Spinal Muscular Atrophy (SMA)
Conditions
Keywords
Spinal Muscular Atrophy (SMA) Biomarkers, Healthy controls, Infants
Brief summary
Spinal muscular atrophy (SMA) is the leading genetic cause of death of infants. Strong preclinical evidence suggests that effective therapy must be delivered as early as possible to prevent progression of the disease. The primary study objective will be to identify prognostic and surrogate biomarkers of disease progression that will facilitate the execution of therapeutic SMA clinical trials in infants.
Detailed description
Aim 1. To establish the validity of putative physiological SMA biomarkers in the immediate postnatal period. A longitudinal, natural history examination of physiological markers of muscle innervation will be performed in healthy and SMA infants. The first week of life is the ideal first time point, with visits occurring at scheduled visits up to the age two. Compound motor action potential (CMAP) amplitude and electrical impedance myography (EIM) will be examined and will be correlated with motor function. Each of these is associated with muscle innervation and provides information on the number and function of lower motor neurons in the spinal cord, the cellular target of SMA therapeutic interventions. This trial will establish the natural history of these putative SMA biomarkers as the disease evolves in affected infants. Moreover, our approach will allow for measurements in pre-symptomatic and early symptomatic subjects and determine their predictive value. Aim 2. To establish the validity of putative molecular SMA biomarkers in the immediate postnatal period. Survival Motor Neuron (SMN2) copy number is a valid, predictive molecular SMA biomarker; however, it is fixed, and therefore not useful as a biomarker of clinical progression or response to therapy. SMN messenger Ribonucleic acid (mRNA) ( and protein expression is variable in different cell types and, in mice, naturally decreases with age postnatally. In this study, SMN expression levels will be measured longitudinally in SMA patients and controls. Additional putative molecular SMA markers that have been identified to correlate with motor function will be determined in an effort to distinguish between predictive markers that change prior to development of weakness and those that change as a consequence of weakness.
Interventions
None listed
Sponsors
National Institute of Neurological Disorders and Stroke (NINDS)
Cure SMA
Massachusetts General Hospital
University of Iowa
Ohio State University
Study design
Observational model
COHORT
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
No minimum to 6 Months
Healthy volunteers
Yes
Inclusion criteria
All infants will be between 0-6 months of age at the time of enrollment. Parents or guardians of the enrolled infants must sign an informed consent form prior to any study procedure being performed. The infants with SMA must have already had a positive DNA test outside of the study to qualify for enrollment. An infant with SMA can have any number of SMN2 gene copies. Knowledge of the number of SMN2 gene copies prior to enrollment is not required. Healthy control infants who meet the following criteria will be enrolled: * Birth between 36 and 42 weeks inclusive of gestation * Siblings of children with SMA must have had prior SMA genetic testing completed con-firming the infant is a healthy control * Principal investigator feels the family/infant is able and willing to comply with study procedures * Parent or guardian able to give informed consent SMA infants who meet the following criteria will be enrolled: * Birth between 36 and 42 weeks inclusive of gestation * Positive SMN1 gene mutation/deletion * Principal investigator feels the family/infant is able and willing to comply with study procedures * Parent or guardian able to give informed consent
Exclusion criteria
* Use of any putative therapy intended to increase the amount of SMN protein in cells * Enrollment in an SMA therapeutic trial at the time of enrollment in the SMA biomarker study * Have a systemic illness requiring ongoing treatment, such as pneumonia * Clinically significant abnormal findings (as determined by the investigator) on the physical examination or medical history (including history of tracheostomy tubes and ventilator-dependency) * Dependency upon non-invasive ventilatory support (ie: BiPAP) for more than 12 hours/day
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Correlation of Biomarkers With Motor Function Tests for Healthy Control Subjects- Weight | 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 AIMS. |
| Motor Function Assessments-Alberta Infant Motor Scale (AIMS) | Up to 24 months | 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. |
| Putative Physiological Biomarker- Compound Motor Action Potential Testing (CMAP) | Up to 24 months | 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. |
