<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/NCT03802188</url>
  </required_header>
  <id_info>
    <org_study_id>MP-37-2019-4340</org_study_id>
    <nct_id>NCT03802188</nct_id>
  </id_info>
  <brief_title>Hydroxychloroquine in Systemic Lupus Erythematosus</brief_title>
  <official_title>Hydroxychloroquine Exposure in Systemic Lupus Erythematosus (SLE)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>McGill University Health Centre/Research Institute of the McGill University Health Centre</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Laval University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of British Columbia</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Calgary</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Dalhousie University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Manitoba</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Toronto</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Alberta</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>McGill University Health Centre/Research Institute of the McGill University Health Centre</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>
      A Systemic lupus erythematosus, SLE is disease in which immune system is over-active causing&#xD;
      inflammation in joints skin or any organ system. There are many areas where better approaches&#xD;
      in SLE could improve outcomes. One example relates to hydroxychloroquine (HCQ) key drug which&#xD;
      can reduce risk of serious disease flares. There are increasing concerns about eye damage&#xD;
      main side effect with long-term use of HCQ. At present investigators cannot precisely predict&#xD;
      which SLE patient is most likely to flare once HCQ is tapered. It is not clear what drives&#xD;
      risk of eye damage. Investigators' study will fill these knowledge gaps. Investigators'&#xD;
      hypothesis is that baseline demographic and clinical factors are associated with risk of SLE&#xD;
      flare after HCQ taper/discontinuation and with risk of retinal toxicity in all HCQ exposed&#xD;
      patients. Research will link and analyze data on 3700 SLE patients across Canada.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      B OBJECTIVES B1 To evaluate in SLE patients who lower but do not discontinue HCQ factors&#xD;
      associated with flare (significant increase in disease activity, augmentation of therapy or&#xD;
      hospitalization for SLE).&#xD;
&#xD;
      B2 To determine in SLE patients who discontinue HCQ factors associated with flare&#xD;
      (significant increase in disease activity, therapy augmentation or hospitalization for SLE).&#xD;
&#xD;
      B3 To evaluate temporal relationship between HCQ use and retinal toxicity in SLE patients and&#xD;
      how this may be associated with demographic and clinical factors.&#xD;
&#xD;
      B4 To assess SLE patient preferences for HCQ therapy and how preferences are associated with&#xD;
      demographic and clinical factors.&#xD;
&#xD;
      B5 To evaluate temporal relationship between antimalarial use and other forms of toxicity in&#xD;
      SLE patients and how this may be associated with demographic and clinical factors.&#xD;
&#xD;
      Team members have prospectively followed cohorts &gt; 3700 adult SLE patients (90% HCQ exposed)&#xD;
      with collected and harmonized data on demographics and clinical factors. Team members&#xD;
      (Bernatsky Abrahamowicz Fortin Hazlewood) are founding members of CAN-AIM CIHR-funded Drug&#xD;
      Safety and Effectiveness Network team.&#xD;
&#xD;
      Members have history of working with patients as research partners (Bartlett Li Bernatsky&#xD;
      Fortin Hazlewood). Investigators' ties to stakeholders including patient research partners&#xD;
      and Lupus Canada facilitates knowledge translation.&#xD;
&#xD;
      METHODS C1 Cohorts: Investigators will use existing data on adult SLE patients enrolled into&#xD;
      study cohorts in Montreal Quebec Halifax Winnipeg Calgary and Toronto.&#xD;
&#xD;
      Investigators are members of national (Canadian Network for Improved Outcomes in SLE CaNIOS)&#xD;
      and/or international (Systemic Lupus International Collaborating Clinics SLICC) research&#xD;
      networks. CaNIOS and SLICC have worked decades on harmonized approach to&#xD;
      prospectively-collected. Cohorts enroll unselected patients when they present to clinic. At&#xD;
