Clinical trial NCT00461630: Treatment of HDL to Reduce the Incidence of Vascular Events HPS2-THRIVE
Official title: A Randomized Trial of the Long-term Clinical Effects of Raising HDL Cholesterol With Extended Release Niacin/Laropiprant
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Cardiovascular Disease
Peripheral Arterial Disease
Diabetes Mellitus
Coronary Heart Disease
Keywords: coronary heart disease
cardiovascular disease
stroke
peripheral arterial disease
diabetes mellitus
cholesterol
HDL cholesterol
simvastatin
ezetimibe
ER niacin
laropiprant
Lead sponsor: University of Oxford
Sponsor class: OTHER
Collaborators: name: Merck Sharp & Dohme LLC
First posted: 2007-04-18
Enrollment: 25673
Sex: ALL
Minimum age (years): 50
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: The primary aim is to assess the effects of raising HDL cholesterol (the good type) with extended release niacin/laropiprant 2g (previously known as MK-0524A) versus matching placebo on the risk of heart attack or coronary death, stroke, or the need for arterial bypass procedures (revascularisation) in people with a history of circulatory problems. The secondary aim is to assess the effects of extended release niacin/laropiprant 2g daily on heart attack, coronary death, stroke, and revascularisation separately and to assess the effects on mortality both overall and in various categories of causes of death, and of the effects on major cardiovascular events in people with a history of different diseases at the beginning of the study.

Detailed description: 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.

Eligibility criteria: 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)

Primary outcomes:
measure: Major Vascular Event
timeFrame: During scheduled treatment period (median duration 3.9 years)
Secondary outcomes:
measure: Major Coronary Events
timeFrame: During scheduled treatment period (median duration 3.9 years)
measure: Stroke
timeFrame: During scheduled treatment period (median duration 3.9 years)
measure: Coronary or Non-coronary Revascularisation
timeFrame: During scheduled treatment period (median duration 3.9 years)
measure: Mortality
timeFrame: During scheduled treatment period (median duration 3.9 years)
Other outcomes:
Locations:
city: Oxford
country: United Kingdom
facility: Clinical Trial Service Unit, University of Oxford
Study officials:
affiliation: Clinical Trial Service Unit, University of Oxford
name: Jane Armitage
role: PRINCIPAL_INVESTIGATOR
affiliation: Clinical Trial service Unit, University of Oxford
name: Colin Baigent
role: PRINCIPAL_INVESTIGATOR
affiliation: Clinical Trial Service Unit, University of Oxford
name: Zhengming Chen
role: PRINCIPAL_INVESTIGATOR
affiliation: Clinical Trial Service Unit, University of Oxford
name: Martin Landray
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.