Clinical trial NCT01516879: Durable Effect of PCSK9 Antibody CompARed wiTh placEbo Study
Official title: A Double-Blind, Randomized, Placebo-controlled, Multicenter Study to Evaluate Long-Term Tolerability and Durable Efficacy of AMG 145 (Evolocumab) on LDL-C in Hyperlipidemic Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Hypercholesterolemia
Keywords: Cholesterol
High Cholesterol
Elevated Cholesterol
Raised Cholesterol
Lead sponsor: Amgen
Sponsor class: INDUSTRY
First posted: 2012-01-25
Enrollment: 905
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: To evaluate the efficacy, safety, and tolerability of 52 weeks of subcutaneous (SC) evolocumab (AMG 145) compared with placebo when added to assigned background lipid-lowering therapy.

Detailed description: Eligible participants with screening central laboratory low-density lipoprotein cholesterol (LDL-C) values ≥ 75 mg/dL (1.9 mmol/L) were instructed to follow National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP) Therapeutic Lifestyle Changes (TLC) diet and were assigned to 1 of the following 4 background lipid-lowering therapies for a 4-week stabilization period based upon their screening LDL-C and its distance from the individual's required goal as stipulated by their NCEP ATP III risk category:

1. no drug therapy required - diet alone
2. low dose drug therapy required - diet plus atorvastatin 10 mg orally (PO) once daily (QD)
3. high dose drug therapy required - diet plus atorvastatin 80 mg PO QD
4. maximal drug therapy required - diet plus atorvastatin 80 mg PO QD plus ezetimibe 10 mg PO QD.

If the participant met entry criteria at the end of the lipid stabilization period they were randomized 2:1 to receive evolocumab 420 mg or placebo subcutaneously once a month for 52 weeks in addition to their background therapy.

Eligibility criteria: Inclusion Criteria:

* Subject has provided informed consent.
* Fasting LDL-C ≥ 75 mg/dL and meeting the following LDL-C values on background lipid-lowering therapy:

  * \< 100 mg/dL for subjects with diagnosed coronary heart disease (CHD) or CHD risk equivalent
  * \< 130 mg/dL for subjects without diagnosed CHD or CHD risk equivalent
  * OR on maximal background lipid-lowering therapy defined as atorvastatin 80 mg PO QD and ezetimibe 10 mg PO QD
* Fasting triglycerides ≤ 400 mg/dL

Exclusion Criteria:

* New York Heart Association (NYHA) II-IV heart failure, or last known left ventricular ejection fraction \< 30%
* Uncontrolled cardiac arrhythmia
* Myocardial infarction, unstable angina, percutaneous coronary intervention (PCI), coronary artery bypass graft (CABG) or stroke within 3 months prior to randomization, type 1 diabetes, newly diagnosed or poorly controlled type 2 diabetes
* Uncontrolled hypertension

Primary outcomes:
measure: Percent Change From Baseline in LDL-C at Week 52
timeFrame: Baseline and Week 52
Secondary outcomes:
measure: Change From Baseline in LDL-C at Week 52
timeFrame: Baseline and Week 52
measure: Percentage of Participants With an LDL-C Response at Week 52
timeFrame: Week 52
measure: Percent Change From Baseline in LDL-C at Week 12
timeFrame: Baseline and Week 12
measure: Percent Change From Baseline in Total Cholesterol at Week 12
timeFrame: Baseline and Week 12
measure: Percent Change From Baseline in Total Cholesterol at Week 52
timeFrame: Baseline and Week 52
measure: Percent Change From Baseline in Non-high-density Lipoprotein Cholesterol (Non-HDL-C) at Week 52
timeFrame: Baseline and Week 52
measure: Percent Change From Baseline in Apolipoprotein B at Week 52
timeFrame: Baseline and Week 52
measure: Percent Change From Baseline in the Total Cholesterol/HDL-C Ratio at Week 52
timeFrame: Baseline and Week 52
measure: Percent Change From Baseline in Apolipoprotein B/Apolipoprotein A1 Ratio at Week 52
timeFrame: Baseline and Week 52
measure: Percent Change From Baseline in Lipoprotein(a) at Week 52
timeFrame: Baseline and Week 52
measure: Percent Change From Baseline in Triglycerides at Week 52
timeFrame: Baseline and Week 52
measure: Percent Change From Baseline in High-density Lipoprotein Cholesterol (HDL-C) at Week 52
timeFrame: Baseline and Week 52
measure: Percent Change From Baseline in Very Low-density Lipoprotein Cholesterol (VLDL-C) at Week 52
timeFrame: Baseline and Week 52
measure: Percent Change From Week 12 to Week 52 in LDL-C
timeFrame: Week 12 and Week 52
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Research Site
state: Alabama
city: Little Rock
country: United States
facility: Research Site
state: Arkansas
city: Anaheim
country: United States
facility: Research Site
state: California
city: Encinitas
country: United States
facility: Research Site
state: California
city: Spring Valley
country: United States
facility: Research Site
state: California
city: Westlake Village
country: United States
facility: Research Site
state: California
city: DeLand
country: United States
facility: Research Site
state: Florida
city: Jacksonville
country: United States
facility: Research Site
state: Florida
city: Jacksonville
country: United States
facility: Research Site
state: Florida
city: Ponte Vedra
country: United States
facility: Research Site
state: Florida
city: Atlanta
country: United States
facility: Research Site
state: Georgia
city: Atlanta
country: United States
facility: Research Site
state: Georgia
city: Savannah
country: United States
facility: Research Site
state: Georgia
city: Chicago
country: United States
facility: Research Site
state: Illinois
city: Indianapolis
country: United States
facility: Research Site
state: Indiana
city: Louisville
country: United States
facility: Research Site
state: Kentucky
city: Auburn
country: United States
facility: Research Site
state: Maine
city: Bethesda
country: United States
facility: Research Site
state: Maryland
city: Chevy Chase
country: United States
facility: Research Site
state: Maryland
city: Columbia
country: United States
facility: Research Site
state: Maryland
city: Brockton
country: United States
facility: Research Site
state: Massachusetts
city: Saint Paul
country: United States
facility: Research Site
state: Minnesota
city: Olive Branch
country: United States
facility: Research Site
state: Mississippi
city: Las Vegas
country: United States
facility: Research Site
state: Nevada
city: Endwell
country: United States
facility: Research Site
state: New York
city: New Windsor
country: United States
facility: Research Site
state: New York
city: Raleigh
country: United States
facility: Research Site
state: North Carolina
city: Raleigh
country: United States
facility: Research Site
state: North Carolina
city: Fargo
country: United States
facility: Research Site
state: North Dakota
city: Akron
country: United States
facility: Research Site
state: Ohio
city: Cincinnati
country: United States
facility: Research Site
state: Ohio
city: Cincinnati
country: United States
facility: Research Site
state: Ohio
city: Cincinnati
country: United States
facility: Research Site
state: Ohio
city: Norman
country: United States
facility: Research Site
state: Oklahoma
city: Duncansville
country: United States
facility: Research Site
state: Pennsylvania
city: Mount Pleasant
country: United States
facility: Research Site
state: South Carolina
city: Rapid City
country: United States
facility: Research Site
state: South Dakota
city: Houston
country: United States
facility: Research Site
state: Texas
city: Richmond
country: United States
facility: Research Site
state: Virginia
city: Renton
country: United States
facility: Research Site
state: Washington
city: Seattle
country: United States
facility: Research Site
state: Washington
city: Camperdown
country: Australia
facility: Research Site
state: New South Wales
city: Maroubra
country: Australia
facility: Research Site
state: New South Wales
city: Carina Heights
country: Australia
facility: Research Site
state: Queensland
city: Milton
country: Australia
facility: Research Site
state: Queensland
city: Fitzroy
country: Australia
facility: Research Site
state: Victoria
city: Perth
country: Australia
facility: Research Site
state: Western Australia
city: Feldkirch
country: Austria
facility: Research Site
city: Innsbruck
country: Austria
facility: Research Site
city: Salzburg
country: Austria
facility: Research Site
city: Wels
country: Austria
facility: Research Site
city: AnthÃ©e
country: Belgium
facility: Research Site
city: Bruxelles
country: Belgium
facility: Research Site
city: Gent
country: Belgium
facility: Research Site
city: Gozee
country: Belgium
facility: Research Site
city: Ham
country: Belgium
facility: Research Site
city: Oostende
country: Belgium
facility: Research Site
city: Victoria
country: Canada
facility: Research Site
state: British Columbia
city: Bay Roberts
country: Canada
facility: Research Site
state: Newfoundland and Labrador
city: Cambridge
country: Canada
facility: Research Site
state: Ontario
city: London
country: Canada
facility: Research Site
state: Ontario
city: Newmarket
country: Canada
facility: Research Site
state: Ontario
city: Sudbury
country: Canada
facility: Research Site
state: Ontario
city: Toronto
country: Canada
facility: Research Site
state: Ontario
city: Toronto
country: Canada
facility: Research Site
state: Ontario
city: Pointe-Claire
country: Canada
facility: Research Site
state: Quebec
city: Quebec
country: Canada
facility: Research Site
city: Brno
country: Czechia
facility: Research Site
city: Brno
country: Czechia
facility: Research Site
city: Chomutov
country: Czechia
facility: Research Site
city: Hradec Kralove
country: Czechia
facility: Research Site
city: Pardubice
country: Czechia
facility: Research Site
city: Plzen
country: Czechia
facility: Research Site
city: Praha 2
country: Czechia
facility: Research Site
city: Praha 4
country: Czechia
facility: Research Site
city: Praha 5
country: Czechia
facility: Research Site
city: Slany
country: Czechia
facility: Research Site
city: Aalborg
country: Denmark
facility: Research Site
city: Ballerup
country: Denmark
facility: Research Site
city: Vejle
country: Denmark
facility: Research Site
city: Baja
country: Hungary
facility: Research Site
city: Budapest
country: Hungary
facility: Research Site
city: Budapest
country: Hungary
facility: Research Site
city: Budapest
country: Hungary
facility: Research Site
city: Komarom
country: Hungary
facility: Research Site
city: Pecs
country: Hungary
facility: Research Site
city: Szeged
country: Hungary
facility: Research Site
city: Zalaegerszeg
country: Hungary
facility: Research Site
city: Lyttelton
country: South Africa
facility: Research Site
state: Gauteng
city: Amanzimtoti
country: South Africa
facility: Research Site
state: KwaZulu-Natal
city: Chatsworth, Durban
country: South Africa
facility: Research Site
state: KwaZulu-Natal
city: Observatory
country: South Africa
facility: Research Site
state: Western Cape
city: Paarl
country: South Africa
facility: Research Site
state: Western Cape
city: Parow
country: South Africa
facility: Research Site
state: Western Cape
city: Somerset West
country: South Africa
facility: Research Site
state: Western Cape
city: Bloemfontein