      annual assessments data are collected on drugs disease activity organ damage etc C2.1 Patient&#xD;
      selection for Objective 1: At baseline and follow up visits records are made of patient HCQ&#xD;
      doses. Starting with first visit with HCQ exposure investigators will determine how many&#xD;
      patients are recorded as receiving lower dose or discontinuing HCQ at follow-up visit.&#xD;
      Patients identified as having lowered HCQ dose will form sub-cohort for time-to-event&#xD;
      (survival) analyses. Investigators will evaluate only first-ever lowering of HCQ. Analysis&#xD;
      will evaluate patients from time zero (annual visit at which lower HCQ dose was recorded) to&#xD;
      assess combined outcome of earliest of a) increase in SLEDAI-2K of at least 4 points and/or&#xD;
      b) hospitalization for SLE and/or c) augmented SLE therapy defined as increase in HCQ or new&#xD;
      start or increase in corticosteroids or other immunosuppressant. In addition to accepted&#xD;
      minimal clinically significant SLEDAI-2K change investigators include drug changes and&#xD;
      SLE-related hospitalizations.&#xD;
&#xD;
      Patients studied in Objective 1 will be right censored if HCQ is discontinued completely;&#xD;
      these will enter into analyses for Objective 2. Otherwise patients will be followed until&#xD;
      outcome of interest or end of study.&#xD;
&#xD;
      C2.3 Subject selection for Objective 2 Analyses will be similarly conducted but time zero&#xD;
      will begin when individual discontinues HCQ. Objective 1 and 2 analyses conducted separately;&#xD;
      patients who have HCQ dose lowered but then discontinued will be in analyses for Objective 1&#xD;
      up to point of discontinuation then patients will be right censored for Objective 1. Subjects&#xD;
      are able to contribute data (from the point of HCQ discontinuation) to analyses for Objective&#xD;
      2. Patient can contribute to analyses for one or both objectives and contributing to&#xD;
      Objective 3. If not right-censored patients will be followed until outcome of interest or end&#xD;
      of study.&#xD;
&#xD;
      C2.3 Subject selection for Objective 3 Outcome is retinal toxicity assessed in HCQ-exposed&#xD;
      patients from time of first visit with HCQ exposure up to time of retinal toxicity&#xD;
      documentation or end of study for patients without outcome. Exposure to CQ (relatively&#xD;
      uncommon drug exposure) is also risk factor for retinal toxicity but essentially patients&#xD;
      exposed to CQ will have prior exposure to HCQ.&#xD;
&#xD;
      C3 Demographic and clinical factors C3.1 Variables assessed include sex age at SLE onset and&#xD;
      race/ethnicity. Analyses adjusted for education as education can alter adherence.&#xD;
&#xD;
      C3.2 Clinical factors for multivariable analyses include smoking BMI baseline disease&#xD;
      activity malignancy data and renal damage. Baseline refers to time zero. Renal damage is&#xD;
      captured with SLICC Damage Index measuring accumulated damage. Baseline disease activity&#xD;
      measured by internationally used SLEDAI-2K reliable validated widely used global score&#xD;
      index.Investigators will model time-varying drug exposures with step-up approach initially&#xD;
      with baseline use ie current, recent, ever or total past dose. Investigators use&#xD;
      sophisticated and novel weighted cumulative dose modelling to flexibly represent exposures&#xD;
      accumulated by individual subjects up to given time-point corresponding to each risk set for&#xD;
      time-to-event analyses. In multivariable analyses approach will allow investigators to&#xD;
      explore how risk of retinal toxicity may depend on details of past HCQ exposure including not&#xD;
      only total cumulative dose but temporal pattern of doses at various time in past with&#xD;
      differential weights for early versus later exposures.&#xD;
&#xD;
      C4 Outcome assessment: SLEDAI-2K and drugs are recorded. SLICC Damage Index has item for&#xD;
      retinal damage and updated yearly.&#xD;
&#xD;
      C5 Model development: Investigators will perform multivariable time-to-event analyses in&#xD;
      patients who lower or discontinue HCQ. Data for outcomes are available longitudinally at&#xD;
      annual visit with actual dates only available for addition/increase in corticosteroid or SLE&#xD;
