Treatment of HDL to Reduce the Incidence of Vascular Events HPS2-THRIVE (HPS2-THRIVE)
A Randomized Trial of the Long-term Clinical Effects of Raising HDL Cholesterol With Extended Release Niacin/Laropiprant
연구 개요
상태
상세 설명
Cardiovascular disease is one of the leading causes of morbidity and mortality in the United Kingdom (UK), as well as in the developed and the developing world. Finding new and safe treatments to reduce the burden of heart disease and strokes is therefore an important contribution to public health and in the wider public interest. HPS2-THRIVE aims to find out whether by combining niacin (a drug that has been available for 50 years) with a new drug laropiprant(which reduces the side-effects of niacin) is beneficial. All participants in HPS2-THRIVE will have established cardiovascular disease and therefore be at very high risk of recurrent vascular events (myocardial infarction, stroke or the need for arterial revascularisation). Two of the most important risk factors for recurrent events in such patients are the blood levels of LDL cholesterol with a positive association, and HDL cholesterol levels with a negative association.
HDL cholesterol has long been known to have a strong inverse correlation with coronary heart disease (CHD) risk. But, randomized trial evidence for beneficial effects from raising HDL cholesterol is limited. One of the most effective HDL-raising agents is niacin but the tolerability of niacin has been severely limited by flushing and cutaneous side-effects, which appear to be mediated largely by prostaglandin D. Laropiprant is a selective prostaglandin D receptor antagonist that substantially reduces the frequency and intensity of niacin-induced flushing. Daily oral doses of extended release (ER) niacin plus Laropiprant 2g(formerly MK-0524A) have been well tolerated in early studies and increase HDL cholesterol by 20-25%. The trial will assess whether this increase in HDL cholesterol translates into clinical benefit as is expected from the observational evidence. In addition, all participants will also be provided with effective LDL-lowering therapy, as either simvastatin 40mg daily alone or with ezetimibe 10mg daily in a combination tablet.
The complementary effects on the HDL (good) and LDL (bad) cholesterol produced by extended release niacin/laropiprant 2 g daily and simvastatin 40 mg with or without ezetimibe 10 mg should provide an excellent treatment option for patients with vascular disease. However, no trials so far have demonstrated clearly that raising HDL cholesterol produces the expected reduction in cardiovascular risk. If HPS2-THRIVE is able to demonstrate reliably that raising HDL cholesterol reduces the risk of further cardiovascular events then this will be relevant to hundreds of millions of people worldwide.
연구 유형
등록 (실제)
단계
- 3단계
연락처 및 위치
연구 장소
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Oxford, 영국, OX3 7LF
- Clinical Trial Service Unit, University of Oxford
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참여기준
자격 기준
공부할 수 있는 나이
건강한 자원 봉사자를 받아들입니다
연구 대상 성별
설명
Inclusion Criteria:
- History of myocardial infarction; or
- Cerebrovascular atherosclerotic disease (history of presumed ischaemic stroke, transient ischaemic attack or carotid revascularisation)
- Peripheral arterial disease (i.e. intermittent claudication or history of revascularisation); or
- Diabetes mellitus with any of the above or with other evidence of symptomatic coronary heart disease (i.e. stable or unstable angina, or a history of coronary revascularisation or acute coronary syndrome).
