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VA Augmentation and Switching Treatments for Improving Depression Outcomes (VAST-D)

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ClinicalTrials.gov Identifier: NCT01421342
Recruitment Status : Completed
First Posted : August 22, 2011
Results First Posted : May 28, 2018
Last Update Posted : May 28, 2018
Sponsor:
Information provided by (Responsible Party):
VA Office of Research and Development

Tracking Information
First Submitted Date  ICMJE August 5, 2011
First Posted Date  ICMJE August 22, 2011
Results First Submitted Date  ICMJE January 29, 2018
Results First Posted Date  ICMJE May 28, 2018
Last Update Posted Date May 28, 2018
Study Start Date  ICMJE December 2012
Actual Primary Completion Date August 2015   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 25, 2018)
Rate of Protocol Remission of Symptoms of Major Depressive Disorder [ Time Frame: During acute phase (12 weeks) ]
Remission of symptoms of major depression during the acute treatment phase (12 weeks) defined as a sustained clinician-rated Quick Inventory of Depressive Symptoms (QIDS-C16) of <= 5 for two consecutive visits.
Original Primary Outcome Measures  ICMJE
 (submitted: August 18, 2011)
Remission of symptoms of major depressive disorder [ Time Frame: During acute phase (12 weeks) ]
Remission of symptoms of major depression during the acute treatment phase (12 weeks) defined as a sustained clinician-rated Quick Inventory of Depressive Symptoms (QIDS-C16) of <= 5 for two consecutive visits.
Change History Complete list of historical versions of study NCT01421342 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: April 25, 2018)
  • Rate of Protocol Relapse of Symptoms of Major Depression After Achieving Remission in the Acute Phase [ Time Frame: Within 36 weeks after randomization (initiation of treatment) ]
    Relapse in symptoms of major depression defined as a QIDS-C16 => 11 among those achieving remission in the acute phase.
  • Rate of Protocol Response as Reduction in Symptoms of Major Depression (>= 50% Reduction in QIDS-C) [ Time Frame: During acute phase (up to 12 weeks) ]
    Response measured as reduction in symptom score for major depression defined as: 1. a reduction in QIDS-C16 of 50% or greater
  • Rate of Protocol Response Measured as a Change in Clinical Global Impression (CGI) - Improvement Scale [ Time Frame: During acute phase (up to 12 weeks) ]
    Clinical assessment of a participant's level of depression and treatment response assessed by the Clinical Global Impression - Improvement (CGI -I) Scale, a 7-point clinician rating scale of improvement from baseline in severity of depression (Guy 1976). A secondary outcome measure of response was defined as achieving a score of 2 (much improved) or 1 (very much improved).
Original Secondary Outcome Measures  ICMJE
 (submitted: August 18, 2011)
  • Relapse in symptoms of major depression [ Time Frame: During acute phase (up to 12 weeks) and continuation phase (from 12 weeks up to 36 weeks) ]
    Relapse in symptoms of major depression defined as a QIDS-C16 > 11 after remission.
  • Response in symptoms of major depression [ Time Frame: During acute phase (up to 12 weeks) and continuation phase (from 12 weeks up to 36 weeks) ]
    Response in symptoms of major depression defined as a reduction in QIDS-C16 of 50% or greater
  • Onset or cessation of akathisia [ Time Frame: During acute phase (up to 12 weeks) and continuation phase (from 12 weeks up to 36 weeks) ]
    Onset or cessation of akathisia, or change in symptom proclivity to as measured by the Barnes Akathisia Scale (Barnes 1989)
  • Onset or cessation of anxiety [ Time Frame: During acute phase (up to 12 weeks) and continuation phase (from 12 weeks up to 36 weeks) ]
    Anxiety will be assessed by Beck Anxiety Inventory (BAI) (Beck, Epstein et al. 1988)
  • Onset or cessation of suicide ideation [ Time Frame: During acute phase (up to 12 weeks) and continuation phase (from 12 weeks up to 36 weeks) ]
    Suicide ideation and behaviors will be assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS)
  • Change in Clinical Global Impression Scale [ Time Frame: During acute phase (up to 12 weeks) and continuation phase (from 12 weeks up to 36 weeks) ]
    Clinical assessment of a participant's level of depression and treatment response assessed by the Clinical Global Impression - Severity (CGI -S) Scale, a 7-point clinician rating scale of the severity of depression and the Clinical Global Impression - Improvement (CGI -I) Scale, a 7-point clinician rating scale of improvement from baseline in severity of depression (Guy 1976).
  • Emergence of adverse experiences [ Time Frame: During acute phase (up to 12 weeks) and continuation phase (from 12 weeks up to 36 weeks) ]
    Side effects, tolerability and discontinuation of medications will be assessed by the patient-rated Frequency and Intensity of Side Effects Rating/Global Rating of Side-Effect Burden (FIBSER) (Wisniewski, Rush et al. 2006) and by recording the occurrence of commonly reported side effects of antidepressant and atypical -psychotic medications, and the occurrence of serious or unexpected adverse experiences.
  • Cost and Cost-Effectiveness [ Time Frame: During acute phase (up to 12 weeks) and continuation phase (from 12 weeks up to 36 weeks) ]
    Costs will be assessed by costs of care and health care utilization; and cost-effectiveness assessed by the ratio of costs to quality-adjusted life years.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE VA Augmentation and Switching Treatments for Improving Depression Outcomes
Official Title  ICMJE CSP #576 - VA Augmentation and Switching Treatments for Improving Depression Outcomes (VAST-D)
Brief Summary The overall purpose is to determine research based 'next-steps' for outpatients with major depressive disorder who have not had satisfactory outcomes to standard 'first-step' treatments. The primary objective is to compare the acute (up to 12 weeks) treatment effectiveness of augmenting an antidepressant with aripiprazole or with bupropion-slow release (SR) vs. switching treatment to bupropion-SR monotherapy on symptom remission in Veterans with Major Depressive Disorder (MDD) who have not achieved optimal response after an adequate trial on antidepressant (a selective serotonin reuptake inhibitor [SSRI] or serotonin and norepinephrine reuptake inhibitor [SNRI] or mirtazapine) monotherapy. The secondary objectives are to compare the acute (up to 12 weeks) and long term (up to 36 weeks) efficacy, safety, effects on functioning, suicidality, quality of life, anxiety and other associated symptoms, costs and cost-effectiveness of each of the three treatments.
Detailed Description

