Depression Clinical Trial
— InfliximabOfficial title:
An Evaluation of the Efficacy of the Tumor Necrosis Factor-alpha Antagonist Infliximab in Treatment Resistant Major Depression: Mechanisms and Mediators
Verified date | November 2018 |
Source | Emory University |
Contact | n/a |
Is FDA regulated | No |
Health authority | |
Study type | Interventional |
Major depression is increasingly recognized to be a chronic and highly recurrent condition,
which results in significantly increased health problems. One possible mechanism that may
contribute to treatment resistance is increased production and release of chemicals called
proinflammatory cytokines in patients with major depression. These chemicals mediate the
body's response to infectious agents like bacteria and have been shown to be increased by
psychological stress. They produce the symptoms that we associate with being sick, including
fever, malaise and changes in sleep and appetite. Several lines of evidence indicate that
proinflammatory cytokines may contribute to the development of major depression and may thus
represent a novel target for the pharmacological treatment of the disorder.
The TNF-alpha antagonist, Infliximab (Remicade®), is an infusion style drug approved by the
FDA for the treatment of inflammatory conditions like Crohns disease and rheumatoid
arthritis. The researchers are conducting a study to see if the infliximab (Remicade®) is
more effective than placebo in acutely reducing symptoms of depression in patients who have
elevated proinflammatory markers and have not responded to, or been unable to tolerate, at
least two previous treatments in the current depressive episode. Proinflammatory markers are
measured by a simple blood test for C-Reactive Protein (CRP) levels in the body.
After appropriate screening to determine eligibility, 64 subjects with treatment resistant
depression will be randomized to receive three infusions of either infliximab (Remicade®) or
placebo (salt water) in the Emory Infliximab Infusion Center in the Division of Digestive
Diseases, Emory University School of Medicine. Subjects will be followed for 12 weeks with
evaluations at weeks 0 (baseline), 1, 2, 3, 4, 6, 8, 10 and 12. The first infliximab
(Remicade®) infusion will occur at the first (Baseline) visit. The second infusion will occur
at Study Week 2 (the third visit). The third infusion will occur at Study Week 6 (Visit 6).
The choice of three infusions, and the infusion schedule, is based on current recommendations
for the use of infliximab (Remicade®) in conditions for which it has received FDA approval.
Subjects will be evaluated for twelve weeks by trained clinicians for changes in depression
symptoms and improvements in quality of life. In addition, a physician will evaluate subjects
each visit to make sure they are remaining healthy. Blood will be drawn at baseline prior to
infusion and all subsequent visits to check labs for safety but also to evaluate potential
relationships between changes in inflammatory activity and therapeutic response. After Study
Week 12, participants will be monitored by phone, every 4 weeks during the 22-Week Post Study
Follow-up Phase to assess physical and psychiatric symptoms in the period following the final
infusion. At the baseline and Week 8 visits, subjects will be admitted to the Atlanta
Clinical Translational Science Institute (ACTSI), a research unit in the Emory Hospital, for
an extended evaluation. The purpose of coming to the ACTSI will be for researchers to
evaluate whether treatment with infliximab improves endocrine function, inflammation, sleep
and thinking abilities in people who are depressed. For all other visits (Week 1, 2, 4, 6, 10
and 12), participants will come for an office visit in the Winship Cancer Institute.
Status | Completed |
Enrollment | 60 |
Est. completion date | June 2011 |
Est. primary completion date | June 2011 |
Accepts healthy volunteers | No |
Gender | All |
Age group | 25 Years to 60 Years |
Eligibility |
Inclusion Criteria: 1. Males or females ages 25-60. Must be able to read and understand English. 2. Currently meets the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-IV) criteria for a major depressive episode. (History of either unipolar major depression (depressive episodes only) or bipolar I disorder (history of manias and depressions) or bipolar II disorder (hypomanias and depressions), current episode depressed acceptable). 3. Must meet criteria for "treatment resistant" depression defined by failure to respond to, or intolerance of, at least 2 treatment trials (antidepressants or ECT) during the current episode. 4. All subjects will be fully ambulatory and in good medical health. 5. Are required to either be antidepressant free for 2 weeks prior to study entry (4 weeks for fluoxetine secondary to long half-life) or be on a fixed psychotropic medication regimen for at least 4 weeks. Subjects and their primary care providers must agree to continue their status (i.e. without antidepressant or on a fixed regimen) until the 12-week assessment is complete. 6. Pre-menopausal female subjects must not be pregnant and must be willing to use adequate contraception during the study period. Exclusion Criteria: 1. Current or history of psychotic symptoms. 2. Active suicidal ideation (defined as a score of =3 on Hamilton Depression Rating Scale (HDRS) suicide item). 3. Prior use of a TNF-alpha antagonist (i.e. etanercept, infliximab, adalimumab) and use of any other immunosuppressant agent (i.e. systemic corticosteroids or anti-proliferative agents such as methotrexate) within one year of study entry. 4. Current use of aspirin, non-steroidal anti-inflammatory agents (NSAIDs) or cyclooxygenase-2 (COX-2) inhibitors during the study. Acetaminophen will be allowed. 5. History of any of the following conditions: Congestive heart failure, abnormal electrocardiogram, malignancy, schizophrenia, neurological disease, auto-immune condition (e.g. rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, lupus), chronic infection (e.g. human immunodeficiency virus, hepatitis B or C), and hematologic, renal or hepatic abnormality. 6. Subjects will be excluded for a positive anti-double stranded DNA antibody test. |
Country | Name | City | State |
---|---|---|---|
United States | Emory Clinic, Emory University Hospital | Atlanta | Georgia |
Lead Sponsor | Collaborator |
---|---|
Emory University | National Institute of Mental Health (NIMH) |
United States,
Mehta D, Raison CL, Woolwine BJ, Haroon E, Binder EB, Miller AH, Felger JC. Transcriptional signatures related to glucose and lipid metabolism predict treatment response to the tumor necrosis factor antagonist infliximab in patients with treatment-resista — View Citation
Raison CL, Rutherford RE, Woolwine BJ, Shuo C, Schettler P, Drake DF, Haroon E, Miller AH. A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: the role of baseline inflammatory biomarkers. J — View Citation
Weinberger JF, Raison CL, Rye DB, Montague AR, Woolwine BJ, Felger JC, Haroon E, Miller AH. Inhibition of tumor necrosis factor improves sleep continuity in patients with treatment resistant depression and high inflammation. Brain Behav Immun. 2015 Jul;47 — View Citation
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Primary | Hamilton Depression Rating Scale 17 (HDRS-17) Scores | The HDRS is a 17-item survey asking respondents to rate the degree of depressive symptoms they are feeling on a scale of 0 to 2-4, where 0 means the symptom is absent and 2-4 means the symptom is very strong. Total scores can range from 0 to 52 where higher scores represent greater symptom severity. Scores of 0-7 are considered normal, scores of 8-16 indicates mild depression, scores of 17-23 indicate moderate depression, and scores of 24 and greater indicate severe depression. | Baseline, Weeks 1, 2, 4, 6, 8, 10 and 12 | |
Secondary | Number of Participants With a 50% Reduction in Hamilton Depression Rating Scale (HDRS) Scores | The number of participants with a 50% reduction in Hamilton Depression Rating Scale (HDRS) scores at any study point are presented here. The HDRS is a 17-item survey asking respondents to rate the degree of depressive symptoms they are feeling on a scale of 0 to 2-4, where 0 means the symptom is absent and 2-4 means the symptom is very strong. Total scores can range from 0 to 52 where higher scores represent greater symptom severity. Scores of 0-7 are considered normal, scores of 8-16 indicates mild depression, scores of 17-23 indicate moderate depression, and scores of 24 and greater indicate severe depression. | Week 12 | |
Secondary | Number of Remitted Patients During Treatment | The number of participants achieving depression remission are presented here. Depression remission is defined as an HDRS score of =7 or a Clinical Global Impression-Improvement (CGI-I) score of 1. The HDRS is a 17-item survey asking respondents to rate the degree of depressive symptoms they are feeling on a scale of 0 to 2-4, where 0 means the symptom is absent and 2-4 means the symptom is very strong. Total scores can range from 0 to 52 where higher scores represent greater symptom severity. Scores of 0-7 are considered normal, scores of 8-16 indicates mild depression, scores of 17-23 indicate moderate depression, and scores of 24 and greater indicate severe depression. The CGI-I scale includes a single item where a health care provider rates the participant's level of clinical improvement on a scale of 1 to 7 where 1 = very much improved since initiation of treatment and 7 = very much worse since initiation of treatment. | Week 12 | |
Secondary | Inventory of Depressive Symptomatology-Self-Report (IDS-SR) Scores | The Inventory of Depressive Symptomatology-Self-Report (IDS-SR) is a 30-item questionnaire asking respondents about symptoms of depression that they have experienced in the past 7 days. Each item is scored on a 4-point scale where 0 means that the symptom is absent and 3 means that the symptom is very strongly felt. Total scores can range between 0 and 84 and higher scores indicate more severe symptoms of depression. | Baseline, Weeks 1, 2, 4, 6, 8, 10 and 12 | |
Secondary | Plasma Concentrations of Interleukin-6 (IL-6) | This study collected blood samples to assess inflammatory markers. IL-6 is a proinflammatory cytokine that is elevated during times of inflammation, infection, illness, and in patients with mood disorders. IL-6 is not present or is low in healthy individuals and exact reference ranges vary by lab, with an example normal reference range of 0.31 to 5.00 picograms per milliliter (pg/mL). | Baseline, Week 12 | |
Secondary | Plasma Concentrations of CRP | This study collected blood samples to assess inflammatory markers. CRP increases when inflammation is present and can be measured with a high sensitivity-CRP (hs-CRP) test. Hs-CRP values <1 milligram per liter (mg/L) indicate low inflammation while values >10mg/L indicate inflammation. | Baseline, Week 12 | |
Secondary | Plasma Concentrations of Tumor Necrosis Factor (TNF)-Alpha | This study collected blood samples to assess inflammatory markers. Tumor necrosis factor (TNF)-alpha values are invalid due to the administration of infliximab which interferes with the assay procedure. | Baseline, Week 12 | |
Secondary | Sleep Efficiency | Sleep efficiency is the percentage of time in bed spent sleeping (total sleep time/sleep period time x 100). A sleep efficiency of 80% or greater is considered normal. This outcome measures examines sleep efficiency between study treatment groups. | Baseline, Week 8 | |
Secondary | Sleep Efficiency in High (CRP>5mg/L) Versus Low (CRP < or =5mg/L) Infliximab-treated Patients | Sleep efficiency is the percentage of time in bed spent sleeping (total sleep time/sleep period time x 100). A sleep efficiency of 80% or greater is considered normal. This outcome measure examines sleep efficiency between participants with high or low baseline CRP. | Baseline, Week 8 | |
Secondary | Change in Hamilton Depression Rating Scale 17 (HDRS-17) Scores Subgrouped by Baseline Hs-CRP. | The effects of baseline high-sensitivity C-reactive protein (hs-CRP) on reduction in depressive symptoms were investigated by examining the least squares mean change in the HDRS score from baseline to week 12 (infliximab minus placebo) among participants with baseline CRP of >1 mg/L, >3 mg/L, and >5 mg/L. A negative change score favors infliximab. The HDRS is a 17-item survey asking respondents to rate the degree of depressive symptoms they are feeling on a scale of 0 to 2-4, where 0 means the symptom is absent and 2-4 means the symptom is very strong. Total scores can range from 0 to 52 where higher scores represent greater symptom severity. Scores of 0-7 are considered normal, scores of 8-16 indicates mild depression, scores of 17-23 indicate moderate depression, and scores of 24 and greater indicate severe depression. | Baseline, Week 12 |
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