<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/NCT01728922</url>
  </required_header>
  <id_info>
    <org_study_id>2012CIS/VD/SVUH</org_study_id>
    <nct_id>NCT01728922</nct_id>
  </id_info>
  <brief_title>Dose-related Effects of Vitamin D3 on Immune Responses in Patients With Clinically Isolated Syndrome</brief_title>
  <acronym>CISAVID</acronym>
  <official_title>Dose-related Effects of Vitamin D3 on Immune Responses in Patients With Clinically Isolated Syndrome and Healthy Control Participants. An Exploratory Double Blind Placebo Randomised Controlled Study.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University College Dublin</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>University of Dublin, Trinity College</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>St Vincent's University Hospital, Ireland</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University College Dublin</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      The primary purpose of this study is to assess the immune response to vitamin D&#xD;
      supplementation at two doses (5,000 IU and 10,000 IU daily) in both healthy controls and&#xD;
      patients with clinically isolated syndrome compared to placebo. Secondary endpoints include&#xD;
      (1) disease outcome in the clinically isolated syndrome in terms of clinical relapses and&#xD;
      evidence of new lesions on MRI (McDonald's MS), 2) Safety of doses used&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Primary endpoint: To determine the effects of vitamin D supplementation at two doses a) 5,000&#xD;
      IU daily b) 10,000 IU daily compared to c) placebo a 24 weeks period on the change from&#xD;
      baseline in frequency of CD4 T cell subsets and cytokine responses by peripheral blood&#xD;
      mononuclear cells in 1) patients with the clinically isolated syndrome. 2) healthy control&#xD;
      participants.&#xD;
&#xD;
      Secondary endpoints:&#xD;
&#xD;
        1. To determine whether there is a dose response effect of supplementation using 5,000 IU&#xD;
           and 10,000 IU of vitamin D versus placebo over 24 weeks on the change from baseline in&#xD;
           the frequency of CD4 T cell subsets and cytokine responses by PBMC in 1) patients with&#xD;
           the clinically isolated syndrome (CIS) 2) healthy control participants&#xD;
&#xD;
        2. To establish whether there is a clinical response to vitamin D measured by a) change in&#xD;
           the number of T2 lesions and Gadolinium enhancing lesions on MRI scanning at 24 weeks&#xD;
           compared to baseline b) reduction in relapses over 24 weeks in treated (both 5,000 IU&#xD;
           and 10,000 IU) CIS patients versus CIS patients receiving placebo.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">November 6, 2012</start_date>
  <completion_date type="Actual">June 5, 2016</completion_date>
  <primary_completion_date type="Actual">June 5, 2015</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>
    <intervention_model_description>double-blind, dose ranging, two doses of vitamin D, randomised parallel groups with placebo arms in clinically isolated syndrome and heathy control participants</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
    <masking_description>similar appearance of placebo and active drug</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>The effects of two doses of vitamin D and placebo therapy on the change in the frequency of CD4 T cell subsets and cytokine responses of PBMC over 24 weeks of therapy from baseline.</measure>
    <time_frame>This outcome measure will be assessed at baseline and at 24 weeks.</time_frame>
    <description>A number of measures will be examined in particular IL-10 production and the frequency of Th17 cells.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>The number of new T2 and gadolinium enhancing lesions compared to baseline amongst the study group.</measure>
    <time_frame>Baseline and 24 weeks</time_frame>
    <description>The MRI out-come measure will assess the a) number of Gadolinium enhancing lesions b) the number of new and enlarging T2 lesions c) the combined unique lesion count (new and enlarging T2 lesions plus Gadolinium enhancing lesions) after 24 weeks of therapy in the three arms, 5000IU, 10,000IU vitamin D and placebo . Mean and median new T2 and gadolinium-enhancing lesions at 24 weeks (end of the trial) will be compared for each treatment allocation group. In addition the mean and median number of new T2 lesions plus gadolinium enhancing lesions in all the CIS patients on vitamin D will be compared to the mean and median in the placebo group.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Relapse occurrence in the CIS patients during 24 weeks of the trial</measure>
    <time_frame>At each clinic visit or as the need arises.</time_frame>
