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Anti-INFLammatory to Address Mood and Endothelial Dysfunction (INFLAMED) (INFLAMED)

Primary Purpose

Major Depressive Disorder, Depression, Depressive Symptoms

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Pentoxifylline
Placebo
Standard Treatment
Sponsored by
Indiana University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Major Depressive Disorder focused on measuring Major Depressive Disorder, Depression, Depressive Symptoms, Cardiovascular Disease (CVD), Coronary Artery Disease (CAD), Heart Disease, Endothelial Function, Inflammation

Eligibility Criteria

40 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Primary care patients
  • Age ≥ 40 years
  • Clinically significant depressive symptoms, defined as a PHQ-9 score ≥15
  • English speaking

Exclusion Criteria:

  • History of clinical cardiovascular disease
  • History of cardiac arrhythmias or cardiomyopathy
  • History of carotid bruits
  • History of certain chronic disorders (HIV/AIDS, kidney disease, liver disease, systemic inflammatory disease, or past-year cancer)
  • History of bleeding disorder, gastrointestinal ulceration or bleeding, cerebrovascular aneurysm or bleeding, or retinal hemorrhage
  • History of migraine headaches
  • History of Raynaud's phenomenon
  • History of bipolar disorder or psychosis
  • Current use of anticoagulants or vasodilators (Lipid-lowering antihypertensive medications are allowed.)
  • Current use of acetazolamide, anticonvulsants, or thyroid replacements
  • Current use of glucocorticoids - including topical, nasal, or oral steroids - or anabolic steroids (Physiologic testosterone replacement therapy is allowed.)
  • Current use of anti-inflammatory agents (including, but not limited to, plaquenil, infliximab, etanercept, mycophenolate mofetil, sirolimus, tacrolimus, cyclosporine, pentoxifylline, thalidomide)
  • Known allergy or intolerance to pentoxifylline or other methylxanthines, such as , theophylline, caffeine, theobromine
  • Known allergy or intolerance to nitroglycerin.
  • Severe cognitive impairment (≥3 errors on 6-item cognitive screen105)
  • Current alcohol use problem (≥2 on CAGE questionnaire106)
  • Very severe depressive symptoms, defined as a PHQ-9 score ≥24
  • Acute risk of suicide
  • Vision or hearing problems
  • Unable to lie flat for 30 minutes at a time
  • Therapy for acute infection or other serious medical illnesses within 14 days prior to the pre-treatment visit (Therapy for acute infection or other serious medical illnesses that overlaps with a main study visit will result in postponement of that study visit until the course of therapy is completed; postponement outside of the allowed study visit timeframe will result in study discontinuation.)
  • Creatinine clearance < 50mL/min using a serum creatinine level measured at the pre-treatment visit
  • Hemoglobin < 9.0mg/dL at the pre-treatment visit
  • Alanine aminotransferase (ALT) level or aspartate aminotransferase (AST) > 3 times ULN at the pre-treatment visit
  • Total bilirubin > 2.5 times ULN at the pre-treatment visit
  • Current evidence of abuse of prescription medications
  • Current evidence of illicit drug use

Sites / Locations

  • Indiana University-Purdue University Indianapolis (IUPUI)

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Pentoxifylline + Standard Treatment

Placebo + Standard Treatment

Arm Description

Pentoxifylline: Pentoxifylline is phosphodiesterase inhibitor that interferes with proinflammatory cytokine signaling and synthesis. Participants will be instructed to take pentoxifylline 400 mg p.o. t.i.d. for 12 weeks. Standard Treatment: Beating the Blues (BtB) is a widely used, empirically supported, computer-based, CBT program for depression designed for use in primary care clinics. BtB utilizes an interactive, multimedia format to deliver and eight 50-minute, weekly therapy sessions.

Placebos: Placebo pills will match the study drug for color, taste, texture, size, and smell. Participants will receive the same instructions as those randomized to pentoxifylline. Standard Treatment: Beating the Blues (BtB) is a widely used, empirically supported, computer-based, CBT program for depression designed for use in primary care clinics. BtB utilizes an interactive, multimedia format to deliver and eight 50-minute, weekly therapy sessions.

Outcomes

Primary Outcome Measures

Change in Brachial Flow-Mediated Dilation (FMD) From Pre- to Post- Treatment
Patients underwent ultrasound assessment of brachial FMD in accordance with established guidelines at pre- (0 weeks) and post- (12 weeks) treatment. After a 10-minute supine rest, high-resolution baseline images of the brachial artery were obtained from 3 consecutive cardiac cycles. Next, the forearm cuff was inflated to 250 mmHg for 5 minutes and then was rapidly deflated. At 60 and 90 seconds post-deflation, images from 3 consecutive cardiac cycles were acquired. FMD values were computed as the % change in brachial diameter at either 60 or 90 seconds after cuff deflation
Change in Depressive Symptoms Severity (Hopkins Symptom Checklist Depression Scale; SCL-20) From Pre- to Post- Treatment
Self-reported depressive symptom severity was measured at pre- (0 weeks) and post- (12 weeks) treatment visits by the 20 depression items from the Symptom Checklist 90 (Hopkins Symptom Checklist depression scale; SCL-20). Each item on the scale ranges from 0 (not at all) to 4 (extremely). Total scores are the average across all response items and range from 0 to 4 with higher scores indicating greater levels of depressive symptoms.

Secondary Outcome Measures

Change in Circulating Tumor Necrosis Factor-Alpha (TNF-a) From Pre- to Post-Treatment
A marker of systemic inflammation measured from blood samples collected at pre- and post-treatment.
Change in Circulating Interleukin-6 (IL-6) From Pre- to Post-Treatment
A marker of systemic inflammation measured from blood samples collected at pre- and post-treatment.
Change in Circulating Interleukin-10 (IL-10) From Pre- to Post-Treatment
An anti-inflammatory cytokine measured from blood samples collected at pre- and post-treatment.
Change in Interleukin-1ra (IL-1ra) From Pre- to Post-Treatment
A marker of systemic inflammation measured from blood samples collected at pre- and post-treatment.
Change in Circulating C-Reactive Protein (CRP) From Pre- to Post-Treatment
A marker of systemic inflammation measured from blood samples collected at pre- and post-treatment.

Full Information

First Posted
June 19, 2012
Last Updated
October 30, 2015
Sponsor
Indiana University
Collaborators
National Institute of Mental Health (NIMH)
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1. Study Identification

Unique Protocol Identification Number
NCT01625845
Brief Title
Anti-INFLammatory to Address Mood and Endothelial Dysfunction (INFLAMED)
Acronym
INFLAMED
Official Title
Targeting Systemic Inflammation to Concurrently Treat Late-Life Depression and Reduce Coronary Artery Disease Risk
Study Type
Interventional

2. Study Status

Record Verification Date
October 2015
Overall Recruitment Status
Completed
Study Start Date
June 2012 (undefined)
Primary Completion Date
May 2014 (Actual)
Study Completion Date
May 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Indiana University
Collaborators
National Institute of Mental Health (NIMH)

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The objective of this clinical trial is to evaluate whether an anti-inflammatory medication, pentoxifylline, reduces depressive symptoms and improves artery function. Participants in this trial will be older primary care patients (60 years and up) who are depressed but do not have a history of cardiovascular disease. Half of these patients will receive pentoxifylline, and half will receive placebo. In addition, participants in both arms will receive an evidence-based psychological treatment called Beating the Blues®, which is a computerized, cognitive behavioral treatment program for depression. The investigators will use questionnaires to assess change in depressive symptoms and an ultrasound test to measure change in artery function from pre- to post-treatment. It is hypothesized that patients who receive pentoxifylline will show greater improvements in both depression and artery function than patients who receive placebo.
Detailed Description
Cardiovascular disease is the leading cause of death, and depression is the leading cause of disability in the United States. Previous research suggests that systemic inflammation may play an important role in the development of both depression and cardiovascular disease. Therefore, Aim #1 of this study is to examine whether adding an anti-inflammatory medication (pentoxifylline) to standard depression treatment (cognitive-behavioral therapy) improves both depressive symptoms and endothelial dysfunction, a sign of early cardiovascular disease. Aim #2 is to evaluate candidate mediators of treatment effects by examining whether reductions in multiple markers of systemic inflammation account for treatment-related improvements in depressive symptoms and endothelial dysfunction. To achieve these aims, a clinical trial of older depressed primary care patients free of cardiovascular disease is being conducted. Patients will be randomized to one of two groups: a standard depression treatment (a cognitive-behavioral treatment program) plus pentoxifylline or standard depression treatment plus placebo. The treatment phase of the study will be 12 weeks. At baseline, 6 weeks, and 12 weeks, patients will undergo assessments of depressive symptoms, various inflammatory markers, and endothelial function. Our index of endothelial function is brachial artery flow-mediated dilation, a noninvasive measure of endothelial function. Demonstrating that medications targeting systemic inflammation are effective for concurrently treating late-life depression and reducing CAD risk would place anti-inflammatory approaches in the collection of depression treatment strategies, as well as CAD prevention strategies, of the primary care provider. This change to clinical practice should result in improved management of both late-life depression and cardiovascular risk, which in turn would reduce disability, CAD morbidity, and mortality among older adults.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Major Depressive Disorder, Depression, Depressive Symptoms, Cardiovascular Disease (CVD), Coronary Artery Disease (CAD), Heart Disease
Keywords
Major Depressive Disorder, Depression, Depressive Symptoms, Cardiovascular Disease (CVD), Coronary Artery Disease (CAD), Heart Disease, Endothelial Function, Inflammation

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
36 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Pentoxifylline + Standard Treatment
Arm Type
Experimental
Arm Description
Pentoxifylline: Pentoxifylline is phosphodiesterase inhibitor that interferes with proinflammatory cytokine signaling and synthesis. Participants will be instructed to take pentoxifylline 400 mg p.o. t.i.d. for 12 weeks. Standard Treatment: Beating the Blues (BtB) is a widely used, empirically supported, computer-based, CBT program for depression designed for use in primary care clinics. BtB utilizes an interactive, multimedia format to deliver and eight 50-minute, weekly therapy sessions.
Arm Title
Placebo + Standard Treatment
Arm Type
Placebo Comparator
Arm Description
Placebos: Placebo pills will match the study drug for color, taste, texture, size, and smell. Participants will receive the same instructions as those randomized to pentoxifylline. Standard Treatment: Beating the Blues (BtB) is a widely used, empirically supported, computer-based, CBT program for depression designed for use in primary care clinics. BtB utilizes an interactive, multimedia format to deliver and eight 50-minute, weekly therapy sessions.
Intervention Type
Drug
Intervention Name(s)
Pentoxifylline
Other Intervention Name(s)
Trental, Pentoxil, Pentopak
Intervention Description
Pentoxifylline 400 mg p.o. t.i.d. for 12 weeks
Intervention Type
Other
Intervention Name(s)
Placebo
Intervention Description
Placebo pills will match the study drug for color, taste, texture, size, and smell. Participants will receive the same instructions as those randomized to pentoxifylline.
Intervention Type
Behavioral
Intervention Name(s)
Standard Treatment
Other Intervention Name(s)
Computer-Based Cognitive Behavioral Therapy (CBT), Computer-Based Psychotherapy
Intervention Description
BtB is a widely used, empirically supported, computer-based, CBT program for depression designed for use in primary care clinics. BtB utilizes an interactive, multimedia format to deliver and eight 50-minute, weekly therapy sessions. General topics covered include identifying and challenging automatic thoughts, cognitive errors, core beliefs, and attributional styles; activity scheduling; problem solving; graded exposure; task breakdown; sleep management; and relapse prevention. In addition to session work, patients are assigned homeworks that are customized to their needs and reviewed at the start of each session. A progress report, including whether the patient is experiencing suicidal ideation, is generated at the end of each session.
Primary Outcome Measure Information:
Title
Change in Brachial Flow-Mediated Dilation (FMD) From Pre- to Post- Treatment
Description
Patients underwent ultrasound assessment of brachial FMD in accordance with established guidelines at pre- (0 weeks) and post- (12 weeks) treatment. After a 10-minute supine rest, high-resolution baseline images of the brachial artery were obtained from 3 consecutive cardiac cycles. Next, the forearm cuff was inflated to 250 mmHg for 5 minutes and then was rapidly deflated. At 60 and 90 seconds post-deflation, images from 3 consecutive cardiac cycles were acquired. FMD values were computed as the % change in brachial diameter at either 60 or 90 seconds after cuff deflation
Time Frame
0 and 12 weeks
Title
Change in Depressive Symptoms Severity (Hopkins Symptom Checklist Depression Scale; SCL-20) From Pre- to Post- Treatment
Description
Self-reported depressive symptom severity was measured at pre- (0 weeks) and post- (12 weeks) treatment visits by the 20 depression items from the Symptom Checklist 90 (Hopkins Symptom Checklist depression scale; SCL-20). Each item on the scale ranges from 0 (not at all) to 4 (extremely). Total scores are the average across all response items and range from 0 to 4 with higher scores indicating greater levels of depressive symptoms.
Time Frame
0 and 12 weeks
Secondary Outcome Measure Information:
Title
Change in Circulating Tumor Necrosis Factor-Alpha (TNF-a) From Pre- to Post-Treatment
