Endothelial Dysfunction, HIV, Inflammation, Insulin Resistance
Conditions
Keywords
HIV, Endothelial dysfunction, Inflammation, Insulin resistance
Brief summary
This is a phase II, open label, randomized-controlled pilot study designed to study both the efficacy and safety of salsalate in decreasing endothelial cell dysfunction, systemic inflammation, and insulin resistance in HIV-infected adults. The investigators hypothesis is that salsalate will reduce inflammation and therefore endothelial cell activation and insulin resistance. The sample size will be 40, with an equal number of people being randomized to one of two groups. The first arm will be randomized to salsalate therapy. The second arm will act as a control group. The study duration will be 13 weeks.
Interventions
DRUGSalsalate
Salsalate 2 grams orally twice a day for 13 weeks. This is the maximum dosage. During the initial 9 days of the study salsalate dose will be titrated to reach this goal dosage.
Sponsors
Bristol-Myers Squibb
University Hospitals Cleveland Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. 18 years of age or older 2. HIV-infected 3. Evidence of durable virologic suppression, i.e., must have HIV-1 RNA \< 400 copies/ml at study entry and for at least 12 weeks prior to entry 4. On a stable antiretroviral (ARV) regimen, i.e., on the same ARV for at least 12 weeks prior to study entry 5. No intention to stop or modify ARV regimen during the study period
Exclusion criteria
1. Current pregnancy or breast feeding, or women of child bearing age who refuse or are unable to use appropriate methods for contraception during the study period 2. Any of the following conditions: diabetes (2 fasting glucose levels \> 126 mg/dL or confirmed random glucose level \> 200), creatinine clearance \< 50, aspirin-sensitive asthma, COPD, history of bleeding gastric or duodenal ulcer, hepatic dysfunction, active hepatitis B or C, and any active infectious or inflammatory condition 3. Need for regular use of any of the following medications: salsalate, aspirin, non-steroidal antiinflammatories (NSAIDS), corticosteroids, warfarin or other anticoagulation therapy, phenytoin, valproic acid, carbonic anhydrase inhibitors, lithium, probenecid or sulfinpyrazone 4. Consumption of alcohol on a daily basis 5. Active use of illicit drugs 6. Unable to attend follow-up appointments 7. Allergy to any salicylic acid-containing medication or salsalate 8. AST or ALT \> 2 upper limit of normal (ULN) within 6 months prior to study entry
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Flow Mediated Dilation (FMD) of the Brachial Artery Measured by Ultrasound Over 13 Weeks | Entry and week 13 visits | Flow mediated dilation (FMD) of the brachial artery was measured by ultrasound. This is a measure of endothelial dependent endothelial cell function. Flow mediated dilation is expressed as a percent change from baseline brachial artery diameter to brachial artery diameter after reactive hyperemia. Reactive hyperemia occurred after occluding the brachial artery with a blood pressure cuff for 5 minutes. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Salsalate Salsalate 2 grams by mouth twice a day for a total daily dosage of 4 grams daily. Salsalate administered in 500 mg tablets. If 4 grams daily not tolerated by the participant, whatever dose up to 4 grams daily was tolerated was continues through the study. | 20 |
| Usual Care No placebo tablet was used in the study. Participants randomized to usual care received all of the study evaluations that the salsalate group did; however, no study medication was administered. | 20 |
| Total | 40 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 0 |
Baseline characteristics
| Characteristic | Usual Care | Salsalate | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 20 Participants | 20 Participants | 40 Participants |
| Age, Continuous | 46 years | 46.5 years | 46 years |
| Region of Enrollment United States | 20 participants | 20 participants | 40 participants |
| Sex: Female, Male Female | 0 Participants | 2 Participants | 2 Participants |
| Sex: Female, Male Male | 20 Participants | 18 Participants | 38 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 18 / 20 | 0 / 20 |
| serious Total, serious adverse events | 0 / 20 | 0 / 20 |
Outcome results
Primary
Change in Flow Mediated Dilation (FMD) of the Brachial Artery Measured by Ultrasound Over 13 Weeks
Flow mediated dilation (FMD) of the brachial artery was measured by ultrasound. This is a measure of endothelial dependent endothelial cell function. Flow mediated dilation is expressed as a percent change from baseline brachial artery diameter to brachial artery diameter after reactive hyperemia. Reactive hyperemia occurred after occluding the brachial artery with a blood pressure cuff for 5 minutes.
Time frame: Entry and week 13 visits
Population: Number of participants for analysis was determined by the number of participants that had 2 FMD tests performed
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Salsalate | Change in Flow Mediated Dilation (FMD) of the Brachial Artery Measured by Ultrasound Over 13 Weeks | 0.99 % change from baseline |
| Usual Care | Change in Flow Mediated Dilation (FMD) of the Brachial Artery Measured by Ultrasound Over 13 Weeks | -0.07 % change from baseline |
Comparison: Using data from a different population, ie, patients with peripheral artery disease, and a different intervention, ie, omega-3 fatty acids, 15 participants were needed per group to achieve 80% power to detect a difference in means of -3.6% (the difference between the control group mean of -0.3% and a treatment group mean of 3.3%) assuming a common standard deviation of 3.3 using a two group t-test with a 0.05 two-sided significance level. 5 patients added to each arm in case nonparametric.p-value: <0.05Wilcoxon rank sum test