Clinical trial NCT00796822: Evaluating the Effectiveness of Pentoxifylline at Improving Blood Vessel Function in HIV-infected People Not Receiving Antiretroviral Medications
Official title: A Randomized, Placebo-Controlled Trial of Pentoxifylline to Improve Endothelial Function in HIV-Infected Patients Not Requiring Antiretroviral Therapy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: HIV
Cardiovascular Diseases
Atherosclerosis
Keywords: Endothelial Function
Inflammation
Lead sponsor: Indiana University
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
First posted: 2008-11-24
Enrollment: 26
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Change in Flow-mediated Dilation of the Brachial Artery
timeFrame: Measured at baseline and Week 8
Secondary outcomes:
measure: Change in Soluble TNF-Receptor I Levels
timeFrame: Measured at baseline and Week 8
Other outcomes:
Locations:
city: Indianapolis
country: United States
facility: Indiana Clinical Research Center
state: Indiana
Study officials:
affiliation: Indiana University School of Medicine
name: Samir K. Gupta, MD, MS
role: PRINCIPAL_INVESTIGATOR
References:
citation: Gupta SK, Mi D, Dube MP, Saha CK, Johnson RM, Stein JH, Clauss MA, Mather KJ, Desta Z, Liu Z. Pentoxifylline, inflammation, and endothelial function in HIV-infected persons: a randomized, placebo-controlled trial. PLoS One. 2013 Apr 9;8(4):e60852. doi: 10.1371/journal.pone.0060852. Print 2013.