<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT04496830</url>
  </required_header>
  <id_info>
    <org_study_id>202004205</org_study_id>
    <nct_id>NCT04496830</nct_id>
  </id_info>
  <brief_title>SPINCOMS Biomarker Study</brief_title>
  <acronym>SPINCOMS</acronym>
  <official_title>Cerebrospinal Fluid-biomarkers-based Diagnostic and Prognostic Models for Multiple Sclerosis</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Washington University School of Medicine</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Institute of Allergy and Infectious Diseases (NIAID)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Colorado, Denver</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Ottawa</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Montana State University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Washington University School of Medicine</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>Yes</is_fda_regulated_device>
    <is_us_export>Yes</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      To determine if biomarker-based CSF testing is reliably detecting differences between&#xD;
      patients with Multiple Sclerosis (MS), different MS-subtypes, and other central nervous&#xD;
      system (CNS) diseases. This study will also look to identify biomarkers that could be used&#xD;
      for the prediction, at the time of diagnosis, of the future disease clinical course and&#xD;
      response to therapy. The SOMAscan assay will be used for CSF samples analysis.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Using machine learning, the investigators have developed from SOMAScan:&#xD;
&#xD;
        1. A molecular diagnostic test that differentiates MS from other inflammatory and&#xD;
           non-inflammatory central nervous system (CNS) diseases (area under receiver-operator&#xD;
           characteristic curve-AUROC of 0.98);&#xD;
&#xD;
        2. A molecular test that differentiates relapsing-remitting MS from progressive MS variants&#xD;
           (AUROC of 0.91); and&#xD;
&#xD;
        3. A molecular test that predicts future rates of disability progression, concordance&#xD;
           coefficient of 0.425 (p&lt;0.001).&#xD;
&#xD;
      Because these results are derived from a single research center (NIAID/NDS), it is imperative&#xD;
      to determine their performance in real clinical practice settings as a necessary step for&#xD;
      their potential regulatory approval.&#xD;
&#xD;
      Consequently, this application has 2 specific aims:&#xD;
&#xD;
      AIM 1. To independently validate afore-mentioned CSF-biomarker-based tests for their clinical&#xD;
      value within the multicenter Spinal fluid Consortium for MS (SPINCOMS). In Aim 1, each of the&#xD;
      3 defined tests will be validated in 100 new SPINCOMS patients. To validate the prognostic&#xD;
      test, 100 MS patients with CSF collected at least 3 years ago will be evaluated at follow-up&#xD;
      examination with standardized clinical outcomes. CSF will be analyzed blinded using&#xD;
      pre-defined statistical models.&#xD;
&#xD;
      AIM 2. To explore whether collected CSF-biomarkers point towards pathogenic heterogeneity&#xD;
      that may predict patient-specific efficacy for different disease-modifying treatments (DMTs)&#xD;
      or identify pathogenic mechanisms not targeted by current DMTs. In Aim 2, clustering analysis&#xD;
      will assess pathogenic heterogeneity and explore potential predictors of response to therapy.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">June 15, 2020</start_date>
  <completion_date type="Anticipated">March 1, 2024</completion_date>
  <primary_completion_date type="Anticipated">December 1, 2023</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>For the MS diagnostic test, the investigators will select 50 patients with definite MS (CIS/RIS excluded) and 50 controls, including 25 non-inflammatory neurological diseases (NIND) that mimic MS (such as patients with vascular-ischemic changes, complex migraines, leukodystrophies, etc.) and 25 other inflammatory neurological diseases (OIND) such as NMO, Susac's syndrome, sarcoidosis, CNS vasculitis.&#xD;
