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

NCT01736553 | Completed Results

• 2 other identifiers: NN101U01NS079163
• Study Type: observational
• Target: 53
• Locations: 1 country
• Sites: 15

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.

Conditions

Spinal Muscular Atrophy (SMA)

Keywords

Spinal Muscular Atrophy (SMA) Biomarkers; Healthy controls; Infants

Outcome Measures

Primary Outcomes (14)

• 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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  up to 24 months

Secondary Outcomes (11)

• Biomarker Prediction of Risk of Death

  Up to 24 months

• Motor Function Assessments- Test for Infant Motor Performance Screening Items (TIMPSI) SMN Copy Number =2 Cohort

  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

  Up to 24 months

• Putative Physiological Biomarker- Compound Motor Action Potential Testing (CMAP) SMN Copy Number = 2 Cohort

  Up to 24 months

• Molecular Biomarkers- mRNA SMA Copy Number = 2 Cohort

  Up to 24 months

Study Arms (2)

Infants with Spinal Muscular Atrophy

Infants diagnosed Spinal Muscular Atrophy

Healthy controls

Healthy control infants

Eligibility Criteria

• Age: Up to 6 Months
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17)
• 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.

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Ohio State University: lead
• National Institute of Neurological Disorders and Stroke (NINDS): collaborator
• Cure SMA: collaborator
• Massachusetts General Hospital: collaborator
• University of Iowa: collaborator

Study Sites (15)

University of California - Davis

Davis, California, 95616, United States

Location

University of California - Los Angeles

Los Angeles, California, 90095, United States

Location

Children's Hospital Colorado

Aurora, Colorado, 80045, United States

Location

Children's National Medical Center

Washington D.C., District of Columbia, 20010, United States

Location

Ann & Robert H. Lurie Children's Hospital of Chicago

Chicago, Illinois, 60611, United States

Location

Boston Children's Hospital

Boston, Massachusetts, 02115, United States

Location

Children's Mercy Hospital

Kansas City, Missouri, 64108, United States

Location

Washington University in St. Louis School of Medicine

St Louis, Missouri, 63110, United States

Location

Columbia University Medical Center

New York, New York, 10032, United States

Location

State University of New York Upstate Medical Center

Syracuse, New York, 13210, United States

Location

Nationwide Children's Hospital

Columbus, Ohio, 43205, United States

Location

Doernbecher Children's Hospital

Portland, Oregon, 97239, United States

Location

Vanderbilt University

Nashville, Tennessee, 37212, United States

Location

Children's Medical Center of Dallas

Dallas, Texas, 75235, United States

Location

University of Utah Health Sciences Center

Salt Lake City, Utah, 84132, United States

Location

Related Publications (17)

• 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.

  PMID: 18300928 BACKGROUND

• 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.

  PMID: 21118896 BACKGROUND

• 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.

  PMID: 18703961 BACKGROUND

• 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.

  PMID: 20190738 BACKGROUND

• 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.

  PMID: 20624852 BACKGROUND

• 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.

  PMID: 16451734 BACKGROUND

• 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.

  PMID: 21482919 BACKGROUND

• 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.

  PMID: 21672919 BACKGROUND

• 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.

  PMID: 21785219 BACKGROUND

• 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.

  PMID: 16565353 BACKGROUND

• 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.

  PMID: 18661558 BACKGROUND

• 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.

  PMID: 21368223 BACKGROUND

• 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.

  PMID: 1468050 BACKGROUND

• 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.

  PMID: 22186025 BACKGROUND

• 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.

  PMID: 21104866 BACKGROUND

• Tiziano FD, Pinto AM, Fiori S, Lomastro R, Messina S, Bruno C, Pini A, Pane M, D'Amico A, Ghezzo A, Bertini E, Mercuri E, Neri G, Brahe C. SMN transcript levels in leukocytes of SMA patients determined by absolute real-time PCR. Eur J Hum Genet. 2010 Jan;18(1):52-8. doi: 10.1038/ejhg.2009.116.

  PMID: 19603064 BACKGROUND

• Valori CF, Ning K, Wyles M, Mead RJ, Grierson AJ, Shaw PJ, Azzouz M. Systemic delivery of scAAV9 expressing SMN prolongs survival in a model of spinal muscular atrophy. Sci Transl Med. 2010 Jun 9;2(35):35ra42. doi: 10.1126/scitranslmed.3000830.

  PMID: 20538619 BACKGROUND

Biospecimen

Retention: SAMPLES WITH DNA

Absolute quantification of full length survival motor neuron (SMN) transcripts will be performed. The SMN1 and SMN2 transcripts will be measured in a multiplex reaction and SMN-del7 will be quantified separately. Droplet digital PCR will be used to determine SMN levels to further increase reliability and reduce variance in the SMN mRNA level determination. SMN protein in PBMCs SMN cell-based immunoassays will be performed. This assay is performed using a single monoclonal antibody for SMN and does not involve the disruption of cells. From the same PBMC sample, a commercially available SMN ELISA will also be performed according to the manufacturer's instructions. The B for SMA pilot study identified over 100 protein analytes that significantly correlated with motor function in SMA patients compared to controls.

MeSH Terms

Conditions

Muscular Atrophy, Spinal

Condition Hierarchy (Ancestors)

Spinal Cord Diseases; Central Nervous System Diseases; Nervous System Diseases; Motor Neuron Disease; Neurodegenerative Diseases; Neuromuscular Diseases

Results Point of Contact

• Title: Dr. Stephen Kolb
• Organization: The Ohio State Unviersity Wexner Medical Center

stephen.kolb@osumc.edu

614-366-9050

Study Officials

• Stephen J Kolb, MD PhD

  Ohio State University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Prinicipal Investigator of NeuroNEXT

Study Record Dates

• First Submitted: November 19, 2012
• First Posted: November 29, 2012
• Study Start: December 1, 2012
• Primary Completion: September 1, 2015
• Study Completion: September 1, 2015
• Last Updated: May 4, 2018
• Results First Posted: May 4, 2018

Record last verified: 2018-04

Locations

US (15)