| Molecular Biomarkers- mRNA | Up to 24 months | 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. |
| Molecular Biomarkers- SMN Protein Levels | Up to 24 months | 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. |
| Putative Physiological Biomarkers-Weight | Up to 24 months | 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. |
| Correlation of Biomarkers With Motor Function Tests for SMA Subjects- CMAP | 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. In the CHOP-INTEND analyses, correlations were not estimable for the 18 and 24 month visits. |
| Correlation of Biomarkers With Motor Function Tests for SMA Subjects- mRNA | 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. |
| Correlation of Biomarkers With Motor Function Tests for SMA Subjects- SMN Protein | 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. In the CHOP-INTEND analyses, the correlation at the 24 month visit was not estimable. |
| Correlation of Biomarkers With Motor Function Tests for SMA Subjects- Weight | 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. |
| Correlation of Biomarkers With Motor Function Tests for Healthy Control Subjects- CMAP | 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 AIMS. |
| Correlation of Biomarkers With Motor Function Tests for Healthy Control Subjects- mRNA | 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 AIMS. |
| Motor Function Assessments- Test for Infant Motor Performance Screening Items (TIMPSI) | Up to 24 months | 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. |
| Motor Function Assessments- The Children's Hospital of Philadelphia Infant Test for Neuromuscular Disorders (CHOP-INTEND) | Up to 24 months | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Motor Function Assessments- Test for Infant Motor Performance Screening Items (TIMPSI) SMN Copy Number =2 Cohort | Up to 24 months | 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. |
| Motor Function Assessments- The Children's Hospital of Philadelphia Infant Test for Neuromuscular Disorders (CHOP-INTEND) SMN Copy Number =2 Cohort | Up to 24 months | 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). |
| Putative Physiological Biomarker- Compound Motor Action Potential Testing (CMAP) SMN Copy Number = 2 Cohort | Up to 24 months | 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. |
| Molecular Biomarkers- mRNA SMA Copy Number = 2 Cohort | Up to 24 months | 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. |
| Molecular Biomarkers- SMN Protein Levels SMA Copy Number = 2 | Up to 24 months | 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. |
| Putative Physiological Biomarkers-Weight SMN Copy Number =2 Cohort | Up to 24 months | 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 |
| Correlation of CMAP Biomarker With Motor Function Tests for SMA Subjects SMN Copy Number =2 Cohort | up to 24 months | 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. |
| Correlation of mRNA Biomarkers With Motor Function Tests for SMA Subjects SMN Copy Number =2 Cohort | up to 24 months | 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. |
| Correlation of Protein Level Biomarkers With Motor Function Tests for SMA Subjects SMN Copy Number =2 Cohort | up to 24 months | 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. |
| Correlation of Biomarkers (Weight) With Motor Function Tests for SMA Subjects SMN Copy Number =2 Cohort | up to 24 months | 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. |
| Biomarker Prediction of Risk of Death | 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). |
Countries
United States
Participant flow
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.
Participants by arm
| Arm | Count |
|---|---|
| Infants With Spinal Muscular Atrophy Infants diagnosed Spinal Muscular Atrophy | 26 |
| Healthy Controls Healthy control infants | 27 |
| Total | 53 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 12 | 0 |
| Overall Study | Lost to Follow-up | 2 | 2 |
| Overall Study | Withdrawal by Subject | 5 | 2 |
Baseline characteristics
| Characteristic | Infants With Spinal Muscular Atrophy | Healthy Controls | Total |
|---|---|---|---|
| Age, Continuous | 39 Weeks STANDARD_DEVIATION 1.5 | 39 Weeks STANDARD_DEVIATION 1.4 | 39 Weeks STANDARD_DEVIATION 1.45 |
| Age, Customized Age at Enrollment 0-2 Months | 4 Participants | 10 Participants | 14 Participants |
| Age, Customized Age at Enrollment 2-4 Months | 16 Participants | 9 Participants | 25 Participants |
| Age, Customized Age at Enrollment 5-6 Months | 6 Participants | 8 Participants | 14 Participants |
| Birth Length | 20 inches STANDARD_DEVIATION 1.2 | 20 inches STANDARD_DEVIATION 1 | 20 inches STANDARD_DEVIATION 1.1 |
| Birth Weight | 7 lbs STANDARD_DEVIATION 1.2 | 7 lbs STANDARD_DEVIATION 1.4 | 7 lbs STANDARD_DEVIATION 1.3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 6 Participants | 3 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 20 Participants | 24 Participants | 44 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 3 Participants | 3 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 24 Participants | 21 Participants | 45 Participants |