For validating the RRMS versus progressive MS classifier, the investigators will select CSF from 50 RRMS and 50 progressive MS patients (25 SPMS and 25 PPMS).&#xD;
Cryopreserved CSF samples from these patients will be analyzed blindly using SOMAscan assay. Probability of MS diagnosis and progressive MS diagnosis will be calculated based on published models. Results will then be unblinded and analyzed for accuracy of diagnostic conclusion.&#xD;
To evaluate the MS severity score, the investigators will select 50 RRMS and 50 progressive MS (25 PPMS and 25 SPMS).</intervention_model_description>
    <primary_purpose>Diagnostic</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Biomarker Predicted Outcomes against NeurEx-based outcomes</measure>
    <time_frame>3 years</time_frame>
    <description>CSF-biomarker-predicted outcomes against measured NeurEx-based outcomes, considering a Bonferroni-adjusted significance level 0.05/3 = 0.017 (to adjust for 3 tests).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>MS Severity Model Analyses</measure>
    <time_frame>3 years</time_frame>
    <description>As secondary analyses of MS severity model,assessment of correlations between CSF-biomarker-predicted outcomes and more traditional MS outcomes. Specifically, correlate CSF-biomarker-based scores of MS severity and MSSS, ARMSSS and by MS-DSS, calculated from the follow-up visit scores. Based on power calculations, 100 relevant patients/classifier will provide &gt; 90% power to externally validate all 3 Somascan CSF-biomarker-based models.</description>
  </primary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Actual">160</enrollment>
  <condition>Multiple Sclerosis</condition>
  <arm_group>
    <arm_group_label>Relapsing Remitting Multiple Sclerosis</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Blood sample collection&#xD;
Vital signs, weight, height and BMI.&#xD;
Complete neurological examination documented in NeurEx (recorded with an iPAD).&#xD;
Clinical data questionnaire&#xD;
25FW &amp; non-dominant hand 9HPT (required for calculating CombiWISE &amp; MS-DSS).&#xD;
Smartphone Apps (include 25FW, SDMT and tests that correlate highly w 9HPT - can be acquired in patient-autonomous manner with minimal assistance).&#xD;
Optical Coherence Tomography (OCT)&#xD;
CSF Analysis</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Progressive Multiple Sclerosis</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Blood sample collection&#xD;
Vital signs, weight, height and BMI.&#xD;
Complete neurological examination documented in NeurEx (recorded with an iPAD).&#xD;
Clinical data questionnaire&#xD;
25FW &amp; non-dominant hand 9HPT (required for calculating CombiWISE &amp; MS-DSS).&#xD;
Smartphone Apps (include 25FW, SDMT and tests that correlate highly w 9HPT - can be acquired in patient-autonomous manner with minimal assistance).&#xD;
Optical Coherence Tomography (OCT)&#xD;
CSF Analysis</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Non-Inflammatory Neurological Diseases</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Clinical data questionnaire&#xD;
CSF Analysis</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Other Non-Inflammatory Neurological Diseases</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Clinical data questionnaire&#xD;
CSF Analysis</description>
  </arm_group>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>SOMAscan</intervention_name>
    <description>Analysis of previously donated cerebrospinal fluid using a SOMAscan assay</description>
    <arm_group_label>Non-Inflammatory Neurological Diseases</arm_group_label>
    <arm_group_label>Other Non-Inflammatory Neurological Diseases</arm_group_label>
    <arm_group_label>Progressive Multiple Sclerosis</arm_group_label>
    <arm_group_label>Relapsing Remitting Multiple Sclerosis</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        MS Patients selection criteria&#xD;
&#xD;
          -  Lumbar puncture (LP) in the untreated stage with cryopreserved CSF (serum/blood&#xD;
             optional) with consent to use it for future research&#xD;
&#xD;
          -  ≥ 3 and ≤ 10 years of follow-up from LP&#xD;
&#xD;
          -  At time of LP untreated and not treated with steroid or off steroids ≥ one month&#xD;
&#xD;
          -  Available/willing to come for in-person follow-up&#xD;
&#xD;
          -  Available/willing to sign the NIH 09-I-0032 &quot;Sample processing only&quot; consent form&#xD;
&#xD;
          -  Diagnosis of MS based on 2017 McDonald criteria at time of follow-up visit&#xD;
&#xD;
        Non-MS Patients selection criteria Required: 25 Non-Inflammatory Neurological Disease&#xD;
        (NIND), 25 Other Inflammatory Neurological Disease (OIND)&#xD;
&#xD;
          -  Lumbar puncture (LP) in the untreated stage with cryopreserved CSF (serum/blood&#xD;
             optional) with consent to use it for future research&#xD;
&#xD;
          -  ≥ 3 and ≤ 10 years of follow-up from LP&#xD;
&#xD;
          -  At time of LP untreated and not treated with steroid or off steroids ≥ one month&#xD;
&#xD;
          -  Up to date contact information&#xD;
&#xD;
          -  Available/willing to sign the NIH 09-I-0032 &quot;Sample processing only&quot; consent form&#xD;
&#xD;
          -  Diagnosis:&#xD;
&#xD;
        NIND: e.g., ischemic-gliotic changes, CADASIL and other leukodystrophies, migraines,&#xD;
        ischemic spinal cord lesions etc OIND: e.g. CNS Sjogren's, SLE, vasculitis, CNS infections,&#xD;
        MOG-associated disorders, NMO spectrum disorders (NMOSD)&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Washington University in St Louis</name>
      <address>
        <city>Saint Louis</city>
        <state>Missouri</state>
        <zip>63110</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
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    <PMID>18184917</PMID>
  </reference>
  <reference>
    <citation>Landis SC, Amara SG, Asadullah K, Austin CP, Blumenstein R, Bradley EW, Crystal RG, Darnell RB, Ferrante RJ, Fillit H, Finkelstein R, Fisher M, Gendelman HE, Golub RM, Goudreau JL, Gross RA, Gubitz AK, Hesterlee SE, Howells DW, Huguenard J, Kelner K, Koroshetz W, Krainc D, Lazic SE, Levine MS, Macleod MR, McCall JM, Moxley RT 3rd, Narasimhan K, Noble LJ, Perrin S, Porter JD, Steward O, Unger E, Utz U, Silberberg SD. A call for transparent reporting to optimize the predictive value of preclinical research. Nature. 2012 Oct 11;490(7419):187-91. doi: 10.1038/nature11556.</citation>
    <PMID>23060188</PMID>
  </reference>
  <verification_date>April 2023</verification_date>
  <study_first_submitted>July 27, 2020</study_first_submitted>
  <study_first_submitted_qc>July 30, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">August 3, 2020</study_first_posted>
  <last_update_submitted>April 28, 2023</last_update_submitted>
  <last_update_submitted_qc>April 28, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">May 1, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Multiple Sclerosis</mesh_term>
    <mesh_term>Sclerosis</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
    <ipd_description>Will be determined based whether or not recruitment numbers will be sufficient to power outcome analyses.</ipd_description>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04496830
org study id: 202004205
nct id: NCT04496830
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: Yes
is us export: Yes
To determine if biomarker-based CSF testing is reliably detecting differences between
      patients with Multiple Sclerosis (MS), different MS-subtypes, and other central nervous
      system (CNS) diseases. This study will also look to identify biomarkers that could be used
      for the prediction, at the time of diagnosis, of the future disease clinical course and
      response to therapy. The SOMAscan assay will be used for CSF samples analysis.
Using machine learning, the investigators have developed from SOMAScan:

        1. A molecular diagnostic test that differentiates MS from other inflammatory and
           non-inflammatory central nervous system (CNS) diseases (area under receiver-operator
           characteristic curve-AUROC of 0.98);

        2. A molecular test that differentiates relapsing-remitting MS from progressive MS variants
           (AUROC of 0.91); and

        3. A molecular test that predicts future rates of disability progression, concordance
           coefficient of 0.425 (p<0.001).

      Because these results are derived from a single research center (NIAID/NDS), it is imperative
      to determine their performance in real clinical practice settings as a necessary step for
      their potential regulatory approval.

      Consequently, this application has 2 specific aims:

      AIM 1. To independently validate afore-mentioned CSF-biomarker-based tests for their clinical
      value within the multicenter Spinal fluid Consortium for MS (SPINCOMS). In Aim 1, each of the
      3 defined tests will be validated in 100 new SPINCOMS patients. To validate the prognostic
      test, 100 MS patients with CSF collected at least 3 years ago will be evaluated at follow-up
      examination with standardized clinical outcomes. CSF will be analyzed blinded using
      pre-defined statistical models.

      AIM 2. To explore whether collected CSF-biomarkers point towards pathogenic heterogeneity
      that may predict patient-specific efficacy for different disease-modifying treatments (DMTs)
      or identify pathogenic mechanisms not targeted by current DMTs. In Aim 2, clustering analysis
      will assess pathogenic heterogeneity and explore potential predictors of response to therapy.
allocation: Non-Randomized
intervention model: Parallel Assignment
intervention model description: For the MS diagnostic test, the investigators will select 50 patients with definite MS (CIS/RIS excluded) and 50 controls, including 25 non-inflammatory neurological diseases (NIND) that mimic MS (such as patients with vascular-ischemic changes, complex migraines, leukodystrophies, etc.) and 25 other inflammatory neurological diseases (OIND) such as NMO, Susac's syndrome, sarcoidosis, CNS vasculitis.
For validating the RRMS versus progressive MS classifier, the investigators will select CSF from 50 RRMS and 50 progressive MS patients (25 SPMS and 25 PPMS).
Cryopreserved CSF samples from these patients will be analyzed blindly using SOMAscan assay. Probability of MS diagnosis and progressive MS diagnosis will be calculated based on published models. Results will then be unblinded and analyzed for accuracy of diagnostic conclusion.
To evaluate the MS severity score, the investigators will select 50 RRMS and 50 progressive MS (25 PPMS and 25 SPMS).
primary purpose: Diagnostic
masking: None (Open Label)
measure: Biomarker Predicted Outcomes against NeurEx-based outcomes
time frame: 3 years
description: CSF-biomarker-predicted outcomes against measured NeurEx-based outcomes, considering a Bonferroni-adjusted significance level 0.05/3 = 0.017 (to adjust for 3 tests).
measure: MS Severity Model Analyses
time frame: 3 years
description: As secondary analyses of MS severity model,assessment of correlations between CSF-biomarker-predicted outcomes and more traditional MS outcomes. Specifically, correlate CSF-biomarker-based scores of MS severity and MSSS, ARMSSS and by MS-DSS, calculated from the follow-up visit scores. Based on power calculations, 100 relevant patients/classifier will provide > 90% power to externally validate all 3 Somascan CSF-biomarker-based models.
arm group label: Relapsing Remitting Multiple Sclerosis
arm group type: Experimental
description: Blood sample collection
Vital signs, weight, height and BMI.
Complete neurological examination documented in NeurEx (recorded with an iPAD).
Clinical data questionnaire
25FW & non-dominant hand 9HPT (required for calculating CombiWISE & MS-DSS).
Smartphone Apps (include 25FW, SDMT and tests that correlate highly w 9HPT - can be acquired in patient-autonomous manner with minimal assistance).
Optical Coherence Tomography (OCT)
CSF Analysis
arm group label: Progressive Multiple Sclerosis
arm group type: Experimental
description: Blood sample collection
Vital signs, weight, height and BMI.
Complete neurological examination documented in NeurEx (recorded with an iPAD).
Clinical data questionnaire
25FW & non-dominant hand 9HPT (required for calculating CombiWISE & MS-DSS).
Smartphone Apps (include 25FW, SDMT and tests that correlate highly w 9HPT - can be acquired in patient-autonomous manner with minimal assistance).
Optical Coherence Tomography (OCT)
CSF Analysis
arm group label: Non-Inflammatory Neurological Diseases
arm group type: Experimental
description: Clinical data questionnaire
CSF Analysis
arm group label: Other Non-Inflammatory Neurological Diseases
arm group type: Experimental
description: Clinical data questionnaire
CSF Analysis
intervention type: Device
intervention name: SOMAscan
description: Analysis of previously donated cerebrospinal fluid using a SOMAscan assay
arm group label: Non-Inflammatory Neurological Diseases
arm group label: Other Non-Inflammatory Neurological Diseases
arm group label: Progressive Multiple Sclerosis
arm group label: Relapsing Remitting Multiple Sclerosis
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
facility: 
country: United States
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PMID: 23060188
responsible party type: Sponsor
mesh term: Multiple Sclerosis
mesh term: Sclerosis
sharing ipd: Undecided
ipd description: Will be determined based whether or not recruitment numbers will be sufficient to power outcome analyses.