Spinal Muscular Atrophy (SMA)NCT01736553

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

An observational study of Spinal Muscular Atrophy (SMA), run by Ohio State University at 15 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial summary

Who is it for?: Ages Up to 6 monthsHealthy volunteers can take part
Conditions the study is for: Spinal Muscular Atrophy (SMA)
How many people: 53 participants
Where: 15 sitesUnited States
Study dates: Dec 2012to Sep 2015
Phase: Observational
Are there results?: Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages Up to 6 months
All sexes
Healthy volunteers accepted
Child

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.

Who may be able to join

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

Show all 12Show fewer

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

Who cannot join

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

Trial locations and contacts

15 sites in 1 country.

City, postcode or hospital

15 sites in 1 country

United States15 sites

Children's Hospital Colorado
Aurora, Colorado, 80045
Boston Children's Hospital
Boston, Massachusetts, 02115
Ann & Robert H. Lurie Children's Hospital of Chicago
Chicago, Illinois, 60611
Nationwide Children's Hospital
Columbus, Ohio, 43205
Children's Medical Center of Dallas
Dallas, Texas, 75235
University of California - Davis
Davis, California, 95616
Children's Mercy Hospital
Kansas City, Missouri, 64108
University of California - Los Angeles
Los Angeles, California, 90095
Vanderbilt University
Nashville, Tennessee, 37212
Columbia University Medical Center
New York, New York, 10032
Doernbecher Children's Hospital
Portland, Oregon, 97239
University of Utah Health Sciences Center
Salt Lake City, Utah, 84132
Washington University in St. Louis School of Medicine
St Louis, Missouri, 63110
State University of New York Upstate Medical Center
Syracuse, New York, 13210
Children's National Medical Center
Washington D.C., District of Columbia, 20010

Other trials in United States

About this study

Official title: Spinal Muscular Atrophy (SMA) Biomarkers in the Immediate Postnatal Period of Development

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.

Read the 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.

Conditions: Spinal Muscular Atrophy (SMA)
Keywords: Spinal Muscular Atrophy (SMA) Biomarkers, Healthy controls, Infants
Medical subject headings: Muscular Atrophy, Spinal

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

Study groups in NCT01736553
Study group	Role	What they receive
Infants with Spinal Muscular Atrophy		Infants diagnosed Spinal Muscular Atrophy
Healthy controls		Healthy control infants

What is being measured

The primary outcome is the main question the study is designed to answer.

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.
Measured: Up to 24 months
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.
Measured: Up to 24 months
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.
Measured: Up to 24 months
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.
Measured: Up to 24 months
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.
Measured: Up to 24 months
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.
Measured: Up to 24 months
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.
Measured: Up to 24 months
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.
Measured: up to 24 months
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.
Measured: up to 24 months
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.
Measured: up to 24 months
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.
Measured: up to 24 months
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.
Measured: up to 24 months
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.
Measured: up to 24 months
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.
Measured: up to 24 months

Secondary outcomes (11)

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).
Measured: Up to 24 months
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.
Measured: Up to 24 months
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).
Measured: Up to 24 months
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.
Measured: Up to 24 months
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.
Measured: Up to 24 months
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.
Measured: Up to 24 months
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
Measured: Up to 24 months
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.
Measured: up to 24 months
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.
Measured: up to 24 months
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.
Measured: up to 24 months
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.
Measured: up to 24 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

Dec 2012Sep 2015

First posted29 Nov 2012 (estimated)
Study startDec 2012
Primary completionSep 2015
Study completionSep 2015

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Publications (17)Papers the sponsor has linked to this study.
Other trials for Spinal Muscular Atrophy (SMA)Studies of the same condition, open and under way.
More trials run by Ohio State UniversityThe sponsor's other registered studies.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Observational
Observational model: Cohort
Time perspective: Prospective
Enrolment: 53 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT01736553
Sponsor's protocol ID: NN101
Other IDs: U01NS079163
Status last verified: Apr 2018
First submitted: 19 Nov 2012
Last updated: 4 May 2018
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: No