| Region of Enrollment United States | 26 Participants | 27 Participants | 53 Participants |
| Sex: Female, Male Female | 15 Participants | 14 Participants | 29 Participants |
| Sex: Female, Male Male | 11 Participants | 13 Participants | 24 Participants |
| SMN2 Copy Number 1 | 0 Participants | 12 Participants | 12 Participants |
| SMN2 Copy Number 2 | 16 Participants | 13 Participants | 29 Participants |
| SMN2 Copy Number 3 | 5 Participants | 1 Participants | 6 Participants |
| SMN2 Copy Number 4 | 1 Participants | 0 Participants | 1 Participants |
| SMN2 Copy Number Unknown | 4 Participants | 1 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 12 / 26 | 0 / 27 |
| other Total, other adverse events | 0 / 26 | 0 / 27 |
| serious Total, serious adverse events | 0 / 26 | 0 / 27 |
Outcome results
Primary
Correlation of Biomarkers With Motor Function Tests for Healthy Control Subjects- CMAP
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
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.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Infants With Spinal Muscular Atrophy | Correlation of Biomarkers With Motor Function Tests for Healthy Control Subjects- CMAP | 6 month | -0.23 mV/scale unit |
| Infants With Spinal Muscular Atrophy | Correlation of Biomarkers With Motor Function Tests for Healthy Control Subjects- CMAP | 12 month | -4.52 mV/scale unit |
| Infants With Spinal Muscular Atrophy | Correlation of Biomarkers With Motor Function Tests for Healthy Control Subjects- CMAP | 18 month | -0.58 mV/scale unit |
| Infants With Spinal Muscular Atrophy | Correlation of Biomarkers With Motor Function Tests for Healthy Control Subjects- CMAP | 24 month | 1.14 mV/scale unit |
| Healthy Controls | Correlation of Biomarkers With Motor Function Tests for Healthy Control Subjects- CMAP | 24 month | 0.21 mV/scale unit |
| Healthy Controls | Correlation of Biomarkers With Motor Function Tests for Healthy Control Subjects- CMAP | 6 month | 0.21 mV/scale unit |
| Healthy Controls | Correlation of Biomarkers With Motor Function Tests for Healthy Control Subjects- CMAP | 18 month | 0.21 mV/scale unit |
| Healthy Controls | Correlation of Biomarkers With Motor Function Tests for Healthy Control Subjects- CMAP | 12 month | 0.21 mV/scale unit |
Primary
Correlation of Biomarkers With Motor Function Tests for Healthy Control Subjects- mRNA
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
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.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Infants With Spinal Muscular Atrophy | Correlation of Biomarkers With Motor Function Tests for Healthy Control Subjects- mRNA | 9.52 (SMN/HPRT Ratio)/scale unit |
| Healthy Controls | Correlation of Biomarkers With Motor Function Tests for Healthy Control Subjects- mRNA | -2.46 (SMN/HPRT Ratio)/scale unit |
Primary
Correlation of Biomarkers With Motor Function Tests for Healthy Control Subjects- Weight
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
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.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Infants With Spinal Muscular Atrophy | Correlation of Biomarkers With Motor Function Tests for Healthy Control Subjects- Weight | 9 month | 0.60 kg/scale unit |
| Infants With Spinal Muscular Atrophy | Correlation of Biomarkers With Motor Function Tests for Healthy Control Subjects- Weight | 18 month | 0.60 kg/scale unit |
| Infants With Spinal Muscular Atrophy | Correlation of Biomarkers With Motor Function Tests for Healthy Control Subjects- Weight | 12 month | 0.60 kg/scale unit |
| Infants With Spinal Muscular Atrophy | Correlation of Biomarkers With Motor Function Tests for Healthy Control Subjects- Weight | 24 month | 0.60 kg/scale unit |
| Infants With Spinal Muscular Atrophy | Correlation of Biomarkers With Motor Function Tests for Healthy Control Subjects- Weight | 6 month | 0.60 kg/scale unit |
| Healthy Controls | Correlation of Biomarkers With Motor Function Tests for Healthy Control Subjects- Weight | 24 month | 3.53 kg/scale unit |
| Healthy Controls | Correlation of Biomarkers With Motor Function Tests for Healthy Control Subjects- Weight | 6 month | 1.48 kg/scale unit |
| Healthy Controls | Correlation of Biomarkers With Motor Function Tests for Healthy Control Subjects- Weight | 9 month | -0.72 kg/scale unit |
| Healthy Controls | Correlation of Biomarkers With Motor Function Tests for Healthy Control Subjects- Weight | 12 month | 1.14 kg/scale unit |
| Healthy Controls | Correlation of Biomarkers With Motor Function Tests for Healthy Control Subjects- Weight | 18 month | -0.46 kg/scale unit |
Primary
Correlation of Biomarkers With Motor Function Tests for SMA Subjects- CMAP
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
