<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/NCT03021317</url>
  </required_header>
  <id_info>
    <org_study_id>IRB16-1390</org_study_id>
    <nct_id>NCT03021317</nct_id>
  </id_info>
  <brief_title>Effects of ACTHAR on Advanced MRI Surrogate Markers of Disease Activity and on Comprehensive Immune Signature During MS Relapses</brief_title>
  <acronym>ACTHAR</acronym>
  <official_title>Effects of ACTHAR on Advanced MRI Surrogate Markers of Disease Activity and on Comprehensive Immune Signature During MS Relapses</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Chicago</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Chicago</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      ACTHAR is a FDA approved drug for MS relapses. The purpose of the study is to examine the&#xD;
      efficacy of this agent in improving relapses as measured by advanced MRI and laboratory&#xD;
      techniques:&#xD;
&#xD;
        1. Advanced serial MRI studies on patients during and after an acute MS relapse. MRI will&#xD;
           be performed at baseline, 1 month after the 1st dose of ACTHAR, and months 3, 6, and 12.&#xD;
           ACTHAR will be administered for 10 days. Patients will start ACTHAR within 48 hours of&#xD;
           relapse assessment.&#xD;
&#xD;
        2. Serial immune assays on patients during and after an acute MS relapse. Serum and blood&#xD;
           samples with be collected at baseline, last day of ACTHAR (day 10 of therapy), 1 month&#xD;
           post 1st dose, and months 3 and 6.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Multiple sclerosis (MS) is a demyelinating disease of the CNS. In a vast majority of&#xD;
      patients, its clinical course is characterized by transient attacks of acute neurological&#xD;
      compromise, followed by variable degree of recovery. Each relapse leaves a patient with some&#xD;
      degree of residual disability. Higher number and longer duration of relapses are associated&#xD;
      with greater loss of function. Hence, it is imperative that these relapses are optimally&#xD;
      treated and curtailed in duration to allow for maximal recovery and repair.&#xD;
&#xD;
      ACTH (ACTHAR or IV formulation) has long been used for the treatment of MS relapses. ACTH has&#xD;
      equivalent efficacy to high-dose IV methylprednisolone in curtailing the duration of MS&#xD;
      relapses. ACTH has an advantage over steroids in that it has a short half-life and much less&#xD;
      deleterious steroid effect on bone and fat metabolism. Importantly, ACTH has a unique&#xD;
      mechanism of action on immune and brain cells through melanocortin receptors (MCRs), which&#xD;
      promote production of regulatory and anti-inflammatory cytokines and support oligodendrocyte&#xD;
      precursors and neuronal function, all of which could lead to better repair of MS lesions and&#xD;
      favorable clinical outcome.&#xD;
&#xD;
      The studies proposed herein will provide a better understanding of the effects of ACTHAR in&#xD;
      improving MRI lesion characteristics over time. The complementary immune and genetic studies&#xD;
      will further provide evidence for the mechanism of action (MOA) of ACTHAR in improving immune&#xD;
      dysfunction related to MS relapse. This is a one of a kind study, involving both&#xD;
      advanced/state-of-the art MRI techniques and immune studies to assess the beneficial effects&#xD;
      of ACTHAR in MS relapses in the same patients over time.&#xD;
&#xD;
      The primary outcome of all MRI techniques is to determine whether there is an improvement and&#xD;
      subsequent stabilization/repair over time of tissue damage caused by inflammatory MS disease&#xD;
      activity. Multiple conventional and nonconventional MR imaging modalities are examined here&#xD;
      to determine which of these are the most sensitive and reliable in detecting microstructural&#xD;
      damage and repair over time. The results of this study will also greatly impact the design of&#xD;
      future MS trials by providing a guide for selecting the most appropriate MRI and immune&#xD;
      methods to assess treatment efficacy in MS.&#xD;
&#xD;
      In terms of laboratory analysis, the following will be examined:&#xD;
&#xD;
        1. Determine immune subset expression in CD4+FOXP3 Tregs and CD8+CD28- T suppressor cells&#xD;
