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

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2014 by Ohio State University
Sponsor:
Collaborators:
Families of Spinal Muscular Atrophy
Massachusetts General Hospital
University of Iowa
Information provided by (Responsible Party):
Stephen J. Kolb, Ohio State University
ClinicalTrials.gov Identifier:
NCT01736553
First received: November 19, 2012
Last updated: July 22, 2014
Last verified: July 2014
  Purpose

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.


Condition
Spinal Muscular Atrophy (SMA)

Study Type: Observational
Study Design: Observational Model: Cohort
Time Perspective: Prospective
Official Title: Spinal Muscular Atrophy (SMA) Biomarkers in the Immediate Postnatal Period of Development

Resource links provided by NLM:


Further study details as provided by Ohio State University:

Primary Outcome Measures:
  • SMA Molecular Biomarker: SMN mRNA Levels [ Time Frame: Up to 24 months ] [ Designated as safety issue: No ]

    SMN mRNA determination:

    Quantitative RT-PCR: Absolute quantification of full length SMN transcripts will be performed essentially as described (Tiziano, Pinto et al. 2010). Briefly, SMN1 and SMN2 transcripts will be measured in a multiplex reaction and SMN-del7 will be quantified separately. Quantification of GAPDH transcripts will serve to control for RNA quantity and reverse transcriptase efficiency. No template and no reverse transcriptase controls will be included to track potential DNA contamination.

    Multiplex digital PCR: Droplet digital PCR (ddPCR) results in an absolute measure of target molecules. It does not rely on measurements in the log phase of PCR but instead measures the absolute count of positive gene copies. ddPCR will be used to determine SMN levels to further increase reliability and reduce variance in the SMN mRNA level determination.


  • SMA Biomarker: SMN protein levels (SMN protein in PBMCs) [ Time Frame: Up to 24 months ] [ Designated as safety issue: No ]

    SMN protein in PBMCs SMN cell-based immunoassay: Cell immunoassays will be performed(Kolb, Gubitz et al. 2006). This assay is performed using a single monoclonal antibody for SMN and does not involve the disruption of cells. The sensitivity and reliability of this assay will be compared to the commercially available ELISA assay.

    SMN ELISA: From the same PBMC sample, a commercially available SMN ELISA will also be performed according to the manufacturer's instructions (Enzo Life Sciences, Farmingdale, NY). It is possible that insufficient blood volumes will be collected at any given visit. The analysis will be prioritized as follows from the CPT tube: 1) SMN protein level using cell-based immunoassay, 2) SMN protein level using SMN ELISA. These samples will be coded, and the parent/guardian may request at any time that the child's samples be destroyed at this processing laboratory.


  • SMA Biomarker: Panel of plasma molecules (SMAF SMA Signature Panel) [ Time Frame: Up to 24 months ] [ Designated as safety issue: No ]
    SMAF SMA Signature Panel The B for SMA pilot study identified over 100 protein analytes that significantly correlated with motor function (as measured by Modified Hammersmith Functional Motor Scale) in SMA patients compared to controls (http://neuinfo.org/bforsma). The SMAF is currently contracted with Myriad Rules-Based Medicine (RBM) to develop a test for a subset of these proteins. The significance of these proteins is uncertain. For example, the proteins that most correlated with motor function in the B for SMA study was cartilage intermediate layer protein 2 and cartilage oligomeric matrix protein. This test analysis will be administered by the company Myriad RBM. These samples will be coded, and the parent/guardian may request at any time that the child's samples be destroyed at Myriad RMB.


Secondary Outcome Measures:
  • SMA Physiological Biomarker: Electrical Impedance Myography (EIM) [ Time Frame: Up to 24 months ] [ Designated as safety issue: No ]
    Convergence Medical Devices, Inc. has developed a handheld device specifically for performing EIM measurements on patients of all ages including infants. Data obtained with this handheld EIM device has shown marked alterations in the data between healthy and sick patients including those neurogenic and myopathic diseases. The device has not been used in infants to date. However, it has undergone independent safety testing by Intertek and has been used in more than 200 individuals, including 92 pediatric subjects ages 3-12, without any adverse events (AEs). EIM non-invasively measures the impedance of skeletal muscle. We anticipate that EIM will thus likely be able to assist in quantifying the severity of the disease affecting various muscle groups as well as in measuring changes in the disease over time. EIM measurements will be conducted on a core set of four muscles: biceps, the wrist extensor compartment, quadriceps, and tibialis anterior.

