Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER)

Tracking Information
First Submitted Date ICMJE	January 8, 2013
First Posted Date ICMJE	January 9, 2013
Results First Submitted Date	December 15, 2017
Results First Posted Date	February 15, 2018
Last Update Posted Date	February 15, 2018
Actual Study Start Date ICMJE	February 8, 2013
Actual Primary Completion Date	November 11, 2016 (Final data collection date for primary outcome measure)
Current Primary Outcome Measures ICMJE; (submitted: January 18, 2018)	Time to Cardiovascular Death, Myocardial Infarction, Hospitalization for Unstable Angina, Stroke, or Coronary Revascularization [ Time Frame: Events that occurred from randomization to the last confirmed survival status date; the median duration of follow-up was 26 months. KM estimates at 6, 12, 18, 24, 30 and 36 months are reported. ]; All deaths and potential endpoint events were adjudicated by an independent external Clinical Events Committee (CEC) led by the Thrombolysis in Myocardial Infarction (TIMI) Study Group, using standardized definitions based on the "Standardized Definitions for Cardiovascular and Stroke End Point Events in Clinical Trials and the Third Universal Definition of Myocardial Infarction". Time to cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization was defined as the time from randomization to the first occurrence of any component of the composite endpoint and was analyzed using Kaplan-Meier (KM) survival analysis. KM estimates of the percentage of participants with an event are reported. Participants with no event were censored based on last non-fatal potential endpoint collection date.
Original Primary Outcome Measures ICMJE; (submitted: January 8, 2013)	Time to cardiovascular death, myocardial infarction, hospitalization for unstable angina, stroke, or coronary revascularization [ Time Frame: 5 years ]; The primary endpoint is the time to cardiovascular death, myocardial infarction, hospitalization for unstable angina, stroke, or coronary revascularization, whichever occurs first.
Change History	Complete list of historical versions of study NCT01764633 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures ICMJE; (submitted: January 18, 2018)	Time to Cardiovascular Death, Myocardial Infarction, or Stroke [ Time Frame: Events that occurred from randomization to the last confirmed survival status date; the median duration of follow-up was 26 months. KM estimates at 6, 12, 18, 24, 30 and 36 months are reported. ]All deaths and potential endpoint events were adjudicated by an independent external CEC led by the TIMI Study Group, using standardized definitions based on the "Standardized Definitions for Cardiovascular and Stroke End Point Events in Clinical Trials and the Third Universal Definition of Myocardial Infarction". Time to cardiovascular death, myocardial infarction, or stroke was defined as the time from randomization to the first occurrence of any component of the composite endpoint and was analyzed using Kaplan-Meier (KM) survival analysis. KM estimates of the percentage of participants with an event are reported. Participants with no event were censored based on last non-fatal potential endpoint collection date.; Time to Cardiovascular Death [ Time Frame: Events that occurred from randomization to the last confirmed survival status date; the median duration of follow-up was 26 months. KM estimates at 6, 12, 18, 24, 30 and 36 months are reported. ]All deaths and potential endpoint events were adjudicated by an independent external CEC led by the TIMI Study Group, using standardized definitions based on the "Standardized Definitions for Cardiovascular and Stroke End Point Events in Clinical Trials and the Third Universal Definition of Myocardial Infarction". Cardiovascular death includes death resulting from an acute myocardial infarction (MI), sudden cardiac death, death due to heart failure (HF), death due to stroke, death due to cardiovascular (CV) procedures, death due to CV hemorrhage, and death due to other CV causes. Time to cardiovascular death was defined as the time from randomization to the date of cardiovascular death and was analyzed using Kaplan-Meier (KM) survival analysis. KM estimates of the percentage of participants with an event are reported. Participants with no event were censored based on the last confirmed survival status date.; Time to All Cause Death [ Time Frame: Events that occurred from randomization to the last confirmed survival status date; the median duration of follow-up was 26 months. KM estimates at 6, 12, 18, 24, 30 and 36 months are reported. ]Time to all-cause death was defined as the time from randomization to the date of death and was analyzed using Kaplan-Meier (KM) survival analysis. KM estimates of the percentage of participants with an event are reported. Participants with no event were censored based on the last confirmed survival status date.; Time to First Myocardial Infarction [ Time Frame: Events that occurred from randomization to the last confirmed survival status date; the median duration of follow-up was 26 months. KM estimates at 6, 12, 18, 24, 30 and 36 months are reported. ]All deaths and potential endpoint events were adjudicated by an independent external CEC led by the