<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/NCT01712945</url>
  </required_header>
  <id_info>
    <org_study_id>EudraCT 2011-005606-30</org_study_id>
    <nct_id>NCT01712945</nct_id>
  </id_info>
  <brief_title>Keratinocyte Growth Factor to Prevent Autoimmunity After Alemtuzumab Treatment of Multiple Sclerosis</brief_title>
  <acronym>CAM-THY</acronym>
  <official_title>Keratinocyte Growth Factor - Promoting Thymic Reconstitution and Preventing Autoimmunity After Alemtuzumab (Campath-1H) Treatment of Multiple Sclerosis</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Cambridge University Hospitals NHS Foundation Trust</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Cambridge University Hospitals NHS Foundation Trust</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to test a novel strategy to prevent the clinical problem of&#xD;
      secondary autoimmunity following alemtuzumab treatment of multiple sclerosis.&#xD;
&#xD;
      The hypothesis is that autoimmunity after alemtuzumab can be prevented by giving a drug that&#xD;
      promotes thymic T cell regeneration (Palifermin, Kepivance®).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is a single-centre, double-blinded, randomised controlled trial of palifermin&#xD;
      (Kepivance) vs. placebo in the prevention of autoimmunity following alemtuzumab treatment of&#xD;
      multiple sclerosis.&#xD;
&#xD;
      The dose of palifermin (kepivance)used in this trial will be informed by a dose-escalation&#xD;
      study.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    interim anlaysis failed: palifermin does not promote thymopoeisis after alemtuzumab&#xD;
  </why_stopped>
  <start_date type="Actual">June 2012</start_date>
  <completion_date type="Actual">October 2017</completion_date>
  <primary_completion_date type="Actual">August 2017</primary_completion_date>
  <phase>Phase 1/Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Prevention</primary_purpose>
    <masking>Triple (Participant, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>incidence of clinical autoimmunity</measure>
    <time_frame>within 30 months of starting treatment with alemtuzumab</time_frame>
    <description>The primary endpoint is incidence of clinical autoimmunity within 30 months of starting treatment with alemtuzumab</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Absolute numbers of naive T cells</measure>
    <time_frame>within 30 months of starting treatment with alemtuzumab</time_frame>
    <description>Absolute numbers of naive T cells</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Safety events</measure>
    <time_frame>within 30 months of starting treatment with alemtuzumab</time_frame>
    <description>Safety outcomes - incidence and nature of adverse events</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Time at which autoimmunity develops</measure>
    <time_frame>Within 30 months after alemtuzumab</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Reconstitution of lymphocyte subsets</measure>
    <time_frame>within 30 months of starting treatment with alemtuzumab</time_frame>
    <description>Percentage of naive, central memory, effector memory and effector memory RA cells within the CD4 and CD8 T cell populations</description>
  </other_outcome>
  <other_outcome>
    <measure>T cell receptor (TCR) clonality</measure>
    <time_frame>within 30 months of starting treatment with alemtuzumab</time_frame>
    <description>T cell receptor (TCR) clonality</description>
  </other_outcome>
  <other_outcome>
    <measure>Thymic function</measure>
    <time_frame>within 30 months of starting treatment with alemtuzumab</time_frame>
    <description>Thymic function - determined by measuring TRECs</description>
  </other_outcome>
  <other_outcome>
    <measure>Thymic volume</measure>
    <time_frame>within 30 months of starting treatment with alemtuzumab</time_frame>
    <description>Thymic volume and density - as assessed by non-contrast enhanced, low dose CT scans of the chest performed at baseline and month 6.</description>
  </other_outcome>
  <other_outcome>
    <measure>Thymic density</measure>
    <time_frame>within 30 months of starting treatment with alemtuzumab</time_frame>
    <description>Thymic volume and density - as assessed by non-contrast enhanced, low dose CT scans of the chest performed at baseline and month 6.</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">40</enrollment>
  <condition>Multiple Sclerosis</condition>
  <arm_group>
