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| ID | Type | Description | Link |
|---|---|---|---|
| R01MH065963 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| National Institute of Mental Health (NIMH) | NIH |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Open-Label Group | Active Comparator | 6-month randomized phase of Venlafaxine XR at a flexible dose of 75 - 225 mg/d |
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| Double-Blind Drug Group | Active Comparator | 6-month randomized, double-blind phase of Venlafaxine XR at a flexible dose of 75 - 225 mg/d occurring between months 6 - 12 of the study |
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| Double-Blind Placebo Group | Placebo Comparator | 6-month randomized, double blind phase of placebo occurring between months 6 - 12 of the study |
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| Double-Blind Drug-After-Drug Group | Active Comparator | 6-month randomized, double blind phase of Venlafaxine XR at a flexible dose of 75 - 225 mg/d occurring between months 13 - 19 of the study |
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| Double-Blind Placebo-After-Drug Group | Placebo Comparator | 6-month randomized, double blind phase of placebo occurring between months 13 - 19 of the study |
|
| Double-Blind Placebo-After-Placebo Group |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Venlafaxine XR | Drug | Six month intervention of Venlafaxine XR treatment with flexible range of 75 to 225 mg/d |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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. | Measured at Months 6 (Open Label), 12 (Double-Blind), and 18 (Double-Blind Relapse) |
| Measure | Description | Time Frame |
|---|---|---|
| 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. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Karl Rickels, MD | University of Pennsylvania | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Pennsylvania, 3535 Market Street, Suite 670 | Philadelphia | Pennsylvania | 19104-3309 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 24061331 | Background | Rickels K, Etemad B, Rynn MA, Lohoff FW, Mandos LA, Gallop R. Remission of generalized anxiety disorder after 6 months of open-label treatment with venlafaxine XR. Psychother Psychosom. 2013;82(6):363-71. doi: 10.1159/000351410. Epub 2013 Sep 20. | |
| 21135327 | Result | Rickels K, Etemad B, Khalid-Khan S, Lohoff FW, Rynn MA, Gallop RJ. Time to relapse after 6 and 12 months' treatment of generalized anxiety disorder with venlafaxine extended release. Arch Gen Psychiatry. 2010 Dec;67(12):1274-81. doi: 10.1001/archgenpsychiatry.2010.170. |
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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.
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
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| ID | Title | Description |
|---|---|---|
| FG000 | Phase 1: Open-Label | Patients received 75mg - 225 mg of open-label venlafaxine XR for 6 months. |
| FG001 | Phase 2: Double-Blind Venlafaxine XR | Responders to 6 months of open-label venlafaxine XR treatment were randomized to double-blind treatment in 60:40 ratio of drug to placebo |
| FG002 | Phase 2: Double-Blind Placebo | Responders to 6 months of open-label venlafaxine XR treatment were randomized to double-blind treatment in a 60:40 ratio of drug to placebo |
| FG003 | Phase 3: Double-Blind Relapse Phase (Drug After Drug) | Patients administered venlafaxine XR in phase 2 continued to take the drug during phase 3 |
| FG004 | Phase 3: Double-Blind Relapse Phase (Placebo After Drug) | Patients administered venlafaxine XR in Phase 2 were given a placebo in Phase 3 |
| FG005 | Phase 3: Double-Blind Relapse Phase (Placebo After Placebo) | Patients administered placebo in Phase 2 continued to take placebo during Phase 3 |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Phase 1: Open-Label |
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| Phase 2: Double-Blind |
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| Phase 3: Double-Blind |
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334 participants were consented, but 64 withdrew consent and 2 deviated from protocol, resulting in 268 participants who entered the initial Phase 1.
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | The primary efficacy analytic method was time-to-relapse analyses estimated using a discrete-time Cox proportional hazards model. | Posted | Mean | Standard Deviation | HAM-A Rating Score | Measured at Months 6 (Open Label), 12 (Double-Blind), and 18 (Double-Blind Relapse) |
|
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Venlafaxine XR | Adverse events were expected with venlafaxine XR. AEs were reported at least once by at least 5% of the study population for all patients who entered treatment. None of the adverse events that were expected or that occurred were considered serious or life threatening. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Abdominal Pain | General disorders | Non-systematic Assessment |
Increased attrition occurring as a function of trial length
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Karl Rickels, M.D. | UPENN | 215-746-6417 | krickels@mail.med.upenn.edu |
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| ID | Term |
|---|---|
| D001008 | Anxiety Disorders |
| D000098647 | Generalized Anxiety Disorder |
| D012008 | Recurrence |
| ID | Term |
|---|---|
| D001523 | Mental Disorders |
| D020969 | Disease Attributes |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
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| ID | Term |
|---|---|
| D000069470 | Venlafaxine Hydrochloride |
| ID | Term |
|---|---|
| D003511 | Cyclohexanols |
| D000441 | Hexanols |
| D005233 | Fatty Alcohols |
| D000438 | Alcohols |
| D009930 |
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| Placebo Comparator |
6-month randomized, double blind phase of placebo occurring between months 13 - 19 of the study |
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| Placebo | Drug | six month intervention with placebo drug |
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| Measured at Months 6 (Open Label), 12 (Double-Blind), 18 (Double-Blind, and 24 (Double-Blind Relapse) |
| 28437668 | Derived | Jung J, Tawa EA, Muench C, Rosen AD, Rickels K, Lohoff FW. Genome-wide association study of treatment response to venlafaxine XR in generalized anxiety disorder. Psychiatry Res. 2017 Aug;254:8-11. doi: 10.1016/j.psychres.2017.04.025. Epub 2017 Apr 14. |
| 24723432 | Derived | Saung WT, Narasimhan S, Lohoff FW. Lack of influence of DAT1 and DRD2 gene variants on antidepressant response in generalized anxiety disorder. Hum Psychopharmacol. 2014 Jul;29(4):316-21. doi: 10.1002/hup.2404. Epub 2014 Apr 10. |
| 23972788 | Derived | Cooper AJ, Narasimhan S, Rickels K, Lohoff FW. Genetic polymorphisms in the PACAP and PAC1 receptor genes and treatment response to venlafaxine XR in generalized anxiety disorder. Psychiatry Res. 2013 Dec 30;210(3):1299-300. doi: 10.1016/j.psychres.2013.07.038. Epub 2013 Aug 22. |
| 23658070 | Derived | Cooper AJ, Rickels K, Lohoff FW. Association analysis between the A118G polymorphism in the OPRM1 gene and treatment response to venlafaxine XR in generalized anxiety disorder. Hum Psychopharmacol. 2013 May;28(3):258-62. doi: 10.1002/hup.2317. Epub 2013 May 8. |
| 22907732 | Derived | Lohoff FW, Narasimhan S, Rickels K. Interaction between polymorphisms in serotonin transporter (SLC6A4) and serotonin receptor 2A (HTR2A) genes predict treatment response to venlafaxine XR in generalized anxiety disorder. Pharmacogenomics J. 2013 Oct;13(5):464-9. doi: 10.1038/tpj.2012.33. Epub 2012 Aug 21. |
| 22417933 | Derived | Narasimhan S, Aquino TD, Multani PK, Rickels K, Lohoff FW. Variation in the catechol-O-methyltransferase (COMT) gene and treatment response to venlafaxine XR in generalized anxiety disorder. Psychiatry Res. 2012 Jun 30;198(1):112-5. doi: 10.1016/j.psychres.2011.12.034. Epub 2012 Mar 13. |
| 22006095 | Derived | Lohoff FW, Aquino TD, Narasimhan S, Multani PK, Etemad B, Rickels K. Serotonin receptor 2A (HTR2A) gene polymorphism predicts treatment response to venlafaxine XR in generalized anxiety disorder. Pharmacogenomics J. 2013 Feb;13(1):21-6. doi: 10.1038/tpj.2011.47. Epub 2011 Oct 18. |
| 21889574 | Derived | Narasimhan S, Aquino TD, Hodge R, Rickels K, Lohoff FW. Association analysis between the Val66Met polymorphism in the brain-derived neurotrophic factor (BDNF) gene and treatment response to venlafaxine XR in generalized anxiety disorder. Neurosci Lett. 2011 Oct 10;503(3):200-2. doi: 10.1016/j.neulet.2011.08.035. Epub 2011 Aug 26. |
| Lack of Efficacy |
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| Protocol Violation |
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| Withdrawal by Subject |
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| Lost to Follow-up |
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| Other |
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| COMPLETED |
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| NOT COMPLETED |
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| COMPLETED |
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| NOT COMPLETED |
|
|
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | years |
|
| Gender | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Double-Blind Venlafaxine XR |
A 6-month double-blind administration of Venlafaxine XR that occurred between months 7 - 12. |
| OG002 | Double-Blind Placebo | A 6-month double-blind administration of placebo that occurred between months 7 - 12. |
| OG003 | Double-Blind Relapse Drug After Drug | A 6-month double-blind administration of Venlafaxine XR that occurred between months 13 - 18. |
| OG004 | Double-Blind Relapse Placebo After Drug | A 6-month double-blind administration of placebo that occurred between months 13 - 18. |
| OG005 | Double-Blind Placebo After Placebo | A 6-month double-blind administration of placebo that occurred between months 13 - 18. |
|
|
| 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. | 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. | Posted | Mean | Standard Deviation | Severity Score | Measured at Months 6 (Open Label), 12 (Double-Blind), 18 (Double-Blind, and 24 (Double-Blind Relapse) |
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|
| 0 |
| 268 |
| 219 |
| 268 |
| Constipation | Gastrointestinal disorders | Non-systematic Assessment |
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| Decreased Orgasm | General disorders | Non-systematic Assessment |
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| Decreased Sex Drive | General disorders | Non-systematic Assessment |
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| Delayed Orgasm | General disorders | Non-systematic Assessment |
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| Diarrhea | Gastrointestinal disorders | Non-systematic Assessment |
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| Drowsiness | General disorders | Non-systematic Assessment |
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| Dry mouth | General disorders | Non-systematic Assessment |
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| Faintness | General disorders | Non-systematic Assessment |
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| Fatigue | General disorders | Non-systematic Assessment |
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| Flatulence | Gastrointestinal disorders | Non-systematic Assessment |
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| Gas | Gastrointestinal disorders | Non-systematic Assessment |
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| Headache | General disorders | Non-systematic Assessment |
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| Increased sweating | General disorders | Non-systematic Assessment |
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| Insomnia | General disorders | Non-systematic Assessment |
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| Jitteriness | General disorders | Non-systematic Assessment |
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| Lightheadedness | General disorders | Non-systematic Assessment |
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| Muscle Aches | General disorders | Non-systematic Assessment |
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| Nausea | General disorders | Non-systematic Assessment |
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| Nightmares | General disorders | Non-systematic Assessment |
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| Organic Chemicals |
| D010627 | Phenethylamines |
| D005021 | Ethylamines |
| D000588 | Amines |
| D003510 | Cyclohexanes |
| D003516 | Cycloparaffins |
| D006840 | Hydrocarbons, Alicyclic |
| D006844 | Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
| D008055 | Lipids |