Publications

Campbell SK, Swanlund A, Smith E, Liao PJ, Zawacki L. Validity of the TIMPSI for estimating concurrent performance on the test of infant motor performance. Pediatr Phys Ther. 2008 Spring;20(1):3-10. doi: 10.1097/PEP.0b013e31815f66a6.
PubMed 18300928
Dominguez E, Marais T, Chatauret N, Benkhelifa-Ziyyat S, Duque S, Ravassard P, Carcenac R, Astord S, Pereira de Moura A, Voit T, Barkats M. Intravenous scAAV9 delivery of a codon-optimized SMN1 sequence rescues SMA mice. Hum Mol Genet. 2011 Feb 15;20(4):681-93. doi: 10.1093/hmg/ddq514. Epub 2010 Nov 30.
PubMed 21118896
Finkel RS, Hynan LS, Glanzman AM, Owens H, Nelson L, Cone SR, Campbell SK, Iannaccone ST; AmSMART Group. The test of infant motor performance: reliability in spinal muscular atrophy type I. Pediatr Phys Ther. 2008 Fall;20(3):242-6. doi: 10.1097/PEP.0b013e318181ae96.
PubMed 18703961
Foust KD, Wang X, McGovern VL, Braun L, Bevan AK, Haidet AM, Le TT, Morales PR, Rich MM, Burghes AH, Kaspar BK. Rescue of the spinal muscular atrophy phenotype in a mouse model by early postnatal delivery of SMN. Nat Biotechnol. 2010 Mar;28(3):271-4. doi: 10.1038/nbt.1610. Epub 2010 Feb 28.
PubMed 20190738
Hua Y, Sahashi K, Hung G, Rigo F, Passini MA, Bennett CF, Krainer AR. Antisense correction of SMN2 splicing in the CNS rescues necrosis in a type III SMA mouse model. Genes Dev. 2010 Aug 1;24(15):1634-44. doi: 10.1101/gad.1941310. Epub 2010 Jul 12.
PubMed 20624852
Kolb SJ, Gubitz AK, Olszewski RF Jr, Ottinger E, Sumner CJ, Fischbeck KH, Dreyfuss G. A novel cell immunoassay to measure survival of motor neurons protein in blood cells. BMC Neurol. 2006 Feb 1;6:6. doi: 10.1186/1471-2377-6-6.
PubMed 16451734
Kolb SJ, Kissel JT. Spinal muscular atrophy: a timely review. Arch Neurol. 2011 Aug;68(8):979-84. doi: 10.1001/archneurol.2011.74. Epub 2011 Apr 11.
PubMed 21482919
Le TT, McGovern VL, Alwine IE, Wang X, Massoni-Laporte A, Rich MM, Burghes AH. Temporal requirement for high SMN expression in SMA mice. Hum Mol Genet. 2011 Sep 15;20(18):3578-91. doi: 10.1093/hmg/ddr275. Epub 2011 Jun 13.
PubMed 21672919
Lutz CM, Kariya S, Patruni S, Osborne MA, Liu D, Henderson CE, Li DK, Pellizzoni L, Rojas J, Valenzuela DM, Murphy AJ, Winberg ML, Monani UR. Postsymptomatic restoration of SMN rescues the disease phenotype in a mouse model of severe spinal muscular atrophy. J Clin Invest. 2011 Aug;121(8):3029-41. doi: 10.1172/JCI57291. Epub 2011 Jul 25.
PubMed 21785219
Morton JP, MacLaren DP, Cable NT, Bongers T, Griffiths RD, Campbell IT, Evans L, Kayani A, McArdle A, Drust B. Time course and differential responses of the major heat shock protein families in human skeletal muscle following acute nondamaging treadmill exercise. J Appl Physiol (1985). 2006 Jul;101(1):176-82. doi: 10.1152/japplphysiol.00046.2006. Epub 2006 Mar 24.
PubMed 16565353
Narver HL, Kong L, Burnett BG, Choe DW, Bosch-Marce M, Taye AA, Eckhaus MA, Sumner CJ. Sustained improvement of spinal muscular atrophy mice treated with trichostatin A plus nutrition. Ann Neurol. 2008 Oct;64(4):465-70. doi: 10.1002/ana.21449.
PubMed 18661558
Passini MA, Bu J, Richards AM, Kinnecom C, Sardi SP, Stanek LM, Hua Y, Rigo F, Matson J, Hung G, Kaye EM, Shihabuddin LS, Krainer AR, Bennett CF, Cheng SH. Antisense oligonucleotides delivered to the mouse CNS ameliorate symptoms of severe spinal muscular atrophy. Sci Transl Med. 2011 Mar 2;3(72):72ra18. doi: 10.1126/scitranslmed.3001777.
PubMed 21368223
Piper MC, Pinnell LE, Darrah J, Maguire T, Byrne PJ. Construction and validation of the Alberta Infant Motor Scale (AIMS). Can J Public Health. 1992 Jul-Aug;83 Suppl 2:S46-50.
PubMed 1468050
Porensky PN, Mitrpant C, McGovern VL, Bevan AK, Foust KD, Kaspar BK, Wilton SD, Burghes AH. A single administration of morpholino antisense oligomer rescues spinal muscular atrophy in mouse. Hum Mol Genet. 2012 Apr 1;21(7):1625-38. doi: 10.1093/hmg/ddr600. Epub 2011 Dec 20.
PubMed 22186025
Rutkove SB, Shefner JM, Gregas M, Butler H, Caracciolo J, Lin C, Fogerson PM, Mongiovi P, Darras BT. Characterizing spinal muscular atrophy with electrical impedance myography. Muscle Nerve. 2010 Dec;42(6):915-21. doi: 10.1002/mus.21784.
PubMed 21104866

