<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/NCT04478526</url>
  </required_header>
  <id_info>
    <org_study_id>PSIY-604-18</org_study_id>
    <nct_id>NCT04478526</nct_id>
  </id_info>
  <brief_title>Efficacy of Online CBT for GAD Compared to Pharmaceutical Interventions</brief_title>
  <official_title>Determining the Efficacy of Online Cognitive Behavioural Therapy for Generalized Anxiety Disorder Compared to Pharmaceutical Interventions</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Queen's University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Online PsychoTherapy Clinic</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Queen's University</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>
      Generalized anxiety disorder (GAD) is an extremely prevalent and debilitating mental health&#xD;
      disorder. Currently, the gold standard treatment for GAD is cognitive behavioural therapy&#xD;
      (CBT) and/or pharmacotherapy. The most common medications used to treat GAD are selective&#xD;
      serotonin reuptake inhibitors (SSRIs) and selective norepinephrine reuptake inhibitors&#xD;
      (SNRIs). While CBT is a gold standard treatment for GAD, it is costly, time-consuming, and&#xD;
      often inaccessible. Fortunately, the electronic delivery of CBT (e-CBT) has emerged as a&#xD;
      promising solution to address these barriers. e-CBT has shown to offer comparable results to&#xD;
      in-person CBT while improving accessibility for patients and time efficiency for clinicians.&#xD;
      The following project aims to investigate the treatment efficacy of e-CBT compared to, and in&#xD;
      conjunction with pharmacotherapy for GAD. This study has been designed using a&#xD;
      quasi-experimental design to allow patients the freedom to choose which treatment modality&#xD;
      they would like to receive. Participants with a diagnosis of GAD will be enrolled in 1 of 3&#xD;
      possible treatment arms: e-CBT, medication, or combination. The e-CBT program will include a&#xD;
      12-week psychotherapy program delivered through the Online Psychotherapy Tool (OPTT), a&#xD;
      secure, cloud-based, digital mental health platform. The treatment efficacy of e-CBT will be&#xD;
      compared to the treatment efficacy of the medication arm and the combination arm.&#xD;
      Conclusions: If e-CBT is shown to either be comparable to medication or that the effects of&#xD;
      both treatments are augmented when used in tandem, these findings could have major&#xD;
      implications on the mental health care system. e-CBT is a more accessible, and affordable&#xD;
      treatment that could increase mental health care capacity by four-folds if proven viable.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Methodology Research Design. This study has been designed using a quasi-experimental design&#xD;
      to allow patients the freedom to choose which treatment modality they would like to&#xD;
      participate in. This research design aims to be naturalistic by mimicking the decisions made&#xD;
      by patients and physicians regarding course of treatment and type of pharmacotherapy&#xD;
      prescribed within mental health services across Ontario. The treatments provided within the&#xD;
      study also aim to replicate evidence-based best practice clinical guidelines for treatment of&#xD;
      GAD.&#xD;
&#xD;
      Research Participants. Patients will be referred to the study by primary care physicians&#xD;
      within Toronto and Kingston, Ontario. Patients will be referred to the Anxiety Outpatient&#xD;
      Clinic at the Hotel Dieu Hospital site of Kingston Health Sciences Centre or the Mood and&#xD;
      Anxiety Clinic within the Centre for Addiction and Mental Health (both sites herein referred&#xD;
      to as &quot;the clinic&quot;). Upon receiving a referral to the clinic, participants will be contacted&#xD;
      by the study's Research Coordinator and asked to indicate their interest (or lack thereof) in&#xD;
      the study. If interest is indicated and the study's inclusion criteria are met, the patient&#xD;
      will have a study intake appointment scheduled for the same day as their intake appointment&#xD;
      at the clinic. To be considered for inclusion within the study, patients must:&#xD;
&#xD;
        -  be 18 years of age or older&#xD;
&#xD;
        -  have consistent and reliable access to the internet&#xD;
&#xD;
        -  be diagnosed with GAD according to the Diagnostic and Statistical Manual of Mental&#xD;
           Disorders, 5th Edition (DSM-V) by a clinician&#xD;
&#xD;
        -  meet the criteria for GAD according to the GAD-7 Screener (GAD-7)&#xD;
&#xD;
        -  Be competent to consent to participate&#xD;
&#xD;
        -  Speak and read English Patients will be deemed ineligible for participation in the study&#xD;
           if they are in acute distress.&#xD;
&#xD;
      Allocation of Subjects between Arms of the Study. Subjects will be presented with all three&#xD;
      arms of the study within their study intake appointment by the Research Coordinator. After&#xD;
      obtaining informed consent, patients will meet with one of the study's psychiatrists during&#xD;
      their clinic intake appointment and discuss the recommended treatment plan. In collaboration&#xD;
      with the psychiatrist, patients will decide whether or not they would like to begin&#xD;
      pharmacotherapy and/or e-CBT treatment.&#xD;
&#xD;
      Criteria for Discontinuation. Patients' participation in the study will be discontinued if&#xD;
