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

• Time to first major vascular event
• (defined as non-fatal myocardial infarction or coronary death
• non-fatal or fatal stroke, or revascularisation) by the end of study

• Major coronary events [ Time Frame: During scheduled treatment period ] [ Designated as safety issue: No ]
  Non-fatal myocardial infarction (MI) or coronary death
• Stroke [ Time Frame: During scheduled treatment period ] [ Designated as safety issue: No ]
  Fatal or non-fatal
• Coronary or non-coronary revascularisation [ Time Frame: During scheduled treatment period ] [ Designated as safety issue: No ]
• Mortality [ Time Frame: During scheduled treatment period ] [ Designated as safety issue: No ]
  Both overall and in particular categories of causes of death

• Major vascular events (non-fatal MI or cardiac death) by the end of the study
• stroke (fatal or non-fatal) by the end of the study
• Coronary or non-coronary revascularisation by the end of the study
• Mortality, both overall and in particular categories of causes of death
• Major cardiovascular events in people with a history of different diseases at the beginning of the study.

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.

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.

• Cardiovascular Disease
• Peripheral Arterial Disease
• Diabetes Mellitus
• Coronary Heart Disease

• Drug: ER niacin/laropiprant
  Other Name: Tredaptive
• Drug: simvastatin
  40 mg simvastatin tablet orally per day as background LDL-lowering treatment allocated at entry based on previous statin treatment and total cholesterol level
  Other Name: Zocor
• Drug: ezetimibe/simvastatin
  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
  Other Names:

  • Inegy
  • Vytorin

• Experimental: ER niacin/laropiprant
  I g ER niacin plus 20mg 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
  Interventions:

  • Drug: ER niacin/laropiprant
  • Drug: simvastatin
  • Drug: ezetimibe/simvastatin
• Active Comparator: 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
  Interventions:

  • Drug: simvastatin
  • Drug: ezetimibe/simvastatin

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)