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.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Infants With Spinal Muscular Atrophy | Correlation of Biomarkers With Motor Function Tests for SMA Subjects- CMAP | 18 month | 17.48 mV/scale unit |
| Infants With Spinal Muscular Atrophy | Correlation of Biomarkers With Motor Function Tests for SMA Subjects- CMAP | 6 month | 9.36 mV/scale unit |
| Infants With Spinal Muscular Atrophy | Correlation of Biomarkers With Motor Function Tests for SMA Subjects- CMAP | 12 month | 22.88 mV/scale unit |
| Infants With Spinal Muscular Atrophy | Correlation of Biomarkers With Motor Function Tests for SMA Subjects- CMAP | 24 month | 18.57 mV/scale unit |
| Healthy Controls | Correlation of Biomarkers With Motor Function Tests for SMA Subjects- CMAP | 6 month | 17.25 mV/scale unit |
| Healthy Controls | Correlation of Biomarkers With Motor Function Tests for SMA Subjects- CMAP | 12 month | 21.53 mV/scale unit |
Primary
Correlation of Biomarkers With Motor Function Tests for SMA Subjects- mRNA
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
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Infants With Spinal Muscular Atrophy | Correlation of Biomarkers With Motor Function Tests for SMA Subjects- mRNA | 6 month | 53.60 (SMN/HPRT ratio)/scale unit |
| Infants With Spinal Muscular Atrophy | Correlation of Biomarkers With Motor Function Tests for SMA Subjects- mRNA | 18 month | 181.22 (SMN/HPRT ratio)/scale unit |
| Infants With Spinal Muscular Atrophy | Correlation of Biomarkers With Motor Function Tests for SMA Subjects- mRNA | 24 month | 46.43 (SMN/HPRT ratio)/scale unit |
| Infants With Spinal Muscular Atrophy | Correlation of Biomarkers With Motor Function Tests for SMA Subjects- mRNA | 12 month | 125.52 (SMN/HPRT ratio)/scale unit |
| Healthy Controls | Correlation of Biomarkers With Motor Function Tests for SMA Subjects- mRNA | 24 month | 0.11 (SMN/HPRT ratio)/scale unit |
| Healthy Controls | Correlation of Biomarkers With Motor Function Tests for SMA Subjects- mRNA | 6 month | 0.11 (SMN/HPRT ratio)/scale unit |
| Healthy Controls | Correlation of Biomarkers With Motor Function Tests for SMA Subjects- mRNA | 12 month | 0.11 (SMN/HPRT ratio)/scale unit |
| Healthy Controls | Correlation of Biomarkers With Motor Function Tests for SMA Subjects- mRNA | 18 month | 0.11 (SMN/HPRT ratio)/scale unit |
Primary
Correlation of Biomarkers With Motor Function Tests for SMA Subjects- SMN Protein
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
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.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Infants With Spinal Muscular Atrophy | Correlation of Biomarkers With Motor Function Tests for SMA Subjects- SMN Protein | 12 month | 0.00066 (pg/10^7 PBMC)/scale unit |
| Infants With Spinal Muscular Atrophy | Correlation of Biomarkers With Motor Function Tests for SMA Subjects- SMN Protein | 6 month | -0.0011 (pg/10^7 PBMC)/scale unit |
| Infants With Spinal Muscular Atrophy | Correlation of Biomarkers With Motor Function Tests for SMA Subjects- SMN Protein | 18 month | 0.026 (pg/10^7 PBMC)/scale unit |
| Healthy Controls | Correlation of Biomarkers With Motor Function Tests for SMA Subjects- SMN Protein | 24 month | -0.0003 (pg/10^7 PBMC)/scale unit |
| Healthy Controls | Correlation of Biomarkers With Motor Function Tests for SMA Subjects- SMN Protein | 6 month | -0.0003 (pg/10^7 PBMC)/scale unit |
| Healthy Controls | Correlation of Biomarkers With Motor Function Tests for SMA Subjects- SMN Protein | 12 month | -0.0003 (pg/10^7 PBMC)/scale unit |
| Healthy Controls | Correlation of Biomarkers With Motor Function Tests for SMA Subjects- SMN Protein | 18 month | -0.0003 (pg/10^7 PBMC)/scale unit |
Primary
Correlation of Biomarkers With Motor Function Tests for SMA Subjects- Weight
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
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Infants With Spinal Muscular Atrophy | Correlation of Biomarkers With Motor Function Tests for SMA Subjects- Weight | 2.27 kg/scale unit |
| Healthy Controls | Correlation of Biomarkers With Motor Function Tests for SMA Subjects- Weight | -2.39 kg/scale unit |
Primary
Molecular Biomarkers- mRNA
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
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.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Infants With Spinal Muscular Atrophy | Molecular Biomarkers- mRNA | 6 month | 0.55 SMN/HPRT Ratio |
| Infants With Spinal Muscular Atrophy | Molecular Biomarkers- mRNA | 12 month | 0.47 SMN/HPRT Ratio |
| Infants With Spinal Muscular Atrophy | Molecular Biomarkers- mRNA | 18 month | 0.50 SMN/HPRT Ratio |
| Infants With Spinal Muscular Atrophy | Molecular Biomarkers- mRNA | 24 month | 0.66 SMN/HPRT Ratio |
| Healthy Controls | Molecular Biomarkers- mRNA | 24 month | 1.20 SMN/HPRT Ratio |
| Healthy Controls | Molecular Biomarkers- mRNA | 6 month | 1.29 SMN/HPRT Ratio |