      they are found to be noncompliant to their treatment. This will be defined as stopping&#xD;
      medications all together or reportedly skipping more than two days in a row of medication.&#xD;
      Patients will be found noncompliant with e-CBT treatment if they miss more than two weeks of&#xD;
      e-CBT sessions or fail to complete weekly homework assignments. Patients' participation&#xD;
      within the study will also be halted if they are deemed to be in acute crisis by self-report&#xD;
      or the psychiatrist in charge of their care.&#xD;
&#xD;
      Study Protocol. After being referred to the study by a clinician uninvolved within the study,&#xD;
      patients will be contacted by the Research Coordinator to determine the patient's interest in&#xD;
      participating in the study. If interest is indicated, an intake appointment for the study&#xD;
      will be scheduled for the same date as the intake appointment to the clinic.&#xD;
&#xD;
      Intake appointment. Upon attending the intake appointment, the Research Coordinator will&#xD;
      explain all three arms of the study and review the study's letter of information. After&#xD;
      sufficient time has been provided to ensure the patient understands the study, informed&#xD;
      consent will be obtained by the Research Coordinator and the patient will complete the State&#xD;
      Trait Anxiety Inventory (STAI), a demographics questionnaire, Quality of Life Enjoyment and&#xD;
      Satisfaction Questionnaire - Short Form (Q-LES-QSF), GAD-7 and the 42-item Depression Anxiety&#xD;
      Stress Scales (DASS-42). Following the intake appointment, patients will, in collaboration&#xD;
      with their psychiatrist, decide on which treatment modalities they would like to participate&#xD;
      in (e-CBT and/or pharmacotherapy). Treatment will then proceed according to the arms below,&#xD;
      with patients participating in e-CBT and pharmacotherapy commencing both arms simultaneously&#xD;
      within their clinic intake appointment.&#xD;
&#xD;
      e-CBT. Weekly sessions of e-CBT through OPTT will consist of approximately 30 slides. Each&#xD;
      session is expected to last approximately 50 minutes. The content and format of each weekly&#xD;
      online session was designed to mirror live CBT. The slides will highlight a different topic&#xD;
      each week and include general information, an overview of skills and homework on that topic.&#xD;
      The homework included in each session will be submitted through OPTT and reviewed by the&#xD;
      clinicians with personalized feedback provided by clinicians within three days of submission.&#xD;
      Weekly homework submission for feedback will be mandatory before being eligible for the next&#xD;
      session. Biweekly GAD-7, DASS-42 and Q-LES-SF questionnaires will be completed through OPTT.&#xD;
      A second STAI will be completed in the final week of e-CBT treatment.&#xD;
&#xD;
      Pharmacotherapy. If patients chose to participate in the pharmacotherapy stream of treatment,&#xD;
      they will attend biweekly medication reconciliation appointments with their psychiatrist at&#xD;
      the clinic. If the patient is participating solely in the pharmacotherapy arm, they will&#xD;
      complete the biweekly GAD-7, DASS-42 and Q-LES-SF within each of their appointments. If the&#xD;
      patient is completing both pharmacotherapy and e-CBT, questionnaires will only be completed&#xD;
      through OPTT. Upon attending their clinic intake appointment, the patient's medication&#xD;
      history (including any current medications) will be collected and all medications prescribed&#xD;
      for GAD prior to the study will be switched to the medications suggested in the protocol and&#xD;
      if needed to be continued the dose will be unchanged 6 weeks prior to start of the study and&#xD;
      during the study. Within the patient's clinic intake appointment, they will commence&#xD;
      pharmacotherapy with the medication class decided according the &quot;starting medication&quot;&#xD;
      protocol below, which was developed in accordance with Canada's best practice guidelines for&#xD;
      the treatment of GAD. The pharmacotherapy protocol is summarized in Figure 1.&#xD;
&#xD;
      General 6-week protocol. At the patient's second appointment (2 weeks on the medication),&#xD;
      their medication will be maintained and optimized, regardless of whether or not a response is&#xD;
      reported. At the patient's third appointment (4 weeks on the medication), the medication will&#xD;
      be optimized if a partial response is reported or the medication will be switched according&#xD;
      to the &quot;medication switch protocol&quot; if no response is reported. Partial response will be&#xD;
      defined as an improvement of 20% or greater in their GAD-7 score compared to baseline. If the&#xD;
      medication is switched (the patient reports less than a 20% improvement in their GAD-7 score&#xD;
      compared to baseline), the 6-week protocol will recommence with the new medication. At the&#xD;
      patient's fourth appointment (6 weeks on the medication), their dosage will be optimized if&#xD;
      the patient is responding well to the medication and reports an improvement greater than 50%&#xD;
      if within the primary medication arm, or 20% if within the secondary medication arm, in their&#xD;
      GAD-7 score compared to baseline, the patient will remain on said medication for the&#xD;
