<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/NCT02977299</url>
  </required_header>
  <id_info>
    <org_study_id>2015P002430</org_study_id>
    <nct_id>NCT02977299</nct_id>
  </id_info>
  <brief_title>Comparative Effectiveness Research Trial for Antidepressant Incomplete and Non-responders With TRD</brief_title>
  <acronym>ASCERTAINTRD</acronym>
  <official_title>Augmentation Versus Switch: Comparative Effectiveness Research Trial for Antidepressant Incomplete and Non-responders With Treatment Resistant Depression (ASCERTAIN-TRD)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Massachusetts General Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Patient-Centered Outcomes Research Institute</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Massachusetts General Hospital</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>Yes</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a multi-site, randomized, open-label, effectiveness trial comparing three treatment&#xD;
      arms for Major Depressive Disorder (MDD) patients with TRD who are currently on ongoing,&#xD;
      stable and adequate antidepressant therapy (ADT). Adequate ADT is defined as a&#xD;
      therapeutically sufficient dose for a sufficient treatment period, which would be expected to&#xD;
      be effective as listed in the MGH Antidepressant Treatment Response Questionnaire (ATRQ).&#xD;
      Patients will be randomized in a 1:1:1 fashion to one of three open-label treatment arms: a)&#xD;
      aripiprazole augmentation, b) rTMS augmentation, and c) switching to venlafaxine XR or&#xD;
      Duloxetine.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">May 1, 2017</start_date>
  <completion_date type="Actual">April 24, 2022</completion_date>
  <primary_completion_date type="Actual">April 24, 2022</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Single (Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Montgomery-Asberg Depression Rating Scale (MADRS)</measure>
    <time_frame>8 weeks</time_frame>
    <description>Assessment of depression severity.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Quality of Life, Enjoyment and Satisfaction Questionnaire - Short Form (Q-LES-Q-SF)</measure>
    <time_frame>8 weeks</time_frame>
    <description>Assessment of quality of life</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Massachusetts General Hospital Cognitive and Physical Symptoms Questionnaire (MGH CPFQ)</measure>
    <time_frame>8 weeks</time_frame>
    <description>Assessment of cognitive symptoms</description>
  </other_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">278</enrollment>
  <condition>Treatment Resistant Major Depressive Disorder</condition>
  <arm_group>
    <arm_group_label>Aripiprazole Augmentation</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients randomized to this treatment arm will be instructed to continue all permitted psychotropics at their current dose throughout the 8-week trial and initiate adjunctive aripiprazole. The starting dose will be 5mg daily. The dose may be reduced to as low as 2mg for tolerability issues (this will be the lowest dose permitted for continuation in the trial). The dose may be adjusted in 2 or 5mg increments. The minimum time per increment will be 7 days. The maximum dose will be set at 15mg daily. For patients who are not on potent cytochrome 2D6 inhibitors (such as paroxetine, fluoxetine, duloxetine) or on potent cytochrome 3A4 inhibitors (such as fluvoxamine and nefazodone) and who are able to tolerate 15mg daily, the maximum dose can be raised to 20mg daily for efficacy.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>rTMS Augmentation</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients randomized to this treatment arm will be instructed to continue all permitted psychotropics at their current dose throughout the 8-week trial. We will use clinical TMS stimulators with focal figure-of-eight coils. We will start by measuring the patient´s motor threshold (MT), which is a measure of cortical excitability used to standardize the intensity of stimulation across subjects.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Switching To Venlafaxine XR</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients randomized to this treatment arm will be instructed to continue all permitted psychotropics throughout the 8-week trial, except for their antidepressant(s). They will be instructed to discontinue all antidepressants and initiate venlafaxine that day, as direct switch to serotonergic antidepressants is well tolerated and avoids loss of precious therapeutic time (Montgomery et al., 2014), including to switching to venlafaxine in STAR*D (Rush et al., 2006b). For patients who do not prefer a direct switch, or when clinically indicated otherwise in the opinion of the site investigator, a gradual tapering during the screening period will be permitted as long as a direct switch to venlafaxine is made on the baseline visit from the final antidepressant dose. The starting dose of venlafaxine will be 75mg daily. The dose may be reduced to as low as 37.5mg for tolerability issues (this will be the lowest dose permitted for continuation in the trial).</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Aripiprazole</intervention_name>
    <description>Oral adjunctive therapy with aripiprazole, dose adjusted for effectiveness and tolerability.</description>
    <arm_group_label>Aripiprazole Augmentation</arm_group_label>
    <other_name>Abilify</other_name>
  </intervention>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>Repetitive transcranial magnetic stimulation (rTMS)</intervention_name>
    <description>Adjunctive therapy with transcranial magnetic stimulation, dose adjusted for effectiveness and tolerability.</description>
    <arm_group_label>rTMS Augmentation</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Venlafaxine XR</intervention_name>
    <description>Oral switch therapy with venlafaxine, dose adjusted for effectiveness and tolerability.</description>
    <arm_group_label>Switching To Venlafaxine XR</arm_group_label>
    <other_name>Effexor XR</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. women and men ages 18-80,&#xD;
&#xD;
          2. with MDD, of at least 12 weeks duration, according to Diagnostic and Statistical&#xD;
             Manual of Mental Disorders, Fifth Edition (DSM-5) criteria confirmed by the Mini&#xD;
             International Neuropsychiatric Interview (MINI; Sheehan et al, 1998),&#xD;
&#xD;
          3. have a Montgomery-Asberg Depression Rating Scale (MADRS - Montgomery and Asberg, 1979)&#xD;
             score of at least 20 at screen and baseline as assessed by site clinicians,&#xD;
&#xD;
          4. meet criteria for TRD during the current major depressive episode documented in the&#xD;
             MGH Antidepressant Treatment History Questionnaire (ATRQ) (Chandler et al., 2010),&#xD;
             which will be defined as being non-responders (less than 50% of symptom improvement)&#xD;
             to two or more depression treatment trials of adequate dose and duration as defined by&#xD;
             the MGH ATRQ,&#xD;
&#xD;
          5. are currently on an antidepressant of adequate dose (as defined by the MGH ATRQ) and&#xD;
             duration (at least 8 weeks), with the antidepressant dose being stable over the past&#xD;
             four weeks, and with documented (in the MGH ATRQ) non-response (less than 50%&#xD;
             improvement) to the current antidepressant.&#xD;
&#xD;
          6. Patients who have passed the MGH CTNI remote assessment, with documentation provided&#xD;
             to sites by MGH CTNI.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. pregnant or breastfeeding women, women of childbearing potential who are not using an&#xD;
             accepted means of birth control, or women with a positive urine pregnancy test,&#xD;
&#xD;
          2. patients who have received treatment with rTMS, aripiprazole, electroconvulsive&#xD;
             therapy (ECT), or venlafaxine during the current episode,&#xD;
&#xD;
          3. patients who express an objection to receiving treatment with at least one of the&#xD;
             three treatment arms of our study,&#xD;
&#xD;
          4. patients with any history of bipolar disorder or psychosis (diagnosed by MINI),&#xD;
&#xD;
          5. patients with active alcohol or substance abuse disorders within the past 6 months&#xD;
             (diagnosed by MINI),&#xD;
&#xD;
          6. patients with suicidal ideation of the degree that, in the opinion of the evaluating&#xD;
             clinician, participation in the study would place them at significantly increased risk&#xD;
             of suicide,&#xD;
&#xD;
          7. patients with unstable medical issues of such degree that, in the opinion of the&#xD;
             evaluating clinician, participation in the study would place them at significant risk&#xD;
             of a serious adverse event, or patients with a screening hemoglobin A1c level greater&#xD;
             than 7.5%, or patients with epilepsy, dementia, Parkinson's disease, or Huntington's&#xD;
             Disease,&#xD;
&#xD;
          8. patients who have received treatment with vagus nerve stimulation (VNS),&#xD;
&#xD;
          9. patients who have not responded to more than five FDA-approved antidepressant&#xD;
             treatment trials of adequate dose and duration during the current episode, or who did&#xD;
             not respond to ECT in previous episodes&#xD;
&#xD;
         10. patients on excluded medications,&#xD;
&#xD;
         11. patients with a positive urine screen drug test for a substance for which they do not&#xD;
             have a valid prescription for a valid medical reason,&#xD;
&#xD;
         12. patients with currently abnormal thyroid function tests,&#xD;
&#xD;
         13. patients who have received at least one dose of a monoamine oxidase inhibitor (MAOI)&#xD;
             four weeks or less prior, and&#xD;
&#xD;