TIMI Study Group, using standardized definitions based on the "Standardized Definitions for Cardiovascular and Stroke End Point Events in Clinical Trials and the Third Universal Definition of Myocardial Infarction". The diagnosis of myocardial infarction required the combination of: Evidence of myocardial necrosis (either changes in cardiac biomarkers or post-mortem pathological findings); and Supporting information derived from the clinical presentation, electrocardiographic changes, or the results of myocardial or coronary artery Imaging. Time to first myocardial infarction was defined as the time from randomization to the date of the first MI and was analyzed using Kaplan-Meier survival analysis. KM estimates of the percentage of participants with an event are reported. Participants with no event were censored based on last non-fatal potential endpoint collection date.; Time to First Stroke [ Time Frame: Events that occurred from randomization to the last confirmed survival status date; the median duration of follow-up was 26 months. KM estimates at 6, 12, 18, 24, 30 and 36 months are reported. ]All deaths and potential endpoint events were adjudicated by an independent external CEC led by the TIMI Study Group, using standardized definitions based on the "Standardized Definitions for Cardiovascular and Stroke End Point Events in Clinical Trials and the Third Universal Definition of Myocardial Infarction". Stroke was defined as an acute episode of focal or global neurological dysfunction caused by brain, spinal cord, or retinal vascular injury as a result of hemorrhage or infarction. Time to first stroke was defined as the time from randomization to the date of the stroke and was analyzed using Kaplan-Meier (KM) survival analysis. KM estimates of the percentage of participants with an event are reported. Participants with no event were censored based on last non-fatal potential endpoint collection date.; Time to First Coronary Revascularization [ Time Frame: Events that occurred from randomization to the last confirmed survival status date; the median duration of follow-up was 26 months. KM estimates at 6, 12, 18, 24, 30 and 36 months are reported. ]All deaths and potential endpoint events were adjudicated by an independent external CEC led by the TIMI Study Group, using standardized definitions based on the "Standardized Definitions for Cardiovascular and Stroke End Point Events in Clinical Trials and the Third Universal Definition of Myocardial Infarction". Time to first coronary revascularization was defined as the time from randomization to the date of the coronary revascularization and was analyzed using Kaplan-Meier (KM) survival analysis. KM estimates of the percentage of participants with an event are reported. Participants with no event were censored based on last non-fatal potential endpoint collection date.; Time to Cardiovascular Death or First Hospitalization for Worsening Heart Failure [ Time Frame: Events that occurred from randomization to the last confirmed survival status date; the median duration of follow-up was 26 months. KM estimates at 6, 12, 18, 24, 30 and 36 months are reported. ]All events were adjudicated by an independent external CEC led by the TIMI Study Group, using standardized definitions. HF hospitalization was defined as an event that met all of the following criteria: Admitted to hospital with a primary diagnosis of HF In hospital for at least 24 hours Documented new or worsening symptoms due to HF, including at least 1 of the following: Dyspnea Decreased exercise tolerance Fatigue Other symptoms of worsened end-organ perfusion or volume overload Evidence of new or worsening HF consisting of at least 2 physical exam findings or 1 physical exam finding and at least 1 laboratory criterion Received new or increased treatment for HF. Time to CV death or first hospitalization for worsening HF was defined as the time from randomization to the first occurrence of any component of the endpoint analyzed using KM survival analysis. Participants with no event were censored based on last non-fatal potential endpoint collection date.; Time to First Ischemic Fatal or Non-Fatal Stroke or Transient Ischemic Attack [ Time Frame: Events that occurred from randomization to the last confirmed survival status date; the median duration of follow-up was 26 months. KM estimates at 6, 12, 18, 24, 30 and 36 months are reported. ]All deaths and potential endpoint events were adjudicated by an independent external CEC led by the TIMI Study Group, using standardized definitions. Ischemic stroke was defined as an acute episode of focal cerebral, spinal, or retinal dysfunction caused by infarction of central nervous system tissue. Transient ischemic attack (TIA) was defined as a transient episode of focal neurological dysfunction caused by brain, spinal cord, or retinal ischemia, without acute infarction. Time to first ischemic fatal or non-fatal stroke or TIA was defined as the time from randomization to the first occurrence of any component of the composite endpoint and was analyzed using KM analysis. KM estimates of the percentage of participants with an event are reported. Participants with no event were censored based on last non-fatal potential endpoint collection date.