      remainder of the 12-week study. If the patient does not report an improvement of more than&#xD;
      20% in their GAD-7 score compared to baseline, the patient's medication will be switched&#xD;
      according to the &quot;medication switch protocol&quot; and the 6-week protocol will recommence with&#xD;
      the new medication. If the patient is within the primary medication arm and reports a 20-50%&#xD;
      improvement in GAD symptoms compared to baseline after six weeks on the new medication, the&#xD;
      medication with be augmented with either olanzapine, risperidone or benzodiazepines.&#xD;
&#xD;
      Starting Medication. If the patient has never taken an SSRI or SNRI, the patient will&#xD;
      commence the primary medication arm. The two classes of medications within the primary arm&#xD;
      will be described to the patient and, with the recommendation of the prescribing&#xD;
      psychiatrist, the patient will begin either an SSRI (sertraline or escitalopram) or&#xD;
      pregabalin/an SNRI (duloxetine or venlafaxine).&#xD;
&#xD;
      If, prior to the beginning of the study, the patient has been deemed unresponsive to either&#xD;
      an SSRI or an SNRI/pregabalin, the patient will commence the primary medication arm. The&#xD;
      patient will start the medication class that they have not been previously deemed&#xD;
      unresponsive to (i.e., if previously unresponsive to sertraline, the patient will commence&#xD;
      the SNRI class). A patient will be considered previously unresponsive if their anxiety did&#xD;
      not improve after treatment with the maximum tolerated dose of the specific medication for an&#xD;
      eight-week duration.&#xD;
&#xD;
      If the patient has been deemed unresponsive to both an SSRI and an SNRI/pregabalin, the&#xD;
      patient will commence the secondary medication arm. The two classes of medications within the&#xD;
      secondary arm will be described to the patient and, with the recommendation of the&#xD;
      prescribing psychiatrist, the patient will begin either bupropion/mirtazepine or&#xD;
      buspirone/imipramine.&#xD;
&#xD;
      Medication switch protocol. If the patient is deemed unresponsive to a medication after 4 or&#xD;
      6 weeks of administration (the patient reports less than a 20% improvement in their GAD-7&#xD;
      score compared to baseline), their medication should be switched to another class. If the&#xD;
      patient has a history of non-response to any of the four medication classes, these classes&#xD;
      should be removed as pharmacotherapy options for their treatment within the study (i.e., if a&#xD;
      patient was deemed unresponsive to SSRIs prior to commencing the study, the patient should&#xD;
      not be prescribed sertraline or escitalopram at any point within the study). If the patient&#xD;
      was started in the primary or secondary medication arm and has not previously demonstrated&#xD;
      non-response to the second class of medications within that arm, the patient should be&#xD;
      switched to the second class of pharmaceuticals within that arm. If the patient was started&#xD;
      in the primary arm and was previously deemed unresponsive to the second class of&#xD;
      pharmaceuticals within that arm, the patient should begin the secondary medication arm if&#xD;
      non-response indicates a medication switch is necessary.&#xD;
&#xD;
      Six Month Follow-up. All patients will be contacted through telephone by the Research&#xD;
      Coordinator 6 months after their 12 weeks within the study have ended to complete follow-up&#xD;
      questionnaires. The patients will complete a third STAI and another Q-LES-SF, DASS-42 and&#xD;
      GAD-7. These measurements will act to determine the longevity of treatment effects.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">April 29, 2020</start_date>
  <completion_date type="Actual">May 1, 2021</completion_date>
  <primary_completion_date type="Actual">May 1, 2021</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>This study has been designed using a quasi-experimental design to allow patients the freedom to choose which treatment modality they would like to participate in. This research design aims to be naturalistic by mimicking the decisions made by patients and physicians regarding the course of treatment and type of pharmacotherapy prescribed within mental health services across Ontario. The treatments provided within the study also aim to replicate evidence-based best practice clinical guidelines for the treatment of GAD. Arms include eCBT, eCBT + Pharmacotherapy, Pharmacotherapy.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in State Trait Anxiety Level</measure>
    <time_frame>Baseline, week 2, 4, 6, 8, 10, 12, plus 6-month follow-up</time_frame>
    <description>State Trait Anxiety Inventory (STAI) - Scale: 1-4 (1 = not at all, 4 = very much)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in Quality of Life</measure>
    <time_frame>Baseline, week 2, 4, 6, 8, 10, 12, plus 6-month follow-up</time_frame>
    <description>Quality of Life Enjoyment and Satisfaction Questionnaire - Short Form (Q-LES-QSF) - Scale: 1-5 (1 = very poor, 5 = very good)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in Generalized Anxiety Levels</measure>
    <time_frame>Baseline, week 2, 4, 6, 8, 10, 12, plus 6-month follow-up</time_frame>
    <description>Generalized Anxiety Disorder - 7 (GAD-7) - Scale: 0-3 (0 = never, 3 = nearly every day)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in Depression and Anxiety Scale</measure>