      hospitalization. For other outcomes investigators will deal with interval-censored data&#xD;
      familiar issue in pharmacoepidemiology.&#xD;
&#xD;
      Models include baseline demographics education BMI SLE duration SLEDAI-2K renal damage and&#xD;
      medications. Simplistic survival analyses often assume linear effects of continuous&#xD;
      covariates and impose conventional proportional hazards (PH) assumptions; investigators know&#xD;
      that prognostic factors may have time-dependent and/or nonlinear effects that violate&#xD;
      assumptions. Investigators will account for this. Methods account for possible changes in&#xD;
      hazard ratio over time (violation of the PH) and allow estimation of relative risks (hazard&#xD;
      ratios) and actual probabilities of event of interest occurring.&#xD;
&#xD;
      Similar approach will be used for Objective 3 in time-to-event analyses of retinal toxicity&#xD;
      in patients exposed to HCQ.&#xD;
&#xD;
      Competing risks occur when subjects can experience one or more events that may compete with&#xD;
      outcome of interest and hinder observation of event of interest or modify chances for event&#xD;
      to occur. In sensitivity analyses investigators use competing risks models to simultaneously&#xD;
      estimate associations between HCQ exposures and hazards of competing event.&#xD;
&#xD;
      D POWER/SAMPLE CALCULATIONS D1 Power calculations for multivariate models Combined cohorts&#xD;
      include over 3300 patients have exposed to HCQ. Patients have had lowering of dose 45% or&#xD;
      discontinuation of HCQ during their follow-up. Power calculations are based on available data&#xD;
      suggesting that 45%-60% of SLE patients may flare over ten years of follow-up.&#xD;
&#xD;
      For baseline SLEDAI-2K assuming 35% of patients score less than 3 investigators would have&#xD;
      90% power to detect unadjusted HR of 1.30 and adjusted HR of 1.37 for variable. Assuming 20%&#xD;
      of patients have renal damage investigators will have 90% power to detect an unadjusted HR of&#xD;
      1.37 and an adjusted HR of 1.45 for variable.&#xD;
&#xD;
      E KNOWLEDGE TRANSLATION activities are informed by history of partnerships between&#xD;
      investigators and knowledge-users directed by Dr. Linda Li Canada Research Chair in&#xD;
      Patient-Oriented KT and Director of Knowledge Translation Research Program at UBC's Arthritis&#xD;
      Research Centre of Canada.&#xD;
&#xD;
      E1 Integrated KT Proposal developed in consultation patients from Lupus Canada patients&#xD;
      Canadian Alliance of Patients with Arthritis (CAPA) and Singer Family Fund for Lupus&#xD;
      Research. Wendy Singer (providing expertise health information dissemination and provides&#xD;
      insight of SLE patient who has been affected by HCQ-induced retinal toxicity) will assist&#xD;
      with educational tool developments. Co-PI Dr. Bartlett has over decade of work with patient&#xD;
      partners through OMERACT (Outcome Measures in Rheumatology) and other organizations to help&#xD;
      disseminate findings patient communities.&#xD;
&#xD;
      E2 Dissemination via MyLupusGuide: Data on HCQ from current study will be incorporated into&#xD;
      MyLupusGuide web-based patient-centred health-management tool developed by Dr. Fortin in&#xD;
      partnership with Jack Digital Productions CaNIOS Lupus Canada. Development&#xD;
      validation/dissemination of current version funded by CIHR operating and dissemination&#xD;
      grants.&#xD;
&#xD;
      E3 Clinicians and professional groups: Dr. Bernatsky is member of CRA Therapeutics Committee&#xD;
      which advises CRA on policies related to drug use for rheumatic diseases. Group monitors&#xD;
      information about adverse events related to drugs used in rheumatology including HCQ.&#xD;
      Investigators submit abstracts to scientific meetings (American College of Rheumatology,&#xD;
      European League Against Rheumatism, CRA meeting). Investigators will seek feedback on&#xD;
      feasibility/approaches to integrate MyLupusGuide as gold standard for patient education tool&#xD;
      concerning HCQ.&#xD;
&#xD;
      E4 Informing future guidelines: Team member Dr. S. Keeling has already produced Canadian SLE&#xD;
      care guidelines (funded by the CIHR and endorsed by the CRA and CaNIOS) . In 2019, again&#xD;