           by flow cytometry at each visit.&#xD;
&#xD;
        2. Global gene expression profiling in MNC with 913,000 probes at each visit.&#xD;
           Bioinformatics will include pathway analysis and ACTHAR-induced RNA signature.&#xD;
&#xD;
        3. Serum protein profiling for immune-regulated cytokines (Th1, Th2, Th17, monokines…) and&#xD;
           neuroprotective proteins (NGF, BDNF, ACTH, HGF, CNTF, IL-10…) at each visit.&#xD;
&#xD;
        4. All data from protein and gene expression, as well as immune subset expression will be&#xD;
           compared to our database generated from therapy-naïve stable and exacerbating MS. ACTHAR&#xD;
           signature will analyzed based on these comparisons.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Not yet recruiting</last_known_status>
  <start_date>February 2017</start_date>
  <completion_date type="Anticipated">May 2019</completion_date>
  <primary_completion_date type="Anticipated">May 2019</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in T1 lesion relaxation time</measure>
    <time_frame>12 month after the completion of intervention</time_frame>
    <description>T1 relaxation time is a MRI marker of injury. The change in this metric will be followed over 12 months to see if lesions recover post ACTHAR intervention.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in immune subset expression in CD4+FOXP3 Tregs by flow cytometry post ACTHAR intervention</measure>
    <time_frame>6 month after the completion of intervention</time_frame>
    <description>Treg cells are unregulated during the healing process in MS relapses. Changes in this population of immune cells will be measured over a course of 6 months post ACTHAR intervention.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">18</enrollment>
  <condition>Multiple Sclerosis</condition>
  <arm_group>
    <arm_group_label>Treated Group</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Open label, single arm treatment study using MRI and laboratory markers to assess efficacy of ACTHAR in MS patients who are undergoing relapses.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>ACTHar</intervention_name>
    <description>The patients will be given 80 Units subcutaneously of ACTHAR at the time of MS relapse daily for 10 days.</description>
    <arm_group_label>Treated Group</arm_group_label>
    <other_name>repository corticotropin injection</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  age &gt; 18&#xD;
&#xD;
          -  undergoing a clinical relapse and associated MRI active lesion&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Recent infection, any&#xD;
&#xD;
          -  use of any glucocorticoid 30 days prior to enrollment&#xD;
&#xD;
          -  unable to consent&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Adil Javed, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Chicago</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Mildred Valentine</last_name>
    <phone>773-702-9812</phone>
    <email>mvalentine@neurology.bsd.uchicago.edu</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Adil Javed, MD, PhD</last_name>
    <phone>7738340558</phone>
    <email>ajaved@neurology.bsd.uchicago.edu</email>
  </overall_contact_backup>
  <verification_date>January 2017</verification_date>
  <study_first_submitted>January 12, 2017</study_first_submitted>
  <study_first_submitted_qc>January 12, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 13, 2017</study_first_posted>
  <last_update_submitted>January 17, 2017</last_update_submitted>
  <last_update_submitted_qc>January 17, 2017</last_update_submitted_qc>
  <last_update_posted type="Estimate">January 19, 2017</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>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Adrenocorticotropic Hormone</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <pending_results>
    <submitted>May 10, 2023</submitted>
    <returned>June 6, 2023</returned>
  </pending_results>
  <!-- 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/NCT03021317
org study id: IRB16-1390
nct id: NCT03021317
lead sponsor: 
has dmc: No
ACTHAR is a FDA approved drug for MS relapses. The purpose of the study is to examine the
      efficacy of this agent in improving relapses as measured by advanced MRI and laboratory
      techniques:

        1. Advanced serial MRI studies on patients during and after an acute MS relapse. MRI will
           be performed at baseline, 1 month after the 1st dose of ACTHAR, and months 3, 6, and 12.
           ACTHAR will be administered for 10 days. Patients will start ACTHAR within 48 hours of
           relapse assessment.

        2. Serial immune assays on patients during and after an acute MS relapse. Serum and blood
           samples with be collected at baseline, last day of ACTHAR (day 10 of therapy), 1 month
           post 1st dose, and months 3 and 6.
Multiple sclerosis (MS) is a demyelinating disease of the CNS. In a vast majority of
      patients, its clinical course is characterized by transient attacks of acute neurological
      compromise, followed by variable degree of recovery. Each relapse leaves a patient with some
      degree of residual disability. Higher number and longer duration of relapses are associated
      with greater loss of function. Hence, it is imperative that these relapses are optimally
      treated and curtailed in duration to allow for maximal recovery and repair.

      ACTH (ACTHAR or IV formulation) has long been used for the treatment of MS relapses. ACTH has
      equivalent efficacy to high-dose IV methylprednisolone in curtailing the duration of MS
      relapses. ACTH has an advantage over steroids in that it has a short half-life and much less
      deleterious steroid effect on bone and fat metabolism. Importantly, ACTH has a unique
      mechanism of action on immune and brain cells through melanocortin receptors (MCRs), which
      promote production of regulatory and anti-inflammatory cytokines and support oligodendrocyte
      precursors and neuronal function, all of which could lead to better repair of MS lesions and
      favorable clinical outcome.

      The studies proposed herein will provide a better understanding of the effects of ACTHAR in
      improving MRI lesion characteristics over time. The complementary immune and genetic studies
      will further provide evidence for the mechanism of action (MOA) of ACTHAR in improving immune
      dysfunction related to MS relapse. This is a one of a kind study, involving both
      advanced/state-of-the art MRI techniques and immune studies to assess the beneficial effects
      of ACTHAR in MS relapses in the same patients over time.

      The primary outcome of all MRI techniques is to determine whether there is an improvement and
      subsequent stabilization/repair over time of tissue damage caused by inflammatory MS disease
      activity. Multiple conventional and nonconventional MR imaging modalities are examined here
      to determine which of these are the most sensitive and reliable in detecting microstructural
      damage and repair over time. The results of this study will also greatly impact the design of
      future MS trials by providing a guide for selecting the most appropriate MRI and immune
      methods to assess treatment efficacy in MS.

      In terms of laboratory analysis, the following will be examined:

        1. Determine immune subset expression in CD4+FOXP3 Tregs and CD8+CD28- T suppressor cells
           by flow cytometry at each visit.

        2. Global gene expression profiling in MNC with 913,000 probes at each visit.
           Bioinformatics will include pathway analysis and ACTHAR-induced RNA signature.

        3. Serum protein profiling for immune-regulated cytokines (Th1, Th2, Th17, monokines…) and
           neuroprotective proteins (NGF, BDNF, ACTH, HGF, CNTF, IL-10…) at each visit.

        4. All data from protein and gene expression, as well as immune subset expression will be
           compared to our database generated from therapy-naïve stable and exacerbating MS. ACTHAR
           signature will analyzed based on these comparisons.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Change in T1 lesion relaxation time
time frame: 12 month after the completion of intervention
description: T1 relaxation time is a MRI marker of injury. The change in this metric will be followed over 12 months to see if lesions recover post ACTHAR intervention.
measure: Change in immune subset expression in CD4+FOXP3 Tregs by flow cytometry post ACTHAR intervention
time frame: 6 month after the completion of intervention
description: Treg cells are unregulated during the healing process in MS relapses. Changes in this population of immune cells will be measured over a course of 6 months post ACTHAR intervention.
arm group label: Treated Group
arm group type: Experimental
description: Open label, single arm treatment study using MRI and laboratory markers to assess efficacy of ACTHAR in MS patients who are undergoing relapses.
intervention type: Drug
intervention name: ACTHar
description: The patients will be given 80 Units subcutaneously of ACTHAR at the time of MS relapse daily for 10 days.
arm group label: Treated Group
other name: repository corticotropin injection
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Adil Javed, MD, PhD
role: Principal Investigator
affiliation: University of Chicago
last name: Mildred Valentine
phone: 773-702-9812
email: mvalentine@neurology.bsd.uchicago.edu
last name: Adil Javed, MD, PhD
phone: 7738340558
email: ajaved@neurology.bsd.uchicago.edu
responsible party type: Sponsor
mesh term: Multiple Sclerosis
mesh term: Adrenocorticotropic Hormone
sharing ipd: No
submitted: May 10, 2023
returned: June 6, 2023