 to -0.67)
Time Frame [Not Specified]
Adverse Event Reporting Description Since this trial was not a treatment study, Adverse Events (AEs) were only collected if they related to the procedures done at the visit. There were no AEs to report.
 
Arm/Group Title Infants With Spinal Muscular Atrophy Healthy Controls
Hide Arm/Group Description Infants diagnosed Spinal Muscular Atrophy Healthy control infants
All-Cause Mortality
Infants With Spinal Muscular Atrophy Healthy Controls
Affected / at Risk (%) Affected / at Risk (%)
Total   12/26 (46.15%)   0/27 (0.00%) 
Show Serious Adverse Events Hide Serious Adverse Events
Infants With Spinal Muscular Atrophy Healthy Controls
Affected / at Risk (%) Affected / at Risk (%)
Total   0/26 (0.00%)   0/27 (0.00%) 
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Infants With Spinal Muscular Atrophy Healthy Controls
Affected / at Risk (%) Affected / at Risk (%)
Total   0/26 (0.00%)   0/27 (0.00%) 
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Name/Title: Dr. Stephen Kolb
Organization: The Ohio State Unviersity Wexner Medical Center
Phone: 614-366-9050
Publications:
Responsible Party: Stephen J. Kolb, Ohio State University
ClinicalTrials.gov Identifier: NCT01736553     History of Changes
Other Study ID Numbers: NN101
U01NS079163 ( U.S. NIH Grant/Contract )
First Submitted: November 19, 2012
First Posted: November 29, 2012
Results First Submitted: April 7, 2017
Results First Posted: May 4, 2018
Last Update Posted: May 4, 2018