    <arm_group_label>Palifermin (and Alemtuzumab)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Palifermin (Kepivance®), at the maximum identified tolerated dose will be administered by intravenous bolus on days -5, -4. -3 prior to, and on days 8, 9 and 10 after each cycle of alemtuzumab, then again on 3 consecutive days at month 1 and month 3 after each cycle of alemtuzumab. Patients will be observed for adverse reactions for at least 1 to 2 hours following each bolus dose. Initial treatment alemtuzumab will be administered as a fixed total dose of 60 mg IV over 5 consecutive days (12mg/day). For re-treatment at Month 12, alemtuzumab will be administered as a fixed total dose of 36mg IV over 3 consecutive days (12mg/day).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo (and Alemtuzumab)</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Initial treatment alemtuzumab will be administered as a fixed total dose of 60 mg IV over 5 consecutive days (12mg/day). For re-treatment at Month 12, alemtuzumab will be administered as a fixed total dose of 36mg IV over 3 consecutive days (12mg/day).</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Palifermin</intervention_name>
    <description>Palifermin (Kepivance®) administered by intravenous bolus on days -5, -4. -3 prior to, and on days 8, 9 and 10 after each cycle of alemtuzumab, then again on 3 consecutive days at month 1 and month 3 after each cycle of alemtuzumab. Patients will be observed for adverse reactions for at least 1 to 2 hours following each bolus dose.</description>
    <arm_group_label>Palifermin (and Alemtuzumab)</arm_group_label>
    <other_name>Kepivance</other_name>
    <other_name>keratinocyte growth factor</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Alemtuzumab</intervention_name>
    <description>Initial treatment alemtuzumab will be administered as a fixed total dose of 60 mg IV over 5 consecutive days (12mg/day). For re-treatment at Month 12, alemtuzumab will be administered as a fixed total dose of 36mg IV over 3 consecutive days (12mg/day).</description>
    <arm_group_label>Palifermin (and Alemtuzumab)</arm_group_label>
    <arm_group_label>Placebo (and Alemtuzumab)</arm_group_label>
    <other_name>Campath-1H</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Male or non-pregnant, non-lactating female patients&#xD;
&#xD;
          -  &gt; 18 years of age, and &lt;50 years of age inclusive&#xD;
&#xD;
          -  Diagnosis of MS using McDonald's 2010 criteria, including MRI abnormalities consistent&#xD;
             with McDonald's 2010 criteria.&#xD;
&#xD;
          -  Onset of first MS symptoms within 10 years on the date the ICF is signed&#xD;
&#xD;
          -  EDSS score 0.0 to 5.0 (inclusive) at screening&#xD;
&#xD;
          -  At least 2 clinical episodes of MS in the 2 years prior to study entry, with at least&#xD;
             1 attack within 12 months, which may have occurred whilst on disease-modifying&#xD;
             therapy, namely any beta interferon or glatiramer acetate.&#xD;
&#xD;
          -  Serum IL-7≤7pg/mL&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Any progressive form of multiple sclerosis&#xD;
&#xD;
          -  Previous thymectomy&#xD;
&#xD;
          -  Previous treatment with alemtuzumab, natalizumab, mitoxantrone, cyclophosphomide,&#xD;
             cladribine, rituximab or any other immunosuppressant or cytotoxic therapy (other than&#xD;
             steroids and disease-modifying therapies listed above)&#xD;
&#xD;
          -  History of malignancy&#xD;
&#xD;
          -  Personal history of clinically significant autoimmune disease, other than multiple&#xD;
             sclerosis (including but not limited to: thyroid disease, immune cytopenias,&#xD;
             inflammatory bowel disease, diabetes, lupus, severe asthma)&#xD;
&#xD;
          -  Intolerance of pulsed corticosteroids, especially a history of steroid psychosis&#xD;
&#xD;
          -  Major systemic disease or other illness that would, in the opinion of the&#xD;
             investigator, compromise patient safety or interfere with the interpretation of study&#xD;
             results.&#xD;
&#xD;
          -  Seropositivity for human immunodeficiency virus (HIV)&#xD;
&#xD;
          -  Past or present hepatitis B infection (positive hepatitis B serology)&#xD;
&#xD;
          -  Pregnant women or male and female patients who do not agree to use effective&#xD;
             contraception during the study.&#xD;
&#xD;
          -  Medical, psychiatric, cognitive or other conditions that, in the investigator's&#xD;
             opinion, compromise the patient's ability to understand the patient information, to&#xD;
             give informed consent, to comply with the trial protocol, or to complete the study.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Months</minimum_age>
    <maximum_age>50 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Alasdair Coles, Phd FRCP</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Cambridge</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Addenbrooke's Hospital</name>
      <address>
        <city>Cambridge</city>
        <state>Cambridgeshire</state>
        <zip>CB2 2QQ</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United Kingdom</country>
  </location_countries>
  <link>
    <url>http://www.colescambridge.org.uk/trial%20participation.htm</url>
    <description>Information for patients on protocol</description>
  </link>
  <reference>
    <citation>Coles AJ, Fox E, Vladic A, Gazda SK, Brinar V, Selmaj KW, Bass AD, Wynn DR, Margolin DH, Lake SL, Moran S, Palmer J, Smith MS, Compston DA. Alemtuzumab versus interferon beta-1a in early relapsing-remitting multiple sclerosis: post-hoc and subset analyses of clinical efficacy outcomes. Lancet Neurol. 2011 Apr;10(4):338-48. doi: 10.1016/S1474-4422(11)70020-5.</citation>
    <PMID>21397567</PMID>
  </reference>
  <reference>
    <citation>Jones JL, Phuah CL, Cox AL, Thompson SA, Ban M, Shawcross J, Walton A, Sawcer SJ, Compston A, Coles AJ. IL-21 drives secondary autoimmunity in patients with multiple sclerosis, following therapeutic lymphocyte depletion with alemtuzumab (Campath-1H). J Clin Invest. 2009 Jul;119(7):2052-61. doi: 10.1172/JCI37878. Epub 2009 Jun 22.</citation>
    <PMID>19546505</PMID>
  </reference>
  <reference>
    <citation>Cox AL, Thompson SA, Jones JL, Robertson VH, Hale G, Waldmann H, Compston DA, Coles AJ. Lymphocyte homeostasis following therapeutic lymphocyte depletion in multiple sclerosis. Eur J Immunol. 2005 Nov;35(11):3332-42. doi: 10.1002/eji.200535075.</citation>
    <PMID>16231285</PMID>
  </reference>
  <reference>
    <citation>CAMMS223 Trial Investigators; Coles AJ, Compston DA, Selmaj KW, Lake SL, Moran S, Margolin DH, Norris K, Tandon PK. Alemtuzumab vs. interferon beta-1a in early multiple sclerosis. N Engl J Med. 2008 Oct 23;359(17):1786-801. doi: 10.1056/NEJMoa0802670.</citation>
    <PMID>18946064</PMID>
  </reference>
  <reference>
    <citation>Bruinsma M, van Soest PL, Leenen PJ, Lambrecht BN, Cupedo T, Lowenberg B, Cornelissen JJ, Braakman E. Keratinocyte growth factor induces expansion of murine peripheral CD4+Foxp3+ regulatory T cells and increases their thymic output. J Immunol. 2007 Dec 1;179(11):7424-30. doi: 10.4049/jimmunol.179.11.7424.</citation>
    <PMID>18025186</PMID>
  </reference>
  <reference>
    <citation>Miller RD, Caulfield MJ, Calkins CE. Expression and regulation of a recurrent anti-erythrocyte autoantibody idiotype in spleen cells from neonatal and adult BALB/c mice. J Immunol. 1992 Apr 15;148(8):2452-5.</citation>
    <PMID>1560201</PMID>
  </reference>
  <reference>
    <citation>Min D, Panoskaltsis-Mortari A, Kuro-O M, Hollander GA, Blazar BR, Weinberg KI. Sustained thymopoiesis and improvement in functional immunity induced by exogenous KGF administration in murine models of aging. Blood. 2007 Mar 15;109(6):2529-37. doi: 10.1182/blood-2006-08-043794. Epub 2006 Nov 30.</citation>
    <PMID>17138819</PMID>
  </reference>
  <verification_date>April 2019</verification_date>
  <study_first_submitted>October 19, 2012</study_first_submitted>
  <study_first_submitted_qc>October 23, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 24, 2012</study_first_posted>
  <last_update_submitted>April 26, 2019</last_update_submitted>
  <last_update_submitted_qc>April 26, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">April 30, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Cambridge University Hospitals NHS Foundation Trust</investigator_affiliation>
    <investigator_full_name>Alasdair Coles</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <keyword>Alemtuzumab</keyword>
  <keyword>Palifermin</keyword>
  <keyword>Reconstitution</keyword>
  <keyword>Thymus</keyword>
  <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>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Alemtuzumab</mesh_term>
  </intervention_browse>
  <!-- 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/NCT01712945
org study id: EudraCT 2011-005606-30
nct id: NCT01712945
lead sponsor: 
has dmc: Yes
The purpose of this study is to test a novel strategy to prevent the clinical problem of
      secondary autoimmunity following alemtuzumab treatment of multiple sclerosis.