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

See locations

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Study at a glance

From the registry record, last updated by the sponsor on 4 May 2018. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: Spinal Muscular Atrophy (SMA) Biomarkers in the Immediate Postnatal Period of Development
ClinicalTrials.gov ID: NCT01736553
Acronym / sponsor ID: NN101
Conditions: Spinal Muscular Atrophy (SMA)
Keywords: Spinal Muscular Atrophy (SMA) Biomarkers, Healthy controls, Infants
Study type: Observational
Recruitment status: Completed
Enrolment: 53 participants (actual)
Lead sponsor: Ohio State UniversityUniversity, hospital or other
Collaborators: National Institute of Neurological Disorders and Stroke (NINDS), Cure SMA, Massachusetts General Hospital, University of Iowa
Study start: Dec 2012
Primary completion: Sep 2015 (actual)
Study completion: Sep 2015 (actual)
First posted: 29 Nov 2012 (estimated)
Results: Posted 4 May 2018

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Detailed description

Study design

Observational model: Cohort
Time perspective: Prospective
Number of arms: 2

Arm	Type	Receives
Infants with Spinal Muscular Atrophy	–	–Infants diagnosed Spinal Muscular Atrophy
Healthy controls	–	–Healthy control infants

Who may qualify

Ages: Up to 6 months
Sex: All
Healthy volunteers: Accepted
Age groups: Child
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.

Key inclusion criteria (12 listed)

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.
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

Key exclusion criteria (5 listed)

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

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Primary outcome

Motor Function Assessments- Test for Infant Motor Performance Screening Items (TIMPSI)
Time frame: 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)
Time frame: 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.
Motor Function Assessments-Alberta Infant Motor Scale (AIMS)
Time frame: 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)
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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- Weight
Time frame: 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.

11 secondary outcomes

Biomarker Prediction of Risk of Death
Time frame: Up to 24 months
Motor Function Assessments- Test for Infant Motor Performance Screening Items (TIMPSI) SMN Copy Number =2 Cohort
Time frame: Up to 24 months
Motor Function Assessments- The Children's Hospital of Philadelphia Infant Test for Neuromuscular Disorders (CHOP-INTEND) SMN Copy Number =2 Cohort
Time frame: Up to 24 months
Putative Physiological Biomarker- Compound Motor Action Potential Testing (CMAP) SMN Copy Number = 2 Cohort
Time frame: Up to 24 months
Molecular Biomarkers- mRNA SMA Copy Number = 2 Cohort
Time frame: Up to 24 months
Molecular Biomarkers- SMN Protein Levels SMA Copy Number = 2
Time frame: Up to 24 months
Putative Physiological Biomarkers-Weight SMN Copy Number =2 Cohort
Time frame: Up to 24 months
Correlation of CMAP Biomarker With Motor Function Tests for SMA Subjects SMN Copy Number =2 Cohort
Time frame: up to 24 months
Correlation of mRNA Biomarkers With Motor Function Tests for SMA Subjects SMN Copy Number =2 Cohort
Time frame: up to 24 months
Correlation of Protein Level Biomarkers With Motor Function Tests for SMA Subjects SMN Copy Number =2 Cohort
Time frame: up to 24 months
Correlation of Biomarkers (Weight) With Motor Function Tests for SMA Subjects SMN Copy Number =2 Cohort
Time frame: up to 24 months

Results and safety

Results posted to the registry on 4 May 2018, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
Infants With Spinal Muscular Atrophy	26	7
Healthy Controls	27	23

Primary outcome: Motor Function Assessments- Test for Infant Motor Performance Screening Items (TIMPSI)

Time frame: Up to 24 months. Mean (95% Confidence Interval). Unit: scores on a scale

Measure	Infants With Spinal Muscular Atrophy n = 19	Healthy Controls n = 26
6 month	36.06 (27.20 to 44.91)	88.47 (80.52 to 96.43)
9 month	40.54 (29.91 to 51.18)	89.44 (81.47 to 97.41)
12 month	32.03 (21.39 to 42.68)	85.39 (77.41 to 93.36)
18 month	26.35 (10.87 to 41.83)	87.35 (79.12 to 95.57)
24 month	23.14 (10.04 to 36.23)	88.65 (80.19 to 97.11)

Population analysed: 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.

Primary outcome: Motor Function Assessments- The Children's Hospital of Philadelphia Infant Test for Neuromuscular Disorders (CHOP-INTEND)

Time frame: Up to 24 months. Mean (95% Confidence Interval). Unit: scores on a scale

Measure	Infants With Spinal Muscular Atrophy n = 14
6 month	18.38 (15.02 to 21.75)
9 month	13.18 (9.24 to 17.12)
12 month	9.74 (5.01 to 14.46)
18 month	7.52 (2.89 to 12.16)
24 month	7.01 (6.82 to 7.19)

Population analysed: 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.

Primary outcome: Motor Function Assessments-Alberta Infant Motor Scale (AIMS)

Time frame: Up to 24 months. Mean (95% Confidence Interval). Unit: Scores on a scale

Measure	Infants With Spinal Muscular Atrophy n = 5	Healthy Controls n = 26
6 month	11.74 (3.91 to 19.58)	19.29 (16.4 to 22.19)
9 month	15.58 (2.51 to 28.64)	34.10 (29.05 to 39.14)
12 month	21.60 (6.66 to 36.53)	37.10 (30.52 to 43.68)
18 month	19.18 (2.03 to 36.32)	38.62 (31.30 to 45.93)
24 month	14.71 (2.17 to 27.25)	37.76 (29.81 to 45.71)

Population analysed: 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.

Primary outcome: Putative Physiological Biomarker- Compound Motor Action Potential Testing (CMAP)

Time frame: Up to 24 months. Mean (95% Confidence Interval). Unit: mV

Measure	Infants With Spinal Muscular Atrophy n = 18	Healthy Controls n = 26
6 month	1.07 (0.17 to 1.96)	6.00 (5.22 to 6.78)
12 month	0.51 (-0.56 to 1.59)	5.95 (5.16 to 6.75)
18 month	0.49 (-0.98 to 1.95)	6.55 (5.75 to 7.36)
24 month	-0.02 (-1.46 to 1.42)	6.74 (5.91 to 7.58)

Population analysed: 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.

11 secondary outcomes are reported in the full results.

Adverse events

Other adverse events reported at 0% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
Infants With Spinal Muscular Atrophy	0 of 26 (0%)	0 of 26 (0%)	12 of 26
Healthy Controls	0 of 27 (0%)	0 of 27 (0%)	0 of 27