      mandated by these groups, Dr. Keeling will spearhead guidelines for SLE therapies.&#xD;
&#xD;
      E5 Health agency stakeholders: Investigators have connections Drug Safety and Effectiveness&#xD;
      Network (DSEN) Health Canada's Marketed Health Product Directorate and Canadian Agency for&#xD;
      Drugs and Technologies in Health (CADTH). Drs. Abrahamowicz and Bernatsky are co-leads&#xD;
      DSEN-funded team.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">May 9, 2018</start_date>
  <completion_date type="Anticipated">March 31, 2025</completion_date>
  <primary_completion_date type="Anticipated">March 31, 2024</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>Retrospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Proportion of SLE flares with decrease or discontinuation of HCQ</measure>
    <time_frame>Through study completion, an average of 1 year</time_frame>
    <description>In patients exposed to HCQ, presence or absence of SLE flare will be measure with SLEDAI-2K. The SLEDAI-2K is a reliable, validated, widely used global score index, consisting of 24 weighted clinical and laboratory variables of nine organ systems. The scores of descriptors range from 1 to 8, and the total score of the SLEDAI-2K is the sum of all 24 descriptor scores. An increase of 4 points or more has been validated as indicating a clinically significant increase in SLE disease activity.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Proportion of participants hospitalized with decrease or discontinuation of HCQ</measure>
    <time_frame>Through study completion, an average of 1 year</time_frame>
    <description>In patients exposed to HCQ, presence or absence of hospitalization in cohort data will be measured in relation to HCQ dosage.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportion of SLE flares relative to augmented SLE therapy</measure>
    <time_frame>Through study completion, an average of 1 year</time_frame>
    <description>Comparison of flares in SLE patients measured with SLEDAI-2K and augmented SLE therapy defined as an increase in HCQ or a new start or increase in corticosteroids (i.e. prednisone, methylprednisolone) or other immunosuppressant (azathioprine, mycophenolate, methotrexate, cyclophosphamide, belimumab, rituximab, chloroquine).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Correlation of retinal toxicity and exposure to HCQ and retinal toxicity</measure>
    <time_frame>Through study completion, an average of 1 year</time_frame>
    <description>Renal damage is captured with the SLICC Damage Index, measuring accumulated damage since SLE onset. This validated index captures irreversible change in an organ or system (that has been present for at least 6 months). The renal item scores 1 for sustained heavy proteinuria, 2 for reduced glomerular filtration rate, and 3 for end-stage renal failure.</description>
  </secondary_outcome>
  <number_of_groups>2</number_of_groups>
  <enrollment type="Anticipated">3700</enrollment>
  <condition>Systemic Lupus Erythematosus</condition>
  <arm_group>
    <arm_group_label>SLE Cohort</arm_group_label>
    <description>Investigators will use existing data collected on adult SLE patients enrolled into respective study cohorts from participating centers.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Qualitative group</arm_group_label>
    <description>For the interviews, patients with SLE who are currently or have taken Hydroxychloroquine will be recruited from rheumatology clinics in Calgary and Montreal to participate in an interview and/or participate in a brief survey.</description>
  </arm_group>
  <eligibility>
    <study_pop>
      <textblock>
        Investigators will use existing data collected on adult SLE patients who have been&#xD;
        consecutively enrolled into the respective study cohorts of the participating researchers&#xD;
        in Montreal , Quebec City, Halifax, Winnipeg, Calgary, and Toronto. The total exceeds 3,300&#xD;
        SLE patients who have been exposed to HCQ.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Must be 18 years of age or over&#xD;
&#xD;
          -  Must be diagnosed with Systemic Lupus Erythematosus (SLE)&#xD;
&#xD;
          -  Must be exposed to hydroxychloroquine&#xD;
&#xD;
          -  Must be enrolled at participating sites&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Under 18 years of age&#xD;
&#xD;
          -  Not diagnosed with SLE&#xD;
&#xD;
