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

Completed

Phase 3 Results

Trial Description

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.

Conditions

Interventions

  • Simvastatin Drug
    Intervention Desc: 40 mg simvastatin tablet orally per day as background LDL-lowering treatment allocated at entry based on previous statin treatment and total cholesterol level
    ARM 1: Kind: Experimental
    Label: ER niacin/laropiprant
    Description: 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
    ARM 2: Kind: Experimental
    Label: Placebo
    Description: 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
  • Statin Drug
    Other Names: Pre-existing statin regimen
    Intervention Desc: The statins (or HMG-CoA reductase inhibitors) form a class of hypolipidemic drugs used to lower cholesterol levels in people with or at risk of cardiovascular disease.
  • Ezetimibe (Zetia)Drug
  • Niacin Extended Release (Niaspan)Drug
    Intervention Desc: organic compound used to improve blood cholesterol or lower fats (called triglycerides or lipids) in the blood.
  • Ezetimibe/simvastatin Drug
    Other Names: Vytorin; Inegy
    Intervention Desc: 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
    ARM 1: Kind: Experimental
    Label: ER niacin/laropiprant
    Description: 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
    ARM 2: Kind: Experimental
    Label: Placebo
    Description: 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
  • ER niacin/laropiprant Drug
    Other Names: Tredaptive
    ARM 1: Kind: Experimental
    Label: ER niacin/laropiprant
    Description: 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

Trial Design

  • Allocation: Randomized
  • Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
  • Purpose: Prevention
  • Endpoint: Safety/Efficacy Study
  • Intervention: Parallel Assignment

Patient Involvement

Patients will be randomized to one of two arms: 1)ER niacin/laropiprant 2 g daily versus 2) matching placebo tablets. All patients receive LDL lowering therapy with either 40 mg of simvastatin or 10/40 mg ezetimibe/simvastatin. All patients will have baseline LDL & HDL blood levels and be followed with blood samples at prescribed intervals during study.

Outcomes

Type Measure Time Frame Safety Issue
Primary 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
Secondary 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.
Primary Time to first major vascular event
Primary (defined as non-fatal myocardial infarction or coronary death
Primary non-fatal or fatal stroke, or revascularisation) by the end of study
Secondary Major vascular events (non-fatal MI or cardiac death) by the end of the study
Secondary stroke (fatal or non-fatal) by the end of the study
Secondary Coronary or non-coronary revascularisation by the end of the study
Secondary Mortality, both overall and in particular categories of causes of death
Secondary Major cardiovascular events in people with a history of different diseases at the beginning of the study.
Secondary Major coronary events During scheduled treatment period No
Secondary Stroke During scheduled treatment period No
Secondary Coronary or non-coronary revascularisation During scheduled treatment period No
Secondary Mortality During scheduled treatment period No
Primary Major Vascular Event During scheduled treatment period (median duration 3.9 years) No

Sponsors