Anxiety Disorders
Conditions
Keywords
Generalized Anxiety Disorder, Chronic Mediation Treatment, Double-Blind, Placebo Controlled, Venlafaxine XR, Relapse
Brief summary
This study will assess the effectiveness of venlafaxine XR, randomized to either venlafaxine XR or placebo in preventing the relapse of generalized anxiety disorder after 6 months of treatment versus 12 months of treatment.
Detailed description
Generalized anxiety disorder (GAD) is a highly prevalent, chronic psychiatric disorder. Despite the fact that GAD frequently demands prolonged treatment with medication, very little is known about the benefits of long-term treatment. GAD is characterized by 6 months or more of exaggerated worry and tension that is unfounded or much more severe than the normal anxiety most people experience. People with GAD are unable to relax and often suffer from insomnia. Venlafaxine XR, a drug used to treat depression, has been shown to be effective in the short-term treatment of GAD. However, its benefits over a course of more than 8 weeks have not been assessed. This study will evaluate the effectiveness of venlafaxine XR in treating GAD on a long-term basis and preventing the relapse of GAD after 6 months of treatment versus 12 months of treatment. Participants in this double-blind study will first receive 6 months of open-label treatment with venlafaxine XR. Upon completion of this initial phase, participants will be randomly assigned to either continue on venlafaxine XR or begin taking placebo. After 12 months, participants taking venlafaxine XR will be randomly assigned to continue on the drug or switch to placebo. Participants will have 22 study visits over at least 18 months. Follow-up visits will occur 24 months after enrollment. Relapse of GAD will be assessed with the Hamilton Anxiety Scale and Global Severity and Improvement Scale. A variety of methods, including questionnaires and standardized scales, will be used to assess secondary outcomes.
Interventions
DRUGVenlafaxine XR
Six month intervention of Venlafaxine XR treatment with flexible range of 75 to 225 mg/d
DRUGPlacebo
six month intervention with placebo drug
Sponsors
National Institute of Mental Health (NIMH)
University of Pennsylvania
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* GAD diagnosis by structured interview * Hamilton Anxiety Scale score of 18 or MORE * Clinical Global Impressions Severity Scale score of at least 4 * Hamilton Depression Scale score of 18 or less * Hamilton Depression Scale suicide item score less than 2 * Use of an effective form of contraception throughout the study
Exclusion criteria
* Hypersensitivity to venlafaxine XR * History of seizures * Episode of major depressive disorder in the previous 6 months * History of any psychotic illness, bipolar disorder, or dementia * Substance abuse and dependence during the past 6 months * Other anxiety disorders with the exception of social phobia as long as GAD is primary * Regular use of anxiolytics or antidepressants within 7 days of study onset * Use of fluoxetine or monoamine oxidase inhibitors within 28 days of study onset (low dose usage of benzodiazepines will not prevent participation) * Use of other psychotropic medication besides benzodiazepines during the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Hamilton Rating Scale for Anxiety | Measured at Months 6 (Open Label), 12 (Double-Blind), and 18 (Double-Blind Relapse) | Hamilton Rating Scale for Anxiety - The assessment of anxiety states by rating Each item is scored on a scale of 0 (not present) to 4 (severe), with a total score range of 0-56, where \<17 indicates mild severity, 18-24 mild to moderate severity and 25-30 moderate to severe. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Global Impressions, Severity of Illness | Measured at Months 6 (Open Label), 12 (Double-Blind), 18 (Double-Blind, and 24 (Double-Blind Relapse) | The CGI provides an overall clinician-determined summary measure that takes into account a knowledge of the patient's history, psychosocial circumstances, symptoms, behavior, and the impact of the symptoms on the patient's ability to function. The CGI is rated on the following seven-point scale: 1=normal, not at all ill; 2=borderline mentally ill; 3=mildly ill; 4=moderately ill; 5=markedly ill; 6=severely ill; 7=among the most extremely ill patients. Results of the Placebo After Placebo group in Phase 3 were not entered due to sample size limitations. |
Countries
United States
Participant flow
Recruitment details
Most patients (n=239) were recruited and seen by Penn research psychiatrists in 4 primary care practices; others (n=95) responded to media advertising (radio & print ads) at the central clinic at the University of Pennsylvania
Pre-assignment details
7-day washout period of any psychoactive medication;other antidepressants and herbal products. Subject on certain medications, such as monamine oxidase inhibitor, investigational and antipsychotic drugs had to be off these medications for at least 30 days.