  • SMA Physiological Biomarker: Compound Motor Action Potential Testing [ Time Frame: Up to 24 months ] [ Designated as safety issue: No ]

    Maximumulnar 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. If the first test does not provide adequate results, the evaluator may do a quick second or third stimulus to confirm the maximal response. Each shock lasts approximately 0.1 millisecond. The testing duration is expected to be approximately 30 seconds.


  • Motor Function Scale: Test for Infant Motor Performance Screening Items (TIMPSI) [ Time Frame: Up to 24 months ] [ Designated as safety issue: No ]
    Test for Infant Motor Performance Screening Items (TIMPSI): The TIMPSI is a reliable and validated, comprehensive assessment of the postural and selective control of movement needed by infants less than 5 months of age for functional activity in the early months of life (Morton, MacLaren et al. 2006; Campbell, Swanlund et al. 2008; Finkel, Hynan et al. 2008). This assessment includes up to 29 different items that assess the child's motor abilities. The test will be performed by a trained pediatric physical therapist. The detailed instructions on administration of the test are provided in the manual of operations. Reliability and validity of the TIMPSI for infants with SMA Type 1 has recently been established.

  • Motor Function Scales: Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND): [ Time Frame: Up to 24 months ] [ Designated as safety issue: No ]
    Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP IN-TEND): The CHOP INTEND was designed to evaluate the motor skills of patients with SMA-1.(Glanzman, Mazzone et al. 2010) The CHOP INTEND is a reliable measure of motor skills in patients with SMA-I and neuromuscular disorders presenting in infancy. However, further vali-dation is needed. The detailed instructions on administration of the test are provided in the ma-nual of operations.

  • Motor Function Scale: Alberta Infant Motor Scale (AIMS): [ Time Frame: Up to 24 months ] [ Designated as safety issue: No ]
    Alberta Infant Motor Scale (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. (Piper, Darrah et al. 1994). The scale follows the principles of dynamical systems because motor skills are tested by observing infants as they move into and out of 4 positions: prone, supine, sitting, and standing. The detailed instructions on administration of the test are provided in the manual of operations.


Biospecimen Retention:   Samples With DNA

Absolute quantification of full length 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.


Estimated Enrollment: 54
Study Start Date: November 2012
Estimated Study Completion Date: June 2015
Estimated Primary Completion Date: September 2014 (Final data collection date for primary outcome measure)
Groups/Cohorts
Infants with Spinal Muscular Atrophy
Infants diagnosed Spinal Muscular Atrophy
Healthy controls
Healthy control infants

Detailed Description:

October 2013 Enrollment Update: The healthy control enrollment has been filled and is now closed. The study is still enrolling eligible infants with SMA.

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.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 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

Ages Eligible for Study:   up to 6 Months
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
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.

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01736553

Contacts
Contact: Amy Bartlett, CCRC 1-855-762-2466 Amy.Bartlett@osumc.edu
Contact: Shelley McCourt, BS 1-617-643-1618 mmccourt1@partners.org

Locations
United States, California
University of California - Davis Recruiting
Davis, California, United States, 95616
Contact: Randev Sandhu, BS CCRP       ucdavisneuronext@gmail.com   
Principal Investigator: Craig McDonald, MD         
University of California - Los Angeles Recruiting
Los Angeles, California, United States, 90095
Contact: Katrina Nguyen       KatrinaNguyen@mednet.ucla.edu   
Principal Investigator: Perry Shieh, MD PhD         
United States, Colorado
Children's Hospital Colorado Recruiting
Aurora, Colorado, United States, 80045
Contact: Melissa Gibbons, MS       melissa.gibbons@childrenscolorado.org   
Principal Investigator: Julie Parsons, MD         
United States, District of Columbia
Children's National Medical Center Recruiting
Washington, District of Columbia, United States, 20010
Contact: Percy Julian       PJulian@childrensnational.org   
Principal Investigator: Jahannaz Dastgir, DO         
United States, Illinois
Ann & Robert H. Lurie Children's Hospital of Chicago Recruiting
Chicago, Illinois, United States, 60611
Contact: Lauren Webb, BA       lwebb@luriechildrens.org   
Principal Investigator: Nancy Kuntz, MD         
United States, Massachusetts
Boston Children's Hospital Recruiting
Boston, Massachusetts, United States, 02115
Contact: Nicole Visyak, MS, MA       Nicole.visyak@childrens.harvard.edu   
Principal Investigator: Basil T Darras, MD         
United States, Missouri
Children's Mercy Hospital Recruiting
Kansas City, Missouri, United States, 64108
Contact: Gloria Womelduff       gwomelduff@cmh.edu   
Principal Investigator: Jean-Baptiste LePichon, MD, PhD         
Washington University in St. Louis School of Medicine Recruiting
Saint Louis, Missouri, United States, 63110
Contact: Traci Christenson, BA       christensont@neuro.wustl.edu   
Principal Investigator: Anne Connolly, MD         
United States, New York
Columbia University Medical Center Recruiting
New York, New York, United States, 10032
Contact: Nicole Holuba, MSN       nh2282@mail.cumc.columbia.edu   
Principal Investigator: Claudia Chiriboga, MD         
State University of New York Upstate Medical Center Recruiting
Syracuse, New York, United States, 13210
Contact: Jennifer Moore       moorej@upstate.edu   
Principal Investigator: Klaus Werner, MD PhD         
United States, Ohio
Nationwide Children's Hospital Recruiting
Columbus, Ohio, United States, 43205
Contact: Karen Carter, CCRC       Karen.Carter@nationwidechildrens.org   
Principal Investigator: Richard Shell, MD         
United States, Oregon
Doernbecher Children's Hospital Recruiting
Portland, Oregon, United States, 97239
Contact: Rhonda Muhly, CCRC       muhly@ohsu.edu   
Principal Investigator: Erika Finanger, MD         
United States, Tennessee
Vanderbilt University Recruiting
Nashville, Tennessee, United States, 37212
Contact: Diana Davis, BS       diana.davis@vanderbilt.edu   
Principal Investigator: W. Bryan Burnette, MD MS         
United States, Texas
Children's Medical Center of Dallas Recruiting
Dallas, Texas, United States, 75235
Contact: Lauren Smith, M.S., CRC       LaurenC.Smith@UTSouthwestern.edu   
Principal Investigator: Diana Castro, MD         
United States, Utah
University of Utah Health Sciences Center Recruiting
Salt Lake City, Utah, United States, 84132
Contact: Sandra P Reyna, MD       sreyna@genetics.utah.edu   
Contact: Tammy L Floore, RN, BSN       Tammy.Floore@hsc.utah.edu   
Principal Investigator: Kathryn J Swoboda, MD         
Sponsors and Collaborators
Ohio State University
Families of Spinal Muscular Atrophy
Massachusetts General Hospital
University of Iowa
Investigators
Principal Investigator: Stephen J Kolb, MD PhD Ohio State University
  More Information

Additional Information:
Publications:

Responsible Party: Stephen J. Kolb, Prinicipal Investigator of NeuroNEXT, Ohio State University
ClinicalTrials.gov Identifier: NCT01736553     History of Changes
Other Study ID Numbers: NN101, U01NS079163
Study First Received: November 19, 2012
Last Updated: July 22, 2014
Health Authority: United States: Institutional Review Board

Keywords provided by Ohio State University:
Spinal Muscular Atrophy (SMA) Biomarkers
Healthy controls
Infants

Additional relevant MeSH terms:
Muscular Atrophy
Muscular Atrophy, Spinal
Atrophy
Spinal Cord Diseases
Neuromuscular Manifestations
Neurologic Manifestations
Nervous System Diseases
Pathological Conditions, Anatomical
Signs and Symptoms
Central Nervous System Diseases
Motor Neuron Disease
Neurodegenerative Diseases
Neuromuscular Diseases

ClinicalTrials.gov processed this record on August 28, 2014