    <time_frame>Baseline, week 2, 4, 6, 8, 10, 12, plus 6-month follow-up</time_frame>
    <description>42-item Depression Anxiety Stress Scales (DASS-42) Scale: 0-3 (0 = not at all, 3 = very much)</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Demographics Information</measure>
    <time_frame>Baseline, week 2, 4, 6, 8, 10, 12, plus 6-month follow-up</time_frame>
    <description>Demographic questionnaire</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">39</enrollment>
  <condition>Generalized Anxiety Disorder</condition>
  <arm_group>
    <arm_group_label>e-CBT</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Weekly sessions of e-CBT through OPTT will consist of approximately 30 slides. Each session is expected to last approximately 50 minutes. The content and format of each weekly online session were designed to mirror live CBT. The slides will highlight a different topic each week and include general information, an overview of skills and homework on that topic. The homework included in each session will be submitted through OPTT and reviewed by the clinicians with personalized feedback provided by clinicians within three days of submission. Weekly homework submission for feedback will be mandatory before being eligible for the next session. Biweekly GAD-7, DASS-42 and Q-LES-SF questionnaires will be completed through OPTT. A second STAI will be completed in the final week of e-CBT treatment.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Pharmacotherapy</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Biweekly meeting with psychiatrist with GAD-7, DASS-42 and Q-LES-SF. Pharmacotherapy class decided according to protocol developed in accordance with Canada's best practice guidelines for GAD treatment. At second appointment, medication will be maintained and optimized, regardless of response. At third appointment, optimized if partial response or switched according to protocol if no response. Partial response is improvement of 20% or more in GAD-7. If switched, 6-week protocol will recommence with new medication. At fourth appointment, dosage optimized if responding well to medication and improvement greater than 50% within primary arm, or 20% if secondary arm, patient will remain on said medication for remainder of 12-week study. If not improving more than 20%, medication switched according to protocol and 6-week protocol will recommence. If primary arm and 20-50% improvement after six weeks on new medication, augmented with olanzapine, risperidone or benzodiazepines.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>e-CBT + Pharmacotherapy</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants will commence both treatments described above simultaneously.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>SSRIs/SNRIs (Selective Serotonin Reuptake Inhibitors/ Serotonin and Norepinephrine Reuptake Inhibitors)</intervention_name>
    <description>If never taken SSRI or SNRI, commence primary medication arm (SSRI: sertraline, escitalopram or Pregabalin/SNRI: duloxetine, venlafaxine) will be described to patient and will begin either. If deemed unresponsive to either prior to study, commence medication they have not been previously unresponsive to. Unresponsive if GAD did not improve after treatment with maximum tolerated dose for 8-weeks. If deemed unresponsive to SSRI and SNRI/pregabalin, commence secondary medication arm (bupropion/mirtazepine, buspirone/imipramine) with both being described to patient and begin either. Switch protocol: If unresponsive after 4 or 6 weeks, switch to another class. If started in primary or secondary and not previously demonstrated non-response to second class of medications within arm, switch to second class within arm. If started in primary and previously deemed unresponsive to second class, begin secondary if non-response indicates switch necessary.</description>
    <arm_group_label>Pharmacotherapy</arm_group_label>
    <arm_group_label>e-CBT + Pharmacotherapy</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Behavioral</intervention_type>
    <intervention_name>Electronic Cognitive Behavioural Therapy</intervention_name>
    <description>Weekly sessions of e-CBT through OPTT will consist of approximately 30 slides. Each session is expected to last approximately 50 minutes. The content and format of each weekly online session was designed to mirror live CBT. The slides will highlight a different topic each week and include general information, an overview of skills and homework on that topic. The homework included in each session will be submitted through OPTT and reviewed by the clinicians with personalized feedback provided by clinicians within three days of submission. Weekly homework submission for feedback will be mandatory before being eligible for the next session. Biweekly GAD-7, DASS-42 and Q-LES-SF questionnaires will be completed through OPTT. A second STAI will be completed in the final week of e-CBT treatment.</description>
    <arm_group_label>e-CBT</arm_group_label>
    <arm_group_label>e-CBT + Pharmacotherapy</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  18 years of age or older&#xD;
&#xD;
          -  Have consistent and reliable access to the internet&#xD;
&#xD;
          -  Be diagnosed with GAD according to the Diagnostic and Statistical Manual of Mental&#xD;
             Disorders, 5th Edition (DSM-V) by a clinician&#xD;
&#xD;
          -  Meet the criteria for GAD according to the GAD-7 Screener (GAD-7)&#xD;
&#xD;
