Initial Severity and Antidepressant Efficacy for Anxiety Disorders: an Individual Patient Data Meta-analysis
Primary Purpose
Anxiety Disorders, Panic Disorder, Obsessive-compulsive Disorder
Status
Unknown status
Phase
Locations
Study Type
Observational
Intervention
paroxetine, duloxetine, fluoxetine or venlafaxine
Sponsored by
About this trial
This is an observational trial for Anxiety Disorders focused on measuring individual patient data meta-analysis, anxiety disorder, antidepressants, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors
Eligibility Criteria
Inclusion Criteria:
- Inclusion in the intent-to-treat population of a randomized controlled trial of a second-generation antidepressant for the short-term treatment of an anxiety disorder
- Diagnosed with an anxiety disorder (GAD, SAD, OCD, PTSD or PD)
Exclusion Criteria:
- Assignment to an active comparator that is not a second-generation antidepressant (e.g. a benzodiazepine)
Sites / Locations
Arms of the Study
Arm 1
Arm 2
Arm Type
Arm Label
Placebo group
Intervention group
Arm Description
Patients participating in one of the included randomized controlled trials, assigned to the placebo group
Patients participating in one of the included randomized controlled trials, assigned to the investigational antidepressant (paroxetine, duloxetine or fluoxetine) or active comparator (venlafaxine) group.
Outcomes
Primary Outcome Measures
Change from baseline on the Hamilton Anxiety Rating Scale (HAM-A)
Change from baseline on the Liebowitz Social Anxiety Scale (LSAS)
Change from baseline on the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS)
Change from baseline on the Clinician-Administered PTSD Scale (CAPS)
The total number of panic attacks
Secondary Outcome Measures
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT02476136
Brief Title
Initial Severity and Antidepressant Efficacy for Anxiety Disorders: an Individual Patient Data Meta-analysis
Official Title
Initial Severity and Antidepressant Efficacy for Anxiety Disorders: an Individual Patient Data Meta-analysis
Study Type
Observational
2. Study Status
Record Verification Date
September 2016
Overall Recruitment Status
Unknown status
Study Start Date
May 2015 (undefined)
Primary Completion Date
March 2016 (Actual)
Study Completion Date
December 2016 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
prof. Peter de Jonge
4. Oversight
Data Monitoring Committee
No
5. Study Description
Brief Summary
Anxiety disorders are common disorders, which pose a major burden to society and the individual. An anxiety disorder may be treated with medication, in particular with antidepressants such as the selective serotonin reuptake inhibitors (SSRIs). However, much of what is known about antidepressants is derived from research in depression rather than anxiety. In recent years, researchers have found that antidepressants are more effective for severely depressed patients than they are for patients with milder symptoms. It is possible that a similar relationship between symptom severity and antidepressant efficacy exists for anxiety disorders, but there is currently little evidence available to answer this question. As antidepressants are frequently prescribed to patients with mild or moderate anxiety, a clear understanding of their effectiveness across the severity range is vital to inform treatment decisions. Therefore, the purpose of this meta-analysis is to examine whether initial symptom severity affects antidepressant efficacy for anxiety disorders.
Detailed Description
Study design:
The proposed project is an individual patient data meta-analysis. The investigators will collate data from 29 randomized controlled trials of second-generation antidepressants (specifically: paroxetine, paroxetine controlled release (CR), duloxetine, and fluoxetine) for the short-term treatment of an anxiety disorder, including a total of approximately 8,800 participants. The anxiety disorders that are included in the proposed project are generalized anxiety disorder (GAD), social anxiety disorder (SAD), obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD), and panic disorder (PD). Generalized linear mixed models will be used to investigate whether initial symptom severity is related to antidepressant efficacy.
Statistical analysis plan:
A separate longitudinal analysis will be conducted for each disorder. For GAD, SAD, OCD, and PTSD, linear mixed models will be used; for PD, a generalized linear mixed model (multilevel negative binomial regression) will be used, as the dependent variable for this disorder (number of panic attacks) is a discrete count variable. Maximum likelihood estimation will be used as the estimation method for the linear mixed models, while Laplace approximation will be used as the estimation method for the multilevel negative binomial regression for PD. In all models, measurement occasion represents level 1, participants represent level 2, and trial represents level 3. The effect measure of interest is the change in symptoms from baseline, except for PD, for which the effect measure of interest is the total number of panic attacks per two weeks.
