Anxiety DisordersNCT02476136
Initial Severity and Antidepressant Efficacy for Anxiety Disorders: an Individual Patient Data Meta-analysis
An observational study of Anxiety Disorders and Panic Disorder, run by prof. Peter de Jonge.
Trial 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). Read more about this study
- Who is it for?
- Ages 14 years and older
- Conditions the study is for
- Anxiety Disorders, Panic Disorder, Obsessive-compulsive Disorder
- What is being tested?
- paroxetine, duloxetine, fluoxetine or venlafaxine
- How many people
- 8,800 participants
- Where
- No sites listed yet
- Study dates
- May 2015to Dec 2016
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 14 years and older
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Study population: 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.
Who may be able to join
- 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)
Who cannot join
- Assignment to an active comparator that is not a second-generation antidepressant (e.g. a benzodiazepine)
About this study
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.
Read the 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.
- Conditions
- Anxiety Disorders, Panic Disorder, Obsessive-compulsive Disorder, Post-traumatic Stress Disorder, Generalized Anxiety Disorder, Social Anxiety Disorder
- Being tested
- paroxetine, duloxetine, fluoxetine or venlafaxine
- Keywords
- individual patient data meta-analysis, anxiety disorder, antidepressants, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors
- Medical subject headings
- Anxiety Disorders, Panic Disorder, Obsessive-Compulsive Disorder, Stress Disorders, Post-Traumatic, Generalized Anxiety Disorder, Phobia, Social
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
paroxetine, duloxetine, fluoxetine or venlafaxineDrug
Also called Paxil, Cymbalta, Prozac, Effexor
| Study group | Role | What they receive |
|---|---|---|
| Placebo group | Patients participating in one of the included randomized controlled trials, assigned to the placebo group | |
| Intervention 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. Receives: Drug: paroxetine, duloxetine, fluoxetine or venlafaxine |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change from baseline on the Hamilton Anxiety Rating Scale (HAM-A)
Measured: Baseline to trial endpoint (8 to 10 weeks)
Change from baseline on the Liebowitz Social Anxiety Scale (LSAS)
Measured: Baseline to trial endpoint (12 weeks)
Change from baseline on the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS)
Measured: Baseline to trial endpoint (12 to 13 weeks)
Change from baseline on the Clinician-Administered PTSD Scale (CAPS)
Measured: Baseline to trial endpoint (12 weeks)
The total number of panic attacks
Measured: Baseline to trial endpoint (10 to 12 weeks)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted19 Jun 2015 (estimated)
- Study startMay 2015
- Primary completionMar 2016
- Study completionDec 2016 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Anxiety DisordersStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Enrolment
- 8,800 participants (estimated)
Sponsor and investigators
- Lead sponsor
- prof. Peter de Jonge
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor-investigator, prof. Peter de Jonge, University Medical Center Groningen
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02476136
- Sponsor's protocol ID
- CSDR-1173
- Status last verified
- Sep 2016
- First submitted
- 3 Jun 2015
- Last updated
- 27 Sep 2016
- Results posted
- No
- Data monitoring committee
- No
- Individual data sharing
- No
Publications
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.
PubMed 29659102
Study at a glance
From the registry record, last updated by the sponsor on 27 Sep 2016. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Initial Severity and Antidepressant Efficacy for Anxiety Disorders: an Individual Patient Data Meta-analysis
- ClinicalTrials.gov ID
- NCT02476136
- Acronym / sponsor ID
- CSDR-1173
- Conditions
- 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
- Study type
- Observational
- Recruitment status
- Unknown status
- Enrolment
- 8,800 participants (estimated)
- Lead sponsor
- prof. Peter de JongeUniversity, hospital or other
- Study start
- May 2015
- Primary completion
- Mar 2016 (actual)
- Study completion
- Dec 2016 (estimated)
- First posted
- 19 Jun 2015 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Placebo group | – | –Patients participating in one of the included randomized controlled trials, assigned to the placebo group |
| Intervention group | – | Drug: paroxetine, duloxetine, fluoxetine or venlafaxinePatients participating in one of the included randomized controlled trials, assigned to the investigational antidepressant (paroxetine, duloxetine or fluoxetine) or active comparator (venlafaxine) group. |
Who may qualify
- Ages
- 14 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
- Study population
- 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.
Key inclusion criteria (2 listed)
- 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)
Key exclusion criteria (1 listed)
- Assignment to an active comparator that is not a second-generation antidepressant (e.g. a benzodiazepine)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| paroxetine, duloxetine, fluoxetine or venlafaxineAlso: Paxil, Cymbalta, Prozac, Effexor | Drug | Intervention group |
Primary outcome
Change from baseline on the Hamilton Anxiety Rating Scale (HAM-A)
Time frame: Baseline to trial endpoint (8 to 10 weeks)
Change from baseline on the Liebowitz Social Anxiety Scale (LSAS)
Time frame: Baseline to trial endpoint (12 weeks)
Change from baseline on the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS)
Time frame: Baseline to trial endpoint (12 to 13 weeks)
Change from baseline on the Clinician-Administered PTSD Scale (CAPS)
Time frame: Baseline to trial endpoint (12 weeks)
The total number of panic attacks
Time frame: Baseline to trial endpoint (10 to 12 weeks)
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 27 Sep 2016.
- Derived from this study: PubMed 29659102de 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.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
Questions about this trial
What is this clinical trial studying?
An observational study of Anxiety Disorders and Panic Disorder, run by prof. Peter de Jonge.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 2 inclusion and 1 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 27 Sep 2016. Status can change between updates, so confirm with the study contact before making plans.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change from baseline on the Hamilton Anxiety Rating Scale (HAM-A) (time frame: Baseline to trial endpoint (8 to 10 weeks)). The study lists 5 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02476136, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 27 Sep 2016.