         14. for patients on concomitant psychotropic agents (anticonvulsants, benzodiazepines,&#xD;
             hypnotics, opiates, triiodothyronine (T3), modafinil, psychostimulants, buspirone,&#xD;
             melatonin, omega-3 fatty acids, folate, l-methylfolate, s-adenosyl methionine,&#xD;
             lithium) not on the same dose for at least four weeks prior to study entry or who do&#xD;
             not agree to continue at the same dose during the acute phase of the study.&#xD;
&#xD;
         15. Patients who do not meet safety criteria for TMS: history of seizures, cardiac&#xD;
             pacemaker, DBS or VNS, brain aneurism clips or other metallic implants in the&#xD;
             intracranial space.&#xD;
&#xD;
         16. Also excluded is an individual who has received any administration of ketamine in the&#xD;
             current episode for the treatment of depression.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>The University of Alabama School of Medicine</name>
      <address>
        <city>Birmingham</city>
        <state>Alabama</state>
        <zip>35294</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Pacific Institute of Medical Research</name>
      <address>
        <city>Los Angeles</city>
        <state>California</state>
        <zip>90095</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Stanford University</name>
      <address>
        <city>Stanford</city>
        <state>California</state>
        <zip>94305</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of South Florida</name>
      <address>
        <city>Tampa</city>
        <state>Florida</state>
        <zip>33613</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Northwestern University, Feinberg School of Medicine</name>
      <address>
        <city>Chicago</city>
        <state>Illinois</state>
        <zip>60611</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>New York University</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10003</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Cincinnati</name>
      <address>
        <city>Cincinnati</city>
        <state>Ohio</state>
        <zip>45219</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Pennsylvania</name>
      <address>
        <city>Philadelphia</city>
        <state>Pennsylvania</state>
        <zip>19104</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Roper St. Francis Hospital</name>
      <address>
        <city>Charleston</city>
        <state>South Carolina</state>
        <zip>29425</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Texas Southwestern Medical Center</name>
      <address>
        <city>Dallas</city>
        <state>Texas</state>
        <zip>75390</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Baylor College of Medicine</name>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <zip>77030</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of British Columbia</name>
      <address>
        <city>Vancouver</city>
        <state>British Columbia</state>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Manitoba St. Boniface Hospital</name>
      <address>
        <city>Winnipeg</city>
        <state>Manitoba</state>
        <zip>R2H 2A6</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Canada</country>
    <country>United States</country>
  </location_countries>
  <removed_countries>
    <country>Italy</country>
  </removed_countries>
  <verification_date>April 2022</verification_date>
  <study_first_submitted>November 28, 2016</study_first_submitted>
  <study_first_submitted_qc>November 29, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 30, 2016</study_first_posted>
  <last_update_submitted>April 26, 2022</last_update_submitted>
  <last_update_submitted_qc>April 26, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">April 27, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Massachusetts General Hospital</investigator_affiliation>
    <investigator_full_name>George I. Papakostas</investigator_full_name>
    <investigator_title>Scientific Director, MGH Clinical Trial Network and Institute (CTNI)</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Depressive Disorder</mesh_term>
    <mesh_term>Depressive Disorder, Major</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Aripiprazole</mesh_term>
    <mesh_term>Venlafaxine Hydrochloride</mesh_term>
  </intervention_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/NCT02977299
org study id: 2015P002430
nct id: NCT02977299
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: Yes
This is a multi-site, randomized, open-label, effectiveness trial comparing three treatment
      arms for Major Depressive Disorder (MDD) patients with TRD who are currently on ongoing,
      stable and adequate antidepressant therapy (ADT). Adequate ADT is defined as a
      therapeutically sufficient dose for a sufficient treatment period, which would be expected to
      be effective as listed in the MGH Antidepressant Treatment Response Questionnaire (ATRQ).