The overall aim of VAST-D is to enhance treatment outcomes for representative outpatients diagnosed with nonpsychotic major depressive disorder (MDD) and treated in primary or psychiatric VA care settings. In particular, VAST-D is designed to determine the comparative effectiveness of different treatment options for participants with MDD who fail to have a satisfactory outcome to treatment with their initial antidepressants.

These options may be conceptualized as representing two overall treatment strategies: 1) Medication Switch - switching from the initial antidepressant to another antidepressant medication, specifically bupropion-SR and 2) Medication Augmentation - augmenting the initial antidepressant with a second antidepressant, specifically bupropion-SR or a second generation antipsychotic, specifically aripiprazole. VAST-D's primary goal is to determine which of these 3 treatment strategies is most likely to lead to remission. Other key objectives include comparisons of response, time to remission, time to response, relapse, anxiety symptoms, suicidal ideation and behaviors, side effects, tolerability, quality of life, health related costs and satisfaction with participation in the study.

VAST-D will enroll 1518 total patients of both genders and all ethnic/racial and socioeconomic backgrounds. All patients will meet Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV-TR (text revised) criteria for nonpsychotic MDD. The diagnostic criteria for eligibility will be established by clinical interview supplemented with the 9-item Patient Health Questionnaire (PHQ-9). Final determination for eligibility will be made by the study clinician. Only participants with a suboptimal outcome to a well documented, adequately delivered (dose and duration), trial with selective serotonin reuptake inhibitor (SSRI) or a serotonin and norepinephrine reuptake inhibitor (SNRI) or mirtazapine will be eligible for the study. Failure to achieve an adequate outcome will be ascertained by a score on the 16-item Quick Inventory of Depressive Symptomatology - Clinician rated (QIDS-C16) scale >= 16 (considered severe depression) after at least 6 weeks of treatment or QIDS-C16 >= 11 (considered moderately severe depression) after at least 8 weeks of treatment. Otherwise, the inclusion criteria are broad and the exclusion criteria are few; participants with most comorbid general medical or psychiatric disorders are generally included to provide a broadly representative sample.

Participants will be randomized (1:1:1 ratio) to switch to bupropion-SR alone (n=506), current antidepressant plus bupropion-SR (n=506), or current antidepressant plus aripiprazole (n=506). Treatment will be guided by clinician-rated symptom measures (the PHQ-9) and global side effects measures (the Frequency, Intensity, and Burden of Side Effects Rating or FIBSER) obtained at each treatment visit. Acute treatment visits will occur at baseline and at weeks 1, 2, 4, 6, 8, 10, and 12 to ensure delivery of appropriate and yet vigorous and tolerable pharmacotherapy. Participants who tolerate the acute treatment and achieve adequate response at 12 weeks will enter the 24-week Continuation Treatment phase, during which the initial treatment will continue and visits will occur every four weeks subsequently until patients have been followed for 36 weeks post-randomization. The QIDS-C16 will be administered at baseline and at each follow-up visit by an independent evaluator (who will be blinded to treatment assignment) to measure symptoms of depression for the study outcomes of remission, response and relapse. Neither the participant nor the treating clinician will be blinded to treatment.

Primary hypotheses:

Primary hypothesis 1.a: Remission rate from major depressive disorder will be higher in patients whose treatment is augmented with bupropion-SR (antidepressant + bupropion-SR) compared to those switched to bupropion-SR monotherapy.

Primary Hypothesis 1.b: Remission rate from major depressive disorder will be higher in patients whose treatment is augmented with aripiprazole (antidepressant + aripiprazole) compared to those switched to bupropion-SR monotherapy.

Secondary hypotheses:

Secondary Hypothesis 2.a: Remission rate will be greater in patients whose treatment is augmented with bupropion-SR (antidepressant + bupropion-SR) than in those augmented with aripiprazole (antidepressant + aripiprazole).

Secondary Hypothesis 2.b: Relapse rate (within 36 weeks of the initiation of treatment) will be lower in patients whose antidepressant is augmented with bupropion-SR (antidepressant + bupropion-SR) than in those whose antidepressant is switched to bupropion-SR monotherapy.

Secondary Hypothesis 2.c: Relapse rate (within 36 weeks of the initiation of treatment) will be lower in patients whose treatment is augmented with aripiprazole (antidepressant + aripiprazole) vs. those switched to bupropion-SR monotherapy.

Secondary Hypothesis 2.d: Relapse rate (within 36 weeks of the initiation of treatment) will be lower in patients whose treatment is augmented with bupropion-SR (antidepressant + bupropion-SR) than in patients whose treatment was augmented with aripiprazole (antidepressant + aripiprazole).

Secondary Hypothesis 2.e: The proportion of patients who develop akathisia, other akathisia-like side effects (e.g., tremor, irritability, motor restlessness) and extrapyramidal side effects will be greater in the patients whose antidepressant treatment is augmented with aripiprazole (antidepressant + aripiprazole) compared to patients whose treatment is augmented with bupropion-SR (antidepressant + bupropion-SR), or switched to bupropion-SR monotherapy.

Secondary Hypothesis 2.f: The relative costs (direct and indirect) of augmenting an antidepressant with aripiprazole (antidepressant + aripiprazole) will be greater than the costs of antidepressant augmentation with bupropion-SR (antidepressant + bupropion-SR), and the costs of antidepressant augmentation with bupropion-SR (antidepressant + bupropion-SR) will be greater than the costs of switching to bupropion-SR monotherapy, and augmentation and monotherapy with bupropion-SR will be more cost-effective than aripiprazole augmentation.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Major Depressive Disorder
Intervention  ICMJE
  • Drug: Switching: Bupropion-SR
    Bupropion-SR (Dose: 150 mg - 400 mg taken per day orally for up to 36 weeks): Initiating with bupropion-SR dose of 150 mg, then increasing dose per protocol up to 400 mg (200 mg BID), maintaining or decreasing dose for up to 36 weeks depending on response and side effect profile through the acute and continuation phases.
  • Drug: Augmenting: Antidepressant + Bupropion-SR

    Current antidepressant (either a SSRI or a SNRI or mirtazapine): Continue the dose prescribed at time of enrollment, or adjust depending on response or side effect profile for up to 36 weeks.