          -  Not exposed to hydroxychloroquine&#xD;
&#xD;
          -  Not enrolled at participating sites&#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>Sasha Bernatsky, MD/PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Research Institute of the McGill University Health Centre</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Jennifer Lee</last_name>
    <phone>514-934-1934</phone>
    <phone_ext>44830</phone_ext>
    <email>Jennifer.Lee@rimuhc.ca</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Autumn Neville</last_name>
    <phone>514-934-1934</phone>
    <phone_ext>44844</phone_ext>
    <email>autumn.neville@rimuch.ca</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Research Institute of the McGill University Health Centre</name>
      <address>
        <city>Montreal</city>
        <state>Quebec</state>
        <zip>H3H 2R9</zip>
        <country>Canada</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location_countries>
    <country>Canada</country>
  </location_countries>
  <link>
    <url>https://www.aao.org/clinical-statement/revised-recommendations-on-screening-chloroquine-h</url>
    <description>AAO Quality of Care Secretariat, Hoskins Center for Quality Eye Care Recommendations on Screening for Chloroquine and Hydroxychloroquine Retinopathy Ophthalmology</description>
  </link>
  <link>
    <url>http://canaim.ca/about-us</url>
    <description>CAnadian Network for Advanced Interdisciplinary Methods for comparative effectiveness research</description>
  </link>
  <link>
    <url>http://www.jrheum.org/content/42/12/2318.full.pdf</url>
    <description>Lack of Interferon and Proinflammatory Cyto/chemokines in Serologically Active Clinically Quiescent SLE.</description>
  </link>
  <link>
    <url>https://grants.nih.gov/grants/guide/rfa-files/RFA-OD-19-012.html</url>
    <description>Racial and Ethnic Categories and Definitions</description>
  </link>
  <link>
    <url>https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4012002/</url>
    <description>Purposeful sampling for qualitative data collection and analysis in mixed method implementation research. Administration and policy in mental health</description>
  </link>
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  <verification_date>January 2019</verification_date>
  <study_first_submitted>December 6, 2018</study_first_submitted>
  <study_first_submitted_qc>January 10, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 14, 2019</study_first_posted>
  <last_update_submitted>January 10, 2019</last_update_submitted>
  <last_update_submitted_qc>January 10, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">January 14, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>McGill University Health Centre/Research Institute of the McGill University Health Centre</investigator_affiliation>
    <investigator_full_name>Dr. Sasha Bernatsky</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <keyword>Retinal toxicity</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Lupus Erythematosus, Systemic</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </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/NCT03802188
org study id: MP-37-2019-4340
nct id: NCT03802188
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
A Systemic lupus erythematosus, SLE is disease in which immune system is over-active causing
      inflammation in joints skin or any organ system. There are many areas where better approaches
      in SLE could improve outcomes. One example relates to hydroxychloroquine (HCQ) key drug which
      can reduce risk of serious disease flares. There are increasing concerns about eye damage
      main side effect with long-term use of HCQ. At present investigators cannot precisely predict
      which SLE patient is most likely to flare once HCQ is tapered. It is not clear what drives
      risk of eye damage. Investigators' study will fill these knowledge gaps. Investigators'
      hypothesis is that baseline demographic and clinical factors are associated with risk of SLE
      flare after HCQ taper/discontinuation and with risk of retinal toxicity in all HCQ exposed
      patients. Research will link and analyze data on 3700 SLE patients across Canada.
B OBJECTIVES B1 To evaluate in SLE patients who lower but do not discontinue HCQ factors
      associated with flare (significant increase in disease activity, augmentation of therapy or
      hospitalization for SLE).