      The hypothesis is that autoimmunity after alemtuzumab can be prevented by giving a drug that
      promotes thymic T cell regeneration (Palifermin, Kepivance®).
This is a single-centre, double-blinded, randomised controlled trial of palifermin
      (Kepivance) vs. placebo in the prevention of autoimmunity following alemtuzumab treatment of
      multiple sclerosis.

      The dose of palifermin (kepivance)used in this trial will be informed by a dose-escalation
      study.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Prevention
masking: Triple (Participant, Investigator, Outcomes Assessor)
measure: incidence of clinical autoimmunity
time frame: within 30 months of starting treatment with alemtuzumab
description: The primary endpoint is incidence of clinical autoimmunity within 30 months of starting treatment with alemtuzumab
measure: Absolute numbers of naive T cells
time frame: within 30 months of starting treatment with alemtuzumab
description: Absolute numbers of naive T cells
measure: Safety events
time frame: within 30 months of starting treatment with alemtuzumab
description: Safety outcomes - incidence and nature of adverse events
measure: Time at which autoimmunity develops
time frame: Within 30 months after alemtuzumab
measure: Reconstitution of lymphocyte subsets
time frame: within 30 months of starting treatment with alemtuzumab
description: Percentage of naive, central memory, effector memory and effector memory RA cells within the CD4 and CD8 T cell populations
measure: T cell receptor (TCR) clonality
time frame: within 30 months of starting treatment with alemtuzumab
description: T cell receptor (TCR) clonality
measure: Thymic function
time frame: within 30 months of starting treatment with alemtuzumab
description: Thymic function - determined by measuring TRECs
measure: Thymic volume
time frame: within 30 months of starting treatment with alemtuzumab
description: Thymic volume and density - as assessed by non-contrast enhanced, low dose CT scans of the chest performed at baseline and month 6.
measure: Thymic density
time frame: within 30 months of starting treatment with alemtuzumab
description: Thymic volume and density - as assessed by non-contrast enhanced, low dose CT scans of the chest performed at baseline and month 6.
arm group label: Palifermin (and Alemtuzumab)
arm group type: Experimental
description: Palifermin (Kepivance®), at the maximum identified tolerated dose will be administered by intravenous bolus on days -5, -4. -3 prior to, and on days 8, 9 and 10 after each cycle of alemtuzumab, then again on 3 consecutive days at month 1 and month 3 after each cycle of alemtuzumab. Patients will be observed for adverse reactions for at least 1 to 2 hours following each bolus dose. Initial treatment alemtuzumab will be administered as a fixed total dose of 60 mg IV over 5 consecutive days (12mg/day). For re-treatment at Month 12, alemtuzumab will be administered as a fixed total dose of 36mg IV over 3 consecutive days (12mg/day).
arm group label: Placebo (and Alemtuzumab)
arm group type: Placebo Comparator
description: Initial treatment alemtuzumab will be administered as a fixed total dose of 60 mg IV over 5 consecutive days (12mg/day). For re-treatment at Month 12, alemtuzumab will be administered as a fixed total dose of 36mg IV over 3 consecutive days (12mg/day).
intervention type: Drug
intervention name: Palifermin
description: Palifermin (Kepivance®) administered by intravenous bolus on days -5, -4. -3 prior to, and on days 8, 9 and 10 after each cycle of alemtuzumab, then again on 3 consecutive days at month 1 and month 3 after each cycle of alemtuzumab. Patients will be observed for adverse reactions for at least 1 to 2 hours following each bolus dose.