Participants by arm
| Arm | Count |
|---|---|
| Venlafaxine XR Venlafaxine XR flexible dose of 75 - 225 mg/d
Venlafaxine XR : All participants will take venlafaxine for 6 months. After this initial 6 months, participants who are not randomized to placebo will continue to take venlafaxine. | 334 |
| Total | 334 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Phase 1: Open-Label | Adverse Event | 31 | 0 | 0 | 0 | 0 | 0 |
| Phase 1: Open-Label | Lack of Efficacy | 13 | 0 | 0 | 0 | 0 | 0 |
| Phase 1: Open-Label | Lost to Follow-up | 33 | 0 | 0 | 0 | 0 | 0 |
| Phase 1: Open-Label | Other | 9 | 0 | 0 | 0 | 0 | 0 |
| Phase 1: Open-Label | Protocol Violation | 11 | 0 | 0 | 0 | 0 | 0 |
| Phase 1: Open-Label | Withdrawal by Subject | 13 | 0 | 0 | 0 | 0 | 0 |
| Phase 2: Double-Blind | Relapsed | 0 | 8 | 29 | 0 | 0 | 0 |
| Phase 2: Double-Blind | Withdrawal by Subject | 0 | 18 | 14 | 0 | 0 | 0 |
| Phase 3: Double-Blind | Relapsed | 0 | 0 | 0 | 1 | 11 | 2 |
| Phase 3: Double-Blind | Withdrawal by Subject | 0 | 0 | 0 | 1 | 9 | 2 |
Baseline characteristics
| Characteristic | Venlafaxine XR |
|---|---|
| Age, Categorical <=18 years | 4 Participants |
| Age, Categorical >=65 years | 50 Participants |
| Age, Categorical Between 18 and 65 years | 280 Participants |
| Age, Continuous | 46.11 years STANDARD_DEVIATION 16.14 |
| Gender Female | 210 Participants |
| Gender Male | 124 Participants |
| Region of Enrollment United States | 334 participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 219 / 268 |
| serious Total, serious adverse events | 0 / 268 |
Outcome results
Primary
Hamilton Rating Scale for Anxiety
Hamilton Rating Scale for Anxiety - The assessment of anxiety states by rating Each item is scored on a scale of 0 (not present) to 4 (severe), with a total score range of 0-56, where \<17 indicates mild severity, 18-24 mild to moderate severity and 25-30 moderate to severe.
Time frame: Measured at Months 6 (Open Label), 12 (Double-Blind), and 18 (Double-Blind Relapse)
Population: The primary efficacy analytic method was time-to-relapse analyses estimated using a discrete-time Cox proportional hazards model.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Open-Label: Venlafaxine XR | Hamilton Rating Scale for Anxiety | 4.17 HAM-A Rating Score | Standard Deviation 3.1 |
| Double-Blind Venlafaxine XR | Hamilton Rating Scale for Anxiety | 6.29 HAM-A Rating Score | Standard Deviation 5.44 |
| Double-Blind Placebo | Hamilton Rating Scale for Anxiety | 11.35 HAM-A Rating Score | Standard Deviation 5.51 |
| Double-Blind Relapse Drug After Drug | Hamilton Rating Scale for Anxiety | 5.80 HAM-A Rating Score | Standard Deviation 4.95 |
| Double-Blind Relapse Placebo After Drug | Hamilton Rating Scale for Anxiety | 8.42 HAM-A Rating Score | Standard Deviation 6.12 |
| Double-Blind Placebo After Placebo | Hamilton Rating Scale for Anxiety | 6.19 HAM-A Rating Score | Standard Deviation 5.76 |
Secondary
Clinical Global Impressions, Severity of Illness
The CGI provides an overall clinician-determined summary measure that takes into account a knowledge of the patient's history, psychosocial circumstances, symptoms, behavior, and the impact of the symptoms on the patient's ability to function. The CGI is rated on the following seven-point scale: 1=normal, not at all ill; 2=borderline mentally ill; 3=mildly ill; 4=moderately ill; 5=markedly ill; 6=severely ill; 7=among the most extremely ill patients. Results of the Placebo After Placebo group in Phase 3 were not entered due to sample size limitations.
Time frame: Measured at Months 6 (Open Label), 12 (Double-Blind), 18 (Double-Blind, and 24 (Double-Blind Relapse)
Population: The primary efficacy analytic method was time to relapse analyses estimated using a discrete time Cox proportional hazards model.Chisquare analyses were used to contrast relapse or responder rates. In the case of small cell sizes, Fisher exact test replaced chisquare analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Open-Label: Venlafaxine XR | Clinical Global Impressions, Severity of Illness | 1.37 Severity Score | Standard Deviation 0.65 |
| Double-Blind Venlafaxine XR | Clinical Global Impressions, Severity of Illness | 1.73 Severity Score | Standard Deviation 1.27 |
| Double-Blind Placebo | Clinical Global Impressions, Severity of Illness | 2.64 Severity Score | Standard Deviation 1.25 |
| Double-Blind Relapse Drug After Drug | Clinical Global Impressions, Severity of Illness | 1.86 Severity Score | Standard Deviation 1.01 |
| Double-Blind Relapse Placebo After Drug | Clinical Global Impressions, Severity of Illness | 2.25 Severity Score | Standard Deviation 1.17 |
| Double-Blind Placebo After Placebo | Clinical Global Impressions, Severity of Illness | 1.95 Severity Score | Standard Deviation 1.31 |