    And

    Bupropion-SR (Dose: 150 mg - 400 mg taken per day orally for up to 36 weeks): Initiating with bupropion-SR dose of 150 mg, then increasing dose per protocol up to 400 mg (200 mg BID), maintaining or decreasing dose for up to 36 weeks depending on response and side effect profile through the acute and continuation phases.

  • Drug: Augmenting: Antidepressant + Aripiprazole

    Current antidepressant (either a SSRI or a SNRI or mirtazapine): Continue the dose prescribed at time of enrollment or adjust depending on response or side effect profile for up to 36 weeks.

    And

    Aripiprazole (Dose: 2 mg - 15 mg taken orally once per day for up to 36 weeks): Initiating with aripiprazole dose of 2 mg for one week, then increasing dose per protocol up to 15 mg, maintaining or decreasing dose for up to 36 weeks depending on response and side effect profile through the acute and continuation phases.

Study Arms  ICMJE
  • Active Comparator: Switching: Bupropion-SR
    Switching: Bupropion-SR
    Intervention: Drug: Switching: Bupropion-SR
  • Active Comparator: Augmenting: Antidepressant + Bupropion-SR
    Augmenting: Antidepressant + Bupropion-SR
    Intervention: Drug: Augmenting: Antidepressant + Bupropion-SR
  • Active Comparator: Augmenting: Antidepressant + Aripiprazole
    Augmenting: Antidepressant + Aripiprazole
    Intervention: Drug: Augmenting: Antidepressant + Aripiprazole
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: April 25, 2018)
1522
Original Estimated Enrollment  ICMJE
 (submitted: August 18, 2011)
1518
Actual Study Completion Date  ICMJE June 2016
Actual Primary Completion Date August 2015   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • DSM-IV diagnosis of single or recurrent, non-psychotic, major depressive disorder
  • Currently taking a selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI) or mirtazapine for major depressive disorder
  • Need for "next-step" treatment based on documented suboptimal outcome from current antidepressant treatment for major depressive episode (at least 6 weeks treatment with a QIDS-C16 >= 16 or at least 8 weeks with a QIDS-C16 >= 11; and at least 3 weeks at a stable "optimal" dose
  • Age: 18 years of age or older

Exclusion Criteria:

  • Prior inadequate response after an adequate treatment trial or clear cut intolerance to either of the study medications (aripiprazole or bupropion)
  • Current treatment with bupropion, aripiprazole or any other antipsychotic agent
  • Lifetime history of bipolar disorder, schizophrenia, schizoaffective disorder, or psychosis not otherwise specified
  • Current diagnosis of Dementia
  • Current diagnosis of an eating disorder or a seizure disorder
  • High suicide risk currently requiring acute intervention (other than outpatient treatment of depression)
  • Unstable, serious medical condition or one requiring acute medical treatment, or anticipation of hospitalization for extended care
  • Requiring immediate hospitalization for psychiatric disorders
  • Physiologic substance dependence requiring detoxification (excluding nicotine) in the past 30 days (substance abuse is not an exclusion criteria)
  • Taking any concomitant medication that contraindicates any of treatment options or augmenting agents known to have an antidepressant effect
  • Concurrent or recent participation (within the last 30 days) in another conflicting clinical trial with a mental health, investigational drug, or medical device intervention
  • Female - pregnant or lactating or planning to become pregnant
  • Patient was not able or willing to provide informed consent; or changed mind about participating prior to randomization
  • Patient was not referred to the study
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01421342
Other Study ID Numbers  ICMJE 576
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party VA Office of Research and Development
Study Sponsor  ICMJE VA Office of Research and Development
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Chair: Somaia Mohamed, PhD VA Connecticut Healthcare System West Haven Campus, West Haven, CT
Study Chair: Sidney Zisook, MD VA San Diego Healthcare System, San Diego, CA
PRS Account VA Office of Research and Development
Verification Date April 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP