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

Diabetes Mellitus Clinical Trial

— HPS2-THRIVE  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00461630
• Other study ID #: CTSUTHRIVE1
• Secondary ID: ISRCTN2950377220
• Status: Completed
• Phase: Phase 3
• First received: April 17, 2007
• Last updated: January 27, 2014
• Start date: January 2007
• Est. completion date: October 2012

Study information

• Verified date: January 2014
• Source: University of Oxford
• Contact: n/a
• Is FDA regulated: No
• Health authority: United Kingdom: Medicines and Healthcare Products Regulatory AgencyChina: Food and Drug AdministrationNorway: Norwegian Medicines AgencySweden: Medical Products AgencyFinland: Finnish Medicines AgencyDenmark: Danish Medicines Agency
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 25673
• Est. completion date: October 2012
• Est. primary completion date: October 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 50 Years to 80 Years

Eligibility

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)

Study Design

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

Related Conditions & MeSH terms

• Cardiovascular Disease
• Cardiovascular Diseases
• Coronary Artery Disease
• Coronary Disease
• Coronary Heart Disease
• Diabetes Mellitus
• Heart Diseases
• Myocardial Ischemia
• Peripheral Arterial Disease
• Peripheral Vascular Diseases

Intervention

Drug:
• ER niacin/laropiprant

• 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
• 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

Locations

Country	Name	City	State
United Kingdom	Clinical Trial Service Unit, University of Oxford	Oxford

Sponsors (2)

Lead Sponsor	Collaborator
University of Oxford	Merck Sharp & Dohme Corp.

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)	No
Secondary	Major Coronary Events	Non-fatal myocardial infarction (MI) or coronary death	During scheduled treatment period (median duration 3.9 years)	No
Secondary	Stroke	Fatal or non-fatal	During scheduled treatment period (median duration 3.9 years)	No
Secondary	Coronary or Non-coronary Revascularisation		During scheduled treatment period (median duration 3.9 years)	No
Secondary	Mortality	All-cause mortality	During scheduled treatment period (median duration 3.9 years)	No

External Links

•   Click here for more information about the HPS2-THRIVE Study, Treatment of HDL to Reduce the Incidence of Vascular Events