Treatment of HDL to Reduce the Incidence of Vascular Events HPS2-THRIVE

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Randomized Trial of the Long-term Clinical Effects of Raising HDL Cholesterol With Extended Release Niacin/Laropiprant

Conditions
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Cardiovascular Disease, Peripheral Arterial Disease, Diabetes Mellitus, Coronary Heart Disease

Intervention / Treatment
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* Drug: ER niacin/laropiprant
* Drug: simvastatin
* Drug: ezetimibe/simvastatin


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ER niacin/laropiprant<br>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 | Drug: ER niacin/laropiprant<br> <br> * Other names: Tredaptive;Drug: simvastatin<br>* 40 mg simvastatin tablet orally per day as background LDL-lowering treatment allocated at entry based on previous statin treatment and total cholesterol level<br>* Other names: Zocor;Drug: ezetimibe/simvastatin<br>* 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<br>* Other names: Vytorin;|
| Active Comparator: Placebo<br>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 | Drug: simvastatin<br>* 40 mg simvastatin tablet orally per day as background LDL-lowering treatment allocated at entry based on previous statin treatment and total cholesterol level<br>* Other names: Zocor;Drug: ezetimibe/simvastatin<br>* 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<br>* Other names: Vytorin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Major Vascular Event | Non-fatal myocardial infarction or coronary death, non-fatal or fatal stroke, or revascularisation | During scheduled treatment period (median duration 3.9 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Major Coronary Events | Non-fatal myocardial infarction (MI) or coronary death | During scheduled treatment period (median duration 3.9 years) | 
| Stroke | Fatal or non-fatal | During scheduled treatment period (median duration 3.9 years) | 
| Coronary or Non-coronary Revascularisation |  | During scheduled treatment period (median duration 3.9 years) | 
| Mortality | All-cause mortality | During scheduled treatment period (median duration 3.9 years) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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coronary heart disease, cardiovascular disease, stroke, peripheral arterial disease, diabetes mellitus, cholesterol, HDL cholesterol, simvastatin, ezetimibe, ER niacin, laropiprant