| Healthy Controls | Molecular Biomarkers- mRNA | 18 month | 1.11 SMN/HPRT Ratio |
| Healthy Controls | Molecular Biomarkers- mRNA | 12 month | 1.21 SMN/HPRT Ratio |
Primary
Molecular Biomarkers- SMN Protein Levels
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
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.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Infants With Spinal Muscular Atrophy | Molecular Biomarkers- SMN Protein Levels | 6 month | 4798.85 pg/10^7 PBMC |
| Infants With Spinal Muscular Atrophy | Molecular Biomarkers- SMN Protein Levels | 12 month | 6719.63 pg/10^7 PBMC |
| Infants With Spinal Muscular Atrophy | Molecular Biomarkers- SMN Protein Levels | 18 month | 3108.79 pg/10^7 PBMC |
| Infants With Spinal Muscular Atrophy | Molecular Biomarkers- SMN Protein Levels | 24 month | 8502.48 pg/10^7 PBMC |
| Healthy Controls | Molecular Biomarkers- SMN Protein Levels | 24 month | 12030 pg/10^7 PBMC |
| Healthy Controls | Molecular Biomarkers- SMN Protein Levels | 6 month | 8325.96 pg/10^7 PBMC |
| Healthy Controls | Molecular Biomarkers- SMN Protein Levels | 18 month | 6635.90 pg/10^7 PBMC |
| Healthy Controls | Molecular Biomarkers- SMN Protein Levels | 12 month | 10247 pg/10^7 PBMC |
Primary
Motor Function Assessments-Alberta Infant Motor Scale (AIMS)
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
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.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Infants With Spinal Muscular Atrophy | Motor Function Assessments-Alberta Infant Motor Scale (AIMS) | 9 month | 15.58 Scores on a scale |
| Infants With Spinal Muscular Atrophy | Motor Function Assessments-Alberta Infant Motor Scale (AIMS) | 6 month | 11.74 Scores on a scale |
| Infants With Spinal Muscular Atrophy | Motor Function Assessments-Alberta Infant Motor Scale (AIMS) | 12 month | 21.60 Scores on a scale |
| Infants With Spinal Muscular Atrophy | Motor Function Assessments-Alberta Infant Motor Scale (AIMS) | 18 month | 19.18 Scores on a scale |
| Infants With Spinal Muscular Atrophy | Motor Function Assessments-Alberta Infant Motor Scale (AIMS) | 24 month | 14.71 Scores on a scale |
| Healthy Controls | Motor Function Assessments-Alberta Infant Motor Scale (AIMS) | 24 month | 37.76 Scores on a scale |
| Healthy Controls | Motor Function Assessments-Alberta Infant Motor Scale (AIMS) | 18 month | 38.62 Scores on a scale |
| Healthy Controls | Motor Function Assessments-Alberta Infant Motor Scale (AIMS) | 6 month | 19.29 Scores on a scale |
| Healthy Controls | Motor Function Assessments-Alberta Infant Motor Scale (AIMS) | 9 month | 34.10 Scores on a scale |
| Healthy Controls | Motor Function Assessments-Alberta Infant Motor Scale (AIMS) | 12 month | 37.10 Scores on a scale |
Primary
Motor Function Assessments- Test for Infant Motor Performance Screening Items (TIMPSI)
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
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.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Infants With Spinal Muscular Atrophy | Motor Function Assessments- Test for Infant Motor Performance Screening Items (TIMPSI) | 6 month | 36.06 scores on a scale |
| Infants With Spinal Muscular Atrophy | Motor Function Assessments- Test for Infant Motor Performance Screening Items (TIMPSI) | 18 month | 26.35 scores on a scale |
| Infants With Spinal Muscular Atrophy | Motor Function Assessments- Test for Infant Motor Performance Screening Items (TIMPSI) | 12 month | 32.03 scores on a scale |
| Infants With Spinal Muscular Atrophy | Motor Function Assessments- Test for Infant Motor Performance Screening Items (TIMPSI) | 24 month | 23.14 scores on a scale |
| Infants With Spinal Muscular Atrophy | Motor Function Assessments- Test for Infant Motor Performance Screening Items (TIMPSI) | 9 month | 40.54 scores on a scale |
| Healthy Controls | Motor Function Assessments- Test for Infant Motor Performance Screening Items (TIMPSI) | 24 month | 88.65 scores on a scale |
| Healthy Controls | Motor Function Assessments- Test for Infant Motor Performance Screening Items (TIMPSI) | 12 month | 85.39 scores on a scale |
| Healthy Controls | Motor Function Assessments- Test for Infant Motor Performance Screening Items (TIMPSI) | 6 month | 88.47 scores on a scale |
| Healthy Controls | Motor Function Assessments- Test for Infant Motor Performance Screening Items (TIMPSI) | 9 month | 89.44 scores on a scale |
| Healthy Controls | Motor Function Assessments- Test for Infant Motor Performance Screening Items (TIMPSI) | 18 month | 87.35 scores on a scale |
Primary
Motor Function Assessments- The Children's Hospital of Philadelphia Infant Test for Neuromuscular Disorders (CHOP-INTEND)
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
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.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Infants With Spinal Muscular Atrophy | Motor Function Assessments- The Children's Hospital of Philadelphia Infant Test for Neuromuscular Disorders (CHOP-INTEND) | 6 month | 18.38 scores on a scale |
