Evaluating the Effectiveness of Pentoxifylline at Improving Blood Vessel Function in HIV-infected People Not Receiving Antiretroviral Medications

• Sponsor: Indiana University (Other)
• Overall Status: Completed
• CT.gov ID: NCT00796822
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI) (NIH)
• Enrollment: 26
• Location: 1
• Arms: 2
• Duration (Months): 33
• Patients Per Site Per Month: 0.8

Study Details

Study Description

Brief Summary

People infected with HIV have a greater risk of developing cardiovascular disease than people not infected with HIV. This may be due to increased inflammation brought on by either the HIV infection itself or the use of antiretroviral medications to treat HIV infection. This study will evaluate an anti-inflammatory drug, pentoxifylline, to determine whether it improves blood vessel function and reduces inflammation in people infected with HIV who are not currently receiving antiretroviral medications.

Condition or Disease	Intervention/Treatment	Phase
HIV; Cardiovascular Diseases; Atherosclerosis	Drug: Pentoxifylline; Drug: Placebo	Phase 2

Detailed Description

People infected with HIV have an increased risk for cardiovascular disease, which is a leading cause of death for those with HIV. The increase in cardiovascular disease has been thought to be linked to the use of several types of antiretroviral medications used to treat HIV infection. These medications have been shown to cause insulin resistance and dyslipidemia, or high cholesterol levels-conditions that can lead to atherosclerosis, which is a build-up of plaque within the arteries, and ultimately to cardiovascular disease. However, new research is emerging that suggests that people infected with HIV who do not receive antiretroviral medications may also have an increased risk of cardiovascular disease as a result of increased endothelial dysfunction. This condition, which involves malfunctioning of the thin layer of cells that line the interior surface of blood vessels, can lead to atherosclerosis and cardiovascular disease. Pentoxifylline is a medication that is currently used to reduce leg pain in people with blockages in the blood vessels in their legs. Previous research has shown that pentoxifylline may reduce inflammation and improve blood vessel function in people infected with HIV, but more research is needed to confirm these benefits. The purpose of this study is to determine whether pentoxifylline reduces inflammation and improves endothelial function in HIV-infected people who are not receiving antiretroviral medications.

This study will enroll HIV-infected people who are not currently receiving antiretroviral medications. At a baseline study visit, participants will undergo a medical history review; physical examination; measurements in blood pressure, heart rate, height, weight, waist, and hip; and blood and urine collection. An ultrasound imaging test of the arm will measure blood vessel function. Participants will then be randomly assigned to receive either pentoxifylline or placebo three times a day for 8 weeks. At study visits at Weeks 4 and 8, participants will undergo repeat baseline measurements.

Study Design

• Study Type: Interventional
• Actual Enrollment: 26 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Placebo-Controlled Trial of Pentoxifylline to Improve Endothelial Function in HIV-Infected Patients Not Requiring Antiretroviral Therapy
• Study Start Date: Jan 1, 2009
• Actual Primary Completion Date: Oct 1, 2011
• Actual Study Completion Date: Oct 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1 Participants will receive pentoxifylline.	Drug: Pentoxifylline; 400 mg three times a day for 8 weeks
Placebo Comparator: 2 Participants will receive placebo.	Drug: Placebo; One pill three times a day for 8 weeks

Outcome Measures

Primary Outcome Measures

1. Change in Flow-mediated Dilation of the Brachial Artery [Measured at baseline and Week 8]

   Flow-mediated dilation is nn in vivo measure of arterial endothelial function. We assessed changes in flow-mediated dilation from baseline to week 8.

Secondary Outcome Measures

1. Change in Soluble TNF-Receptor I Levels [Measured at baseline and Week 8]

   Measure of systemic inflammation

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Documentation of HIV infection with a positive HIV enzyme-linked immunosorbent assay (ELISA) test and confirmatory western blot test

• CD4 cell count greater than 350/µL at the time of screening

• Has not received any antiretroviral therapies in the 6 months before screening

• No anticipated need for any antiretroviral therapies during the course of this study, as determined by the principal investigator or by the participant's HIV caregiver

Note: There is no HIV-1 RNA level eligibility criterion.

Exclusion Criteria:

• Incarceration at the time of screening or at any study visit

• Diagnosed vascular disease, including history of angina pectoris, coronary disease, peripheral vascular disease, cerebrovascular disease, aortic aneurysm, or otherwise known atherosclerotic disease

• Diagnosed disease or process, other than HIV infection, associated with increased systemic inflammation (including, but not limited to, systemic lupus erythematosis, inflammatory bowel diseases, or other collagen vascular diseases). Hepatitis B or C co-infections are NOT exclusionary.