          -  Be competent to consent to participate&#xD;
&#xD;
          -  Speak and read English&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        - Patients will be deemed ineligible for participation in the study if they are in acute&#xD;
        distress.&#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>Nazanin Alavi</last_name>
    <role>Principal Investigator</role>
    <affiliation>Queen's University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Hotel Dieu Hospital</name>
      <address>
        <city>Kingston</city>
        <state>Ontario</state>
        <zip>K7L 5G3</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Canada</country>
  </location_countries>
  <verification_date>September 2021</verification_date>
  <study_first_submitted>July 15, 2020</study_first_submitted>
  <study_first_submitted_qc>July 17, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 20, 2020</study_first_posted>
  <last_update_submitted>September 7, 2021</last_update_submitted>
  <last_update_submitted_qc>September 7, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">September 9, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Queen's University</investigator_affiliation>
    <investigator_full_name>Dr. Nazanin Alavi</investigator_full_name>
    <investigator_title>Principal Investigator, Assistant Professor</investigator_title>
  </responsible_party>
  <keyword>Generalized Anxiety Disorder</keyword>
  <keyword>Online Psychotherapy</keyword>
  <keyword>Cognitive Behavioural Therapy</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Anxiety Disorders</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Norepinephrine</mesh_term>
    <mesh_term>Serotonin</mesh_term>
    <mesh_term>Selective Serotonin Reuptake Inhibitors</mesh_term>
    <mesh_term>Serotonin and Noradrenaline Reuptake Inhibitors</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
    <ipd_description>Information from study is confidential and anonymity will be protected. Each patient participating in e-CBT will have password-protected encrypted file through web-based platform OPTT. Questionnaires and homework submitted via OPTT can only be accessed by psychiatrists involved within study and participating clinicians. Data from research will be saved without mention of patient names with all patients being identified with unique identification number in all data from this study. Master file of participant ID numbers and participant names will be maintained in password-protected encrypted file and destroyed once study has been completed. Hard copies files will be stored in locked cabinets and offices and will be available only to clinicians providing treatment and Research Coordinator. Participants will not be identified in any publication or reports and electronic data will be saved in password-protected encrypted files for 5 years after last publication then permanently destroyed.</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/NCT04478526
org study id: PSIY-604-18
nct id: NCT04478526
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Generalized anxiety disorder (GAD) is an extremely prevalent and debilitating mental health
      disorder. Currently, the gold standard treatment for GAD is cognitive behavioural therapy
      (CBT) and/or pharmacotherapy. The most common medications used to treat GAD are selective
      serotonin reuptake inhibitors (SSRIs) and selective norepinephrine reuptake inhibitors
      (SNRIs). While CBT is a gold standard treatment for GAD, it is costly, time-consuming, and
      often inaccessible. Fortunately, the electronic delivery of CBT (e-CBT) has emerged as a
      promising solution to address these barriers. e-CBT has shown to offer comparable results to
      in-person CBT while improving accessibility for patients and time efficiency for clinicians.
      The following project aims to investigate the treatment efficacy of e-CBT compared to, and in
      conjunction with pharmacotherapy for GAD. This study has been designed using a
      quasi-experimental design to allow patients the freedom to choose which treatment modality
      they would like to receive. Participants with a diagnosis of GAD will be enrolled in 1 of 3
      possible treatment arms: e-CBT, medication, or combination. The e-CBT program will include a
      12-week psychotherapy program delivered through the Online Psychotherapy Tool (OPTT), a
      secure, cloud-based, digital mental health platform. The treatment efficacy of e-CBT will be
      compared to the treatment efficacy of the medication arm and the combination arm.
      Conclusions: If e-CBT is shown to either be comparable to medication or that the effects of
      both treatments are augmented when used in tandem, these findings could have major
      implications on the mental health care system. e-CBT is a more accessible, and affordable
      treatment that could increase mental health care capacity by four-folds if proven viable.
Methodology Research Design. This study has been designed using a quasi-experimental design
      to allow patients the freedom to choose which treatment modality they would like to
      participate in. This research design aims to be naturalistic by mimicking the decisions made
      by patients and physicians regarding course of treatment and type of pharmacotherapy
      prescribed within mental health services across Ontario. The treatments provided within the
      study also aim to replicate evidence-based best practice clinical guidelines for treatment of
      GAD.

