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Randomized Placebo-Controlled Trial of Atorvastatin in HIV-Positive Patients Not on Antiretroviral Therapy (STATIN)

2020년 2월 24일 업데이트: Frank Maldarelli, M.D., National Institute of Allergy and Infectious Diseases (NIAID)

A Randomized Placebo Controlled Trial of Atorvastatin in HIV Positive Patients Not on Antiretroviral Medications With the Specific Aims of Studying the Effects of Atorvastatin on HIV Viral Load and Immune Activation Markers

This study will examine the effects of atorvastatin, a statin (drug that lowers cholesterol) on the human immunodeficiency virus (HIV). If not treated, HIV infection causes an incurable, progressive deficiency in the immune system that leads to death, usually from disease that takes advantage of weakened immunity. Previous studies, however, have suggested that if the amount of cholesterol in infected cells is reduced, multiplication of HIV is also reduced. In this study, researchers will examine the HIV viral loads, that is, amount of the virus in the blood. They will evaluate the composition of the strain of the virus that patients carry (HIV genotype), response of the immune system to the virus, and how genes may determine the way in which the drug may or may not work against the strain of virus. Researchers plan to enroll 22 participants, anticipating a study to last 30 weeks for each participant.

Patients ages 18 or older with HIV infection, who are not pregnant or breastfeeding, who do not have a known allergy to atorvastatin use, and who have not had a serious illness or infection that required hospitalization within the 30 days before entering the study may be eligible for this study. They will be assigned to random groups: one that to receive atorvastatin and the other to receive a placebo, which has no effect on cholesterol or ability of the HIV infection to multiply. Patients will remain in their groups and treatments for 8 weeks. At the completion of 8 weeks, no matter the study group, all patients will be required to discontinue all study-related medications for 4 weeks. After that period, the study assignments will be switched, so that those previously taking the placebo will take atorvastatin, and vice versa. The study will proceed for another 8 weeks, followed by a period of stopping study-related medications and patients being observed for 4 weeks. Throughout the study, patients will have regularly scheduled visits at the clinic. At those visits there will be collection of blood samples, assessments of symptoms, physical examinations, and questionnaires to complete. Blood tests may require fasting beforehand, and blood samples will be used in standard tests, including those regarding the liver, kidneys, muscles, blood cells, and pregnancy status. Specialized blood tests will determine viral load, effects of the drug on the immune cells, and genetic influence on the drug's effectiveness.

연구 개요

상태

완전한

정황

개입 / 치료

상세 설명

This protocol is a randomized, double blind, placebo controlled trial designed to study the effects of the lipid lowering statin, atorvastatin on HIV-1 viremia.

Untreated HIV-1 infection results in an incurable, progressive immunodeficiency and death, usually from opportunistic infections. Combination antiretroviral therapy (ARV) has been successful in suppressing HIV replication and reducing morbidity and mortality. Long term ARV therapy is associated with the development of HIV-1 drug resistance, and significant adverse side effects including metabolic and cardiovascular complications. Prolonged therapy with certain antiretrovirals is associated with increased risk of cardiovascular disease and a number of dyslipidemic syndromes, including increased levels of cholesterol, LDL, and triglycerides in peripheral blood. New therapeutic strategies to suppress HIV-1 infection are essential.

Previously, in vitro studies suggested that exposure to cholesterol-lowering statins results in decreases in HIV-1 replication. The mechanisms of inhibition remain uncertain, but possibilities include disrupting membrane trafficking or cytoskeletal processes necessary for intracellular transport of viral proteins, or altering cellular activation state necessary for viral gene expression. Initial in vivo studies of the effects of statins on HIV-1 have been largely anecdotal in nature and have yielded conflicting results. Although statin therapy is commonly used in HIV-1 infection, adverse effects from the combination of antiretrovirals and statins are possible. A more thorough understanding of the effects of statins on HIV-1 replication is essential to determine the potential therapeutic effect and to investigate the risks and benefits of this approach in vivo.

We plan to conduct a double blind randomized placebo controlled trial, with a cross over design, to study the effects of atorvastatin in 22 HIV-infected patients not currently taking antiretroviral therapy. Patients will be randomized to receive either placebo or atorvastatin 80mg for 8 weeks. After a 4-week wash out period patients on the atorvastatin arm will crossover to placebo and, vice versa patients in the placebo arm will cross over to atorvastatin for an additional 8 weeks. Upon completion of study medications all patients will be followed for 4 weeks. Each arm will have a minimum of 11 patients each. The primary outcome measure in this study is the effect of lipid lowering agents on HIV-1 RNA levels; additional secondary outcome measures include effects of lipid lowering agents on lipid profile, markers of inflammation and immune activation and investigations of host and viral genetic factors.

연구 유형

중재적

등록 (실제)

24

단계

  • 2 단계

연락처 및 위치

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연구 장소

    • California
      • San Diego, California, 미국, 92134-5000
        • Naval Medical Center, San Diego
    • Maryland
      • Bethesda, Maryland, 미국, 20892
        • National Institutes of Health Clinical Center, 9000 Rockville Pike
      • Bethesda, Maryland, 미국, 20889
        • National Naval Medical Center

참여기준

연구원은 적격성 기준이라는 특정 설명에 맞는 사람을 찾습니다. 이러한 기준의 몇 가지 예는 개인의 일반적인 건강 상태 또는 이전 치료입니다.

자격 기준

공부할 수 있는 나이

18년 이상 (성인, 고령자)

건강한 자원 봉사자를 받아들입니다

아니

연구 대상 성별

모두

설명

  • INCLUSION CRITERIA:
  • Adults 18 years of age or older.
  • Human Immunodeficiency Virus -1 (HIV-1) infection, as documented by a licensed Enzyme-Linked Immunosorbent Assay (ELISA) test kit and confirmed by a Western blot assay at any time point prior to study entry or at study entry (May do after informed consent if no test results are available).

Off all antiretroviral (ARV) for greater than or equal to three months prior to study entry, no documented evidence of viral resistance, and no evidence of acute HIV infection.

  • Willingness to use a method of contraception during the study period.
  • Willingness to have blood drawn.
  • No known allergy or contraindication to atorvastatin use.
  • Ability to understand and willingness to sign the informed consent.
  • Willingness to have blood stored for future phenotyping and genotyping.
  • Cluster of differentiation 4 (CD4) cell count greater than 350 cells/ml.
  • 3 viral loads that average greater than 1000 copies/ml within a 4-week period.
  • The viral loads will be done using the branched deoxyribonucleic acid (bDNA) method in the National Institutes of Health (NIH) laboratory and must be within 20% (log10bDNA of each other).
  • A fasting total cholesterol lower than 240mg/dl and an Low-density lipoprotein (LDL) cholesterol lower than 130mg/dl.
  • Liver function tests (aspartate aminotransferase (AST) or alanine aminotransferase (ALT)) not greater than 1.5 times the upper limit of normal.
  • Creatine phosphokinase elevations (CPK) not greater than 3 times the upper limit of normal (ULN) on two sequential determinations and, in the opinion of the investigator, without clear association with exercise.
  • Laboratory values:

Absolute neutrophil count (ANC) greater than or equal to 1000/mm(3).

Hemoglobin greater than or equal to 11.0 g/dL.

Platelet count greater than or equal to 100,000/mm(3).

Creatinine less than or equal to 2 x ULN.

Serum amylase and lipase less than or equal to 1.25 x ULN.

  • Negative serum pregnancy test at randomization.

EXCLUSION CRITERIA:

  • Pregnancy or breast feeding.
  • Active drug use or alcohol abuse/dependence, which in the opinion of the investigators, will interfere with the patient's ability to participate in the study.
  • Serious illness requiring systemic treatment and/or hospitalization within 30 days of entry.
  • Evidence of active opportunistic infections or neoplasms that require chemotherapy during the study period except cutaneous Kaposi Sarcoma.
  • Allergy or hypersensitivity to atorvastatin or any of its components.
  • History of myositis or rhabdomyolysis with use of any statins.
  • History of inflammatory muscle disease such as poly or dermatomyositis.
  • Concomitant use of fibric acid derivatives or other lipid lowering agents including patients on statins and Ezetimibe.
  • Concomitant use of drugs that have significant interactions with atorvastatin. Please see appendix II for a listing.
  • Concomitant use of St.Johns wort.
  • Concomitant use of Valproic acid.
  • Patients who are on concurrent immunomodulatory agents, including systemic corticosteroids, will be ineligible for 3 months after completion of therapy with the immunomodulating agents. Topical, nasal or inhaled corticosteroids use is not an exclusion criterion.
  • Serum LDL cholesterol less than 40 mg/dl.
  • Vaccinations within 6 weeks of study entry.
  • Vaccinations within 6 weeks of study entry.