| Infants With Spinal Muscular Atrophy | Motor Function Assessments- The Children's Hospital of Philadelphia Infant Test for Neuromuscular Disorders (CHOP-INTEND) | 9 month | 13.18 scores on a scale |
| Infants With Spinal Muscular Atrophy | Motor Function Assessments- The Children's Hospital of Philadelphia Infant Test for Neuromuscular Disorders (CHOP-INTEND) | 12 month | 9.74 scores on a scale |
| Infants With Spinal Muscular Atrophy | Motor Function Assessments- The Children's Hospital of Philadelphia Infant Test for Neuromuscular Disorders (CHOP-INTEND) | 18 month | 7.52 scores on a scale |
| Infants With Spinal Muscular Atrophy | Motor Function Assessments- The Children's Hospital of Philadelphia Infant Test for Neuromuscular Disorders (CHOP-INTEND) | 24 month | 7.01 scores on a scale |
Primary
Putative Physiological Biomarker- Compound Motor Action Potential Testing (CMAP)
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
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.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Infants With Spinal Muscular Atrophy | Putative Physiological Biomarker- Compound Motor Action Potential Testing (CMAP) | 24 month | -0.02 mV |
| Infants With Spinal Muscular Atrophy | Putative Physiological Biomarker- Compound Motor Action Potential Testing (CMAP) | 12 month | 0.51 mV |
| Infants With Spinal Muscular Atrophy | Putative Physiological Biomarker- Compound Motor Action Potential Testing (CMAP) | 18 month | 0.49 mV |
| Infants With Spinal Muscular Atrophy | Putative Physiological Biomarker- Compound Motor Action Potential Testing (CMAP) | 6 month | 1.07 mV |
| Healthy Controls | Putative Physiological Biomarker- Compound Motor Action Potential Testing (CMAP) | 18 month | 6.55 mV |
| Healthy Controls | Putative Physiological Biomarker- Compound Motor Action Potential Testing (CMAP) | 12 month | 5.95 mV |
| Healthy Controls | Putative Physiological Biomarker- Compound Motor Action Potential Testing (CMAP) | 24 month | 6.74 mV |
| Healthy Controls | Putative Physiological Biomarker- Compound Motor Action Potential Testing (CMAP) | 6 month | 6.00 mV |
Primary
Putative Physiological Biomarkers-Weight
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
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.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Infants With Spinal Muscular Atrophy | Putative Physiological Biomarkers-Weight | 18 month | 9.95 kg |
| Infants With Spinal Muscular Atrophy | Putative Physiological Biomarkers-Weight | 6 month | 6.88 kg |
| Infants With Spinal Muscular Atrophy | Putative Physiological Biomarkers-Weight | 9 month | 7.92 kg |
| Infants With Spinal Muscular Atrophy | Putative Physiological Biomarkers-Weight | 12 month | 8.71 kg |
| Infants With Spinal Muscular Atrophy | Putative Physiological Biomarkers-Weight | 24 month | 10.47 kg |
| Healthy Controls | Putative Physiological Biomarkers-Weight | 24 month | 12.74 kg |
| Healthy Controls | Putative Physiological Biomarkers-Weight | 12 month | 9.88 kg |
| Healthy Controls | Putative Physiological Biomarkers-Weight | 6 month | 7.83 kg |
| Healthy Controls | Putative Physiological Biomarkers-Weight | 18 month | 11.40 kg |
| Healthy Controls | Putative Physiological Biomarkers-Weight | 9 month | 8.94 kg |
Secondary
Biomarker Prediction of Risk of Death
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
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Infants With Spinal Muscular Atrophy | Biomarker Prediction of Risk of Death | TIMPSI (per 10 unit increase) | 0.72 Hazard Ratio |
| Infants With Spinal Muscular Atrophy | Biomarker Prediction of Risk of Death | CHOP-INTEND (per 10 unit increase) | 0.94 Hazard Ratio |
| Infants With Spinal Muscular Atrophy | Biomarker Prediction of Risk of Death | CMAP Peak Amplitude (per 1 unit increase) | 0.37 Hazard Ratio |
| Infants With Spinal Muscular Atrophy | Biomarker Prediction of Risk of Death | mRNA (per 1 unit increase) | 0.28 Hazard Ratio |
| Infants With Spinal Muscular Atrophy | Biomarker Prediction of Risk of Death | Protein Level (per 1000 unit increase) | 1.27 Hazard Ratio |
| Infants With Spinal Muscular Atrophy | Biomarker Prediction of Risk of Death | Weight (per 10kg increase) | 0.02 Hazard Ratio |
Secondary
Correlation of Biomarkers (Weight) With Motor Function Tests for SMA Subjects SMN Copy Number =2 Cohort
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
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.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Infants With Spinal Muscular Atrophy | Correlation of Biomarkers (Weight) With Motor Function Tests for SMA Subjects SMN Copy Number =2 Cohort | -2.50 kg/scores on a scale |
| Healthy Controls | Correlation of Biomarkers (Weight) With Motor Function Tests for SMA Subjects SMN Copy Number =2 Cohort | -2.43 kg/scores on a scale |
