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A Study of Infliximab for Treatment Resistant Major Depression (Infliximab)

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ClinicalTrials.gov Identifier: NCT00463580
Recruitment Status : Completed
First Posted : April 20, 2007
Results First Posted : May 12, 2014
Last Update Posted : December 4, 2018
Sponsor:
Collaborator:
National Institute of Mental Health (NIMH)
Information provided by (Responsible Party):
Andrew H Miller, Emory University

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Depression Drug: Infliximab Drug: Placebo Phase 4

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 60 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: An Evaluation of the Efficacy of the Tumor Necrosis Factor-alpha Antagonist Infliximab in Treatment Resistant Major Depression: Mechanisms and Mediators
Study Start Date : December 2008
Actual Primary Completion Date : June 2011
Actual Study Completion Date : June 2011

Resource links provided by the National Library of Medicine

Drug Information available for: Infliximab

Arm Intervention/treatment
Experimental: Infliximab
Participants in this arm will receive an infusion of infliximab.
Drug: Infliximab
Participants will receive three infusions 5mg/kg of infliximab (at Baseline, Week 2 and Week 6)
Other Name: Remicade

Placebo Comparator: Placebo
Participants in this arm will receive an infusion of normal saline.
Drug: Placebo
Participants will receive three infusions of a placebo (at Baseline, Week 2 and Week 6)
Other Name: Normal saline




Primary Outcome Measures :
  1. Hamilton Depression Rating Scale 17 (HDRS-17) Scores [ Time Frame: Baseline, Weeks 1, 2, 4, 6, 8, 10 and 12 ]
    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.


Secondary Outcome Measures :
  1. Number of Participants With a 50% Reduction in Hamilton Depression Rating Scale (HDRS) Scores [ Time Frame: Week 12 ]
    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.

  2. Number of Remitted Patients During Treatment [ Time Frame: Week 12 ]
    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.

  3. Inventory of Depressive Symptomatology-Self-Report (IDS-SR) Scores [ Time Frame: Baseline, Weeks 1, 2, 4, 6, 8, 10 and 12 ]
    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.

  4. Plasma Concentrations of Interleukin-6 (IL-6) [ Time Frame: Baseline, Week 12 ]
    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).

  5. Plasma Concentrations of CRP [ Time Frame: Baseline, Week 12 ]
    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.

  6. Plasma Concentrations of Tumor Necrosis Factor (TNF)-Alpha [ Time Frame: Baseline, Week 12 ]
    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.

  7. Sleep Efficiency [ Time Frame: Baseline, Week 8 ]
    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.

  8. Sleep Efficiency in High (CRP>5mg/L) Versus Low (CRP < or =5mg/L) Infliximab-treated Patients [ Time Frame: Baseline, Week 8 ]
    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.

  9. Change in Hamilton Depression Rating Scale 17 (HDRS-17) Scores Subgrouped by Baseline Hs-CRP. [ Time Frame: Baseline, Week 12 ]
    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.



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Ages Eligible for Study:   25 Years to 60 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00463580


Locations
United States, Georgia
Emory Clinic, Emory University Hospital
Atlanta, Georgia, United States, 30322
Sponsors and Collaborators
Emory University
National Institute of Mental Health (NIMH)
Investigators
Principal Investigator: Andrew H. Miller, MD Emory University

Publications of Results:
Responsible Party: Andrew H Miller, Professor, Emory University
ClinicalTrials.gov Identifier: NCT00463580     History of Changes
Other Study ID Numbers: IRB00011734
1R21MH077172-01A2 ( U.S. NIH Grant/Contract )
First Posted: April 20, 2007    Key Record Dates
Results First Posted: May 12, 2014
Last Update Posted: December 4, 2018
Last Verified: November 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Andrew H Miller, Emory University:
depression
TNF-alpha antagonist
infliximab
treatment resistant depression
major depressive disorder (MDD)
bipolar I disorder
bipolar II disorder

Additional relevant MeSH terms:
Depression
Depressive Disorder
Depressive Disorder, Major
Behavioral Symptoms
Mood Disorders
Mental Disorders
Infliximab
Dermatologic Agents
Gastrointestinal Agents
Antirheumatic Agents