      B2 To determine in SLE patients who discontinue HCQ factors associated with flare
      (significant increase in disease activity, therapy augmentation or hospitalization for SLE).

      B3 To evaluate temporal relationship between HCQ use and retinal toxicity in SLE patients and
      how this may be associated with demographic and clinical factors.

      B4 To assess SLE patient preferences for HCQ therapy and how preferences are associated with
      demographic and clinical factors.

      B5 To evaluate temporal relationship between antimalarial use and other forms of toxicity in
      SLE patients and how this may be associated with demographic and clinical factors.

      Team members have prospectively followed cohorts > 3700 adult SLE patients (90% HCQ exposed)
      with collected and harmonized data on demographics and clinical factors. Team members
      (Bernatsky Abrahamowicz Fortin Hazlewood) are founding members of CAN-AIM CIHR-funded Drug
      Safety and Effectiveness Network team.

      Members have history of working with patients as research partners (Bartlett Li Bernatsky
      Fortin Hazlewood). Investigators' ties to stakeholders including patient research partners
      and Lupus Canada facilitates knowledge translation.

      METHODS C1 Cohorts: Investigators will use existing data on adult SLE patients enrolled into
      study cohorts in Montreal Quebec Halifax Winnipeg Calgary and Toronto.

      Investigators are members of national (Canadian Network for Improved Outcomes in SLE CaNIOS)
      and/or international (Systemic Lupus International Collaborating Clinics SLICC) research
      networks. CaNIOS and SLICC have worked decades on harmonized approach to
      prospectively-collected. Cohorts enroll unselected patients when they present to clinic. At
      annual assessments data are collected on drugs disease activity organ damage etc C2.1 Patient
      selection for Objective 1: At baseline and follow up visits records are made of patient HCQ
      doses. Starting with first visit with HCQ exposure investigators will determine how many
      patients are recorded as receiving lower dose or discontinuing HCQ at follow-up visit.
      Patients identified as having lowered HCQ dose will form sub-cohort for time-to-event
      (survival) analyses. Investigators will evaluate only first-ever lowering of HCQ. Analysis
      will evaluate patients from time zero (annual visit at which lower HCQ dose was recorded) to
      assess combined outcome of earliest of a) increase in SLEDAI-2K of at least 4 points and/or
      b) hospitalization for SLE and/or c) augmented SLE therapy defined as increase in HCQ or new
      start or increase in corticosteroids or other immunosuppressant. In addition to accepted
      minimal clinically significant SLEDAI-2K change investigators include drug changes and
      SLE-related hospitalizations.

      Patients studied in Objective 1 will be right censored if HCQ is discontinued completely;
      these will enter into analyses for Objective 2. Otherwise patients will be followed until
      outcome of interest or end of study.

      C2.3 Subject selection for Objective 2 Analyses will be similarly conducted but time zero
      will begin when individual discontinues HCQ. Objective 1 and 2 analyses conducted separately;
      patients who have HCQ dose lowered but then discontinued will be in analyses for Objective 1
      up to point of discontinuation then patients will be right censored for Objective 1. Subjects
      are able to contribute data (from the point of HCQ discontinuation) to analyses for Objective
      2. Patient can contribute to analyses for one or both objectives and contributing to
      Objective 3. If not right-censored patients will be followed until outcome of interest or end
      of study.

      C2.3 Subject selection for Objective 3 Outcome is retinal toxicity assessed in HCQ-exposed
      patients from time of first visit with HCQ exposure up to time of retinal toxicity
      documentation or end of study for patients without outcome. Exposure to CQ (relatively
      uncommon drug exposure) is also risk factor for retinal toxicity but essentially patients
      exposed to CQ will have prior exposure to HCQ.

      C3 Demographic and clinical factors C3.1 Variables assessed include sex age at SLE onset and
      race/ethnicity. Analyses adjusted for education as education can alter adherence.

      C3.2 Clinical factors for multivariable analyses include smoking BMI baseline disease
      activity malignancy data and renal damage. Baseline refers to time zero. Renal damage is
      captured with SLICC Damage Index measuring accumulated damage. Baseline disease activity
      measured by internationally used SLEDAI-2K reliable validated widely used global score
      index.Investigators will model time-varying drug exposures with step-up approach initially
      with baseline use ie current, recent, ever or total past dose. Investigators use
      sophisticated and novel weighted cumulative dose modelling to flexibly represent exposures
      accumulated by individual subjects up to given time-point corresponding to each risk set for
      time-to-event analyses. In multivariable analyses approach will allow investigators to
      explore how risk of retinal toxicity may depend on details of past HCQ exposure including not
      only total cumulative dose but temporal pattern of doses at various time in past with
      differential weights for early versus later exposures.