Exclusion Criteria:
- Age <50 or >80 years at invitation to Screening;
- Less than 3 months since presentation with acute myocardial infarction, coronary syndrome or stroke (but such patients may be entered later, if appropriate);
- Planned revascularisation procedure within 3 months after randomization (but such patients may be entered later, if appropriate);
- Definite history of chronic liver disease, or abnormal liver function (i.e. Alanine transaminase (ALT) >1.5 times upper limit of normal (ULN). (Note: Patients with a history of acute hepatitis are eligible provided this ALT limit is not exceeded);
- Breathlessness at rest for any reason;
- Severe renal insufficiency (i.e. creatinine >200 µmol/L);
- Evidence of active inflammatory muscle disease (e.g. dermatomyositis, polymyositis), or Creatine kinase (CK) >3 times upper limit of normal (3xULN);
- Previous significant adverse reaction to a statin, ezetimibe, niacin or laropiprant;
- Active peptic ulcer disease;
- Concurrent treatment with:
- fibric acid derivative ("fibrate")
- niacin (nicotinic acid) at doses more than 100 mg daily
- ezetimibe in combination with either simvastatin 80 mg, or atorvastatin 20-80 mg, or rosuvastatin 10-40 mg daily
- any potent cytochrome P450 3A4 (CYP3A4) inhibitor, including: macrolide antibiotics (erythromycin, clarithromycin, telithromycin); systemic use of imidazole or triazole antifungals (e.g. itraconazole, ketoconazole); protease inhibitors (antiretroviral drugs for HIV infection); and nefazodone
- ciclosporin
- amiodarone
- verapamil
- danazol (Note: Patients who are temporarily taking such drugs may be re-screened when they discontinue them, if considered appropriate.);
- Known to be poorly compliant with clinic visits or prescribed medication;
- Medical history that might limit the individual's ability to take trial treatments for the duration of the study (e.g. severe respiratory disease, history of cancer or evidence of spread within last 5 years other than non-melanoma skin cancer, or recent history of alcohol or substance misuse)
공부 계획
연구는 어떻게 설계됩니까?
디자인 세부사항
- 주 목적: 방지
- 할당: 무작위
- 중재 모델: 병렬 할당
- 마스킹: 네 배로
무기와 개입
참가자 그룹 / 팔 |
개입 / 치료 |
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실험적: ER niacin/laropiprant
1 g ER niacin plus 20 mg laropiprant per tablet.
2 tablets orally per day.
With either 40 mg simvastatin tablet or ezetimibe/simvastatin (10 mg/40 mg) in single tablet taken once daily
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다른 이름들:
40 mg simvastatin tablet orally per day as background LDL-lowering treatment allocated at entry based on previous statin treatment and total cholesterol level
다른 이름들:
10 mg ezetimibe plus 40 mg simvastatin in single tablet taken once daily as background LDL-lowering treatment allocated at entry based on previous statin treatment and total cholesterol level
다른 이름들:
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활성 비교기: Placebo
Placebo (for ER niacin/laropiprant) 2 tablets orally per day.
With either 40 mg simvastatin tablet orally per day or ezetimibe/simvastatin (10 mg/40 mg) in single tablet taken once daily
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40 mg simvastatin tablet orally per day as background LDL-lowering treatment allocated at entry based on previous statin treatment and total cholesterol level
다른 이름들:
10 mg ezetimibe plus 40 mg simvastatin in single tablet taken once daily as background LDL-lowering treatment allocated at entry based on previous statin treatment and total cholesterol level
다른 이름들:
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연구는 무엇을 측정합니까?
주요 결과 측정
결과 측정 |
측정값 설명 |
기간 |
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Major Vascular Event
기간: During scheduled treatment period (median duration 3.9 years)
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Non-fatal myocardial infarction or coronary death, non-fatal or fatal stroke, or revascularisation
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During scheduled treatment period (median duration 3.9 years)
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2차 결과 측정
결과 측정 |
측정값 설명 |
기간 |
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Major Coronary Events
기간: During scheduled treatment period (median duration 3.9 years)
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Non-fatal myocardial infarction (MI) or coronary death
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During scheduled treatment period (median duration 3.9 years)
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Stroke
기간: During scheduled treatment period (median duration 3.9 years)
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Fatal or non-fatal
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During scheduled treatment period (median duration 3.9 years)
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Coronary or Non-coronary Revascularisation
기간: During scheduled treatment period (median duration 3.9 years)
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During scheduled treatment period (median duration 3.9 years)
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Mortality
기간: During scheduled treatment period (median duration 3.9 years)
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All-cause mortality
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During scheduled treatment period (median duration 3.9 years)
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공동 작업자 및 조사자
수사관
- 수석 연구원: Jane Armitage, Clinical Trial Service Unit, University of Oxford
- 수석 연구원: Colin Baigent, Clinical Trial Service Unit, University of Oxford
- 수석 연구원: Zhengming Chen, Clinical Trial Service Unit, University of Oxford
- 수석 연구원: Martin Landray, Clinical Trial Service Unit, University of Oxford
간행물 및 유용한 링크
일반 간행물
- HPS2-THRIVE Collaborative Group; Haynes R, Chen F, Wincott E, Dayanandan R, Lay MJ, Parish S, Bowman L, Landray MJ, Armitage J. Investigating modifications to participant information materials to improve recruitment into a large randomized trial. Trials. 2019 Dec 5;20(1):681. doi: 10.1186/s13063-019-3779-4.
- Haynes R, Valdes-Marquez E, Hopewell JC, Chen F, Li J, Parish S, Landray MJ, Armitage J; HPS2-THRIVE Collaborative Group; HPS2-THRIVE Writing Committee members; HPS2-THRIVE Steering Committee members. Serious Adverse Effects of Extended-release Niacin/Laropiprant: Results From the Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) Trial. Clin Ther. 2019 Sep;41(9):1767-1777. doi: 10.1016/j.clinthera.2019.06.012. Epub 2019 Aug 22.
- Offer A, Arnold M, Clarke R, Bennett D, Bowman L, Bulbulia R, Haynes R, Li J, Hopewell JC, Landray M, Armitage J, Collins R, Parish S; Heart Protection Study (HPS), Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH), and Treatment of HDL (High-Density Lipoprotein) to Reduce the Incidence of Vascular Events (HPS2-THRIVE) Collaborative Grou. Assessment of Vascular Event Prevention and Cognitive Function Among Older Adults With Preexisting Vascular Disease or Diabetes: A Secondary Analysis of 3 Randomized Clinical Trials. JAMA Netw Open. 2019 Mar 1;2(3):e190223. doi: 10.1001/jamanetworkopen.2019.0223. Erratum In: JAMA Netw Open. 2019 Mar 1;2(3):e192236.
- Parish S, Hopewell JC, Hill MR, Marcovina S, Valdes-Marquez E, Haynes R, Offer A, Pedersen TR, Baigent C, Collins R, Landray M, Armitage J; HPS2-THRIVE Collaborative Group. Impact of Apolipoprotein(a) Isoform Size on Lipoprotein(a) Lowering in the HPS2-THRIVE Study. Circ Genom Precis Med. 2018 Feb;11(2):e001696. doi: 10.1161/CIRCGEN.117.001696.
- Kent S, Haynes R, Hopewell JC, Parish S, Gray A, Landray MJ, Collins R, Armitage J, Mihaylova B; HPS2-THRIVE Collaborative Group. Effects of Vascular and Nonvascular Adverse Events and of Extended-Release Niacin With Laropiprant on Health and Healthcare Costs. Circ Cardiovasc Qual Outcomes. 2016 Jul;9(4):348-54. doi: 10.1161/CIRCOUTCOMES.115.002592. Epub 2016 Jul 12.
- HPS2-THRIVE Collaborative Group; Landray MJ, Haynes R, Hopewell JC, Parish S, Aung T, Tomson J, Wallendszus K, Craig M, Jiang L, Collins R, Armitage J. Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med. 2014 Jul 17;371(3):203-12. doi: 10.1056/NEJMoa1300955.
연구 기록 날짜
연구 주요 날짜
연구 시작
기본 완료 (실제)
연구 완료 (실제)
연구 등록 날짜
최초 제출
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처음 게시됨 (추정)
연구 기록 업데이트
마지막 업데이트 게시됨 (추정)
QC 기준을 충족하는 마지막 업데이트 제출
마지막으로 확인됨
추가 정보
이 연구와 관련된 용어
추가 관련 MeSH 약관
기타 연구 ID 번호
- CTSUTHRIVE1
- ISRCTN29503772
- 2006-001885-17 (EudraCT 번호)
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ER niacin/laropiprant에 대한 임상 시험
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Medical University of South CarolinaGeorgia State University완전한불안 장애 | 스트레스 장애, 외상 후 | 정신 이상 | 외상성 스트레스 장애미국
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