      Patients will be randomized in a 1:1:1 fashion to one of three open-label treatment arms: a)
      aripiprazole augmentation, b) rTMS augmentation, and c) switching to venlafaxine XR or
      Duloxetine.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Single (Outcomes Assessor)
measure: Montgomery-Asberg Depression Rating Scale (MADRS)
time frame: 8 weeks
description: Assessment of depression severity.
measure: Quality of Life, Enjoyment and Satisfaction Questionnaire - Short Form (Q-LES-Q-SF)
time frame: 8 weeks
description: Assessment of quality of life
measure: Massachusetts General Hospital Cognitive and Physical Symptoms Questionnaire (MGH CPFQ)
time frame: 8 weeks
description: Assessment of cognitive symptoms
arm group label: Aripiprazole Augmentation
arm group type: Experimental
description: Patients randomized to this treatment arm will be instructed to continue all permitted psychotropics at their current dose throughout the 8-week trial and initiate adjunctive aripiprazole. The starting dose will be 5mg daily. The dose may be reduced to as low as 2mg for tolerability issues (this will be the lowest dose permitted for continuation in the trial). The dose may be adjusted in 2 or 5mg increments. The minimum time per increment will be 7 days. The maximum dose will be set at 15mg daily. For patients who are not on potent cytochrome 2D6 inhibitors (such as paroxetine, fluoxetine, duloxetine) or on potent cytochrome 3A4 inhibitors (such as fluvoxamine and nefazodone) and who are able to tolerate 15mg daily, the maximum dose can be raised to 20mg daily for efficacy.
arm group label: rTMS Augmentation
arm group type: Experimental
description: Patients randomized to this treatment arm will be instructed to continue all permitted psychotropics at their current dose throughout the 8-week trial. We will use clinical TMS stimulators with focal figure-of-eight coils. We will start by measuring the patient´s motor threshold (MT), which is a measure of cortical excitability used to standardize the intensity of stimulation across subjects.
arm group label: Switching To Venlafaxine XR
arm group type: Experimental
description: Patients randomized to this treatment arm will be instructed to continue all permitted psychotropics throughout the 8-week trial, except for their antidepressant(s). They will be instructed to discontinue all antidepressants and initiate venlafaxine that day, as direct switch to serotonergic antidepressants is well tolerated and avoids loss of precious therapeutic time (Montgomery et al., 2014), including to switching to venlafaxine in STAR*D (Rush et al., 2006b). For patients who do not prefer a direct switch, or when clinically indicated otherwise in the opinion of the site investigator, a gradual tapering during the screening period will be permitted as long as a direct switch to venlafaxine is made on the baseline visit from the final antidepressant dose. The starting dose of venlafaxine will be 75mg daily. The dose may be reduced to as low as 37.5mg for tolerability issues (this will be the lowest dose permitted for continuation in the trial).
intervention type: Drug
intervention name: Aripiprazole
description: Oral adjunctive therapy with aripiprazole, dose adjusted for effectiveness and tolerability.
arm group label: Aripiprazole Augmentation
other name: Abilify
intervention type: Device
intervention name: Repetitive transcranial magnetic stimulation (rTMS)
description: Adjunctive therapy with transcranial magnetic stimulation, dose adjusted for effectiveness and tolerability.
arm group label: rTMS Augmentation
intervention type: Drug
intervention name: Venlafaxine XR
description: Oral switch therapy with venlafaxine, dose adjusted for effectiveness and tolerability.
arm group label: Switching To Venlafaxine XR
other name: Effexor XR
criteria: 
gender: All
minimum age: 18 Years
maximum age: 80 Years
healthy volunteers: No
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: Canada
country: United States
country: Italy
responsible party type: Principal Investigator
investigator affiliation: Massachusetts General Hospital
investigator full name: George I. Papakostas
investigator title: Scientific Director, MGH Clinical Trial Network and Institute (CTNI)
mesh term: Depressive Disorder
mesh term: Depressive Disorder, Major
mesh term: Aripiprazole
mesh term: Venlafaxine Hydrochloride
sharing ipd: No