• History of bleeding diathesis, gastrointestinal ulceration or bleeding, cerebrovascular aneurysm or bleeding, or retinal hemorrhage

• Known or suspected cancer requiring systemic treatment in the 6 months before screening

• History of American Diabetes Association (ADA)-defined diabetes mellitus. History of gestational diabetes is not exclusionary if the potential participant does not have current ADA-defined diabetes.

• History of migraine headaches

• History of Raynaud's phenomenon

• History of cardiac arrhythmias or cardiomyopathy

• History of hypothyroidism or hyperthyroidism, even if treated

• Known allergy or intolerance to pentoxifylline or other methylxanthines (e.g., theophylline, caffeine, theobromine). Use of caffeinated products, except on the mornings of the study visits, is not exclusionary.

• Known allergy or intolerance to nitroglycerin

• History of carotid bruits

• Creatinine clearance less than 50 mL/min, using the Cockcroft-Gault equation and a serum creatinine level measured in the 28 days before screening or at the screening visit

• Hemoglobin less than 9.0 mg/dL in the 28 days before screening or at the screening visit

• Alanine aminotransferase (ALT) level or aspartate aminotransferase (AST) greater than three times the upper limit of normal (ULN) in the 28 days before screening or at the screening visit

• Total bilirubin greater than 2.5 times the ULN in the 28 days before screening or at the screening visit

• Fever, defined as a temperature greater than or equal to 38.0 C in the 48 hours before screening. Fever in the 48 hours before each study visit will require postponement of that study visit until the participant's temperature has been lower than 38.0 C for at least 48 hours; fevers continuing past the allowed study visit timeframe will result in study discontinuation.

• Therapy for acute infection or other serious medical illnesses in the 14 days before screening. Therapy for acute infection or other serious medical illnesses that overlaps with a 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.

• Pregnant or breastfeeding

• Hypotension, defined as systolic blood pressure less than 90 mm Hg, at time of screening. Hypotension noted prior to brachial artery reactivity testing at each study visit will result in study visit postponement of at least 1 day until systolic pressure is greater than or equal to 90 mm Hg the morning of brachial reactivity testing; postponement outside of the allowed study visit timeframe will result in study discontinuation.

• Hypertension, defined as the receipt of any antihypertensive medication in the 28 days before screening or systolic blood pressure greater than 160 mm Hg at the screening visit

• Receipt of anti-inflammatory agents (including, but not limited to, plaquenil, infliximab, etanercept, mycophenolate mofetil, sirolimus, tacrolimus, cyclosporine, pentoxifylline, or thalidomide) in the 28 days before screening

• Receipt of investigational agents, cytotoxic chemotherapy, systemic or topical glucocorticoids (of any dose), or anabolic steroids in the 28 days before screening. Physiologic testosterone replacement therapy is not exclusionary.

• Receipt of lipid-lowering drugs, aspirin, other non-steroidal anti-inflammatory drugs (NSAIDS), acetazolamide, anticoagulants, anticonvulsants, or thyroid replacements in the 28 days before screening

• Use of sildenafil, vardenafil, or tadalafil in the 72 hours before or after each study visit

• Active drug or alcohol use or dependence that, in the opinion of the investigator, would interfere with adherence to study requirements

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Indiana Clinical Research Center	Indianapolis	Indiana	United States	46202

Sponsors and Collaborators

• Indiana University
• National Heart, Lung, and Blood Institute (NHLBI)

Investigators

• Principal Investigator: Samir K. Gupta, MD, MS, Indiana University School of Medicine

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Samir K Gupta, MD, MS, Associate Professor of Medicine, Indiana University
• ClinicalTrials.gov Identifier: NCT00796822
• Other Study ID Numbers: 614; R01HL095149
• First Posted: Nov 24, 2008
• Last Update Posted: Nov 28, 2017
• Last Verified: Oct 1, 2017

• Keywords provided by Samir K Gupta, MD, MS, Associate Professor of Medicine, Indiana University: Endothelial Function; Inflammation
• Additional relevant MeSH terms: Cardiovascular Diseases; Atherosclerosis; Pentoxifylline

Study Results

Participant Flow

Recruitment Details	Study recruitment, enrollment, and follow-up assessments were performed from May 2009 through October 2011, at the HIV outpatient clinics of the Indiana University Health medical system.
Pre-assignment Detail	Potential participants underwent a screening visit to evaluate eligibility within 21 days of randomization.

