Atorvastatin on Biomarkers of Inflammation, Coagulopathy, Angiogenesis & T-cells

Phase 2

Completed

Conditions: HIV-1 Infection

Interventions: Drug: atorvastatin
Drug: placebo for atorvastin

Registration Number: NCT01351025

Lead Sponsor: Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections

Brief Summary: ACTG A5275 was a prospective, double-blind, randomized, placebo-controlled cross-over design pilot study evaluating the effect of atorvastatin on biomarkers of inflammation, coagulopathy, angiogenesis, and T-lymphocyte activation in HIV-1 infected individuals with suppressed HIV-1 RNA on stable protease inhibitor based antiretroviral therapy with fasting LDL cholesterol \< 130 mg/dL.

Atorvastatin is a drug approved by the Food and Drug Administration (FDA) for treating high cholesterol. Atorvastatin has also been able to lower the level of inflammation blood tests in certain other diseases but has not been studied for this purpose in people who have HIV. The main goal of this experimental study is to see how taking atorvastatin affects inflammation blood tests in people infected with HIV who do not need to take medicine for high cholesterol. In addition to observing the effects of atorvastatin on the level of inflammation measured in the blood, this study evaluated if atorvastatin is safe for people with HIV who are also taking medication for HIV.

Detailed Description: Since people started taking HIV medications, illness from AIDS has decreased, but other serious diseases like heart disease (heart attacks) and certain kinds of cancer have increased. HIV causes inflammation (irritation) inside the body that cannot be felt but can be measured by levels of certain inflammation blood tests. Inflammation may contribute to diseases (such as heart attacks) that have become some of the leading causes of death in people with HIV. HIV therapy can partially lower levels of inflammation measured in blood, however, levels of inflammation in people who have HIV who are taking certain kinds of anti-HIV drugs may remain high compared with those found in people not infected with HIV.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 98

Inclusion Criteria

HIV-1 infected
Combination ART that includes any boosted PI regimen for at least 6 months prior to study entry
No plans to change the antiretroviral regimen in the next year
Must have been on the same HAART regimen for at least 12 weeks with no change prior to study entry. More information on this criterion can be found in the study protocol.
If on vitamin D replacement therapy, must have been on stable regimen for ≥ 1 mo. prior to study entry.
CD4+ T-cell count obtained within 45 days prior to study entry at any laboratory that has a Clinical Laboratory Improvement Amendments (CLIA) certification or its equivalent.
Screening HIV-1 RNA < 40 copies/mL by Abbott RealTime PCR at a laboratory certified by the DAIDS Virology Quality Assurance (VQA) program within 45 days prior to study entry.
All known HIV-1 RNA levels obtained within 180 days prior to study entry are below the limits of quantification on all tests, with documentation of at least 1 test by any FDA-approved assay at a CLIA-certified laboratory obtained between 90 to 180 days prior to study entry. A single RNA "blip" of < 500 copies/mL during this time period was permissible if RNA levels immediately before and after were below the limits of quantification for the assay.
Laboratory values obtained within 45 days prior to study entry- Absolute neutrophil count (ANC) 750/mm3, Hemoglobin ≥ 9.0 g/dL for female subjects,10.0 g/dL for male subjects, Platelet count ≥ 100,000/mm3, Calculated creatinine clearance (CrCl) 30 mL/min, as estimated by the Cockcroft-Gault equation, Creatine kinase (CK) < 3 x ULN, AST ≤ 2.0 x ULN, ALT ≤ 2.0 x ULN, Total bilirubin ≤ 2.5 x ULN. If the subject was taking an indinavir- or atazanavir-containing regimen at the time of screening, a total bilirubin of ≤ 5 x ULN is acceptable, Fasting LDL cholesterol ≥ 70 mg/dL and < 130 mg/dL, Fasting triglycerides < 400 mg/dL, Fasting glucose < 110 mg/dL
Screening plasma D-dimer > 0.34 μg/mL from a sample obtained within 45 days prior to study entry was the original D-dimer criterion. It was revised to ≥ 0.25 ug/mL four months after the first enrollment, and subsequently the D-dimer eligibility criterion was completely cut off a year later.
For females of reproductive potential (women who had not been post-menopausal for at least 24 consecutive months, i.e., who had menses within 24 months prior to study entry), or women who had not undergone surgical sterilization, specifically hysterectomy or bilateral oophorectomy or tubal ligation) required a negative serum or urine pregnancy test within 48 hours prior to entry. More information on this criterion can be found in the study protocol.
Must agree not to participate in the conception process (e.g., active attempt to become pregnant or to impregnate, sperm donation, in vitro fertilization), and if participating in sexual activity that could lead to pregnancy, the subject/partner must use at least 2 reliable methods of contraception, (condoms, without a spermicidal agent; a diaphragm or cervical cap without spermicide; an IUD; or hormone-based contraceptive), for 2 weeks before study treatment, while receiving study treatment, and for 6 weeks after receiving study treatment. As hormone-based contraceptives (oral, transdermal, or subdermal) can affect coagulopathy biomarkers, subjects who plan on using such a contraceptive during the study must be taking the same product for ≥ 4 weeks prior to screening and be encouraged to continue throughout the duration of the study if medically feasible.
Karnofsky performance score ≥ 70 on at least one occasion within 45 days prior to study entry
Confirmation of the availability of the stored pre-entry fasting plasma, serum, and cell samples. The site had to confirm that these samples had entered into the Laboratory Data Management System (LDMS).

Exclusion Criteria

Current or past malignancy (except non-melanoma cancer of the skin)
Coronary artery disease (CAD) or CAD equivalent including diabetes mellitus or National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) calculated 10-year coronary heart disease (CHD) risk of > 20%.
Known cirrhosis.
Known chronic active hepatitis B or C.
Thyroid-stimulating hormone (TSH) < 1.0 x lower limit of normal or > 1.0 x ULN.
Known inflammatory conditions, such as, but not limited to, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), sarcoidosis, inflammatory bowel disease (IBD), chronic pancreatitis, autoimmune hepatitis, myositis, or myopathy.
Pregnant or breast-feeding.
Previous intolerance to any statin or any of its components.
Use of any lipid-lowering therapies including all statin drugs, Omega 3 fatty acids/fish oil, red yeast rice, and niacin products ≥ 1 g/day (e.g., niacin, nicotinic acid, vitamin B3) taken within 45 days prior to study entry. More information on this criterion can be found in the study protocol.
Immunosuppressant use, such as, but not limited to, systemic or potentially systemic glucocorticoids (including nasal or inhaled steroids), azathioprine, tacrolimus, mycophenolate, sirolimus, rapamycin, or cyclosporine within 45 days prior to study entry.
Use of any systemic antineoplastic or immunomodulatory treatment, investigational vaccines, interleukins, interferons, growth factors, or intravenous immunoglobulin (IVIG) within 45 days prior to study entry. More information on this criterion can be found in the study protocol.
Concurrent use of prohibited medications. More information on this criterion can be found in the study protocol.
Heavy alcohol use as defined by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) (http://pubs.niaaa.nih.gov/publications/Practitioner/pocketguide/pocket_guide3.htm) and alcohol or drug use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements.
Current use of anticoagulation therapy other than ≤ 325 mg of daily aspirin.
Known coagulopathy, deep venous thrombosis, pulmonary embolism within 6 months prior to study entry.
Known active or recent (not fully resolved within 4 weeks prior to study entry) bacterial, fungal, parasitic, or viral infections.
Known history of recurrent rectal and/or genital herpes simplex virus (HSV) or varicella zoster virus (VZV) infection within 12 weeks prior to study entry.
Serious illness or trauma requiring systemic treatment and/or hospitalization within 4 weeks prior to study entry.
History of stroke.

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Arm B: placebo / atorvastatin	placebo for atorvastin	At study entry (week 0), participants continued the entry boosted PI-based antiretroviral regimen (not provided by the study) and initiated placebo for 4 weeks. If no symptoms or lab findings suggestive of toxicity were found, the dose of placebo was doubled at the week 4 visit. At week 20, the placebo was stopped for a 4-week washout period. At week 24, atorvastatin was started at a daily dose of 10 mg for 4 weeks. If no symptoms or lab findings suggestive of atorvastatin toxicity were found, the dose of atorvastatin was increased to 20 mg daily at week 28. At week 44, atorvastatin was stopped to allow for another 4-week washout period.
Arm A: atorvastatin / placebo	placebo for atorvastin	At study entry (week 0), participants continued the entry boosted PI-based antiretroviral regimen (not provided by the study) and initiated atorvastatin at a daily dose of 10 mg for 4 weeks. If no symptoms or lab findings suggestive of atorvastatin toxicity were found, the dose of atorvastatin was increased to 20 mg daily at the week 4 visit. At week 20, atorvastatin was stopped for a 4-week washout period. At week 24, placebo was started for 4 weeks. If no symptoms or lab findings suggestive of toxicity were found, the placebo dose was doubled at week 28. At week 44, the placebo was stopped to allow for another 4-week washout period.
Arm A: atorvastatin / placebo	atorvastatin	At study entry (week 0), participants continued the entry boosted PI-based antiretroviral regimen (not provided by the study) and initiated atorvastatin at a daily dose of 10 mg for 4 weeks. If no symptoms or lab findings suggestive of atorvastatin toxicity were found, the dose of atorvastatin was increased to 20 mg daily at the week 4 visit. At week 20, atorvastatin was stopped for a 4-week washout period. At week 24, placebo was started for 4 weeks. If no symptoms or lab findings suggestive of toxicity were found, the placebo dose was doubled at week 28. At week 44, the placebo was stopped to allow for another 4-week washout period.
Arm B: placebo / atorvastatin	atorvastatin	At study entry (week 0), participants continued the entry boosted PI-based antiretroviral regimen (not provided by the study) and initiated placebo for 4 weeks. If no symptoms or lab findings suggestive of toxicity were found, the dose of placebo was doubled at the week 4 visit. At week 20, the placebo was stopped for a 4-week washout period. At week 24, atorvastatin was started at a daily dose of 10 mg for 4 weeks. If no symptoms or lab findings suggestive of atorvastatin toxicity were found, the dose of atorvastatin was increased to 20 mg daily at week 28. At week 44, atorvastatin was stopped to allow for another 4-week washout period.

Primary Outcome Measures

Name	Time	Method
Difference Between [Change From Week 24 to Week 44] and [Change From Baseline to Week 20] in log10 IL-6	baseline, week 20, week 24, and week 44	IL-6 (Interleukin 6) in log10 pg/mL: Difference between \[change from week 24 to week 44\] and \[change from baseline to week 20\] (i.e. \[week 44 - week 24\] - \[week 20 - baseline\])
Difference Between [Change From Week 24 to Week 44] and [Change From Baseline to Week 20] in CD4+ T-cell Activation Percent	baseline, week 20, week 24, and week 44	CD4+ T-cell activation percent (% CD38+/DR+ of CD4+): Difference between \[change from week 24 to week 44\] and \[change from baseline to week 20\] (i.e. \[week 44 - week 24\] - \[week 20 - baseline\])
Difference Between [Change From Week 24 to Week 44] and [Change From Baseline to Week 20] in log10 D-dimer	baseline, week 20, week 24, and week 44	D-dimer in log10 ng/mL: Difference between \[change from week 24 to week 44\] and \[change from baseline to week 20\] (i.e. \[week 44 - week 24\] - \[week 20 - baseline\])
Difference Between [Change From Week 24 to Week 44] and [Change From Baseline to Week 20] in CD8+ T-cell Activation Percent	baseline, week 20, week 24, and week 44	CD8+ T-cell activation percent (% CD38+/DR+ of CD8+): Difference between \[change from week 24 to week 44\] and \[change from baseline to week 20\] (i.e. \[week 44 - week 24\] - \[week 20 - baseline\])

Secondary Outcome Measures

Name	Time	Method
Difference Between [Change From Week 24 to Week 44] and Change From [Baseline to Week 20] in MCP-1 (log10 Transformed)	baseline, week 20, week 24, and week 44	Monocyte chemoattractant protein-1 (MCP-1/CCL2) is one of the key chemokines that regulate migration and infiltration of monocytes/macrophages. Difference between \[change from week 24 to week 44\] and change from \[baseline to week 20\] is defined as \[week 44 - week 24\] - \[week 20 - baseline\].
Difference Between [Change From Week 24 to Week 44] and Change From [Baseline to Week 20] in IP-10 (log10 Transformed)	baseline, week 20, week 24, and week 44	IFN-gamma-inducible protein 10 (IP-10 or CXCL10) is a chemokine secreted from cells stimulated with type I and II IFNs and LPS, is also a chemoattractant for activated T cells. Difference between \[change from week 24 to week 44\] and change from \[baseline to week 20\] is defined as \[week 44 - week 24\] - \[week 20 - baseline\].
Difference Between [Change From Week 24 to Week 44] and Change From [Baseline to Week 20] in CD40L (log10 Transformed)	baseline, week 20, week 24, and week 44	Cluster of differentiation 40 (CD40L) is a costimulatory protein found on antigen presenting cells and is required for their activation. Difference between \[change from week 24 to week 44\] and change from \[baseline to week 20\] is defined as \[week 44 - week 24\] - \[week 20 - baseline\].
Difference Between [Change From Week 24 to Week 44] and Change From [Baseline to Week 20] in sCD14 (log10 Transformed)	baseline, week 20, week 24, and week 44	Soluble cluster of differentiation 14 (sCD14) is a human gene. Difference between \[change from week 24 to week 44\] and change from \[baseline to week 20\] is defined as \[week 44 - week 24\] - \[week 20 - baseline\].
Difference Between [Change From Week 24 to Week 44] and Change From [Baseline to Week 20] in P-selectin (log10 Transformed)	baseline, week 20, week 24, and week 44	P-selectin is a protein that in humans encoded by the SELP gene. P-selectin functions as a cell adhesion molecule (CAM) on the surfaces of activated endothelial cells, which line the inner surface of blood vessels, and activated platelets. Difference between \[change from week 24 to week 44\] and change from \[baseline to week 20\] is defined as \[week 44 - week 24\] - \[week 20 - baseline\].
Difference Between [Change From Week 24 to Week 44] and Change From [Baseline to Week 20] in sCD163 (log10 Transformed)	baseline, week 20, week 24, and week 44	CD163 (Cluster of Differentiation 163) is a protein that in humans encoded by the CD163 gene; and sCD163 is soluble CD163. Difference between \[change from week 24 to week 44\] and change from \[baseline to week 20\] is defined as \[week 44 - week 24\] - \[week 20 - baseline\].
Number of Participants With Safety Endpoints Before Study Treatment Cross-over (Baseline to Week 24)	week 0 to week 24	Safety endpoints are defined as grade ≥ 2 signs and symptoms, laboratory abnormalities, AST/ALT \> 3 X ULN, and adverse events prior to study treatment cross-over (baseline to week 24). The DAIDS Adverse Event (AE) Grading Table, Version 1.0, December 2004 (Clarification, August 2009) was used for grading of AEs.
Number of Participants With Safety Endpoints After Study Treatment Cross-over (Week 24 to Week 48)	week 24 to week 48	Safety endpoints are defined as grade ≥ 2 signs and symptoms, laboratory abnormalities, AST/ALT \> 3 X ULN, and adverse events after study treatment cross-over (week 24 to week 48). The DAIDS Adverse Event (AE) Grading Table, Version 1.0, December 2004 (Clarification, August 2009) was used for grading of AEs.

Trial Locations

Locations (31): Georgetown University CRS (GU CRS) (1008)
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Washington, District of Columbia, United States
Hosp. of the Univ. of Pennsylvania CRS (6201)
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Philadelphia, Pennsylvania, United States
Massachusetts General Hospital ACTG CRS (101)
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Boston, Massachusetts, United States
Beth Israel Deaconess Med. Ctr., ACTG CRS (103)
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Boston, Massachusetts, United States
Univ. of Cincinnati CRS (2401)
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Cincinnati, Ohio, United States
University of Washington AIDS CRS (1401)
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Seattle, Washington, United States
Case CRS (2501)
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Cleveland, Ohio, United States
Metro Health CRS (2503)
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Cleveland, Ohio, United States
Houston AIDS Research Team CRS (31473)
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Houston, Texas, United States
Duke Univ. Med. Ctr. Adult CRS (1601)
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Durham, North Carolina, United States
University of Colorado Hospital CRS (6101)
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Aurora, Colorado, United States
Washington U CRS (2101)
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Saint Louis, Missouri, United States
Cooper Univ. Hosp. CRS (31476)
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Camden, New Jersey, United States
Pitt CRS (1001)
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Pittsburgh, Pennsylvania, United States
Virginia Commonwealth Univ. Medical Ctr. CRS (31475)
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Richmond, Virginia, United States
31788 Alabama CRS
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Birmingham, Alabama, United States
Wayne State Univ. CRS (31478)
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Detroit, Michigan, United States
Henry Ford Hosp. CRS (31472)
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Detroit, Michigan, United States
UCLA CARE Center CRS (601)
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Los Angeles, California, United States
Harbor-UCLA Med. Ctr. CRS (603)
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Torrance, California, United States
Ucsd, Avrc Crs (701)
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San Diego, California, United States
Brigham and Women's Hosp. ACTG CRS (107)
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Boston, Massachusetts, United States
Northwestern University CRS (2701)
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Chicago, Illinois, United States
Puerto Rico-AIDS CRS (5401)
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San Juan, Puerto Rico
New Jersey Medical School-Adult Clinical Research Ctr. CRS (31486)
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Newark, New Jersey, United States
Unc Aids Crs (3201)
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Chapel Hill, North Carolina, United States
Cornell CRS (7804)
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New York, New York, United States
NY Univ. HIV/AIDS CRS (401)
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New York, New York, United States
University of Rochester Adult HIV Therapeutic Strategies Network CRS (31787)
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Rochester, New York, United States
AIDS Care CRS (1101)
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Rochester, New York, United States
The Ohio State Univ. AIDS CRS (2301)
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Columbus, Ohio, United States