공부 계획

이 섹션에서는 연구 설계 방법과 연구가 측정하는 내용을 포함하여 연구 계획에 대한 세부 정보를 제공합니다.

연구는 어떻게 설계됩니까?

디자인 세부사항

  • 주 목적: 기초 과학
  • 할당: 무작위
  • 중재 모델: 크로스오버 할당
  • 마스킹: 네 배로

무기와 개입

참가자 그룹 / 팔
개입 / 치료
실험적: Atorvastatin, then Placebo
Patients were randomized to receive Atorvastatin first for 8 weeks, followed by 4 weeks wash out, and then cross over to placebo for 8 weeks.
80 mg atorvastatin oral daily
다른 이름들:
  • 리피토
patients will be administered placebo
다른 이름들:
  • no other name for placebo
실험적: Placebo, Then Atorvastatin
Patients were randomized to receive placebo first for 8 weeks, followed by 4 weeks wash out, and then cross over to 80 mg atorvastatin daily for 8 weeks.
80 mg atorvastatin oral daily
다른 이름들:
  • 리피토
patients will be administered placebo
다른 이름들:
  • no other name for placebo

연구는 무엇을 측정합니까?

주요 결과 측정

결과 측정
측정값 설명
기간
Change in Human Immunodeficiency Virus 1 (HIV-1) Ribonucleic Acid (RNA) Levels
기간: Baseline and 8 weeks
The change in HIV viral RNA level in plasma in response to lipid lowering agents was measured as log10 plasma RNA copy number, and the change in the log10 viral RNA level is included in table.
Baseline and 8 weeks

2차 결과 측정

결과 측정
측정값 설명
기간
Change in Percentage of Cluster of Differentiation 4 (CD4+) Human Leukocyte Antigen DR (HLA-DR+) in Peripheral Blood
기간: Baseline and 8 weeks
CD4+HLA-DR+ are cellular markers of immune activation that is present in HIV infected individuals. This marker was measured before and after the statin/placebo intervention by standard lymphocyte phenotyping.
Baseline and 8 weeks
Number of Participants With Serious and Non-Serious Adverse Events
기간: Date treatment consent signed to date off study, approximately 26 weeks.
Here is the count of participants with serious and non-serious adverse events. A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.
Date treatment consent signed to date off study, approximately 26 weeks.
Change in Percentage of Cluster of Differentiation 8 (CD8+) Human Leukocyte Antigen DR (HLA-DR+) in Peripheral Blood
기간: Baseline and 8 weeks
CD8+HLA-DR+ are cellular markers of immune activation that is present in HIV infected individuals. This marker was measured before and after the statin/placebo intervention by standard lymphocyte phenotyping.
Baseline and 8 weeks
Change in Percentage of Cluster of Differentiation 8 (CD8+) Human Leukocyte Antigen DR (HLA-DR+), CD8+(CD8+HLADR+CD38+) in Peripheral Blood
기간: Baseline and 8 weeks
CD8+HLADR+CD38+ are cellular markers of immune activation that is present in HIV infected individuals. This marker was measured before and after the statin/placebo intervention by standard lymphocyte phenotyping.
Baseline and 8 weeks

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스폰서

수사관

  • 수석 연구원: Frank Maldarelli, M.D. Ph.D., National Cancer Institute (NCI), National Institutes of Health (NIH)

간행물 및 유용한 링크

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연구 기록 날짜

이 날짜는 ClinicalTrials.gov에 대한 연구 기록 및 요약 결과 제출의 진행 상황을 추적합니다. 연구 기록 및 보고된 결과는 공개 웹사이트에 게시되기 전에 특정 품질 관리 기준을 충족하는지 확인하기 위해 국립 의학 도서관(NLM)에서 검토합니다.

연구 주요 날짜

연구 시작 (실제)

2006년 10월 18일

기본 완료 (실제)

2008년 6월 19일

연구 완료 (실제)

2008년 6월 19일

연구 등록 날짜

최초 제출

2006년 8월 22일

QC 기준을 충족하는 최초 제출

2006년 8월 22일

처음 게시됨 (추정)

2006년 8월 23일

연구 기록 업데이트

마지막 업데이트 게시됨 (실제)

2020년 2월 26일

QC 기준을 충족하는 마지막 업데이트 제출

2020년 2월 24일

마지막으로 확인됨

2020년 2월 1일

추가 정보

이 연구와 관련된 용어

기타 연구 ID 번호

  • 060197
  • 06-I-0197 (기타 식별자: NIAID IRB)

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