      Research Participants. Patients will be referred to the study by primary care physicians
      within Toronto and Kingston, Ontario. Patients will be referred to the Anxiety Outpatient
      Clinic at the Hotel Dieu Hospital site of Kingston Health Sciences Centre or the Mood and
      Anxiety Clinic within the Centre for Addiction and Mental Health (both sites herein referred
      to as "the clinic"). Upon receiving a referral to the clinic, participants will be contacted
      by the study's Research Coordinator and asked to indicate their interest (or lack thereof) in
      the study. If interest is indicated and the study's inclusion criteria are met, the patient
      will have a study intake appointment scheduled for the same day as their intake appointment
      at the clinic. To be considered for inclusion within the study, patients must:

        -  be 18 years of age or older

        -  have consistent and reliable access to the internet

        -  be diagnosed with GAD according to the Diagnostic and Statistical Manual of Mental
           Disorders, 5th Edition (DSM-V) by a clinician

        -  meet the criteria for GAD according to the GAD-7 Screener (GAD-7)

        -  Be competent to consent to participate

        -  Speak and read English Patients will be deemed ineligible for participation in the study
           if they are in acute distress.

      Allocation of Subjects between Arms of the Study. Subjects will be presented with all three
      arms of the study within their study intake appointment by the Research Coordinator. After
      obtaining informed consent, patients will meet with one of the study's psychiatrists during
      their clinic intake appointment and discuss the recommended treatment plan. In collaboration
      with the psychiatrist, patients will decide whether or not they would like to begin
      pharmacotherapy and/or e-CBT treatment.

      Criteria for Discontinuation. Patients' participation in the study will be discontinued if
      they are found to be noncompliant to their treatment. This will be defined as stopping
      medications all together or reportedly skipping more than two days in a row of medication.
      Patients will be found noncompliant with e-CBT treatment if they miss more than two weeks of
      e-CBT sessions or fail to complete weekly homework assignments. Patients' participation
      within the study will also be halted if they are deemed to be in acute crisis by self-report
      or the psychiatrist in charge of their care.

      Study Protocol. After being referred to the study by a clinician uninvolved within the study,
      patients will be contacted by the Research Coordinator to determine the patient's interest in
      participating in the study. If interest is indicated, an intake appointment for the study
      will be scheduled for the same date as the intake appointment to the clinic.

      Intake appointment. Upon attending the intake appointment, the Research Coordinator will
      explain all three arms of the study and review the study's letter of information. After
      sufficient time has been provided to ensure the patient understands the study, informed
      consent will be obtained by the Research Coordinator and the patient will complete the State
      Trait Anxiety Inventory (STAI), a demographics questionnaire, Quality of Life Enjoyment and
      Satisfaction Questionnaire - Short Form (Q-LES-QSF), GAD-7 and the 42-item Depression Anxiety
      Stress Scales (DASS-42). Following the intake appointment, patients will, in collaboration
      with their psychiatrist, decide on which treatment modalities they would like to participate
      in (e-CBT and/or pharmacotherapy). Treatment will then proceed according to the arms below,
      with patients participating in e-CBT and pharmacotherapy commencing both arms simultaneously
      within their clinic intake appointment.

      e-CBT. Weekly sessions of e-CBT through OPTT will consist of approximately 30 slides. Each
      session is expected to last approximately 50 minutes. The content and format of each weekly
      online session was designed to mirror live CBT. The slides will highlight a different topic
      each week and include general information, an overview of skills and homework on that topic.
      The homework included in each session will be submitted through OPTT and reviewed by the
      clinicians with personalized feedback provided by clinicians within three days of submission.
      Weekly homework submission for feedback will be mandatory before being eligible for the next
      session. Biweekly GAD-7, DASS-42 and Q-LES-SF questionnaires will be completed through OPTT.
      A second STAI will be completed in the final week of e-CBT treatment.

      Pharmacotherapy. If patients chose to participate in the pharmacotherapy stream of treatment,
      they will attend biweekly medication reconciliation appointments with their psychiatrist at
      the clinic. If the patient is participating solely in the pharmacotherapy arm, they will
      complete the biweekly GAD-7, DASS-42 and Q-LES-SF within each of their appointments. If the
      patient is completing both pharmacotherapy and e-CBT, questionnaires will only be completed
      through OPTT. Upon attending their clinic intake appointment, the patient's medication
      history (including any current medications) will be collected and all medications prescribed
      for GAD prior to the study will be switched to the medications suggested in the protocol and
      if needed to be continued the dose will be unchanged 6 weeks prior to start of the study and
      during the study. Within the patient's clinic intake appointment, they will commence
      pharmacotherapy with the medication class decided according the "starting medication"
      protocol below, which was developed in accordance with Canada's best practice guidelines for
      the treatment of GAD. The pharmacotherapy protocol is summarized in Figure 1.

