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

• Sponsor: Indiana University (Other)
• Overall Status: Completed
• CT.gov ID: NCT01625845
• Collaborator: National Institute of Mental Health (NIMH) (NIH)
• Enrollment: 36
• Location: 1
• Arms: 2
• Duration (Months): 23
• Patients Per Site Per Month: 1.6

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Major Depressive Disorder; Depression; Depressive Symptoms; Cardiovascular Disease (CVD); Coronary Artery Disease (CAD); Heart Disease	Drug: Pentoxifylline; Other: Placebo; Behavioral: Standard Treatment	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 36 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Targeting Systemic Inflammation to Concurrently Treat Late-Life Depression and Reduce Coronary Artery Disease Risk
• Study Start Date: Jun 1, 2012
• Actual Primary Completion Date: May 1, 2014
• Actual Study Completion Date: May 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Pentoxifylline + Standard Treatment 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.	Drug: Pentoxifylline; Pentoxifylline 400 mg p.o. t.i.d. for 12 weeks; Other Names: Trental Pentoxil Pentopak ; Behavioral: Standard Treatment; 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.; Other Names: Computer-Based Cognitive Behavioral Therapy (CBT) Computer-Based Psychotherapy
Placebo Comparator: Placebo + Standard Treatment 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.	Other: Placebo; 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.; Behavioral: Standard Treatment; 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.; Other Names: Computer-Based Cognitive Behavioral Therapy (CBT) Computer-Based Psychotherapy

Outcome Measures

Primary Outcome Measures

1. Change in Brachial Flow-Mediated Dilation (FMD) From Pre- to Post- Treatment [0 and 12 weeks]

   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

2. Change in Depressive Symptoms Severity (Hopkins Symptom Checklist Depression Scale; SCL-20) From Pre- to Post- Treatment [0 and 12 weeks]

   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

1. Change in Circulating Tumor Necrosis Factor-Alpha (TNF-a) From Pre- to Post-Treatment [0 and12 weeks]

   A marker of systemic inflammation measured from blood samples collected at pre- and post-treatment.

2. Change in Circulating Interleukin-6 (IL-6) From Pre- to Post-Treatment [0 and 12 weeks]

   A marker of systemic inflammation measured from blood samples collected at pre- and post-treatment.

3. Change in Circulating Interleukin-10 (IL-10) From Pre- to Post-Treatment [0 and 12 weeks]

   An anti-inflammatory cytokine measured from blood samples collected at pre- and post-treatment.

4. Change in Interleukin-1ra (IL-1ra) From Pre- to Post-Treatment [0 and 12 weeks]

   A marker of systemic inflammation measured from blood samples collected at pre- and post-treatment.

5. Change in Circulating C-Reactive Protein (CRP) From Pre- to Post-Treatment [0 and 12 weeks]

   A marker of systemic inflammation measured from blood samples collected at pre- and post-treatment.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Indiana University-Purdue University Indianapolis (IUPUI)	Indianapolis	Indiana	United States	46202

Sponsors and Collaborators

• Indiana University
• National Institute of Mental Health (NIMH)

Investigators

• Principal Investigator: Jesse C Stewart, PhD, Indiana University School of Medicine

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Indiana University
• ClinicalTrials.gov Identifier: NCT01625845
• Other Study ID Numbers: 1110007119; R24MH080827; 1737
• First Posted: Jun 21, 2012
• Last Update Posted: Dec 3, 2015
• Last Verified: Oct 1, 2015

• Keywords provided by Indiana University: Major Depressive Disorder; Depression; Depressive Symptoms; Cardiovascular Disease (CVD); Coronary Artery Disease (CAD); Heart Disease; Endothelial Function; Inflammation
• Additional relevant MeSH terms: Cardiovascular Diseases; Coronary Artery Disease; Myocardial Ischemia; Coronary Disease; Heart Diseases; Depression; Depressive Disorder; Depressive Disorder, Major; Pentoxifylline

Study Results

Participant Flow

Recruitment Details	Recruitment was open from June 28, 2012 to February 28, 2014. Participants were recruited from Eskenazi Health and Indiana University Health primary care clinics in Indianapolis. 1369 patients were screened, of whom 36 (2.6%) were eligible and provided informed consent. 16 patients (44%) attended the pre-treatment visit and were randomized.

Arm/Group Title	Pentoxifylline + Standard Treatment	Placebo + Standard Treatment
Arm/Group 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.
Period Title: Overall Study
STARTED	10	6
COMPLETED	5	3
NOT COMPLETED	5	3

Baseline Characteristics

Arm/Group Title	Pentoxifylline + Standard Treatment	Placebo + Standard Treatment	Total
Arm/Group 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.	Total of all reporting groups
Overall Participants	10	6	16
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	9 90%	6 100%	15 93.8%
>=65 years	1 10%	0 0%	1 6.3%
Sex: Female, Male (Count of Participants)
Female	5 50%	4 66.7%	9 56.3%
Male	5 50%	2 33.3%	7 43.8%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pentoxifylline + Standard Treatment	Placebo + Standard Treatment
Arm/Group 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.
Measure Participants	5	3
Mean (Standard Error) [% change in brachial diameter]	-1.18 (1.48)	0.79 (1.95)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pentoxifylline + Standard Treatment, Placebo + Standard Treatment
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.474
	Comments
	Method	ANCOVA
	Comments

2. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pentoxifylline + Standard Treatment	Placebo + Standard Treatment
Arm/Group 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.
Measure Participants	5	3
Mean (Standard Error) [Change in Total Score]	-0.35 (0.25)	-1.41 (0.34)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pentoxifylline + Standard Treatment, Placebo + Standard Treatment
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.068
	Comments
	Method	ANCOVA
	Comments

3. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Participants with missing TNF-a data were excluded from this analysis.

Arm/Group Title	Pentoxifylline + Standard Treatment	Placebo + Standard Treatment
Arm/Group 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.
Measure Participants	3	2
Mean (Standard Error) [pg/mL]	-0.65 (0.08)	-0.47 (0.10)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pentoxifylline + Standard Treatment, Placebo + Standard Treatment
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.296
	Comments
	Method	ANCOVA
	Comments

4. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pentoxifylline + Standard Treatment	Placebo + Standard Treatment
Arm/Group 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.
Measure Participants	5	3
Mean (Standard Error) [pg/mL]	-0.69 (1.02)	1.84 (1.34)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pentoxifylline + Standard Treatment, Placebo + Standard Treatment
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.203
	Comments
	Method	ANCOVA
	Comments

5. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

One participant, with extreme outlier values at pre- and post-treatment, was excluded from analyses.

Arm/Group Title	Pentoxifylline + Standard Treatment	Placebo + Standard Treatment
Arm/Group 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.
Measure Participants	5	2
Mean (Standard Error) [pg/mL]	-0.58 (0.34)	-0.66 (0.54)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pentoxifylline + Standard Treatment, Placebo + Standard Treatment
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.906
	Comments
	Method	ANCOVA
	Comments

6. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pentoxifylline + Standard Treatment	Placebo + Standard Treatment
Arm/Group 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.
Measure Participants	5	3
Mean (Standard Error) [pg/mL]	2.32 (75.03)	25.00 (99.55)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pentoxifylline + Standard Treatment, Placebo + Standard Treatment
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.869
	Comments
	Method	ANCOVA
	Comments

7. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pentoxifylline + Standard Treatment	Placebo + Standard Treatment
Arm/Group 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.
Measure Participants	5	3
Mean (Standard Error) [mg/L]	-0.49 (1.34)	6.44 (1.74)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pentoxifylline + Standard Treatment, Placebo + Standard Treatment
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.026
	Comments
	Method	ANCOVA
	Comments

Adverse Events

Time Frame	Adverse event data were collected the recruitment initiation in June 2012 until study completion in May 2014. For each participant, adverse event data were collected between the pre- and post-treatment visits.
Adverse Event Reporting Description	A brief questionnaire created by the investigators was administered at each study visit to identify potential adverse events. Each event was evaluated by the study physician, who also provided severity and study involvement ratings. Clinical management decisions were made by the study physician in conjunction with the participant's provider(s).
Arm/Group Title	Pentoxifylline + Standard Treatment		Placebo + Standard Treatment
Arm/Group 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.
All Cause Mortality
	Pentoxifylline + Standard Treatment		Placebo + Standard Treatment
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Pentoxifylline + Standard Treatment		Placebo + Standard Treatment
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/10 (30%)		0/6 (0%)
General disorders
Complications after removing nodules during endoscopy (Chest pain, esophagitis, dizziness, bleeding)	1/10 (10%)	1	0/6 (0%)	0
Injury, poisoning and procedural complications
Hearing issues after explosion	1/10 (10%)	1	0/6 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Nasolabial abscess (Facial swelling)	1/10 (10%)	1	0/6 (0%)	0
Other (Not Including Serious) Adverse Events
	Pentoxifylline + Standard Treatment		Placebo + Standard Treatment
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/10 (80%)		5/6 (83.3%)
Blood and lymphatic system disorders
Hemolyzed blood sample	0/10 (0%)	0	1/6 (16.7%)	1
Hypercalcemia	1/10 (10%)	1	0/6 (0%)	0
Abnormalities in the complete blood cell count	0/10 (0%)	0	1/6 (16.7%)	1
Impaired fasting glucose	1/10 (10%)	1	0/6 (0%)	0
Gastrointestinal disorders
Nausea	2/10 (20%)	2	1/6 (16.7%)	1
General disorders
Flushed	1/10 (10%)	1	2/6 (33.3%)	2
Hot flashes	0/10 (0%)	0	1/6 (16.7%)	1
Dizziness	3/10 (30%)	3	3/6 (50%)	3
Facial Pimple	0/10 (0%)	0	1/6 (16.7%)	1
Leg swelling	0/10 (0%)	0	1/6 (16.7%)	1
Headaches	3/10 (30%)	3	0/6 (0%)	0
Heartburn	1/10 (10%)	1	0/6 (0%)	0
Racing heart	1/10 (10%)	1	0/6 (0%)	0
Red eye	1/10 (10%)	1	0/6 (0%)	0
Diarrhea	3/10 (30%)	3	0/6 (0%)	0
Blurred vision	2/10 (20%)	2	1/6 (16.7%)	1
Low energy	1/10 (10%)	1	0/6 (0%)	0
Sleep disturbance	1/10 (10%)	1	0/6 (0%)	0
Stomach Pain	0/10 (0%)	0	1/6 (16.7%)	1
Nervousness / jittery hands	1/10 (10%)	1	0/6 (0%)	0
Leg pain	1/10 (10%)	1	0/6 (0%)	0
Back pain	1/10 (10%)	1	0/6 (0%)	0
Sweating	1/10 (10%)	1	0/6 (0%)	0
Skin and subcutaneous tissue disorders
Rash	1/10 (10%)	1	1/6 (16.7%)	1

Limitations/Caveats

Missing data precluded analysis of two secondary outcome variables: IL-1α and IL-1β. Due to the very small sample of randomized patients, conclusions should not be drawn from the results of this pilot trial.

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Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.