arm group label: Palifermin (and Alemtuzumab)
other name: Kepivance
other name: keratinocyte growth factor
intervention type: Drug
intervention name: Alemtuzumab
description: Initial treatment alemtuzumab will be administered as a fixed total dose of 60 mg IV over 5 consecutive days (12mg/day). For re-treatment at Month 12, alemtuzumab will be administered as a fixed total dose of 36mg IV over 3 consecutive days (12mg/day).
arm group label: Palifermin (and Alemtuzumab)
arm group label: Placebo (and Alemtuzumab)
other name: Campath-1H
criteria: 
gender: All
minimum age: 18 Months
maximum age: 50 Years
healthy volunteers: No
last name: Alasdair Coles, Phd FRCP
role: Principal Investigator
affiliation: University of Cambridge
facility: 
country: United Kingdom
url: http://www.colescambridge.org.uk/trial%20participation.htm
description: Information for patients on protocol
citation: Coles AJ, Fox E, Vladic A, Gazda SK, Brinar V, Selmaj KW, Bass AD, Wynn DR, Margolin DH, Lake SL, Moran S, Palmer J, Smith MS, Compston DA. Alemtuzumab versus interferon beta-1a in early relapsing-remitting multiple sclerosis: post-hoc and subset analyses of clinical efficacy outcomes. Lancet Neurol. 2011 Apr;10(4):338-48. doi: 10.1016/S1474-4422(11)70020-5.
PMID: 21397567
citation: Jones JL, Phuah CL, Cox AL, Thompson SA, Ban M, Shawcross J, Walton A, Sawcer SJ, Compston A, Coles AJ. IL-21 drives secondary autoimmunity in patients with multiple sclerosis, following therapeutic lymphocyte depletion with alemtuzumab (Campath-1H). J Clin Invest. 2009 Jul;119(7):2052-61. doi: 10.1172/JCI37878. Epub 2009 Jun 22.
PMID: 19546505
citation: Cox AL, Thompson SA, Jones JL, Robertson VH, Hale G, Waldmann H, Compston DA, Coles AJ. Lymphocyte homeostasis following therapeutic lymphocyte depletion in multiple sclerosis. Eur J Immunol. 2005 Nov;35(11):3332-42. doi: 10.1002/eji.200535075.
PMID: 16231285
citation: CAMMS223 Trial Investigators; Coles AJ, Compston DA, Selmaj KW, Lake SL, Moran S, Margolin DH, Norris K, Tandon PK. Alemtuzumab vs. interferon beta-1a in early multiple sclerosis. N Engl J Med. 2008 Oct 23;359(17):1786-801. doi: 10.1056/NEJMoa0802670.
PMID: 18946064
citation: Bruinsma M, van Soest PL, Leenen PJ, Lambrecht BN, Cupedo T, Lowenberg B, Cornelissen JJ, Braakman E. Keratinocyte growth factor induces expansion of murine peripheral CD4+Foxp3+ regulatory T cells and increases their thymic output. J Immunol. 2007 Dec 1;179(11):7424-30. doi: 10.4049/jimmunol.179.11.7424.
PMID: 18025186
citation: Miller RD, Caulfield MJ, Calkins CE. Expression and regulation of a recurrent anti-erythrocyte autoantibody idiotype in spleen cells from neonatal and adult BALB/c mice. J Immunol. 1992 Apr 15;148(8):2452-5.
PMID: 1560201
citation: Min D, Panoskaltsis-Mortari A, Kuro-O M, Hollander GA, Blazar BR, Weinberg KI. Sustained thymopoiesis and improvement in functional immunity induced by exogenous KGF administration in murine models of aging. Blood. 2007 Mar 15;109(6):2529-37. doi: 10.1182/blood-2006-08-043794. Epub 2006 Nov 30.
PMID: 17138819
responsible party type: Principal Investigator
investigator affiliation: Cambridge University Hospitals NHS Foundation Trust
investigator full name: Alasdair Coles
investigator title: Principal Investigator
mesh term: Multiple Sclerosis
mesh term: Sclerosis
mesh term: Alemtuzumab