Statin Therapy to Improve Atherosclerosis in HIV Patients

• Sponsor: Massachusetts General Hospital (Other)
• Overall Status: Completed
• CT.gov ID: NCT00965185
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI) (NIH)
• Enrollment: 40
• Location: 1
• Arms: 2
• Duration (Months): 52
• Patients Per Site Per Month: 0.8

Study Details

Study Description

Brief Summary

In HIV patients, statin therapy will attenuate plaque inflammation, thus, making plaques less vulnerable, will deter plaque progression, and improve endothelial function. In addition to known cholesterol-lowering and C-reactive protein lowering effects, immunomodulatory effects of statins will lead to a shift from pro-inflammatory monocyte and T cell subsets to less atherogenic subpopulations.

Condition or Disease	Intervention/Treatment	Phase
Cardiovascular Disease; HIV; Atherosclerosis; Inflammation; Statins, HMG-CoA; HIV Infections	Drug: atorvastatin; Drug: Placebo	N/A

Study Design

• Study Type: Interventional
• Actual Enrollment: 40 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Statin Therapy to Improve Inflammation and Atherosclerosis in HIV Patients
• Study Start Date: Sep 1, 2009
• Actual Primary Completion Date: Jan 1, 2014
• Actual Study Completion Date: Jan 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Atorvastatin 20 mg PO QD for the first 3 months, followed by 40 mg PO QD for the final 9 months.	Drug: atorvastatin; 20 mg PO QD for the first 3 months, followed by 40 mg PO QD for the final 9 months.
Placebo Comparator: placebo	Drug: Placebo; Placebo

Outcome Measures

Primary Outcome Measures

1. Coronary and Aortic Plaque Inflammation [Measured at baseline and 1 year]

   12 month change in mean FDG-PET TBR (18-fluorodeoxyglucose positron emission tomography target-to-background ratio)

Secondary Outcome Measures

1. Plaque Progression [Measured at baseline and 1 year]

   12 month percent change in plaque volume

2. Endothelial Function [1 year]

   Assessment of endothelial function was to be measured by endothelial vasodilator function.

3. Immune Function [Measured at baseline and 1 year]

   12 month change in CD4 T-lymphocytes

4. Lipid Profile [Measured at baseline and 1 year]

   12 month change in lipid profile

5. C-reactive Protein (CRP) [Measured at baseline and 1 year]

   12 month change in Log CRP concentration

6. Adipocytokines [Measured at baseline and 1 year]

   12 month change in IL-6

7. Liver Function Tests (LFTs) [Measured at baseline, 1, 3, 6, 9, and 12 months]

   Number of participants with LFT abnormalities (greater than or equal to 3 times the upper limit of normal). For reference, the normal ranges for AST and ALT are shown below. Please note that the normal range for ALT at Labcorp changed over the course of the study. AST and ALT elevations were determined based on the normal range at the time the lab test was performed. ALT: 0-40 IU/L, 0-44 IU/L, or 0-55 IU/L AST: 0-40 IU/L

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 60 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion criteria:

1. Men and women age 18-60 with previously diagnosed HIV disease

2. Subclinical coronary artery disease as defined by presence of one or more plaque on coronary CTA without history of cardiac events or cardiac symptoms and no evidence of critical coronary stenosis. Target to background ratio (TBR) as determined by PET of > 1.6.

3. Stable anti-retroviral (ARV) therapy as defined by no changes in ARV regimen for >6 months

4. LDL-cholesterol >70 mg/dL and <130 mg/dL

Exclusion criteria:

1. History of acute coronary syndrome

2. Contraindication to statin therapy

3. Current statin use

4. AST or ALT two times greater than the upper limit of normal or receiving treatment for active liver disease

5. Renal disease or creatinine >1.5 mg/dL (given the risk of contrast nephropathy during CT angiography of the heart)

6. Infectious illness within past 3 months

7. Contraindication to beta-blocker (including moderate to severe asthma or heart block) or nitroglycerin use as these drugs are given as part of the standard cardiac CT protocol. Previous allergic reaction to beta blocker or nitroglycerin.

8. Body weight greater than 300 lbs due to CT scanner table limitations

9. Patients with previous allergic reactions to iodine-containing contrast media

10. Active illicit drug use

11. Patients who report any significant radiation exposure over the course of the year prior to randomization. Significant exposure is defined as:

12. More than 2 percutaneous coronary interventions (PCI) within 12 months of randomization

13. More than 2 myocardial perfusion studies within the past 12 months

14. More than 2 CT angiograms within the past 12 months

15. Any subjects with history of radiation therapy.

16. Patients already scheduled or being considered for a procedure or treatment requiring significant radiation exposure (e.g., radiation therapy, PCI, or catheter ablation of arrhythmia) within 12 months of randomization

17. Pregnancy or breastfeeding

18. Coronary artery luminal narrowing >70% seen on coronary CTA

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Massachusetts General Hospital	Boston	Massachusetts	United States	02114

Sponsors and Collaborators

• Massachusetts General Hospital
• National Heart, Lung, and Blood Institute (NHLBI)

Investigators

• Principal Investigator: Steven K. Grinspoon, MD, Massachusetts General Hospital

Study Documents (Full-Text)

None provided.

More Information

Publications

• Subramanian S, Tawakol A, Burdo TH, Abbara S, Wei J, Vijayakumar J, Corsini E, Abdelbaky A, Zanni MV, Hoffmann U, Williams KC, Lo J, Grinspoon SK. Arterial inflammation in patients with HIV. JAMA. 2012 Jul 25;308(4):379-86. doi: 10.1001/jama.2012.6698.

• Responsible Party: Steven K. Grinspoon, MD, Professor of Medicine, Harvard Medical School, Massachusetts General Hospital
• ClinicalTrials.gov Identifier: NCT00965185
• Other Study ID Numbers: 2008-P-000257; R01HL095123; HL 095123
• First Posted: Aug 25, 2009
• Last Update Posted: Dec 11, 2017
• Last Verified: Nov 1, 2017

• Keywords provided by Steven K. Grinspoon, MD, Professor of Medicine, Harvard Medical School, Massachusetts General Hospital: Cardiovascular Disease; HIV; Atherosclerosis; Inflammation; Statins; treatment experienced
• Additional relevant MeSH terms: Cardiovascular Diseases; Atherosclerosis; Inflammation; Atorvastatin

Study Results

Participant Flow

Recruitment Details	This study enrolled men and women with HIV disease, no history of cardiovascular disease or cardiac symptoms, and evidence of subclinical atherosclerosis at Massachusetts General Hospital in Boston, MA USA. The study was done from November, 2009 to January, 2014.
Pre-assignment Detail	Of the 81 patients screened for the study, 40 completed the screening and were randomized to the two study arms.

Arm/Group Title	Atorvastatin	Placebo
Arm/Group Description	Participants received 20 mg atorvastatin given orally daily for the first 3 months, followed by 40 mg atorvastatin daily for the final 9 months.	Participants received 20 mg placebo given orally daily for the first three months followed by 40 mg placebo daily for the next 9 months.
Period Title: Overall Study
STARTED	19	21
1 Month Visit	18	21
3 Month Visit	18	21
6 Month Visit	18	21
9 Month Visit	18	21
COMPLETED	17	20
NOT COMPLETED	2	1

Baseline Characteristics

Arm/Group Title	Atorvastatin	Placebo	Total
Arm/Group Description	Participants received 20 mg atorvastatin given orally daily for the first 3 months, followed by 40 mg atorvastatin daily for the final 9 months.	Participants received 20 mg placebo given orally daily for the first three months followed by 40 mg placebo daily for the next 9 months.	Total of all reporting groups
Overall Participants	19	21	40
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	19 100%	21 100%	40 100%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	52.2 (3.8)	50.0 (5.6)	51.1 (4.9)
Sex: Female, Male (Count of Participants)
Female	4 21.1%	4 19%	8 20%
Male	15 78.9%	17 81%	32 80%
Race/Ethnicity, Customized (participants) [Number]
White	13 68.4%	13 61.9%	26 65%
Black	3 15.8%	3 14.3%	6 15%
Asian	0 0%	1 4.8%	1 2.5%
Hispanic	1 5.3%	1 4.8%	2 5%
More than one race	2 10.5%	1 4.8%	3 7.5%
Unknown	0 0%	2 9.5%	2 5%
Region of Enrollment (participants) [Number]
United States	19 100%	21 100%	40 100%

Outcome Measures

1. Primary Outcome

Title	Coronary and Aortic Plaque Inflammation
Description	12 month change in mean FDG-PET TBR (18-fluorodeoxyglucose positron emission tomography target-to-background ratio)
Time Frame	Measured at baseline and 1 year

Outcome Measure Data

Analysis Population Description

All participants with baseline and 12 month PET and CT scans of acceptable image quality to permit assessment of change over time in identical regions in serial scans. As a result, only a limited number of participants could be included.

Arm/Group Title	Atorvastatin	Placebo
Arm/Group Description	Participants received 20 mg atorvastatin given orally daily for the first 3 months, followed by 40 mg atorvastatin daily for the final 9 months.	Participants received 20 mg placebo given orally daily for the first three months followed by 40 mg placebo daily for the next 9 months.
Measure Participants	10	11
Mean FDG-PET TBR of aorta	0.04	-0.05
Mean FDG-PET TBR of most diseased segment of aorta	-0.03	-0.06

2. Secondary Outcome

Title	Plaque Progression
Description	12 month percent change in plaque volume
Time Frame	Measured at baseline and 1 year

Outcome Measure Data

Analysis Population Description

All available data were used.

Arm/Group Title	Atorvastatin	Placebo
Arm/Group Description	Participants received 20 mg atorvastatin given orally daily for the first 3 months, followed by 40 mg atorvastatin daily for the final 9 months.	Participants received 20 mg placebo given orally daily for the first three months followed by 40 mg placebo daily for the next 9 months.
Measure Participants	17	20
12 month change in total plaque volume	-4.7	18.2
12 month change in non-calcified plaque volume	-19.4	20.4

3. Secondary Outcome

Title	Endothelial Function
Description	Assessment of endothelial function was to be measured by endothelial vasodilator function.
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

Please note that we were unable to collect data for this outcome measure, entitled "Endothelial Function" due to equipment malfunction.

Arm/Group Title	Atorvastatin	Placebo
Arm/Group Description	20 mg PO QD for the first 3 months, followed by 40 mg PO QD for the final 9 months. atorvastatin: 20 mg PO QD for the first 3 months, followed by 40 mg PO QD for the final 9 months.	Placebo: Placebo
Measure Participants	0	0

4. Secondary Outcome

Title	Immune Function
Description	12 month change in CD4 T-lymphocytes
Time Frame	Measured at baseline and 1 year

Outcome Measure Data

Analysis Population Description

All available data were used; data were not available for one subject who completed the study.

Arm/Group Title	Atorvastatin	Placebo
Arm/Group Description	Participants received 20 mg atorvastatin given orally daily for the first 3 months, followed by 40 mg atorvastatin daily for the final 9 months.	Participants received 20 mg placebo given orally daily for the first three months followed by 40 mg placebo daily for the next 9 months.
Measure Participants	17	19
Mean (95% Confidence Interval) [cells per microliter]	17	4

5. Secondary Outcome

Title	Lipid Profile
Description	12 month change in lipid profile
Time Frame	Measured at baseline and 1 year

Outcome Measure Data

Analysis Population Description

All available data were used.

Arm/Group Title	Atorvastatin	Placebo
Arm/Group Description	Participants received 20 mg atorvastatin given orally daily for the first 3 months, followed by 40 mg atorvastatin daily for the final 9 months.	Participants received 20 mg placebo given orally daily for the first three months followed by 40 mg placebo daily for the next 9 months.
Measure Participants	17	20
12 month change in total cholesterol	-1.23	0.12
12 month change in HDL cholesterol	0.02	-0.04
12 month change in direct LDL	-1.00	0.30
12 month change in triglycerides	-0.10	0.08

6. Secondary Outcome

Title	C-reactive Protein (CRP)
Description	12 month change in Log CRP concentration
Time Frame	Measured at baseline and 1 year

Outcome Measure Data

Analysis Population Description

All available data were used.

Arm/Group Title	Atorvastatin	Placebo
Arm/Group Description	Participants received 20 mg atorvastatin given orally daily for the first 3 months, followed by 40 mg atorvastatin daily for the final 9 months.	Participants received 20 mg placebo given orally daily for the first three months followed by 40 mg placebo daily for the next 9 months.
Measure Participants	17	20
Mean (95% Confidence Interval) [log(mg/L)]	-0.3	0.1

7. Secondary Outcome

Title	Adipocytokines
Description	12 month change in IL-6
Time Frame	Measured at baseline and 1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Atorvastatin	Placebo
Arm/Group Description	Participants received 20 mg atorvastatin given orally daily for the first 3 months, followed by 40 mg atorvastatin daily for the final 9 months.	Participants received 20 mg placebo given orally daily for the first three months followed by 40 mg placebo daily for the next 9 months.
Measure Participants	17	20
Mean (95% Confidence Interval) [pg/ml]	-1.25	0.41

8. Secondary Outcome

Title	Liver Function Tests (LFTs)
Description	Number of participants with LFT abnormalities (greater than or equal to 3 times the upper limit of normal). For reference, the normal ranges for AST and ALT are shown below. Please note that the normal range for ALT at Labcorp changed over the course of the study. AST and ALT elevations were determined based on the normal range at the time the lab test was performed. ALT: 0-40 IU/L, 0-44 IU/L, or 0-55 IU/L AST: 0-40 IU/L
Time Frame	Measured at baseline, 1, 3, 6, 9, and 12 months

Outcome Measure Data

Analysis Population Description

All available data were used.

Arm/Group Title	Atorvastatin	Placebo
Arm/Group Description	Participants received 20 mg atorvastatin given orally daily for the first 3 months, followed by 40 mg atorvastatin daily for the final 9 months.	Participants received 20 mg placebo given orally daily for the first three months followed by 40 mg placebo daily for the next 9 months.
Measure Participants	19	21
Number [participants]	3 15.8%	2 9.5%

Adverse Events

Time Frame	1 year
Arm/Group Title	Atorvastatin		Placebo
Arm/Group Description	Participants received 20 mg atorvastatin given orally daily for the first 3 months, followed by 40 mg atorvastatin daily for the final 9 months.		Participants received 20 mg placebo given orally daily for the first three months followed by 40 mg placebo daily for the next 9 months.
All Cause Mortality
	Atorvastatin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Atorvastatin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/19 (10.5%)		1/21 (4.8%)
Gastrointestinal disorders
Gastrointestinal virus induced dehydration	1/19 (5.3%)	1	0/21 (0%)	0
Hepatobiliary disorders
Hepatocellular carcinoma	0/19 (0%)	0	1/21 (4.8%)	1
Reproductive system and breast disorders
Fallopian tube cyst	1/19 (5.3%)	1	0/21 (0%)	0
Other (Not Including Serious) Adverse Events
	Atorvastatin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/19 (68.4%)		14/21 (66.7%)
Gastrointestinal disorders
Loose stools	3/19 (15.8%)		1/21 (4.8%)
Nausea	1/19 (5.3%)		2/21 (9.5%)
General disorders
Abdominal Pain	0/19 (0%)		1/21 (4.8%)
Hepatobiliary disorders
Liver function test abnormalities	3/19 (15.8%)		2/21 (9.5%)
Metabolism and nutrition disorders
Elevated fasting blood glucose	0/19 (0%)		2/21 (9.5%)
Musculoskeletal and connective tissue disorders
Muscle aches or cramps	6/19 (31.6%)		5/21 (23.8%)
Skin and subcutaneous tissue disorders
Rash	0/19 (0%)		1/21 (4.8%)

Limitations/Caveats

FDG-PET scan data was interpretable in only a limited subset of participants as a result of technical problems with manual co-registration (outcome 1). We were unable to collect data for endothelial function due to equipment malfunction (outcome 3).

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.