Arm/Group Title	Pentoxifylline	Placebo
Arm/Group Description	Participants will receive pentoxifylline. Pentoxifylline : 400 mg three times a day for 8 weeks	Participants will receive placebo. Placebo : One pill three times a day for 8 weeks
Period Title: Overall Study
STARTED	13	13
COMPLETED	10	13
NOT COMPLETED	3	0

Baseline Characteristics

Arm/Group Title	Pentoxifylline	Placebo	Total
Arm/Group Description	Participants will receive pentoxifylline. Pentoxifylline : 400 mg three times a day for 8 weeks	Participants will receive placebo. Placebo : One pill three times a day for 8 weeks	Total of all reporting groups
Overall Participants	13	13	26
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	13 100%	13 100%	26 100%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	34 (10.9)	40 (11.6)	37 (11.5)
Sex: Female, Male (Count of Participants)
Female	2 15.4%	5 38.5%	7 26.9%
Male	11 84.6%	8 61.5%	19 73.1%
Region of Enrollment (participants) [Number]
United States	13 100%	13 100%	26 100%

Outcome Measures

1. Primary Outcome

Title	Change in Flow-mediated Dilation of the Brachial Artery
Description	Flow-mediated dilation is nn in vivo measure of arterial endothelial function. We assessed changes in flow-mediated dilation from baseline to week 8.
Time Frame	Measured at baseline and Week 8

Outcome Measure Data

Analysis Population Description

Number of remaining participants at week 8 with evaluable vascular ultrasonography. In the Pentoxifylline group, 10 participants were evaluated at week 8 but only 9 had evaluable ultrasonography.

Arm/Group Title	Pentoxifylline	Placebo
Arm/Group Description	Participants will receive pentoxifylline. Pentoxifylline : 400 mg three times a day for 8 weeks	Participants will receive placebo. Placebo : One pill three times a day for 8 weeks
Measure Participants	9	13
Mean (Standard Deviation) [absolute percentage]	-1.93 (3.03)	-1.06 (1.45)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pentoxifylline, Placebo
	Comments	The sample size was determined based on a two-sample, independent, two-tailed t-test with 5% type I error. Using the results from our pilot trial, we conservatively estimated a predicted absolute change in FMD of 3.5% with PTX (assuming no change with placebo) and we assumed a common standard deviation of 2.6%. A sample size of 10 per group was estimated to provide at least 80% power to detect this effect size. Allowing for a 20% dropout rate, we planned to recruit 13 subjects per group.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.44
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.87
	Confidence Interval	(2-Sided) 95%; -1.53 to 3.28
	Parameter Dispersion	Type: Standard Deviation; Value: 1.09
	Estimation Comments

2. Secondary Outcome

Title	Change in Soluble TNF-Receptor I Levels
Description	Measure of systemic inflammation
Time Frame	Measured at baseline and Week 8

Outcome Measure Data

Analysis Population Description

Those who had both baseline and Week 8 data available

Arm/Group Title	Pentoxifylline	Placebo
Arm/Group Description	Participants will receive pentoxifylline. Pentoxifylline : 400 mg three times a day for 8 weeks	Participants will receive placebo. Placebo : One pill three times a day for 8 weeks
Measure Participants	10	13
Mean (Standard Deviation) [pg/mL]	65.9 (168.97)	-83.2 (137.45)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pentoxifylline, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments	There was no formal power calculation for this outcome measure as the study was powered on the primary outcome measure.
Statistical Test of Hypothesis	p-Value	0.03
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Net)
	Estimated Value	149.1
	Confidence Interval	(2-Sided) 95%; 16.4 to 281.9
	Parameter Dispersion	Type: Standard Deviation; Value: 151.8
	Estimation Comments

Adverse Events

Time Frame	8 weeks
Arm/Group Title	Pentoxifylline		Placebo
Arm/Group Description	Participants will receive pentoxifylline. Pentoxifylline : 400 mg three times a day for 8 weeks		Participants will receive placebo. Placebo : One pill three times a day for 8 weeks
All Cause Mortality
	Pentoxifylline		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Pentoxifylline		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/13 (0%)		0/13 (0%)
Other (Not Including Serious) Adverse Events
	Pentoxifylline		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	10/13 (76.9%)		10/13 (76.9%)
Blood and lymphatic system disorders
Neutropenia	2/13 (15.4%)	2	0/13 (0%)	0
Endocrine disorders
Hyperglycemia	1/13 (7.7%)	1	0/13 (0%)	0
Gastrointestinal disorders
All gastrointestinal	5/13 (38.5%)	7	5/13 (38.5%)	8
General disorders
Headache	2/13 (15.4%)	2	1/13 (7.7%)	1
Hepatobiliary disorders
Elevated liver function tests	1/13 (7.7%)	1	1/13 (7.7%)	1
Renal and urinary disorders
Hypokalemia	1/13 (7.7%)	1	0/13 (0%)	0
Hyperkalemia	0/13 (0%)	0	1/13 (7.7%)	1
Proteinuria	1/13 (7.7%)	1	0/13 (0%)	0
Respiratory, thoracic and mediastinal disorders
Cough	0/13 (0%)	0	2/13 (15.4%)	2
Skin and subcutaneous tissue disorders
Rash	1/13 (7.7%)	1	2/13 (15.4%)	2
Flushing	0/13 (0%)	0	2/13 (15.4%)	2

Limitations/Caveats

[Not Specified]

More Information

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.