      C4 Outcome assessment: SLEDAI-2K and drugs are recorded. SLICC Damage Index has item for
      retinal damage and updated yearly.

      C5 Model development: Investigators will perform multivariable time-to-event analyses in
      patients who lower or discontinue HCQ. Data for outcomes are available longitudinally at
      annual visit with actual dates only available for addition/increase in corticosteroid or SLE
      hospitalization. For other outcomes investigators will deal with interval-censored data
      familiar issue in pharmacoepidemiology.

      Models include baseline demographics education BMI SLE duration SLEDAI-2K renal damage and
      medications. Simplistic survival analyses often assume linear effects of continuous
      covariates and impose conventional proportional hazards (PH) assumptions; investigators know
      that prognostic factors may have time-dependent and/or nonlinear effects that violate
      assumptions. Investigators will account for this. Methods account for possible changes in
      hazard ratio over time (violation of the PH) and allow estimation of relative risks (hazard
      ratios) and actual probabilities of event of interest occurring.

      Similar approach will be used for Objective 3 in time-to-event analyses of retinal toxicity
      in patients exposed to HCQ.

      Competing risks occur when subjects can experience one or more events that may compete with
      outcome of interest and hinder observation of event of interest or modify chances for event
      to occur. In sensitivity analyses investigators use competing risks models to simultaneously
      estimate associations between HCQ exposures and hazards of competing event.

      D POWER/SAMPLE CALCULATIONS D1 Power calculations for multivariate models Combined cohorts
      include over 3300 patients have exposed to HCQ. Patients have had lowering of dose 45% or
      discontinuation of HCQ during their follow-up. Power calculations are based on available data
      suggesting that 45%-60% of SLE patients may flare over ten years of follow-up.

      For baseline SLEDAI-2K assuming 35% of patients score less than 3 investigators would have
      90% power to detect unadjusted HR of 1.30 and adjusted HR of 1.37 for variable. Assuming 20%
      of patients have renal damage investigators will have 90% power to detect an unadjusted HR of
      1.37 and an adjusted HR of 1.45 for variable.

      E KNOWLEDGE TRANSLATION activities are informed by history of partnerships between
      investigators and knowledge-users directed by Dr. Linda Li Canada Research Chair in
      Patient-Oriented KT and Director of Knowledge Translation Research Program at UBC's Arthritis
      Research Centre of Canada.

      E1 Integrated KT Proposal developed in consultation patients from Lupus Canada patients
      Canadian Alliance of Patients with Arthritis (CAPA) and Singer Family Fund for Lupus
      Research. Wendy Singer (providing expertise health information dissemination and provides
      insight of SLE patient who has been affected by HCQ-induced retinal toxicity) will assist
      with educational tool developments. Co-PI Dr. Bartlett has over decade of work with patient
      partners through OMERACT (Outcome Measures in Rheumatology) and other organizations to help
      disseminate findings patient communities.

      E2 Dissemination via MyLupusGuide: Data on HCQ from current study will be incorporated into
      MyLupusGuide web-based patient-centred health-management tool developed by Dr. Fortin in
      partnership with Jack Digital Productions CaNIOS Lupus Canada. Development
      validation/dissemination of current version funded by CIHR operating and dissemination
      grants.

      E3 Clinicians and professional groups: Dr. Bernatsky is member of CRA Therapeutics Committee
      which advises CRA on policies related to drug use for rheumatic diseases. Group monitors
      information about adverse events related to drugs used in rheumatology including HCQ.
      Investigators submit abstracts to scientific meetings (American College of Rheumatology,
      European League Against Rheumatism, CRA meeting). Investigators will seek feedback on
      feasibility/approaches to integrate MyLupusGuide as gold standard for patient education tool
      concerning HCQ.

      E4 Informing future guidelines: Team member Dr. S. Keeling has already produced Canadian SLE
      care guidelines (funded by the CIHR and endorsed by the CRA and CaNIOS) . In 2019, again
      mandated by these groups, Dr. Keeling will spearhead guidelines for SLE therapies.

      E5 Health agency stakeholders: Investigators have connections Drug Safety and Effectiveness
      Network (DSEN) Health Canada's Marketed Health Product Directorate and Canadian Agency for
      Drugs and Technologies in Health (CADTH). Drs. Abrahamowicz and Bernatsky are co-leads
      DSEN-funded team.
observational model: Cohort
time perspective: Retrospective
measure: Proportion of SLE flares with decrease or discontinuation of HCQ
time frame: Through study completion, an average of 1 year
description: In patients exposed to HCQ, presence or absence of SLE flare will be measure with SLEDAI-2K. The SLEDAI-2K is a reliable, validated, widely used global score index, consisting of 24 weighted clinical and laboratory variables of nine organ systems. The scores of descriptors range from 1 to 8, and the total score of the SLEDAI-2K is the sum of all 24 descriptor scores. An increase of 4 points or more has been validated as indicating a clinically significant increase in SLE disease activity.
measure: Proportion of participants hospitalized with decrease or discontinuation of HCQ
time frame: Through study completion, an average of 1 year
description: In patients exposed to HCQ, presence or absence of hospitalization in cohort data will be measured in relation to HCQ dosage.
measure: Proportion of SLE flares relative to augmented SLE therapy
time frame: Through study completion, an average of 1 year
description: Comparison of flares in SLE patients measured with SLEDAI-2K and augmented SLE therapy defined as an increase in HCQ or a new start or increase in corticosteroids (i.e. prednisone, methylprednisolone) or other immunosuppressant (azathioprine, mycophenolate, methotrexate, cyclophosphamide, belimumab, rituximab, chloroquine).
measure: Correlation of retinal toxicity and exposure to HCQ and retinal toxicity
time frame: Through study completion, an average of 1 year
description: Renal damage is captured with the SLICC Damage Index, measuring accumulated damage since SLE onset. This validated index captures irreversible change in an organ or system (that has been present for at least 6 months). The renal item scores 1 for sustained heavy proteinuria, 2 for reduced glomerular filtration rate, and 3 for end-stage renal failure.
arm group label: SLE Cohort
description: Investigators will use existing data collected on adult SLE patients enrolled into respective study cohorts from participating centers.
arm group label: Qualitative group
description: For the interviews, patients with SLE who are currently or have taken Hydroxychloroquine will be recruited from rheumatology clinics in Calgary and Montreal to participate in an interview and/or participate in a brief survey.
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Sasha Bernatsky, MD/PhD
role: Principal Investigator
affiliation: Research Institute of the McGill University Health Centre
last name: Jennifer Lee
phone: 514-934-1934
phone ext: 44830
email: Jennifer.Lee@rimuhc.ca
last name: Autumn Neville
phone: 514-934-1934
phone ext: 44844
email: autumn.neville@rimuch.ca
facility: 
status: Recruiting
country: Canada
url: https://www.aao.org/clinical-statement/revised-recommendations-on-screening-chloroquine-h
description: AAO Quality of Care Secretariat, Hoskins Center for Quality Eye Care Recommendations on Screening for Chloroquine and Hydroxychloroquine Retinopathy Ophthalmology
url: http://canaim.ca/about-us
description: CAnadian Network for Advanced Interdisciplinary Methods for comparative effectiveness research
url: http://www.jrheum.org/content/42/12/2318.full.pdf
description: Lack of Interferon and Proinflammatory Cyto/chemokines in Serologically Active Clinically Quiescent SLE.
url: https://grants.nih.gov/grants/guide/rfa-files/RFA-OD-19-012.html
description: Racial and Ethnic Categories and Definitions
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4012002/
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responsible party type: Principal Investigator
investigator affiliation: McGill University Health Centre/Research Institute of the McGill University Health Centre
investigator full name: Dr. Sasha Bernatsky
investigator title: Principal Investigator
mesh term: Lupus Erythematosus, Systemic
sharing ipd: No