country: South Africa
facility: Research Site
Study officials:
affiliation: Amgen
name: MD
role: STUDY_DIRECTOR
References:
citation: Toth PP, Sattar N, Blom DJ, Martin SS, Jones SR, Monsalvo ML, Elliott M, Davis M, Somaratne R, Preiss D. Effect of Evolocumab on Lipoprotein Particles. Am J Cardiol. 2018 Feb 1;121(3):308-314. doi: 10.1016/j.amjcard.2017.10.028. Epub 2017 Nov 8.
citation: Blom DJ, Koren MJ, Roth E, Monsalvo ML, Djedjos CS, Nelson P, Elliott M, Wasserman SM, Ballantyne CM, Holman RR. Evaluation of the efficacy, safety and glycaemic effects of evolocumab (AMG 145) in hypercholesterolaemic patients stratified by glycaemic status and metabolic syndrome. Diabetes Obes Metab. 2017 Jan;19(1):98-107. doi: 10.1111/dom.12788. Epub 2016 Oct 14.
citation: Blom DJ, Djedjos CS, Monsalvo ML, Bridges I, Wasserman SM, Scott R, Roth E. Effects of Evolocumab on Vitamin E and Steroid Hormone Levels: Results From the 52-Week, Phase 3, Double-Blind, Randomized, Placebo-Controlled DESCARTES Study. Circ Res. 2015 Sep 25;117(8):731-41. doi: 10.1161/CIRCRESAHA.115.307071. Epub 2015 Jul 30.
citation: Blom DJ, Hala T, Bolognese M, Lillestol MJ, Toth PD, Burgess L, Ceska R, Roth E, Koren MJ, Ballantyne CM, Monsalvo ML, Tsirtsonis K, Kim JB, Scott R, Wasserman SM, Stein EA; DESCARTES Investigators. A 52-week placebo-controlled trial of evolocumab in hyperlipidemia. N Engl J Med. 2014 May 8;370(19):1809-19. doi: 10.1056/NEJMoa1316222. Epub 2014 Mar 29.
citation: Daviglus ML, Ferdinand KC, Lopez JAG, Wu Y, Monsalvo ML, Rodriguez CJ. Effects of Evolocumab on Low-Density Lipoprotein Cholesterol, Non-High Density Lipoprotein Cholesterol, Apolipoprotein B, and Lipoprotein(a) by Race and Ethnicity: A Meta-Analysis of Individual Participant Data From Double-Blind and Open-Label Extension Studies. J Am Heart Assoc. 2021 Jan 5;10(1):e016839. doi: 10.1161/JAHA.120.016839. Epub 2020 Dec 16.
citation: Kuchimanchi M, Grover A, Emery MG, Somaratne R, Wasserman SM, Gibbs JP, Doshi S. Population pharmacokinetics and exposure-response modeling and simulation for evolocumab in healthy volunteers and patients with hypercholesterolemia. J Pharmacokinet Pharmacodyn. 2018 Jun;45(3):505-522. doi: 10.1007/s10928-018-9592-y. Epub 2018 May 7.
citation: Kasichayanula S, Grover A, Emery MG, Gibbs MA, Somaratne R, Wasserman SM, Gibbs JP. Clinical Pharmacokinetics and Pharmacodynamics of Evolocumab, a PCSK9 Inhibitor. Clin Pharmacokinet. 2018 Jul;57(7):769-779. doi: 10.1007/s40262-017-0620-7.
citation: Sattar N, Toth PP, Blom DJ, Koren MJ, Soran H, Uhart M, Elliott M, Cyrille M, Somaratne R, Preiss D. Effect of the Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitor Evolocumab on Glycemia, Body Weight, and New-Onset Diabetes Mellitus. Am J Cardiol. 2017 Nov 1;120(9):1521-1527. doi: 10.1016/j.amjcard.2017.07.047. Epub 2017 Jul 31.
citation: Toth PP, Descamps O, Genest J, Sattar N, Preiss D, Dent R, Djedjos C, Wu Y, Geller M, Uhart M, Somaratne R, Wasserman SM; PROFICIO Investigators. Pooled Safety Analysis of Evolocumab in Over 6000 Patients From Double-Blind and Open-Label Extension Studies. Circulation. 2017 May 9;135(19):1819-1831. doi: 10.1161/CIRCULATIONAHA.116.025233. Epub 2017 Mar 1.
citation: Toth PP, Jones SR, Monsalvo ML, Elliott-Davey M, Lopez JAG, Banach M. Effect of Evolocumab on Non-High-Density Lipoprotein Cholesterol, Apolipoprotein B, and Lipoprotein(a): A Pooled Analysis of Phase 2 and Phase 3 Studies. J Am Heart Assoc. 2020 Mar 3;9(5):e014129. doi: 10.1161/JAHA.119.014129. Epub 2020 Mar 2.
citation: Wasserman SM, Sabatine MS, Koren MJ, Giugliano RP, Legg JC, Emery MG, Doshi S, Liu T, Somaratne R, Gibbs JP. Comparison of LDL-C Reduction Using Different Evolocumab Doses and Intervals: Biological Insights and Treatment Implications. J Cardiovasc Pharmacol Ther. 2018 Sep;23(5):423-432. doi: 10.1177/1074248418774043. Epub 2018 May 16.
citation: Schludi B, Giugliano RP, Sabatine MS, Raal FJ, Teramoto T, Koren MJ, Stein EA, Wang H, Monsalvo ML. Time-averaged low-density lipoprotein cholesterol lowering with evolocumab: Pooled analysis of phase 2 trials. J Clin Lipidol. 2022 Jul-Aug;16(4):538-543. doi: 10.1016/j.jacl.2022.05.069. Epub 2022 Jun 6.