Original Secondary Outcome Measures ICMJE; (submitted: January 8, 2013)	Time to cardiovascular death, myocardial infarction, or stroke [ Time Frame: 5 years ]Time to cardiovascular death, myocardial infarction, or stroke, whichever occurs first; Time to death by any cause [ Time Frame: 5 years ]Time to death by any cause; Time to cardiovascular death or hospitalization for worsening heart failure [ Time Frame: 5 years ]Time to cardiovascular death or hospitalization for worsening heart failure, whichever occurs first; Time to ischemic fatal or non-fatal stroke or TIA [ Time Frame: 5 years ]Time to ischemic fatal or non-fatal stroke or TIA, whichever occurs first
Current Other Outcome Measures ICMJE	Not Provided
Original Other Outcome Measures ICMJE	Not Provided
Descriptive Information
Brief Title ICMJE	Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk
Official Title ICMJE	A Double-blind, Randomized, Placebo-controlled, Multicenter Study Assessing the Impact of Additional LDL-Cholesterol Reduction on Major Cardiovascular Events When Evolocumab (AMG 145) is Used in Combination With Statin Therapy In Patients With Clinically Evident Cardiovascular Disease
Brief Summary	The primary objective was to evaluate the effect of treatment with evolocumab, compared with placebo, on the risk for cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization, whichever occurs first, in patients with clinically evident cardiovascular disease.
Detailed Description	Not Provided
Study Type ICMJE	Interventional
Study Phase	Phase 3
Study Design ICMJE	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
Condition ICMJE	Dyslipidemia
Intervention ICMJE	Biological: Evolocumab Administered subcutaneously using a spring-based prefilled 1.0 mL autoinjector/pen. Other Names: AMG 145 Repatha; Drug: Placebo Administered subcutaneously using a spring-based prefilled 1.0 mL autoinjector/pen.
Study Arms	Placebo Comparator: Placebo Participants received placebo subcutaneous injections either once every 2 weeks (Q2W) or once a month (QM) according to their own preference. Intervention: Drug: Placebo; Experimental: Evolocumab Participants received evolocumab 140 mg Q2W or 420 mg QM subcutaneous injections according to their own preference. Intervention: Biological: Evolocumab
Publications *	Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy SA, Kuder JF, Wang H, Liu T, Wasserman SM, Sever PS, Pedersen TR; FOURIER Steering Committee and Investigators. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl J Med. 2017 May 4;376(18):1713-1722. doi: 10.1056/NEJMoa1615664. Epub 2017 Mar 17.; Sabatine MS, De Ferrari GM, Giugliano RP, Huber K, Lewis BS, Ferreira J, Kuder JF, Murphy SA, Wiviott SD, Kurtz CE, Honarpour N, Keech AC, Sever PS, Pedersen TR. Clinical Benefit of Evolocumab by Severity and Extent of Coronary Artery Disease: An Analysis from FOURIER. Circulation. 2018 Apr 6. pii: CIRCULATIONAHA.118.034309. doi: 10.1161/CIRCULATIONAHA.118.034309. [Epub ahead of print]; Bohula EA, Giugliano RP, Leiter LA, Verma S, Park JG, Sever PS, Pineda AL, Honarpour N, Wang H, Murphy SA, Keech A, Pedersen TR, Sabatine MS. Inflammatory and Cholesterol Risk in the FOURIER Trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Patients With Elevated Risk). Circulation. 2018 Mar 12. pii: CIRCULATIONAHA.118.034032. doi: 10.1161/CIRCULATIONAHA.118.034032. [Epub ahead of print]; Bonaca MP, Nault P, Giugliano RP, Keech AC, Pineda AL, Kanevsky E, Kuder J, Murphy SA, Jukema JW, Lewis BS, Tokgozoglu L, Somaratne R, Sever PS, Pedersen TR, Sabatine MS. Low-Density Lipoprotein Cholesterol Lowering With Evolocumab and Outcomes in Patients With Peripheral Artery Disease: Insights From the FOURIER Trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk). Circulation. 