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 4 May 2018.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Background: PubMed 18300928Campbell SK, Swanlund A, Smith E, Liao PJ, Zawacki L. Validity of the TIMPSI for estimating concurrent performance on the test of infant motor performance. Pediatr Phys Ther. 2008 Spring;20(1):3-10. doi: 10.1097/PEP.0b013e31815f66a6.
Background: PubMed 21118896Dominguez E, Marais T, Chatauret N, Benkhelifa-Ziyyat S, Duque S, Ravassard P, Carcenac R, Astord S, Pereira de Moura A, Voit T, Barkats M. Intravenous scAAV9 delivery of a codon-optimized SMN1 sequence rescues SMA mice. Hum Mol Genet. 2011 Feb 15;20(4):681-93. doi: 10.1093/hmg/ddq514. Epub 2010 Nov 30.
Background: PubMed 18703961Finkel RS, Hynan LS, Glanzman AM, Owens H, Nelson L, Cone SR, Campbell SK, Iannaccone ST; AmSMART Group. The test of infant motor performance: reliability in spinal muscular atrophy type I. Pediatr Phys Ther. 2008 Fall;20(3):242-6. doi: 10.1097/PEP.0b013e318181ae96.
Background: PubMed 20190738Foust KD, Wang X, McGovern VL, Braun L, Bevan AK, Haidet AM, Le TT, Morales PR, Rich MM, Burghes AH, Kaspar BK. Rescue of the spinal muscular atrophy phenotype in a mouse model by early postnatal delivery of SMN. Nat Biotechnol. 2010 Mar;28(3):271-4. doi: 10.1038/nbt.1610. Epub 2010 Feb 28.
Background: PubMed 20624852Hua Y, Sahashi K, Hung G, Rigo F, Passini MA, Bennett CF, Krainer AR. Antisense correction of SMN2 splicing in the CNS rescues necrosis in a type III SMA mouse model. Genes Dev. 2010 Aug 1;24(15):1634-44. doi: 10.1101/gad.1941310. Epub 2010 Jul 12.
Background: PubMed 16451734Kolb SJ, Gubitz AK, Olszewski RF Jr, Ottinger E, Sumner CJ, Fischbeck KH, Dreyfuss G. A novel cell immunoassay to measure survival of motor neurons protein in blood cells. BMC Neurol. 2006 Feb 1;6:6. doi: 10.1186/1471-2377-6-6.
Background: PubMed 21482919Kolb SJ, Kissel JT. Spinal muscular atrophy: a timely review. Arch Neurol. 2011 Aug;68(8):979-84. doi: 10.1001/archneurol.2011.74. Epub 2011 Apr 11.
Background: PubMed 21672919Le TT, McGovern VL, Alwine IE, Wang X, Massoni-Laporte A, Rich MM, Burghes AH. Temporal requirement for high SMN expression in SMA mice. Hum Mol Genet. 2011 Sep 15;20(18):3578-91. doi: 10.1093/hmg/ddr275. Epub 2011 Jun 13.
Background: PubMed 21785219Lutz CM, Kariya S, Patruni S, Osborne MA, Liu D, Henderson CE, Li DK, Pellizzoni L, Rojas J, Valenzuela DM, Murphy AJ, Winberg ML, Monani UR. Postsymptomatic restoration of SMN rescues the disease phenotype in a mouse model of severe spinal muscular atrophy. J Clin Invest. 2011 Aug;121(8):3029-41. doi: 10.1172/JCI57291. Epub 2011 Jul 25.
Background: PubMed 16565353Morton JP, MacLaren DP, Cable NT, Bongers T, Griffiths RD, Campbell IT, Evans L, Kayani A, McArdle A, Drust B. Time course and differential responses of the major heat shock protein families in human skeletal muscle following acute nondamaging treadmill exercise. J Appl Physiol (1985). 2006 Jul;101(1):176-82. doi: 10.1152/japplphysiol.00046.2006. Epub 2006 Mar 24.
Background: PubMed 18661558Narver HL, Kong L, Burnett BG, Choe DW, Bosch-Marce M, Taye AA, Eckhaus MA, Sumner CJ. Sustained improvement of spinal muscular atrophy mice treated with trichostatin A plus nutrition. Ann Neurol. 2008 Oct;64(4):465-70. doi: 10.1002/ana.21449.
Background: PubMed 21368223Passini MA, Bu J, Richards AM, Kinnecom C, Sardi SP, Stanek LM, Hua Y, Rigo F, Matson J, Hung G, Kaye EM, Shihabuddin LS, Krainer AR, Bennett CF, Cheng SH. Antisense oligonucleotides delivered to the mouse CNS ameliorate symptoms of severe spinal muscular atrophy. Sci Transl Med. 2011 Mar 2;3(72):72ra18. doi: 10.1126/scitranslmed.3001777.

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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Stephen J Kolb, MD PhD principal investigator

Ohio State University

15 sites in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

An observational study of Spinal Muscular Atrophy (SMA), run by Ohio State University at 15 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 12 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 4 May 2018. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 15 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

Are results available for this study?

Yes. Results are posted in the registry (first posted 4 May 2018). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Motor Function Assessments- Test for Infant Motor Performance Screening Items (TIMPSI) (time frame: Up to 24 months). The study lists 14 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01736553, which also lists 17 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 4 May 2018.