Description
A marker of systemic inflammation measured from blood samples collected at pre- and post-treatment.
Time Frame
0 and12 weeks
Title
Change in Circulating Interleukin-6 (IL-6) From Pre- to Post-Treatment
Description
A marker of systemic inflammation measured from blood samples collected at pre- and post-treatment.
Time Frame
0 and 12 weeks
Title
Change in Circulating Interleukin-10 (IL-10) From Pre- to Post-Treatment
Description
An anti-inflammatory cytokine measured from blood samples collected at pre- and post-treatment.
Time Frame
0 and 12 weeks
Title
Change in Interleukin-1ra (IL-1ra) From Pre- to Post-Treatment
Description
A marker of systemic inflammation measured from blood samples collected at pre- and post-treatment.
Time Frame
0 and 12 weeks
Title
Change in Circulating C-Reactive Protein (CRP) From Pre- to Post-Treatment
Description
A marker of systemic inflammation measured from blood samples collected at pre- and post-treatment.
Time Frame
0 and 12 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
40 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Primary care patients Age ≥ 40 years Clinically significant depressive symptoms, defined as a PHQ-9 score ≥15 English speaking Exclusion Criteria: History of clinical cardiovascular disease History of cardiac arrhythmias or cardiomyopathy History of carotid bruits History of certain chronic disorders (HIV/AIDS, kidney disease, liver disease, systemic inflammatory disease, or past-year cancer) History of bleeding disorder, gastrointestinal ulceration or bleeding, cerebrovascular aneurysm or bleeding, or retinal hemorrhage History of migraine headaches History of Raynaud's phenomenon History of bipolar disorder or psychosis Current use of anticoagulants or vasodilators (Lipid-lowering antihypertensive medications are allowed.) Current use of acetazolamide, anticonvulsants, or thyroid replacements Current use of glucocorticoids - including topical, nasal, or oral steroids - or anabolic steroids (Physiologic testosterone replacement therapy is allowed.) Current use of anti-inflammatory agents (including, but not limited to, plaquenil, infliximab, etanercept, mycophenolate mofetil, sirolimus, tacrolimus, cyclosporine, pentoxifylline, thalidomide) Known allergy or intolerance to pentoxifylline or other methylxanthines, such as , theophylline, caffeine, theobromine Known allergy or intolerance to nitroglycerin. Severe cognitive impairment (≥3 errors on 6-item cognitive screen105) Current alcohol use problem (≥2 on CAGE questionnaire106) Very severe depressive symptoms, defined as a PHQ-9 score ≥24 Acute risk of suicide Vision or hearing problems Unable to lie flat for 30 minutes at a time Therapy for acute infection or other serious medical illnesses within 14 days prior to the pre-treatment visit (Therapy for acute infection or other serious medical illnesses that overlaps with a main study visit will result in postponement of that study visit until the course of therapy is completed; postponement outside of the allowed study visit timeframe will result in study discontinuation.) Creatinine clearance < 50mL/min using a serum creatinine level measured at the pre-treatment visit Hemoglobin < 9.0mg/dL at the pre-treatment visit Alanine aminotransferase (ALT) level or aspartate aminotransferase (AST) > 3 times ULN at the pre-treatment visit Total bilirubin > 2.5 times ULN at the pre-treatment visit Current evidence of abuse of prescription medications Current evidence of illicit drug use
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jesse C Stewart, PhD
Organizational Affiliation
Indiana University School of Medicine
Official's Role
Principal Investigator
Facility Information:
Facility Name
Indiana University-Purdue University Indianapolis (IUPUI)
City
Indianapolis
State/Province
Indiana
ZIP/Postal Code
46202
Country
United States

12. IPD Sharing Statement

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Anti-INFLammatory to Address Mood and Endothelial Dysfunction (INFLAMED)

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