2018 Jan 23;137(4):338-350. doi: 10.1161/CIRCULATIONAHA.117.032235. Epub 2017 Nov 13.; Sabatine MS, Leiter LA, Wiviott SD, Giugliano RP, Deedwania P, De Ferrari GM, Murphy SA, Kuder JF, Gouni-Berthold I, Lewis BS, Handelsman Y, Pineda AL, Honarpour N, Keech AC, Sever PS, Pedersen TR. Cardiovascular safety and efficacy of the PCSK9 inhibitor evolocumab in patients with and without diabetes and the effect of evolocumab on glycaemia and risk of new-onset diabetes: a prespecified analysis of the FOURIER randomised controlled trial. Lancet Diabetes Endocrinol. 2017 Dec;5(12):941-950. doi: 10.1016/S2213-8587(17)30313-3. Epub 2017 Sep 15.; Giugliano RP, Pedersen TR, Park JG, De Ferrari GM, Gaciong ZA, Ceska R, Toth K, Gouni-Berthold I, Lopez-Miranda J, Schiele F, Mach F, Ott BR, Kanevsky E, Pineda AL, Somaratne R, Wasserman SM, Keech AC, Sever PS, Sabatine MS; FOURIER Investigators. Clinical efficacy and safety of achieving very low LDL-cholesterol concentrations with the PCSK9 inhibitor evolocumab: a prespecified secondary analysis of the FOURIER trial. Lancet. 2017 Oct 28;390(10106):1962-1971. doi: 10.1016/S0140-6736(17)32290-0. Epub 2017 Aug 28.
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status ICMJE	Completed
Actual Enrollment ICMJE; (submitted: June 25, 2015)	27564
Original Estimated Enrollment ICMJE; (submitted: January 8, 2013)	22500
Actual Study Completion Date	November 11, 2016
Actual Primary Completion Date	November 11, 2016 (Final data collection date for primary outcome measure)
Eligibility Criteria ICMJE	Inclusion Criteria: Male or female ≥ 40 to ≤ 85 years of age; History of clinically evident cardiovascular disease at high risk for a recurrent event; Fasting low-density lipoprotein cholesterol (LDL-C) ≥ 70 mg/dL (≥ 1.8 mmol/L) ) or non-high-density lipoprotein cholesterol (non-HDL-C) ≥ 100 mg/dL (> 2.6 mmol/L); Fasting triglycerides ≤ 400 mg/dL (4.5 mmol/L) Exclusion Criteria: New York Heart Association (NYHA) class III or IV, or last known left ventricular ejection fraction < 30%; Uncontrolled hypertension; Uncontrolled or recurrent ventricular tachycardia; Untreated hyperthyroidism or hypothyroidism; Homozygous familial hypercholesterolemia; LDL or plasma apheresis
Sex/Gender	Sexes Eligible for Study: All
Ages	40 Years to 85 Years (Adult, Senior)
Accepts Healthy Volunteers	No
Contacts ICMJE	Contact information is only displayed when the study is recruiting subjects
Listed Location Countries ICMJE	Argentina, Australia, Austria, Belgium, Brazil, Bulgaria, Canada, Chile, China, Colombia, Czechia, Denmark, Estonia, Finland, France, Germany, Greece, Hong Kong, Hungary, Iceland, India, Ireland, Israel, Italy, Japan, Korea, Republic of, Latvia, Lithuania, Malaysia, Mexico, Netherlands, New Zealand, Norway, Philippines, Poland, Portugal, Romania, Russian Federation, Singapore, Slovakia, South Africa, Spain, Sweden, Switzerland, Taiwan, Turkey, Ukraine, United Kingdom, United States
Removed Location Countries	Czech Republic
Administrative Information
NCT Number ICMJE	NCT01764633
Other Study ID Numbers ICMJE	20110118; 2014/01/004324 ( Registry Identifier: Clinical Trials Registry- India (CTRI) ); 2012-001398-97 ( EudraCT Number )
Has Data Monitoring Committee	Yes
U.S. FDA-regulated Product	Not Provided
IPD Sharing Statement	Not Provided
Responsible Party	Amgen
Study Sponsor ICMJE	Amgen
Collaborators ICMJE	Not Provided
Investigators ICMJE	Study Director: MD Amgen
PRS Account	Amgen
Verification Date	January 2018
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP