Clinical trial NCT01351025: Atorvastatin on Biomarkers of Inflammation, Coagulopathy, Angiogenesis & T-cells
Official title: A 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 and LDL Cholesterol < 130 mg/dL
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: HIV-1 Infection
Lead sponsor: Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections
Sponsor class: NETWORK
Collaborators: name: National Institute of Allergy and Infectious Diseases (NIAID)
name: Pfizer
First posted: 2011-05-10
Enrollment: 98
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Difference Between [Change From Week 24 to Week 44] and [Change From Baseline to Week 20] in log10 IL-6
timeFrame: baseline, week 20, week 24, and week 44
measure: Difference Between [Change From Week 24 to Week 44] and [Change From Baseline to Week 20] in CD4+ T-cell Activation Percent
timeFrame: baseline, week 20, week 24, and week 44
measure: Difference Between [Change From Week 24 to Week 44] and [Change From Baseline to Week 20] in log10 D-dimer
timeFrame: baseline, week 20, week 24, and week 44
measure: Difference Between [Change From Week 24 to Week 44] and [Change From Baseline to Week 20] in CD8+ T-cell Activation Percent
timeFrame: baseline, week 20, week 24, and week 44
Secondary outcomes:
measure: Difference Between [Change From Week 24 to Week 44] and Change From [Baseline to Week 20] in MCP-1 (log10 Transformed)
timeFrame: baseline, week 20, week 24, and week 44
measure: Difference Between [Change From Week 24 to Week 44] and Change From [Baseline to Week 20] in IP-10 (log10 Transformed)
timeFrame: baseline, week 20, week 24, and week 44
measure: Difference Between [Change From Week 24 to Week 44] and Change From [Baseline to Week 20] in CD40L (log10 Transformed)
timeFrame: baseline, week 20, week 24, and week 44
measure: Difference Between [Change From Week 24 to Week 44] and Change From [Baseline to Week 20] in sCD14 (log10 Transformed)
timeFrame: baseline, week 20, week 24, and week 44
measure: Difference Between [Change From Week 24 to Week 44] and Change From [Baseline to Week 20] in P-selectin (log10 Transformed)
timeFrame: baseline, week 20, week 24, and week 44
measure: Difference Between [Change From Week 24 to Week 44] and Change From [Baseline to Week 20] in sCD163 (log10 Transformed)
timeFrame: baseline, week 20, week 24, and week 44
measure: Number of Participants With Safety Endpoints Before Study Treatment Cross-over (Baseline to Week 24)
timeFrame: week 0 to week 24
measure: Number of Participants With Safety Endpoints After Study Treatment Cross-over (Week 24 to Week 48)
timeFrame: week 24 to week 48
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: 31788 Alabama CRS
state: Alabama
city: Los Angeles
country: United States
facility: UCLA CARE Center CRS (601)
state: California
city: San Diego
country: United States
facility: Ucsd, Avrc Crs (701)
state: California
city: Torrance
country: United States
facility: Harbor-UCLA Med. Ctr. CRS (603)
state: California
city: Aurora
country: United States
facility: University of Colorado Hospital CRS (6101)
state: Colorado
city: Washington
country: United States
facility: Georgetown University CRS (GU CRS) (1008)
state: District of Columbia
city: Chicago
country: United States
facility: Northwestern University CRS (2701)
state: Illinois
city: Boston
country: United States
facility: Massachusetts General Hospital ACTG CRS (101)
state: Massachusetts
city: Boston
country: United States
facility: Brigham and Women's Hosp. ACTG CRS (107)
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess Med. Ctr., ACTG CRS (103)
state: Massachusetts
city: Detroit
country: United States
facility: Wayne State Univ. CRS (31478)
state: Michigan
city: Detroit
country: United States
facility: Henry Ford Hosp. CRS (31472)
state: Michigan
city: Saint Louis
country: United States
facility: Washington U CRS (2101)
state: Missouri
city: Camden
country: United States
facility: Cooper Univ. Hosp. CRS (31476)
state: New Jersey
city: Newark
country: United States
facility: New Jersey Medical School-Adult Clinical Research Ctr. CRS (31486)
state: New Jersey
city: New York
country: United States
facility: Cornell CRS (7804)
state: New York
city: New York
country: United States
facility: NY Univ. HIV/AIDS CRS (401)
state: New York
city: Rochester
country: United States
facility: AIDS Care CRS (1101)
state: New York
city: Rochester
country: United States
facility: University of Rochester Adult HIV Therapeutic Strategies Network CRS (31787)
state: New York
city: Chapel Hill
country: United States
facility: Unc Aids Crs (3201)
state: North Carolina
city: Durham
country: United States
facility: Duke Univ. Med. Ctr. Adult CRS (1601)
state: North Carolina
city: Cincinnati
country: United States
facility: Univ. of Cincinnati CRS (2401)
state: Ohio
city: Cleveland
country: United States
facility: Case CRS (2501)
state: Ohio
city: Cleveland
country: United States
facility: Metro Health CRS (2503)
state: Ohio
city: Columbus
country: United States
facility: The Ohio State Univ. AIDS CRS (2301)
state: Ohio
city: Philadelphia
country: United States
facility: Hosp. of the Univ. of Pennsylvania CRS (6201)
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Pitt CRS (1001)
state: Pennsylvania
city: Houston
country: United States
facility: Houston AIDS Research Team CRS (31473)
state: Texas
city: Richmond
country: United States
facility: Virginia Commonwealth Univ. Medical Ctr. CRS (31475)
state: Virginia
city: Seattle
country: United States
facility: University of Washington AIDS CRS (1401)
state: Washington
city: San Juan
country: Puerto Rico
facility: Puerto Rico-AIDS CRS (5401)
Study officials:
affiliation: NYU/Bellevue/HIV/AIDS CTU
name: Judith A. Aberg, M.D.
role: STUDY_CHAIR
affiliation: Virginia Commonwealth University Medical Center
name: Daniel E Nixon, D.O., Ph.D.
role: STUDY_CHAIR
References: