Safety and Efficacy of Salsalate to Treat Endothelial Dysfunction in HIV-infected Adults

• Sponsor: University Hospitals Cleveland Medical Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT01046682
• Collaborator: Bristol-Myers Squibb (Industry)
• Enrollment: 40
• Location: 1
• Arms: 2
• Duration (Months): 5.9
• Patients Per Site Per Month: 6.7

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
HIV; Endothelial Dysfunction; Inflammation; Insulin Resistance	Drug: Salsalate	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 40 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Assessment of the Use of Salsalate to Decrease Endothelial Cell Activation and Inflammation in HIV-infected Adults
• Study Start Date: Jan 1, 2009
• Actual Primary Completion Date: Jul 1, 2009
• Actual Study Completion Date: Jul 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Salsalate	Drug: Salsalate; 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.
No Intervention: Usual care

Outcome Measures

Primary Outcome Measures

1. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University Hospitals Case Medical Center	Cleveland	Ohio	United States	44106

Sponsors and Collaborators

• University Hospitals Cleveland Medical Center
• Bristol-Myers Squibb

Investigators

• Principal Investigator: Grace A Mccomsey, M.D., University Hospitals Case Medical Center and Case Western Reserve University
• Principal Investigator: Corrilynn O Hileman, MD, Case Western Reserve University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Grace McComsey, Principal Investigator, University Hospitals Cleveland Medical Center
• ClinicalTrials.gov Identifier: NCT01046682
• Other Study ID Numbers: 02-08-02
• First Posted: Jan 12, 2010
• Last Update Posted: Jan 7, 2015
• Last Verified: Dec 1, 2014

• Keywords provided by Grace McComsey, Principal Investigator, University Hospitals Cleveland Medical Center: HIV; Endothelial dysfunction; Inflammation; Insulin resistance
• Additional relevant MeSH terms: Insulin Resistance; Inflammation; Salicylsalicylic acid

Study Results

Participant Flow

Arm/Group Title	Salsalate	Usual Care
Arm/Group Description	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.	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.
Period Title: Overall Study
STARTED	20	20
COMPLETED	18	20
NOT COMPLETED	2	0

Baseline Characteristics

Arm/Group Title	Salsalate	Usual Care	Total
Arm/Group Description	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.	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.	Total of all reporting groups
Overall Participants	20	20	40
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	20 100%	20 100%	40 100%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	46.5	46	46
Sex: Female, Male (Count of Participants)
Female	2 10%	0 0%	2 5%
Male	18 90%	20 100%	38 95%
Region of Enrollment (participants) [Number]
United States	20 100%	20 100%	40 100%

Outcome Measures

1. Primary Outcome

Title	Change in Flow Mediated Dilation (FMD) of the Brachial Artery Measured by Ultrasound Over 13 Weeks
Description	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

Outcome Measure Data

Analysis Population Description

Number of participants for analysis was determined by the number of participants that had 2 FMD tests performed

Arm/Group Title	Salsalate	Usual Care
Arm/Group Description	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.	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.
Measure Participants	18	20
Median (Inter-Quartile Range) [% change from baseline]	0.99	-0.07

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Salsalate, Usual Care
	Comments	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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.05
	Comments
	Method	Wilcoxon rank sum test
	Comments

Adverse Events

Arm/Group Title	Salsalate		Usual Care
Arm/Group Description	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.		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.
All Cause Mortality
	Salsalate		Usual Care
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Salsalate		Usual Care
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/20 (0%)		0/20 (0%)
Other (Not Including Serious) Adverse Events
	Salsalate		Usual Care
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	18/20 (90%)		0/20 (0%)
Blood and lymphatic system disorders
Neutropenia	2/20 (10%)	2	0/20 (0%)	0
Thrombocytopenia	2/20 (10%)	2	0/20 (0%)	0
Ear and labyrinth disorders
Tinnitus	9/20 (45%)	9	0/20 (0%)	0
Gastrointestinal disorders
Abdominal pain	1/20 (5%)	1	0/20 (0%)	0
Nausea	2/20 (10%)	2	0/20 (0%)	0
General disorders
Headache	2/20 (10%)	2	0/20 (0%)	0
Hepatobiliary disorders
Transaminitis	8/20 (40%)	8	0/20 (0%)	0
Skin and subcutaneous tissue disorders
Rash	1/20 (5%)	1	0/20 (0%)	0

Limitations/Caveats

Lack of placebo in the control group precluded blinding of the study investigators. Adherence was measured utilizing pill counts which assumes that pills not returned were taken by the participant. Sample size too small to detect a small effect.

More Information

Certain Agreements

Principal Investigators are NOT 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.