      General 6-week protocol. At the patient's second appointment (2 weeks on the medication),
      their medication will be maintained and optimized, regardless of whether or not a response is
      reported. At the patient's third appointment (4 weeks on the medication), the medication will
      be optimized if a partial response is reported or the medication will be switched according
      to the "medication switch protocol" if no response is reported. Partial response will be
      defined as an improvement of 20% or greater in their GAD-7 score compared to baseline. If the
      medication is switched (the patient reports less than a 20% improvement in their GAD-7 score
      compared to baseline), the 6-week protocol will recommence with the new medication. At the
      patient's fourth appointment (6 weeks on the medication), their dosage will be optimized if
      the patient is responding well to the medication and reports an improvement greater than 50%
      if within the primary medication arm, or 20% if within the secondary medication arm, in their
      GAD-7 score compared to baseline, the patient will remain on said medication for the
      remainder of the 12-week study. If the patient does not report an improvement of more than
      20% in their GAD-7 score compared to baseline, the patient's medication will be switched
      according to the "medication switch protocol" and the 6-week protocol will recommence with
      the new medication. If the patient is within the primary medication arm and reports a 20-50%
      improvement in GAD symptoms compared to baseline after six weeks on the new medication, the
      medication with be augmented with either olanzapine, risperidone or benzodiazepines.

      Starting Medication. If the patient has never taken an SSRI or SNRI, the patient will
      commence the primary medication arm. The two classes of medications within the primary arm
      will be described to the patient and, with the recommendation of the prescribing
      psychiatrist, the patient will begin either an SSRI (sertraline or escitalopram) or
      pregabalin/an SNRI (duloxetine or venlafaxine).

      If, prior to the beginning of the study, the patient has been deemed unresponsive to either
      an SSRI or an SNRI/pregabalin, the patient will commence the primary medication arm. The
      patient will start the medication class that they have not been previously deemed
      unresponsive to (i.e., if previously unresponsive to sertraline, the patient will commence
      the SNRI class). A patient will be considered previously unresponsive if their anxiety did
      not improve after treatment with the maximum tolerated dose of the specific medication for an
      eight-week duration.

      If the patient has been deemed unresponsive to both an SSRI and an SNRI/pregabalin, the
      patient will commence the secondary medication arm. The two classes of medications within the
      secondary arm will be described to the patient and, with the recommendation of the
      prescribing psychiatrist, the patient will begin either bupropion/mirtazepine or
      buspirone/imipramine.

      Medication switch protocol. If the patient is deemed unresponsive to a medication after 4 or
      6 weeks of administration (the patient reports less than a 20% improvement in their GAD-7
      score compared to baseline), their medication should be switched to another class. If the
      patient has a history of non-response to any of the four medication classes, these classes
      should be removed as pharmacotherapy options for their treatment within the study (i.e., if a
      patient was deemed unresponsive to SSRIs prior to commencing the study, the patient should
      not be prescribed sertraline or escitalopram at any point within the study). If the patient
      was started in the primary or secondary medication arm and has not previously demonstrated
      non-response to the second class of medications within that arm, the patient should be
      switched to the second class of pharmaceuticals within that arm. If the patient was started
      in the primary arm and was previously deemed unresponsive to the second class of
      pharmaceuticals within that arm, the patient should begin the secondary medication arm if
      non-response indicates a medication switch is necessary.

      Six Month Follow-up. All patients will be contacted through telephone by the Research
      Coordinator 6 months after their 12 weeks within the study have ended to complete follow-up
      questionnaires. The patients will complete a third STAI and another Q-LES-SF, DASS-42 and
      GAD-7. These measurements will act to determine the longevity of treatment effects.
allocation: Non-Randomized
intervention model: Parallel Assignment
intervention model description: This study has been designed using a quasi-experimental design to allow patients the freedom to choose which treatment modality they would like to participate in. This research design aims to be naturalistic by mimicking the decisions made by patients and physicians regarding the course of treatment and type of pharmacotherapy prescribed within mental health services across Ontario. The treatments provided within the study also aim to replicate evidence-based best practice clinical guidelines for the treatment of GAD. Arms include eCBT, eCBT + Pharmacotherapy, Pharmacotherapy.
primary purpose: Treatment
masking: None (Open Label)
measure: Change in State Trait Anxiety Level
time frame: Baseline, week 2, 4, 6, 8, 10, 12, plus 6-month follow-up
description: State Trait Anxiety Inventory (STAI) - Scale: 1-4 (1 = not at all, 4 = very much)
measure: Change in Quality of Life
time frame: Baseline, week 2, 4, 6, 8, 10, 12, plus 6-month follow-up
description: Quality of Life Enjoyment and Satisfaction Questionnaire - Short Form (Q-LES-QSF) - Scale: 1-5 (1 = very poor, 5 = very good)
measure: Change in Generalized Anxiety Levels
time frame: Baseline, week 2, 4, 6, 8, 10, 12, plus 6-month follow-up
description: Generalized Anxiety Disorder - 7 (GAD-7) - Scale: 0-3 (0 = never, 3 = nearly every day)
measure: Change in Depression and Anxiety Scale
time frame: Baseline, week 2, 4, 6, 8, 10, 12, plus 6-month follow-up
description: 42-item Depression Anxiety Stress Scales (DASS-42) Scale: 0-3 (0 = not at all, 3 = very much)
measure: Demographics Information
time frame: Baseline, week 2, 4, 6, 8, 10, 12, plus 6-month follow-up
description: Demographic questionnaire
arm group label: e-CBT
arm group type: Experimental
description: Weekly sessions of e-CBT through OPTT will consist of approximately 30 slides. Each session is expected to last approximately 50 minutes. The content and format of each weekly online session were designed to mirror live CBT. The slides will highlight a different topic each week and include general information, an overview of skills and homework on that topic. The homework included in each session will be submitted through OPTT and reviewed by the clinicians with personalized feedback provided by clinicians within three days of submission. Weekly homework submission for feedback will be mandatory before being eligible for the next session. Biweekly GAD-7, DASS-42 and Q-LES-SF questionnaires will be completed through OPTT. A second STAI will be completed in the final week of e-CBT treatment.
arm group label: Pharmacotherapy
arm group type: Experimental
description: Biweekly meeting with psychiatrist with GAD-7, DASS-42 and Q-LES-SF. Pharmacotherapy class decided according to protocol developed in accordance with Canada's best practice guidelines for GAD treatment. At second appointment, medication will be maintained and optimized, regardless of response. At third appointment, optimized if partial response or switched according to protocol if no response. Partial response is improvement of 20% or more in GAD-7. If switched, 6-week protocol will recommence with new medication. At fourth appointment, dosage optimized if responding well to medication and improvement greater than 50% within primary arm, or 20% if secondary arm, patient will remain on said medication for remainder of 12-week study. If not improving more than 20%, medication switched according to protocol and 6-week protocol will recommence. If primary arm and 20-50% improvement after six weeks on new medication, augmented with olanzapine, risperidone or benzodiazepines.
arm group label: e-CBT + Pharmacotherapy
arm group type: Experimental
description: Participants will commence both treatments described above simultaneously.
intervention type: Drug
intervention name: SSRIs/SNRIs (Selective Serotonin Reuptake Inhibitors/ Serotonin and Norepinephrine Reuptake Inhibitors)
description: If never taken SSRI or SNRI, commence primary medication arm (SSRI: sertraline, escitalopram or Pregabalin/SNRI: duloxetine, venlafaxine) will be described to patient and will begin either. If deemed unresponsive to either prior to study, commence medication they have not been previously unresponsive to. Unresponsive if GAD did not improve after treatment with maximum tolerated dose for 8-weeks. If deemed unresponsive to SSRI and SNRI/pregabalin, commence secondary medication arm (bupropion/mirtazepine, buspirone/imipramine) with both being described to patient and begin either. Switch protocol: If unresponsive after 4 or 6 weeks, switch to another class. If started in primary or secondary and not previously demonstrated non-response to second class of medications within arm, switch to second class within arm. If started in primary and previously deemed unresponsive to second class, begin secondary if non-response indicates switch necessary.
arm group label: Pharmacotherapy
arm group label: e-CBT + Pharmacotherapy
intervention type: Behavioral
intervention name: Electronic Cognitive Behavioural Therapy
description: Weekly sessions of e-CBT through OPTT will consist of approximately 30 slides. Each session is expected to last approximately 50 minutes. The content and format of each weekly online session was designed to mirror live CBT. The slides will highlight a different topic each week and include general information, an overview of skills and homework on that topic. The homework included in each session will be submitted through OPTT and reviewed by the clinicians with personalized feedback provided by clinicians within three days of submission. Weekly homework submission for feedback will be mandatory before being eligible for the next session. Biweekly GAD-7, DASS-42 and Q-LES-SF questionnaires will be completed through OPTT. A second STAI will be completed in the final week of e-CBT treatment.
arm group label: e-CBT
arm group label: e-CBT + Pharmacotherapy
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Nazanin Alavi
role: Principal Investigator
affiliation: Queen's University
facility: 
country: Canada
responsible party type: Principal Investigator
investigator affiliation: Queen's University
investigator full name: Dr. Nazanin Alavi
investigator title: Principal Investigator, Assistant Professor
mesh term: Anxiety Disorders
mesh term: Norepinephrine
mesh term: Serotonin
mesh term: Selective Serotonin Reuptake Inhibitors
mesh term: Serotonin and Noradrenaline Reuptake Inhibitors
sharing ipd: No
ipd description: Information from study is confidential and anonymity will be protected. Each patient participating in e-CBT will have password-protected encrypted file through web-based platform OPTT. Questionnaires and homework submitted via OPTT can only be accessed by psychiatrists involved within study and participating clinicians. Data from research will be saved without mention of patient names with all patients being identified with unique identification number in all data from this study. Master file of participant ID numbers and participant names will be maintained in password-protected encrypted file and destroyed once study has been completed. Hard copies files will be stored in locked cabinets and offices and will be available only to clinicians providing treatment and Research Coordinator. Participants will not be identified in any publication or reports and electronic data will be saved in password-protected encrypted files for 5 years after last publication then permanently destroyed.