The initial model will be built by including all the fixed effects of interest, regardless of significance. These include initial severity, treatment group and covariates (see below). Linear and quadratic terms for time (in days since baseline) will be included. For each participant, the actual visit dates will be used (if available) rather than the intended weekly visit date. The following two- and three-way interactions will also be included: severity x group, severity x linear time, group x linear time, severity x group x linear time, severity x quadratic time, group x quadratic time, severity x group x quadratic time.
Using this first model, the variance-covariance structure of the nested data will be modeled by including random effects. Random effects for study, subject and (linear and quadratic) time, as well as various covariance structures (unstructured, autocorrelated errors, Toeplitz, etc.) will be considered. Restricted maximum likelihood (REML) will be used for estimation, and the best-fitting model will be selected based upon the Akaike Information Criterion (AICc).
In this best-fitting model, backward selection with maximum likelihood (ML) will be used to select the significant fixed effects. Non-significant interaction terms will be removed from the model (unless the three-way interaction of group x severity x (linear or quadratic) time is significant, in which case all two-way interactions and main effects that use these variables will be retained). The best-fitting model will again be selected based upon the Akaike Information Criterion (AICc).
Covariates: Models with and without the following covariates will be tested: age, gender, and duration of illness (if available). Only the main effect of these covariates will be included; no interactions with other variables will be included.
Missing data: Baseline variables (such as initial severity) are likely to be essentially complete, but some change scores are likely to be missing due to dropout or missed measurement occasions. The assumption is made that these data are missing at random (MAR), that is: missingness of the dependent variable may depend upon observed variables (such as previous symptom scores or covariates), but it does not depend upon the value of the unobserved (missing) variable. When MAR holds, the mixed model yields unbiased estimates of coefficients and standard errors even when some data is missing, and no other methods for handling missing data are required.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Anxiety Disorders, Panic Disorder, Obsessive-compulsive Disorder, Post-traumatic Stress Disorder, Generalized Anxiety Disorder, Social Anxiety Disorder
Keywords
individual patient data meta-analysis, anxiety disorder, antidepressants, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors
7. Study Design
Enrollment
8800 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Placebo group
Arm Description
Patients participating in one of the included randomized controlled trials, assigned to the placebo group
Arm Title
Intervention group
Arm Description
Patients participating in one of the included randomized controlled trials, assigned to the investigational antidepressant (paroxetine, duloxetine or fluoxetine) or active comparator (venlafaxine) group.
Intervention Type
Drug
Intervention Name(s)
paroxetine, duloxetine, fluoxetine or venlafaxine
Other Intervention Name(s)
Paxil, Cymbalta, Prozac, Effexor
Primary Outcome Measure Information:
Title
Change from baseline on the Hamilton Anxiety Rating Scale (HAM-A)
Time Frame
Baseline to trial endpoint (8 to 10 weeks)
Title
Change from baseline on the Liebowitz Social Anxiety Scale (LSAS)
Time Frame
Baseline to trial endpoint (12 weeks)
Title
Change from baseline on the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS)
Time Frame
Baseline to trial endpoint (12 to 13 weeks)
Title
Change from baseline on the Clinician-Administered PTSD Scale (CAPS)
Time Frame
Baseline to trial endpoint (12 weeks)
Title
The total number of panic attacks
Time Frame
Baseline to trial endpoint (10 to 12 weeks)
10. Eligibility
Sex
All
Minimum Age & Unit of Time
14 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Inclusion in the intent-to-treat population of a randomized controlled trial of a second-generation antidepressant for the short-term treatment of an anxiety disorder
Diagnosed with an anxiety disorder (GAD, SAD, OCD, PTSD or PD)
Exclusion Criteria:
Assignment to an active comparator that is not a second-generation antidepressant (e.g. a benzodiazepine)
Study Population Description
The study population consists of adults aged 18 and older (with the exception of OCD trials, which may include adolescents aged 14 and older) who have been diagnosed with generalized anxiety disorder (GAD), social anxiety disorder (SAD), obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD), or panic disorder (PD) and who were randomized to placebo or to treatment with a second-generation antidepressant.
Sampling Method
Non-Probability Sample
12. IPD Sharing Statement
Plan to Share IPD
No
Citations:
PubMed Identifier
29659102
Citation
de Vries YA, Roest AM, Burgerhof JGM, de Jonge P. Initial severity and antidepressant efficacy for anxiety disorders, obsessive-compulsive disorder, and posttraumatic stress disorder: An individual patient data meta-analysis. Depress Anxiety. 2018 Jun;35(6):515-522. doi: 10.1002/da.22737. Epub 2018 Apr 16.
Results Reference
derived
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Initial Severity and Antidepressant Efficacy for Anxiety Disorders: an Individual Patient Data Meta-analysis
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