Clinical trial NCT00099684: Safety, Effectiveness, and Tolerability of Ezetimibe Combined With Statins for the Treatment of High Cholesterol in HIV Infected Adults
Official title: A Pilot Study of the Safety, Efficacy, and Tolerability of Ezetimibe (Zetia) in Combination With Statin Therapy for the Treatment of Elevated LDL Cholesterol in HIV-Infected Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: HIV Infections
Keywords: Treatment Experienced
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
First posted: 2004-12-20
Enrollment: 44
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: Anti-HIV drugs, especially protease inhibitors (PIs), have been linked to lipid metabolism problems, including elevations in low density lipoprotein cholesterol (LDL-c), triglycerides, and total cholesterol. Ezetimibe is a lipid-controlling drug; statins are part of another class of lipid-lowering drugs popularly prescribed to people with high cholesterol. The purpose of this study is to determine the safety, effectiveness, and tolerability of ezetimibe in combination with statin therapy in adults who are taking anti-HIV drugs and have high cholesterol.

Study hypothesis: In HIV infected adults, ezetimibe in combination with statin therapy will result in significantly lower LDL-c compared to statin therapy alone.

Detailed description: Lipid metabolism abnormalities are common complications of HIV therapy, particularly with PIs. Statins and other lipid-lowering agents are often prescribed to control elevated cholesterol levels in both HIV infected and uninfected people. However, both antiretroviral therapy (ART) and lipid-lowering drugs may be associated with cardiovascular disease, so there is a clear need to find a lipid-lowering drug with low toxicity. This study will evaluate the safety, efficacy, and tolerability of ezetimibe, a lipid-controlling agent, in combination with ongoing statin therapy in HIV infected people currently on ART.

This study will last 28 weeks. All participants will be required to continue their current stable statin therapy and ART for the duration of the study.

Participants will be randomly assigned to one of two arms. Arm 1 participants will receive ezetimibe daily for 12 weeks, no treatment for 4 weeks, then placebo daily for 12 weeks. Arm 2 participants will receive placebo daily for 12 weeks, no treatment for 4 weeks, and then ezetimibe daily for 12 weeks. There will be 9 study visits; they will occur at study screening, at study entry, and every 4 weeks thereafter. Clinical assessment and blood collection will occur at all visits. Participants will be asked to complete an adherence questionnaire at Weeks 4, 12, 20, and 28, and will also be encouraged to coenroll in ACTG A5128 (Consent for Use of Stored Patient Specimens for Future Testing).

Eligibility criteria: Inclusion Criteria:

* HIV infected
* On ART for at least 3 months prior to study entry, and on stable ART for at least 30 days prior to study entry
* Taking one of the study-recommended statins for at least 3 months prior to study entry, and on stable statin therapy for at least 30 days immediately prior to study entry
* On lipid-lowering diet and exercise program for at least 30 days prior to screening, and willing to continue both for the duration of the study
* LDL-c of 130 mg/dL or greater within 30 days prior to study entry
* Willing to use acceptable forms of contraception
* If on hormone replacement therapy, must be on a stable dose or dose-equivalent therapy for at least 30 days prior to study entry, and must be willing to continue the same dose for the duration of the study. People taking physiologic testosterone replacement therapy are not excluded.
* If taking oral contraceptives, must be on a stable dose or dose-equivalent therapy for at least 30 days prior to study entry, and must be willing to continue the same dose for the duration of the study

Exclusion Criteria:

* Active cancer or new diagnosis of cancer within the last 5 years. People with skin cancers, including Kaposi's sarcoma, that do not require systemic treatment are not excluded.
* Prior use of ezetimibe
* Known allergy or sensitivity to ezetimibe or its components
* Diabetes mellitus or use of any diabetic medications within 30 days prior to study entry
* History of coronary heart disease
* History of or current congestive heart failure (New York Heart Association Class III or IV)
* Known atherosclerotic disease risk (e.g., history of myocardial infection, bypass surgery, angioplasty, angina pectoris with a positive stress test or angiographic documentation)
* Vascular abnormalities (e.g., cerebrovascular disease, peripheral vascular disease, abdominal aortic aneurysm, or leg artery blockages)
* Untreated or uncontrolled hypothyroidism
* Current drug or alcohol abuse that may interfere with the study
* Testosterone therapy beyond normal physiologic levels of the hormone within 3 months prior to study entry
* Initiation or change in physiologic testosterone replacement therapy within 3 months prior to study entry
* Hormonal anabolic therapies within 3 months prior to study entry
* Systemic cancer chemotherapy or immunomodulators (e.g., growth factors, immune globulin, interleukins, and interferons) within 60 days prior to study entry
* Lipid-lowering agents (except statins) within 30 days prior to study entry
* Any corticosteroid therapy above replacement levels within 30 days prior to study entry
* Untreated or uncontrolled hypertension
* Active AIDS-defining opportunistic infection (OI) within 30 days prior to study entry. People who have no evidence of active disease and are receiving maintenance therapy for AIDS-related OIs are not excluded.
* Acute illness that would interfere with the study within 30 days prior to study entry
* Investigational agents. People using expanded access investigational antiretroviral drugs are not excluded.
* Decreased mental capacity that may interfere with the study
* Pregnant or breastfeeding

Primary outcomes:
measure: Change in directly measured fasting LDL-c while receiving ezetimibe compared to change while receiving placebo
measure: changes in clinical symptoms and safety labs while receiving ezetimibe compared to changes in clinical symptoms while receiving placebo
Secondary outcomes:
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Los Angeles
country: United States
facility: UCLA School of Medicine
state: California
city: Los Angeles
country: United States
facility: University of Southern California
state: California
city: San Diego
country: United States
facility: University of California, San Diego Antiviral Research Center
state: California
city: San Francisco
country: United States
facility: San Francisco General Hospital
state: California
city: Stanford
country: United States
facility: San Mateo County AIDS Program
state: California
city: Stanford
country: United States
facility: Santa Clara Valley Medical Center
state: California
city: Stanford
country: United States
facility: Stanford University
state: California
city: Stanford
country: United States
facility: Willow Clinic
state: California
city: Washington
country: United States
facility: Georgetown University Medical Center
state: District of Columbia
city: Miami
country: United States
facility: University of Miami
state: Florida
city: Honolulu
country: United States
facility: University of Hawaii
state: Hawaii
city: Chicago, 60611-3015
country: United States
facility: Feinberg School of Medicine, HIV/ACTU
state: Illinois
city: Chicago
country: United States
facility: Rush-Presbyterian/St. Lukes (Chicago)
state: Illinois
city: Chicago
country: United States
facility: Cook County Hospital Core Center
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University Hospital
state: Indiana
city: Indianapolis
country: United States
facility: Wishard Hospital
state: Indiana
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: Omaha
country: United States
facility: Nebraska Health System
state: Nebraska
city: Buffalo
country: United States
facility: SUNY - Buffalo (Rochester)
state: New York
city: New York
country: United States
facility: Beth Israel Medical Center
state: New York
city: New York
country: United States
facility: Chelsea Clinic
state: New York
city: New York
country: United States
facility: NYU/Bellevue
state: New York
city: New York
country: United States
facility: The Cornell Clinical Trials Unit
state: New York
city: New York
country: United States
facility: Columbia University
state: New York
city: Rochester
country: United States
facility: Community Health Network, Inc.
state: New York
city: Rochester
country: United States
facility: University of Rochester Medical Center
state: New York
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Cincinnati
country: United States
facility: University of Cincinnati
state: Ohio
city: Cleveland
country: United States
facility: MetroHealth Medical Center
state: Ohio
city: Columbus
country: United States
facility: Ohio State University
state: Ohio
city: Philadelphia
country: United States
facility: Presbyterian Medical Center - Univ. of PA
state: Pennsylvania
city: Philadelphia
country: United States
facility: University of Pennsylvania, Philadelphia
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh
state: Pennsylvania
city: Providence
country: United States
facility: Rhode Island Hospital
state: Rhode Island
city: Providence
country: United States
facility: Stanley Street Treatment and Resource
state: Rhode Island
city: Providence
country: United States
facility: The Miriam Hospital
state: Rhode Island
city: Nashville
country: United States
facility: Comprehensive Care Clinic
state: Tennessee
city: Dallas
country: United States
facility: Dallas VA Medical Center
state: Texas
city: Galveston
country: United States
facility: University of Texas, Galveston
state: Texas
city: Seattle
country: United States
facility: University of Washington (Seattle)
state: Washington
city: San Juan
country: Puerto Rico
facility: University of Puerto Rico
Study officials:
affiliation: Division of Infectious Diseases, Ohio State University
name: Susan Koletar, MD
role: STUDY_CHAIR
affiliation: University of Hawaii, Hawaii AIDS Clinical Research Program, Leahi Hospital
name: Dominic Chow, MD, MPH
role: STUDY_CHAIR
References:
citation: Calza L, Manfredi R, Chiodo F. Dyslipidaemia associated with antiretroviral therapy in HIV-infected patients. J Antimicrob Chemother. 2004 Jan;53(1):10-4. doi: 10.1093/jac/dkh013. Epub 2003 Nov 25.
citation: Colagreco JP. Cardiovascular considerations in patients treated with HIV protease inhibitors. J Assoc Nurses AIDS Care. 2004 Jan-Feb;15(1):30-41. doi: 10.1177/1055329003256922.
citation: Martinez E, Tuset M, Milinkovic A, Miro JM, Gatell JM. Management of dyslipidaemia in HIV-infected patients receiving antiretroviral therapy. Antivir Ther. 2004 Oct;9(5):649-63.
citation: Visnegarwala F, Maldonado M, Sajja P, Minihan JL, Rodriguez-Barradas MC, Ong O, Lahart CJ, Hasan MQ, Balasubramanyam A, White AC Jr. Lipid lowering effects of statins and fibrates in the management of HIV dyslipidemias associated with antiretroviral therapy in HIV clinical practice. J Infect. 2004 Nov;49(4):283-90. doi: 10.1016/j.jinf.2003.09.006.