<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/NCT04472975</url>
  </required_header>
  <id_info>
    <org_study_id>H18--00407</org_study_id>
    <secondary_id>CIHR PJT-156363</secondary_id>
    <secondary_id>CIHR FDN-159934</secondary_id>
    <nct_id>NCT04472975</nct_id>
  </id_info>
  <brief_title>Prescription Drug Safety and Effectiveness in Multiple Sclerosis</brief_title>
  <acronym>DRUMS</acronym>
  <official_title>Disease-modifying Drug Safety and Effectiveness in Multiple Sclerosis [DRUMS]</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of British Columbia</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>University of Manitoba</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Dalhousie University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Saskatchewan</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Alberta Health services</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Alberta</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University of British Columbia</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The goal of our research is to find out how safe and effective the drugs used to treat&#xD;
      multiple sclerosis (MS) are when used in the everyday, real world. To achieve these study&#xD;
      goals, we have two main study Themes. The first Theme focuses on how effective the MS drugs&#xD;
      are. We will examine whether the MS drugs can extend life expectancy or prolong a person's&#xD;
      ability to stay mobile and walk. We will also look at whether the MS drugs have a beneficial&#xD;
      effect on reducing the number of times a person with MS is admitted to a hospital or visits a&#xD;
      physician. The second Theme focuses on side effects, including whether the MS drugs are&#xD;
      associated with harmful effects, such as cancer, stroke or depression. We will be able to&#xD;
      compare the different MS drugs to each other. Also, we will see if men and women or people of&#xD;
      different ages and with other illnesses (such as having both MS and diabetes) respond to the&#xD;
      MS drugs differently. Our findings will help people with MS and their physicians when trying&#xD;
      to make decisions as to which MS drug might be best for them.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Study population:&#xD;
&#xD;
      A validated case definition of multiple sclerosis (MS) will be applied to the health&#xD;
      administrative data to identify all MS patients in 5 Canadian provinces (British Columbia,&#xD;
      Manitoba, Nova Scotia, Saskatchewan and Alberta; Studies 1,2,4-6). Developed in Manitoba, the&#xD;
      positive predictive value was 80.5% and negative predictive value (NPV) was 75.5% among a&#xD;
      population of persons with ≥1 claim for any demyelinating disease. The NPV would be &gt;99% at&#xD;
      the general population level where more than 98% of individuals have no claims for&#xD;
      demyelinating disease. The algorithm has been successfully applied in British Columbia, Nova&#xD;
      Scotia and Saskatchewan.&#xD;
&#xD;
      When MS-specific clinical data are used (British Columbia, Manitoba, Nova Scotia; Study 3),&#xD;
      the diagnosis is neurologist confirmed, according to the prevailing international criteria.&#xD;
&#xD;
      Study period:&#xD;
&#xD;
      The earliest study start is Jan/1996 (the 1st full year that DMDs were available and the&#xD;
      first year of available administrative and DMD-related data), and the latest study end is&#xD;
      March 31, 2018; this represents &gt;2 decades of drug and patient-related follow-up.&#xD;
&#xD;
      Study entry:&#xD;
&#xD;
      Most recent of 1-Jan-1996, an individual's 18th birthday, date of 1st MS-related claim or&#xD;
      date of 1st MS clinic visit (when clinical data are accessed [Study 3]).&#xD;
&#xD;
      Study end:&#xD;
&#xD;
      Earliest of death, emigration from the respective province, last MS clinic visit (when&#xD;
      clinical data are accessed [Study 3]), or 31-December-2017 (British Columbia, Manitoba, Nova&#xD;
      Scotia, Alberta) or 31-March-2018 (Saskatchewan).&#xD;
&#xD;
      DMD exposure:&#xD;
&#xD;
      DMD use, as identified using prescription data. An individual's exposure status can change&#xD;
      over time and will be dynamically classified as: 1) no DMD, 2) any DMD, then by generation:&#xD;
      2a) any 1st or 2b) 2nd generation DMD. When possible, the individual drug classes will be&#xD;
      explored (beta-interferon [as one class], glatiramer acetate, natalizumab, fingolimod,&#xD;
      dimethyl fumarate, teriflunomide, alemtuzumab).&#xD;
&#xD;
      Time perspective:&#xD;
&#xD;
      Analyses of prospectively recorded health administrative, prescription and clinical data.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">January 1, 1996</start_date>
  <completion_date type="Actual">March 31, 2018</completion_date>
  <primary_completion_date type="Actual">March 31, 2018</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Other</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Study 1: All-cause hospitalizations</measure>
    <time_frame>As recurrent events from study entry to study end, up to 22 years.</time_frame>
    <description>The outcome (all-cause hospitalizations) will be derived from the comprehensive hospital data, excluding pregnancy-related events, in 5 Canadian provinces (British Columbia, Manitoba, Nova Scotia, Saskatchewan and Alberta).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Study 2: All-cause mortality</measure>
    <time_frame>Measured using Cox proportional hazards models (time from study entry to death), up to 22 years.</time_frame>
    <description>The outcome (all-cause mortality) will be derived from the province-wide death data (e.g., Vital Statistics or the equivalent) in 5 Canadian provinces (British Columbia, Manitoba, Nova Scotia, Saskatchewan and Alberta).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Study 3: Change in disability (Expanded Disability Status Scale [EDSS]) over time</measure>
    <time_frame>Assessed using mixed effects model from study entry to study end, up to 22 years.</time_frame>
    <description>The outcomes (change in EDSS) will be derived from the MS clinical data in 3 Canadian provinces (British Columbia, Manitoba and Nova Scotia).</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Study 1: Physician consultation rates (overall and by physician specialty)</measure>
    <time_frame>Overall numbers of physician consultations will be measured from study entry to study end, up to 22 years of follow-up.</time_frame>
    <description>The outcome (physician consultation) will be derived from the physician data, excluding pregnancy-related events, in 5 Canadian provinces (British Columbia, Manitoba, Nova Scotia, Saskatchewan and Alberta).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Study 3: MS disability, measured using the Expanded Disability Status Scale (EDSS) and assessed as time to sustained EDSS 6</measure>
    <time_frame>Measured using Cox proportional hazards models (time from study entry to sustained EDSS 6 confirmed after at least 6 months with no subsequent improvement), up to 22 years of follow-up.</time_frame>
    <description>The outcome (sustained EDSS 6) will be derived from the MS clinical data in 3 Canadian provinces (British Columbia, Manitoba and Nova Scotia).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Study 3: Sustained EDSS 4</measure>
    <time_frame>Measured using Cox proportional hazards models (time from study entry to sustained EDSS 4), up to 22 years of follow-up.</time_frame>
    <description>The outcomes (sustained EDSS 4) will be derived from the MS clinical data in 3 Canadian provinces (British Columbia, Manitoba and Nova Scotia).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Study 4: Explore the modifying effects</measure>
    <time_frame>From study entry to study end, up to 22 years of follow-up.</time_frame>
    <description>Effects of sex, age, comorbidity and DMD treatment duration on outcomes (all-cause hospitalizations, physician consultation rates, all-cause mortality, changes in EDSS) will be assessed.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Study 5: Potential incident adverse events</measure>
    <time_frame>Time from study entry to the incident adverse event of interest will be assessed using Cox proportional hazards with time-varying DMD exposure, up to 22 years of follow-up.</time_frame>
    <description>'Incident' event defined as not present in the year before DMD initiation. The outcomes (incident adverse events) will be identified using physician and hospital claims, coded using International Classification of Diseases [ICD]-9/10 and prescriptions filled (by ATC levels), in 5 Canadian provinces (British Columbia, Manitoba, Nova Scotia, Saskatchewan and Alberta). An additional, data mining, discovery approach will assess the associations between exposure and adverse events using unsupervised machine learning techniques. Cases of PML will be described.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Study 6: Characteristics associated with risk of adverse events</measure>
    <time_frame>From study entry to study end, up to 22 years of follow-up.</time_frame>
    <description>Examine demographic and clinical characteristics associated with risk of adverse events, including sex, age, comorbidity and DMD treatment duration.</description>
  </secondary_outcome>
  <number_of_groups>1</number_of_groups>
  <enrollment type="Actual">35000</enrollment>
  <condition>Multiple Sclerosis</condition>
  <arm_group>
    <arm_group_label>Multiple sclerosis (MS) cohort</arm_group_label>
    <description>Individuals with multiple sclerosis without any exposure to disease-mofidying drugs (DMDs) and with exposure to one or more DMDs.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Exposure to one or more disease-modifying drug(s)(DMDs) used to treat MS</intervention_name>
    <description>Individuals with MS exposed to one or more DMDs (beta-interferon, glatiramer acetate, natalizumab, fingolimod, dimethyl fumarate, teriflunomide, alemtuzumab, daclizumab or ocrelizumab; regardless of dose, frequency or duration of treatment) between 1st January 1996 and 31st March 2018 in five Canadian provinces.</description>