    <description>Relapse occurrence in the CIS patients during 24 weeks of the trial;(i) annualised relapse rates (ARR), (ii) percentage of patients free from relapses and (iii) time to first relapse will be compared for each treatment allocation group. In addition the same relapse measures will be applied to both vitamin D treated groups combined and compared to those in the placebo group.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The percentage of CIS patients in each treatment arm free from any evidence of disease activity (No relapses, no new T2 lesions, no gadolinium enhancing lesions).</measure>
    <time_frame>At 24 weeks.</time_frame>
  </secondary_outcome>
  <other_outcome>
    <measure>Serum calcium</measure>
    <time_frame>Every 4 weeks for 24 weeks</time_frame>
    <description>a measure of calcium homeostasis</description>
  </other_outcome>
  <other_outcome>
    <measure>Number of participants with adverse events as a measure of safety and tolerability of vitamin D in doses of 5,000IU and 10,000IU daily</measure>
    <time_frame>four weekly assessments over 24 weeks</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>serum urea</measure>
    <time_frame>4 weekly over 24 weeks</time_frame>
    <description>a measure of renal function</description>
  </other_outcome>
  <other_outcome>
    <measure>serum creatinine</measure>
    <time_frame>4 weekly over 24 weeks</time_frame>
    <description>a measure of renal function</description>
  </other_outcome>
  <other_outcome>
    <measure>serum 25(OH)D levels</measure>
    <time_frame>4 weekly over 24 weeks</time_frame>
    <description>a measure of response to oral dosing and adherence to therapy.</description>
  </other_outcome>
  <other_outcome>
    <measure>serum parathormone (iPTH)</measure>
    <time_frame>4 weekly over 24 weeks</time_frame>
    <description>a measure of parathyroid function</description>
  </other_outcome>
  <number_of_arms>6</number_of_arms>
  <enrollment type="Actual">64</enrollment>
  <condition>Clinically Isolated Syndrome</condition>
  <condition>Multiple Sclerosis</condition>
  <arm_group>
    <arm_group_label>Healthy control - 5,000 IU vitamin D</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>13 healthy controls will be administered 5,000 IU vitamin D. Primary outcome and safety outcome measures will be assessed.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Healthy control - 10,000 IU vitamin D</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>13 healthy controls will be administered 10,000 IU vitamin D. Primary outcome and safety outcome measures will be assessed.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>CIS - placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>15 patients will be administered placebo and all outcome measures will be assessed.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>CIS - 5,000 IU vitamin D</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>15 patients will be administered 5,000 IU vitamin D and all outcomes will be assessed.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>CIS - 10,000 IU vitamin D</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>15 patients will be administered 10,000 IU of vitamin D and all outcome measures assessed.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Healthy control - placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>13 control participants who will be administered placebo. These will be assessed for the primary outcome and safety outcomes only.</description>
  </arm_group>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>5000IU vitamin D</intervention_name>
    <description>Vigantol Oil</description>
    <arm_group_label>CIS - 5,000 IU vitamin D</arm_group_label>
    <arm_group_label>Healthy control - 5,000 IU vitamin D</arm_group_label>
    <other_name>Vigantol Oil</other_name>
  </intervention>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>10000IU vitamin D</intervention_name>
    <description>Vigantol Oil</description>
    <arm_group_label>CIS - 10,000 IU vitamin D</arm_group_label>
    <arm_group_label>Healthy control - 10,000 IU vitamin D</arm_group_label>
    <other_name>Vigantol Oil</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Placebo Oil</description>
    <arm_group_label>CIS - placebo</arm_group_label>
    <arm_group_label>Healthy control - placebo</arm_group_label>
    <other_name>Placebo Oil</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria: To be eligible for inclusion, each subject must meet each of the&#xD;
        following criteria at Screening (Visit 1) and must continue to fulfil these criteria at&#xD;
        Baseline (Visit 2).&#xD;
&#xD;
          -  CIS: Patients with a clinically isolated syndrome with onset relapse within the&#xD;
             previous three months and two or more than two asymptomatic T2 lesions on MRI brain&#xD;
             scan.&#xD;
&#xD;
          -  Aged 18-55yrs.&#xD;
&#xD;
          -  Not receiving any disease modifying therapy.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients in whom any disease other than demyelination could explain their signs and&#xD;
             symptoms.&#xD;
&#xD;
          -  Participants with known disease of the parathyroids, a history of vitamin D&#xD;
             intolerance, sarcoidosis, a history of hypercalcaemia of any cause.&#xD;
&#xD;
          -  Participants with a baseline abnormality in serum urea, creatinine, calcium,&#xD;
             parathormone.&#xD;
&#xD;
          -  Participants on thiazide diuretics (hypercalcaemia risk).&#xD;
&#xD;
          -  Patients with occurrence of a relapse less than six weeks prior to entry to study.&#xD;
&#xD;
          -  Previous treatment with beta-interferons or glatiramer acetate or steroids in the last&#xD;
             three months.&#xD;
&#xD;
          -  Any previous treatment with mitoxantrone or other immunosuppressant.&#xD;
&#xD;
          -  Participants already taking supplemental vitamin D.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>55 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Michael Hutchinson, MB, FRCP</last_name>
    <role>Principal Investigator</role>
    <affiliation>St Vincent's University Hospital</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>St Vincent's University Hospital</name>
      <address>
        <city>Dublin</city>
        <state>Dublin 4</state>
        <country>Ireland</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Ireland</country>
  </location_countries>
  <verification_date>May 2017</verification_date>
  <study_first_submitted>November 8, 2012</study_first_submitted>
  <study_first_submitted_qc>November 19, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 20, 2012</study_first_posted>
  <last_update_submitted>May 1, 2017</last_update_submitted>
  <last_update_submitted_qc>May 1, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">May 3, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University College Dublin</investigator_affiliation>
    <investigator_full_name>Professor Michael Hutchinson</investigator_full_name>
    <investigator_title>Consultant Neurologist, Newman Clinical Research Professor</investigator_title>
  </responsible_party>
  <keyword>Clinically isolated syndrome</keyword>
  <keyword>Multiple sclerosis</keyword>
  <keyword>Vitamin D</keyword>
  <keyword>Immune response</keyword>
  <keyword>CD4 T cell subsets</keyword>
  <keyword>Cytokine</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Multiple Sclerosis</mesh_term>
    <mesh_term>Syndrome</mesh_term>
    <mesh_term>Sclerosis</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Vitamin D</mesh_term>
    <mesh_term>Ergocalciferols</mesh_term>
    <mesh_term>Cholecalciferol</mesh_term>
    <mesh_term>Vitamins</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>all demographic details and outcome measures may be obtained directly from the PI by e-mail</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/NCT01728922
org study id: 2012CIS/VD/SVUH
nct id: NCT01728922
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
is us export: No
The primary purpose of this study is to assess the immune response to vitamin D
      supplementation at two doses (5,000 IU and 10,000 IU daily) in both healthy controls and
      patients with clinically isolated syndrome compared to placebo. Secondary endpoints include
      (1) disease outcome in the clinically isolated syndrome in terms of clinical relapses and
      evidence of new lesions on MRI (McDonald's MS), 2) Safety of doses used
Primary endpoint: To determine the effects of vitamin D supplementation at two doses a) 5,000
      IU daily b) 10,000 IU daily compared to c) placebo a 24 weeks period on the change from
      baseline in frequency of CD4 T cell subsets and cytokine responses by peripheral blood
      mononuclear cells in 1) patients with the clinically isolated syndrome. 2) healthy control
      participants.

      Secondary endpoints:

        1. To determine whether there is a dose response effect of supplementation using 5,000 IU
           and 10,000 IU of vitamin D versus placebo over 24 weeks on the change from baseline in
           the frequency of CD4 T cell subsets and cytokine responses by PBMC in 1) patients with
           the clinically isolated syndrome (CIS) 2) healthy control participants

        2. To establish whether there is a clinical response to vitamin D measured by a) change in
           the number of T2 lesions and Gadolinium enhancing lesions on MRI scanning at 24 weeks
           compared to baseline b) reduction in relapses over 24 weeks in treated (both 5,000 IU
           and 10,000 IU) CIS patients versus CIS patients receiving placebo.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: double-blind, dose ranging, two doses of vitamin D, randomised parallel groups with placebo arms in clinically isolated syndrome and heathy control participants
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
masking description: similar appearance of placebo and active drug
measure: The effects of two doses of vitamin D and placebo therapy on the change in the frequency of CD4 T cell subsets and cytokine responses of PBMC over 24 weeks of therapy from baseline.
time frame: This outcome measure will be assessed at baseline and at 24 weeks.
description: A number of measures will be examined in particular IL-10 production and the frequency of Th17 cells.
measure: The number of new T2 and gadolinium enhancing lesions compared to baseline amongst the study group.
time frame: Baseline and 24 weeks
description: The MRI out-come measure will assess the a) number of Gadolinium enhancing lesions b) the number of new and enlarging T2 lesions c) the combined unique lesion count (new and enlarging T2 lesions plus Gadolinium enhancing lesions) after 24 weeks of therapy in the three arms, 5000IU, 10,000IU vitamin D and placebo . Mean and median new T2 and gadolinium-enhancing lesions at 24 weeks (end of the trial) will be compared for each treatment allocation group. In addition the mean and median number of new T2 lesions plus gadolinium enhancing lesions in all the CIS patients on vitamin D will be compared to the mean and median in the placebo group.
measure: Relapse occurrence in the CIS patients during 24 weeks of the trial
time frame: At each clinic visit or as the need arises.
description: Relapse occurrence in the CIS patients during 24 weeks of the trial;(i) annualised relapse rates (ARR), (ii) percentage of patients free from relapses and (iii) time to first relapse will be compared for each treatment allocation group. In addition the same relapse measures will be applied to both vitamin D treated groups combined and compared to those in the placebo group.
measure: The percentage of CIS patients in each treatment arm free from any evidence of disease activity (No relapses, no new T2 lesions, no gadolinium enhancing lesions).
time frame: At 24 weeks.
measure: Serum calcium
time frame: Every 4 weeks for 24 weeks
description: a measure of calcium homeostasis
measure: Number of participants with adverse events as a measure of safety and tolerability of vitamin D in doses of 5,000IU and 10,000IU daily
time frame: four weekly assessments over 24 weeks
measure: serum urea
time frame: 4 weekly over 24 weeks
description: a measure of renal function
measure: serum creatinine
time frame: 4 weekly over 24 weeks
description: a measure of renal function
measure: serum 25(OH)D levels
time frame: 4 weekly over 24 weeks
description: a measure of response to oral dosing and adherence to therapy.
measure: serum parathormone (iPTH)
time frame: 4 weekly over 24 weeks
description: a measure of parathyroid function
arm group label: Healthy control - 5,000 IU vitamin D
arm group type: Active Comparator
description: 13 healthy controls will be administered 5,000 IU vitamin D. Primary outcome and safety outcome measures will be assessed.
arm group label: Healthy control - 10,000 IU vitamin D
arm group type: Active Comparator
description: 13 healthy controls will be administered 10,000 IU vitamin D. Primary outcome and safety outcome measures will be assessed.
arm group label: CIS - placebo
arm group type: Placebo Comparator
description: 15 patients will be administered placebo and all outcome measures will be assessed.
arm group label: CIS - 5,000 IU vitamin D
arm group type: Active Comparator
description: 15 patients will be administered 5,000 IU vitamin D and all outcomes will be assessed.
arm group label: CIS - 10,000 IU vitamin D
arm group type: Active Comparator
description: 15 patients will be administered 10,000 IU of vitamin D and all outcome measures assessed.
arm group label: Healthy control - placebo
arm group type: Placebo Comparator
description: 13 control participants who will be administered placebo. These will be assessed for the primary outcome and safety outcomes only.
intervention type: Dietary Supplement
intervention name: 5000IU vitamin D
description: Vigantol Oil
arm group label: CIS - 5,000 IU vitamin D
arm group label: Healthy control - 5,000 IU vitamin D
other name: Vigantol Oil
intervention type: Dietary Supplement
intervention name: 10000IU vitamin D
description: Vigantol Oil
arm group label: CIS - 10,000 IU vitamin D
arm group label: Healthy control - 10,000 IU vitamin D
other name: Vigantol Oil
intervention type: Other
intervention name: Placebo
description: Placebo Oil
arm group label: CIS - placebo
arm group label: Healthy control - placebo
other name: Placebo Oil
criteria: 
gender: All
minimum age: 18 Years
maximum age: 55 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Michael Hutchinson, MB, FRCP
role: Principal Investigator
affiliation: St Vincent's University Hospital
facility: 
country: Ireland
responsible party type: Principal Investigator
investigator affiliation: University College Dublin
investigator full name: Professor Michael Hutchinson
investigator title: Consultant Neurologist, Newman Clinical Research Professor
mesh term: Multiple Sclerosis
mesh term: Syndrome
mesh term: Sclerosis
mesh term: Vitamin D
mesh term: Ergocalciferols
mesh term: Cholecalciferol
mesh term: Vitamins
sharing ipd: Yes
ipd description: all demographic details and outcome measures may be obtained directly from the PI by e-mail