Secondary
Correlation of CMAP Biomarker With Motor Function Tests for SMA Subjects SMN Copy Number =2 Cohort
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
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.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Infants With Spinal Muscular Atrophy | Correlation of CMAP Biomarker With Motor Function Tests for SMA Subjects SMN Copy Number =2 Cohort | 5.10 mV/scores on a scale |
| Healthy Controls | Correlation of CMAP Biomarker With Motor Function Tests for SMA Subjects SMN Copy Number =2 Cohort | 3.71 mV/scores on a scale |
Secondary
Correlation of mRNA Biomarkers With Motor Function Tests for SMA Subjects SMN Copy Number =2 Cohort
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
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.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Infants With Spinal Muscular Atrophy | Correlation of mRNA Biomarkers With Motor Function Tests for SMA Subjects SMN Copy Number =2 Cohort | -6.39 (SMN/HPRT)/scores on a scale |
| Healthy Controls | Correlation of mRNA Biomarkers With Motor Function Tests for SMA Subjects SMN Copy Number =2 Cohort | 0.097 (SMN/HPRT)/scores on a scale |
Secondary
Correlation of Protein Level Biomarkers With Motor Function Tests for SMA Subjects SMN Copy Number =2 Cohort
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
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.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Infants With Spinal Muscular Atrophy | 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 |
| Healthy Controls | Correlation of Protein Level Biomarkers With Motor Function Tests for SMA Subjects SMN Copy Number =2 Cohort | 0.00048 (pg/10^7 PBMC0/scores on a scale |
Secondary
Molecular Biomarkers- mRNA SMA Copy Number = 2 Cohort
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
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.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Infants With Spinal Muscular Atrophy | Molecular Biomarkers- mRNA SMA Copy Number = 2 Cohort | 6 month | 0.46 SMN/HPRT Ratio |
| Infants With Spinal Muscular Atrophy | Molecular Biomarkers- mRNA SMA Copy Number = 2 Cohort | 12 month | 0.38 SMN/HPRT Ratio |
| Infants With Spinal Muscular Atrophy | Molecular Biomarkers- mRNA SMA Copy Number = 2 Cohort | 18 month | 0.29 SMN/HPRT Ratio |
| Infants With Spinal Muscular Atrophy | Molecular Biomarkers- mRNA SMA Copy Number = 2 Cohort | 24 month | 0.40 SMN/HPRT Ratio |
| Healthy Controls | Molecular Biomarkers- mRNA SMA Copy Number = 2 Cohort | 24 month | 1.23 SMN/HPRT Ratio |
| Healthy Controls | Molecular Biomarkers- mRNA SMA Copy Number = 2 Cohort | 6 month | 1.29 SMN/HPRT Ratio |
| Healthy Controls | Molecular Biomarkers- mRNA SMA Copy Number = 2 Cohort | 18 month | 1.12 SMN/HPRT Ratio |
| Healthy Controls | Molecular Biomarkers- mRNA SMA Copy Number = 2 Cohort | 12 month | 1.21 SMN/HPRT Ratio |
Secondary
Molecular Biomarkers- SMN Protein Levels SMA Copy Number = 2
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
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.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Infants With Spinal Muscular Atrophy | Molecular Biomarkers- SMN Protein Levels SMA Copy Number = 2 | 6 month | 3785.02 pg/10^7 PBMC |
| Infants With Spinal Muscular Atrophy | Molecular Biomarkers- SMN Protein Levels SMA Copy Number = 2 | 12 month | 5800.63 pg/10^7 PBMC |
| Infants With Spinal Muscular Atrophy | Molecular Biomarkers- SMN Protein Levels SMA Copy Number = 2 | 18 month | 1612.35 pg/10^7 PBMC |
| Infants With Spinal Muscular Atrophy | Molecular Biomarkers- SMN Protein Levels SMA Copy Number = 2 | 24 month | 6912.88 pg/10^7 PBMC |
| Healthy Controls | Molecular Biomarkers- SMN Protein Levels SMA Copy Number = 2 | 24 month | 11727 pg/10^7 PBMC |
| Healthy Controls | Molecular Biomarkers- SMN Protein Levels SMA Copy Number = 2 | 6 month | 8598.73 pg/10^7 PBMC |
| Healthy Controls | Molecular Biomarkers- SMN Protein Levels SMA Copy Number = 2 | 18 month | 6426.06 pg/10^7 PBMC |
| Healthy Controls | Molecular Biomarkers- SMN Protein Levels SMA Copy Number = 2 | 12 month | 10614 pg/10^7 PBMC |
Secondary
Motor Function Assessments- Test for Infant Motor Performance Screening Items (TIMPSI) SMN Copy Number =2 Cohort
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
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.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Infants With Spinal Muscular Atrophy | Motor Function Assessments- Test for Infant Motor Performance Screening Items (TIMPSI) SMN Copy Number =2 Cohort | 12 month | 13.82 Scores on a scale |
| Infants With Spinal Muscular Atrophy | Motor Function Assessments- Test for Infant Motor Performance Screening Items (TIMPSI) SMN Copy Number =2 Cohort | 6 month | 24.53 Scores on a scale |
| Infants With Spinal Muscular Atrophy | Motor Function Assessments- Test for Infant Motor Performance Screening Items (TIMPSI) SMN Copy Number =2 Cohort | 18 month | 8.82 Scores on a scale |
| Infants With Spinal Muscular Atrophy | Motor Function Assessments- Test for Infant Motor Performance Screening Items (TIMPSI) SMN Copy Number =2 Cohort | 24 month | 7.51 Scores on a scale |
| Infants With Spinal Muscular Atrophy | Motor Function Assessments- Test for Infant Motor Performance Screening Items (TIMPSI) SMN Copy Number =2 Cohort | 9 month | 20.08 Scores on a scale |
| Healthy Controls | Motor Function Assessments- Test for Infant Motor Performance Screening Items (TIMPSI) SMN Copy Number =2 Cohort | 24 month | 88.92 Scores on a scale |
| Healthy Controls | Motor Function Assessments- Test for Infant Motor Performance Screening Items (TIMPSI) SMN Copy Number =2 Cohort | 6 month | 88.25 Scores on a scale |
| Healthy Controls | Motor Function Assessments- Test for Infant Motor Performance Screening Items (TIMPSI) SMN Copy Number =2 Cohort | 12 month | 85.15 Scores on a scale |
| Healthy Controls | Motor Function Assessments- Test for Infant Motor Performance Screening Items (TIMPSI) SMN Copy Number =2 Cohort | 18 month | 87.36 Scores on a scale |
| Healthy Controls | Motor Function Assessments- Test for Infant Motor Performance Screening Items (TIMPSI) SMN Copy Number =2 Cohort | 9 month | 89.20 Scores on a scale |
Secondary
Motor Function Assessments- The Children's Hospital of Philadelphia Infant Test for Neuromuscular Disorders (CHOP-INTEND) SMN Copy Number =2 Cohort
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
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.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Infants With Spinal Muscular Atrophy | 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 |
| Infants With Spinal Muscular Atrophy | 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 |
| Infants With Spinal Muscular Atrophy | 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 |
| Infants With Spinal Muscular Atrophy | 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 |
| Infants With Spinal Muscular Atrophy | 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 |
Secondary
Putative Physiological Biomarker- Compound Motor Action Potential Testing (CMAP) SMN Copy Number = 2 Cohort
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
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.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Infants With Spinal Muscular Atrophy | Putative Physiological Biomarker- Compound Motor Action Potential Testing (CMAP) SMN Copy Number = 2 Cohort | 12 month | 0.33 mV |
| Infants With Spinal Muscular Atrophy | Putative Physiological Biomarker- Compound Motor Action Potential Testing (CMAP) SMN Copy Number = 2 Cohort | 6 month | 0.36 mV |
| Infants With Spinal Muscular Atrophy | Putative Physiological Biomarker- Compound Motor Action Potential Testing (CMAP) SMN Copy Number = 2 Cohort | 18 month | 0.90 mV |
| Healthy Controls | Putative Physiological Biomarker- Compound Motor Action Potential Testing (CMAP) SMN Copy Number = 2 Cohort | 12 month | 5.92 mV |
| Healthy Controls | Putative Physiological Biomarker- Compound Motor Action Potential Testing (CMAP) SMN Copy Number = 2 Cohort | 18 month | 6.49 mV |
| Healthy Controls | Putative Physiological Biomarker- Compound Motor Action Potential Testing (CMAP) SMN Copy Number = 2 Cohort | 6 month | 5.95 mV |
| Healthy Controls | Putative Physiological Biomarker- Compound Motor Action Potential Testing (CMAP) SMN Copy Number = 2 Cohort | 24 month | 6.63 mV |
Secondary
Putative Physiological Biomarkers-Weight SMN Copy Number =2 Cohort
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
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.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Infants With Spinal Muscular Atrophy | Putative Physiological Biomarkers-Weight SMN Copy Number =2 Cohort | 9 month | 7.70 kg |
| Infants With Spinal Muscular Atrophy | Putative Physiological Biomarkers-Weight SMN Copy Number =2 Cohort | 18 month | 9.65 kg |
| Infants With Spinal Muscular Atrophy | Putative Physiological Biomarkers-Weight SMN Copy Number =2 Cohort | 12 month | 8.51 kg |
| Infants With Spinal Muscular Atrophy | Putative Physiological Biomarkers-Weight SMN Copy Number =2 Cohort | 24 month | 9.77 kg |
| Infants With Spinal Muscular Atrophy | Putative Physiological Biomarkers-Weight SMN Copy Number =2 Cohort | 6 month | 6.63 kg |
| Healthy Controls | Putative Physiological Biomarkers-Weight SMN Copy Number =2 Cohort | 24 month | 12.72 kg |
| Healthy Controls | Putative Physiological Biomarkers-Weight SMN Copy Number =2 Cohort | 6 month | 7.83 kg |
| Healthy Controls | Putative Physiological Biomarkers-Weight SMN Copy Number =2 Cohort | 9 month | 8.93 kg |
| Healthy Controls | Putative Physiological Biomarkers-Weight SMN Copy Number =2 Cohort | 12 month | 9.88 kg |
| Healthy Controls | Putative Physiological Biomarkers-Weight SMN Copy Number =2 Cohort | 18 month | 11.40 kg |