    <arm_group_label>Multiple sclerosis (MS) cohort</arm_group_label>
  </intervention>
  <eligibility>
    <study_pop>
      <textblock>
        A MS cohort study (Studies 1, 2, 4-6) will be identified using a validated case definition&#xD;
        of MS that will be applied to the whole-population linked administrative health data in&#xD;
        five Canadian provinces spanning from west to east coast: British Columbia (BC; population&#xD;
        4.65 million [2016]), Alberta (AB; 4.07 million population [2016]), Saskatchewan (SK;&#xD;
        population 1.10 million [2016]), Manitoba (MB; population 1.28 million [2016]) and Nova&#xD;
        Scotia (NS; population 924,000 [2016]).&#xD;
&#xD;
        When MS-specific clinical data are used (British Columbia, Manitoba, Nova Scotia; Study 3),&#xD;
        the diagnosis is neurologist confirmed, according to the prevailing international criteria.&#xD;
&#xD;
        Within each province, we anticipate finding virtually the whole population of people living&#xD;
        with MS via the administrative data, and, in the clinical data, ≈60-80% or 100% of those&#xD;
        seeking DMDs (the MS clinics are the sole prescribers of the DMDs).&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  All MS patients (Studies 1, 2, 4-6) who have resided in one of the 5 Canadian&#xD;
             provinces (British Columbia, Manitoba, Nova Scotia, Saskatchewan or Alberta) over the&#xD;
             study period as identified using a validated case definition of MS that will be&#xD;
             applied to health administrative data (≥ 3 records related to MS coded during&#xD;
             physician or hospital visits, or prescription filled for a MS-specific DMDs).&#xD;
&#xD;
          -  Subjects require 1 year of residency in a province before study entry to enable&#xD;
             sufficient data to facilitate covariate creation, e.g. comorbidity, and to identify&#xD;
             those with prior DMD use.&#xD;
&#xD;
          -  All adults who visited a MS clinic in British Columbia, Manitoba or Nova Scotia (Study&#xD;
             3), were diagnosed with MS and had a relapsing-onset disease course and at least one&#xD;
             EDSS score of 6.5 or less, recorded on or after: January 1st 1996 (British Columbia)&#xD;
             or April 1st 1996 (Manitoba) or January 1st 1998 (Nova Scotia).&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Helen Tremlett, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of British Columbia</affiliation>
  </overall_official>
  <verification_date>July 2020</verification_date>
  <study_first_submitted>July 3, 2020</study_first_submitted>
  <study_first_submitted_qc>July 10, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 16, 2020</study_first_posted>
  <last_update_submitted>July 10, 2020</last_update_submitted>
  <last_update_submitted_qc>July 10, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">July 16, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of British Columbia</investigator_affiliation>
    <investigator_full_name>Helen Tremlett</investigator_full_name>
    <investigator_title>Professor, Canada Research Chair in Neuroepidemiology and Multiple Sclerosis</investigator_title>
  </responsible_party>
  <keyword>disease-modifying drugs</keyword>
  <keyword>health administrative data</keyword>
  <keyword>population-based</keyword>
  <keyword>Canada</keyword>
  <keyword>cohort studies</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>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
    <ipd_description>The data that were used for this study reside on a limited access secure research environment and for legal and ethical reasons, the data cannot leave this secure research environment. However, researchers can apply to access the health administrative data held within each province.</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/NCT04472975
org study id: H18--00407
secondary id: CIHR PJT-156363
secondary id: CIHR FDN-159934
nct id: NCT04472975
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
The goal of our research is to find out how safe and effective the drugs used to treat
      multiple sclerosis (MS) are when used in the everyday, real world. To achieve these study
      goals, we have two main study Themes. The first Theme focuses on how effective the MS drugs
      are. We will examine whether the MS drugs can extend life expectancy or prolong a person's
      ability to stay mobile and walk. We will also look at whether the MS drugs have a beneficial
      effect on reducing the number of times a person with MS is admitted to a hospital or visits a
      physician. The second Theme focuses on side effects, including whether the MS drugs are
      associated with harmful effects, such as cancer, stroke or depression. We will be able to
      compare the different MS drugs to each other. Also, we will see if men and women or people of
      different ages and with other illnesses (such as having both MS and diabetes) respond to the
      MS drugs differently. Our findings will help people with MS and their physicians when trying
      to make decisions as to which MS drug might be best for them.
Study population:

      A validated case definition of multiple sclerosis (MS) will be applied to the health
      administrative data to identify all MS patients in 5 Canadian provinces (British Columbia,
      Manitoba, Nova Scotia, Saskatchewan and Alberta; Studies 1,2,4-6). Developed in Manitoba, the
      positive predictive value was 80.5% and negative predictive value (NPV) was 75.5% among a
      population of persons with ≥1 claim for any demyelinating disease. The NPV would be >99% at
      the general population level where more than 98% of individuals have no claims for
      demyelinating disease. The algorithm has been successfully applied in British Columbia, Nova
      Scotia and Saskatchewan.

      When MS-specific clinical data are used (British Columbia, Manitoba, Nova Scotia; Study 3),
      the diagnosis is neurologist confirmed, according to the prevailing international criteria.

      Study period:

      The earliest study start is Jan/1996 (the 1st full year that DMDs were available and the
      first year of available administrative and DMD-related data), and the latest study end is
      March 31, 2018; this represents >2 decades of drug and patient-related follow-up.

      Study entry:

      Most recent of 1-Jan-1996, an individual's 18th birthday, date of 1st MS-related claim or
      date of 1st MS clinic visit (when clinical data are accessed [Study 3]).

      Study end:

      Earliest of death, emigration from the respective province, last MS clinic visit (when
      clinical data are accessed [Study 3]), or 31-December-2017 (British Columbia, Manitoba, Nova
      Scotia, Alberta) or 31-March-2018 (Saskatchewan).

      DMD exposure:

      DMD use, as identified using prescription data. An individual's exposure status can change
      over time and will be dynamically classified as: 1) no DMD, 2) any DMD, then by generation:
      2a) any 1st or 2b) 2nd generation DMD. When possible, the individual drug classes will be
      explored (beta-interferon [as one class], glatiramer acetate, natalizumab, fingolimod,
      dimethyl fumarate, teriflunomide, alemtuzumab).

      Time perspective:

      Analyses of prospectively recorded health administrative, prescription and clinical data.
observational model: Cohort
time perspective: Other
measure: Study 1: All-cause hospitalizations
time frame: As recurrent events from study entry to study end, up to 22 years.
description: The outcome (all-cause hospitalizations) will be derived from the comprehensive hospital data, excluding pregnancy-related events, in 5 Canadian provinces (British Columbia, Manitoba, Nova Scotia, Saskatchewan and Alberta).
measure: Study 2: All-cause mortality
time frame: Measured using Cox proportional hazards models (time from study entry to death), up to 22 years.
description: The outcome (all-cause mortality) will be derived from the province-wide death data (e.g., Vital Statistics or the equivalent) in 5 Canadian provinces (British Columbia, Manitoba, Nova Scotia, Saskatchewan and Alberta).
measure: Study 3: Change in disability (Expanded Disability Status Scale [EDSS]) over time
time frame: Assessed using mixed effects model from study entry to study end, up to 22 years.
description: The outcomes (change in EDSS) will be derived from the MS clinical data in 3 Canadian provinces (British Columbia, Manitoba and Nova Scotia).
measure: Study 1: Physician consultation rates (overall and by physician specialty)
time frame: Overall numbers of physician consultations will be measured from study entry to study end, up to 22 years of follow-up.
description: The outcome (physician consultation) will be derived from the physician data, excluding pregnancy-related events, in 5 Canadian provinces (British Columbia, Manitoba, Nova Scotia, Saskatchewan and Alberta).
measure: Study 3: MS disability, measured using the Expanded Disability Status Scale (EDSS) and assessed as time to sustained EDSS 6
time frame: Measured using Cox proportional hazards models (time from study entry to sustained EDSS 6 confirmed after at least 6 months with no subsequent improvement), up to 22 years of follow-up.
description: The outcome (sustained EDSS 6) will be derived from the MS clinical data in 3 Canadian provinces (British Columbia, Manitoba and Nova Scotia).
measure: Study 3: Sustained EDSS 4
time frame: Measured using Cox proportional hazards models (time from study entry to sustained EDSS 4), up to 22 years of follow-up.
description: The outcomes (sustained EDSS 4) will be derived from the MS clinical data in 3 Canadian provinces (British Columbia, Manitoba and Nova Scotia).
measure: Study 4: Explore the modifying effects
time frame: From study entry to study end, up to 22 years of follow-up.
description: Effects of sex, age, comorbidity and DMD treatment duration on outcomes (all-cause hospitalizations, physician consultation rates, all-cause mortality, changes in EDSS) will be assessed.
measure: Study 5: Potential incident adverse events
time frame: Time from study entry to the incident adverse event of interest will be assessed using Cox proportional hazards with time-varying DMD exposure, up to 22 years of follow-up.
description: 'Incident' event defined as not present in the year before DMD initiation. The outcomes (incident adverse events) will be identified using physician and hospital claims, coded using International Classification of Diseases [ICD]-9/10 and prescriptions filled (by ATC levels), in 5 Canadian provinces (British Columbia, Manitoba, Nova Scotia, Saskatchewan and Alberta). An additional, data mining, discovery approach will assess the associations between exposure and adverse events using unsupervised machine learning techniques. Cases of PML will be described.
measure: Study 6: Characteristics associated with risk of adverse events
time frame: From study entry to study end, up to 22 years of follow-up.
description: Examine demographic and clinical characteristics associated with risk of adverse events, including sex, age, comorbidity and DMD treatment duration.
arm group label: Multiple sclerosis (MS) cohort
description: Individuals with multiple sclerosis without any exposure to disease-mofidying drugs (DMDs) and with exposure to one or more DMDs.
intervention type: Drug
intervention name: Exposure to one or more disease-modifying drug(s)(DMDs) used to treat MS
description: Individuals with MS exposed to one or more DMDs (beta-interferon, glatiramer acetate, natalizumab, fingolimod, dimethyl fumarate, teriflunomide, alemtuzumab, daclizumab or ocrelizumab; regardless of dose, frequency or duration of treatment) between 1st January 1996 and 31st March 2018 in five Canadian provinces.
arm group label: Multiple sclerosis (MS) cohort
study pop: 
sampling method: Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: Accepts Healthy Volunteers
last name: Helen Tremlett, PhD
role: Principal Investigator
affiliation: University of British Columbia
responsible party type: Principal Investigator
investigator affiliation: University of British Columbia
investigator full name: Helen Tremlett
investigator title: Professor, Canada Research Chair in Neuroepidemiology and Multiple Sclerosis
mesh term: Multiple Sclerosis
mesh term: Sclerosis
sharing ipd: No
ipd description: The data that were used for this study reside on a limited access secure research environment and for legal and ethical reasons, the data cannot leave this secure research environment. However, researchers can apply to access the health administrative data held within each province.