Clinical trial NCT01736553: Spinal Muscular Atrophy (SMA) Biomarkers Study in the Immediate Postnatal Period of Development
Official title: Spinal Muscular Atrophy (SMA) Biomarkers in the Immediate Postnatal Period of Development
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Spinal Muscular Atrophy (SMA)
Keywords: Spinal Muscular Atrophy (SMA) Biomarkers
Healthy controls
Infants
Lead sponsor: Ohio State University
Sponsor class: OTHER
Collaborators: name: National Institute of Neurological Disorders and Stroke (NINDS)
name: Cure SMA
name: Massachusetts General Hospital
name: University of Iowa
First posted: 2012-11-29
Enrollment: 53
Sex: ALL
Maximum age (years): 6
Standard ages: CHILD
Accepts healthy volunteers: yes
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Fifty four (54) volunteers will be enrolled at 15 NeuroNEXT Network centers. Any volunteer who signs an informed consent form and has blood collected for the study is considered enrolled.

Recruitment will be coordinated nationally through the Families of SMA Patient Network and NeuroNEXT who will help with the following:

* Identifying infants diagnosed genetically with SMA because of a clinical suspicion prior to 6 months of age.
* Publicize the project to raise awareness in medical and non-medical communities.

Any normal infant may enroll in this study.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Motor Function Assessments- Test for Infant Motor Performance Screening Items (TIMPSI)
timeFrame: Up to 24 months
measure: Motor Function Assessments- The Children's Hospital of Philadelphia Infant Test for Neuromuscular Disorders (CHOP-INTEND)
timeFrame: Up to 24 months
measure: Motor Function Assessments-Alberta Infant Motor Scale (AIMS)
timeFrame: Up to 24 months
measure: Putative Physiological Biomarker- Compound Motor Action Potential Testing (CMAP)
timeFrame: Up to 24 months
measure: Molecular Biomarkers- mRNA
timeFrame: Up to 24 months
measure: Molecular Biomarkers- SMN Protein Levels
timeFrame: Up to 24 months
measure: Putative Physiological Biomarkers-Weight
timeFrame: Up to 24 months
measure: Correlation of Biomarkers With Motor Function Tests for SMA Subjects- CMAP
timeFrame: up to 24 months
measure: Correlation of Biomarkers With Motor Function Tests for SMA Subjects- mRNA
timeFrame: up to 24 months
measure: Correlation of Biomarkers With Motor Function Tests for SMA Subjects- SMN Protein
timeFrame: up to 24 months
measure: Correlation of Biomarkers With Motor Function Tests for SMA Subjects- Weight
timeFrame: up to 24 months
measure: Correlation of Biomarkers With Motor Function Tests for Healthy Control Subjects- CMAP
timeFrame: up to 24 months
measure: Correlation of Biomarkers With Motor Function Tests for Healthy Control Subjects- mRNA
timeFrame: up to 24 months
measure: Correlation of Biomarkers With Motor Function Tests for Healthy Control Subjects- Weight
timeFrame: up to 24 months
Secondary outcomes:
measure: Biomarker Prediction of Risk of Death
timeFrame: Up to 24 months
measure: Motor Function Assessments- Test for Infant Motor Performance Screening Items (TIMPSI) SMN Copy Number =2 Cohort
timeFrame: Up to 24 months
measure: Motor Function Assessments- The Children's Hospital of Philadelphia Infant Test for Neuromuscular Disorders (CHOP-INTEND) SMN Copy Number =2 Cohort
timeFrame: Up to 24 months
measure: Putative Physiological Biomarker- Compound Motor Action Potential Testing (CMAP) SMN Copy Number = 2 Cohort
timeFrame: Up to 24 months
measure: Molecular Biomarkers- mRNA SMA Copy Number = 2 Cohort
timeFrame: Up to 24 months
measure: Molecular Biomarkers- SMN Protein Levels SMA Copy Number = 2
timeFrame: Up to 24 months
measure: Putative Physiological Biomarkers-Weight SMN Copy Number =2 Cohort
timeFrame: Up to 24 months
measure: Correlation of CMAP Biomarker With Motor Function Tests for SMA Subjects SMN Copy Number =2 Cohort
timeFrame: up to 24 months
measure: Correlation of mRNA Biomarkers With Motor Function Tests for SMA Subjects SMN Copy Number =2 Cohort
timeFrame: up to 24 months
measure: Correlation of Protein Level Biomarkers With Motor Function Tests for SMA Subjects SMN Copy Number =2 Cohort
timeFrame: up to 24 months
measure: Correlation of Biomarkers (Weight) With Motor Function Tests for SMA Subjects SMN Copy Number =2 Cohort
timeFrame: up to 24 months
Other outcomes:
Locations:
city: Davis
country: United States
facility: University of California - Davis
state: California
city: Los Angeles
country: United States
facility: University of California - Los Angeles
state: California
city: Aurora
country: United States
facility: Children's Hospital Colorado
state: Colorado
city: Washington
country: United States
facility: Children's National Medical Center
state: District of Columbia
city: Chicago
country: United States
facility: Ann & Robert H. Lurie Children's Hospital of Chicago
state: Illinois
city: Boston
country: United States
facility: Boston Children's Hospital
state: Massachusetts
city: Kansas City
country: United States
facility: Children's Mercy Hospital
state: Missouri
city: Saint Louis
country: United States
facility: Washington University in St. Louis School of Medicine
state: Missouri
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: Syracuse
country: United States
facility: State University of New York Upstate Medical Center
state: New York
city: Columbus
country: United States
facility: Nationwide Children's Hospital
state: Ohio
city: Portland
country: United States
facility: Doernbecher Children's Hospital
state: Oregon
city: Nashville
country: United States
facility: Vanderbilt University
state: Tennessee
city: Dallas
country: United States
facility: Children's Medical Center of Dallas
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah Health Sciences Center
state: Utah
Study officials:
affiliation: Ohio State University
name: Stephen J Kolb, MD PhD
role: PRINCIPAL_INVESTIGATOR
References:
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