LDL-C Assessment With PCSK9 Monoclonal Antibody Inhibition Combined With Statin Therapy-2

Hyperlipidemia Clinical Trial

— LAPLACE-2  

Official title:

A Double-blind, Randomized, Placebo and Ezetimibe Controlled, Multicenter Study to Evaluate Safety, Tolerability and Efficacy of AMG 145 on LDL-C in Combination With Statin Therapy in Subjects With Primary Hypercholesterolemia and Mixed Dyslipidemia

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01763866
• Other study ID #: 20110115
• Secondary ID: 2012-001363-70
• Status: Completed
• Phase: Phase 3
• Start date: January 15, 2013
• Est. completion date: December 4, 2013

Study information

• Verified date: November 2022
• Source: Amgen
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The primary objective was to evaluate the effect of 12 weeks of evolocumab administered subcutaneously every 2 weeks (Q2W) and monthly (QM) when used in combination with a statin, compared with placebo, on percent change from baseline in low-density lipoprotein cholesterol (LDL-C) in patients with primary hypercholesterolemia and mixed dyslipidemia.

Description:

Prior to the first randomization, participants entered a screening period to determine eligibility. During screening, all participants received subcutaneous placebo corresponding to the once monthly dose volume. Participants who completed the screening period and met eligibility criteria were randomized to 1 of 5 open-label statin cohorts (atorvastatin 10 mg or 80 mg, rosuvastatin 5 mg or 40 mg, or simvastatin 40 mg) for a 4 week lipid stabilization period based on statin therapy at the time of study entry (no statin use vs non-intensive statin use vs intensive statin use).

After the 4-week lipid-stabilization period, eligible patients taking rosuvastatin or simvastatin during the lipid-stabilization phase were then randomized to 1 of 4 treatment groups: evolocumab (140 mg, subcutaneous, every 2 weeks) or matching placebo (subcutaneous, every 2 weeks), or evolocumab (420 mg, subcutaneous, monthly) or matching placebo (subcutaneous, monthly). Patients taking atorvastatin during the lipid-stabilization phase were then randomized to 1 of 6 treatment groups: evolocumab (140 mg, subcutaneous, every 2 weeks) and placebo (oral, daily), evolocumab (420 mg, subcutaneous, monthly) and placebo (oral, daily), placebo (subcutaneous, every 2 weeks) and placebo (oral, daily) or ezetimibe (10 mg, oral, daily), or placebo (subcutaneous, monthly) and placebo (oral, daily) or ezetimibe (10 mg, oral, daily).

A participant was considered randomized into the study after successfully completing the screening period, meeting all inclusion/exclusion criteria, and undergoing both randomization procedures.

Participants randomized to simvastatin who were taking verapamil or diltiazem prior to randomization received simvastatin 10 mg once daily (QD) while participants who were taking amlodipine, amiodarone or ranolazine prior to randomization received simvastatin 20 mg QD. All other participants randomized to simvastatin received simvastatin 40 mg QD.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 2067
• Est. completion date: December 4, 2013
• Est. primary completion date: November 12, 2013
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

Inclusion Criteria:

• Male or female = 18 to = 80 years of age

• Subjects not taking a statin must have fasting LDL-C of at least 150 mg/dL (4.0 mmol/L)

• Subjects already on a non-intensive statin must have fasting LDL-C at screening = 100 mg/dL (2.6 mmol/L)

• Subjects already on a intensive statin must have fasting LDL-C at screening = 80 mg/dL (2.1 mmol/L)

• Fasting triglycerides = 400 mg/dL (4.5 mmol/L)

Exclusion Criteria:

• Statin intolerance

• New York Heart association (NYHA) III or IV heart failure

• Uncontrolled hypertension

• Uncontrolled cardiac arrhythmia

• Type 1 diabetes, poorly controlled type 2 diabetes

• Uncontrolled hypothyroidism or hyperthyroidism

Related Conditions & MeSH terms

• Hyperlipidemia
• Hyperlipidemias

Intervention

Biological:
• Evolocumab
Administered by subcutaneous injection

Drug:
• Ezetimibe
Administered orally once a day
• Placebo to Evolocumab
Administered by subcutaneous injection
• Placebo to Ezetimibe
Administered orally once a day
• Atorvastatin
Administered orally once a day
• Rosuvastatin
Administered orally once a day
• Simvastatin
Administered orally once a day

Locations

Country	Name	City	State
Australia	Research Site	Ashford	South Australia
Australia	Research Site	Fitzroy	Victoria
Australia	Research Site	Fullarton	South Australia
Australia	Research Site	Heidelberg Heights	Victoria
Australia	Research Site	Richmond	Victoria
Australia	Research Site	Sydney	New South Wales
Belgium	Research Site	Blankenberge
Belgium	Research Site	Chênée
Belgium	Research Site	Hasselt
Belgium	Research Site	Oostende
Belgium	Research Site	Tremelo
Belgium	Research Site	Vilvoorde
Canada	Research Site	Brossard	Quebec
Canada	Research Site	Burnaby	British Columbia
Canada	Research Site	Cambridge	Ontario
Canada	Research Site	Greenfield Park	Quebec
Canada	Research Site	Hamilton	Ontario
Canada	Research Site	Kelowna	British Columbia
Canada	Research Site	Kelowna	British Columbia
Canada	Research Site	Lachine	Quebec
Canada	Research Site	London	Ontario
Canada	Research Site	Longueuil	Quebec
Canada	Research Site	Montreal	Quebec
Canada	Research Site	Newmarket	Ontario
Canada	Research Site	Oshawa	Ontario
Canada	Research Site	Pointe-Claire	Quebec
Canada	Research Site	Saint John’s	Newfoundland and Labrador
Canada	Research Site	Sarnia	Ontario
Canada	Research Site	Scarborough	Ontario
Canada	Research Site	Surrey	British Columbia
Canada	Research Site	Toronto	Ontario
Canada	Research Site	Toronto	Ontario
Canada	Research Site	Woodstock	Ontario
Czechia	Research Site	Brno
Czechia	Research Site	Brno
Czechia	Research Site	Kladno
Czechia	Research Site	Litomerice
Czechia	Research Site	Moravske Budejovice
Czechia	Research Site	Olomouc
Czechia	Research Site	Pardubice
Czechia	Research Site	Praha 2
Czechia	Research Site	Praha 3
Czechia	Research Site	Praha 4
Czechia	Research Site	Slany
Czechia	Research Site	Svitavy
Czechia	Research Site	Usti nad Orlici
Denmark	Research Site	Aalborg
Denmark	Research Site	Ballerup
Denmark	Research Site	Vejle
France	Research Site	Brest Cedex 2
France	Research Site	Caen Cedex 9
France	Research Site	Dijon
France	Research Site	Le Creusot
France	Research Site	Montpellier cedex 05
France	Research Site	Nantes Cedex 1
France	Research Site	Paris
France	Research Site	Paris cedex 12
France	Research Site	Poitiers
France	Research Site	Strasbourg
Germany	Research Site	Bad Krozingen
Germany	Research Site	Berlin
Germany	Research Site	Berlin
Germany	Research Site	Berlin (Hellersdorf)
Germany	Research Site	Freiburg
Germany	Research Site	Heidelberg
Germany	Research Site	Homburg
Germany	Research Site	Leipzig
Germany	Research Site	Magdeburg
Germany	Research Site	Messkirch
Germany	Research Site	Witten
Hong Kong	Research Site	Hong Kong
Hong Kong	Research Site	New Territories
Hungary	Research Site	Baja
Hungary	Research Site	Berettyoujfalu
Hungary	Research Site	Dunaujvaros
Hungary	Research Site	Eger
Hungary	Research Site	Gyongyos
Hungary	Research Site	Hodmezovasarhely
Hungary	Research Site	Jaszbereny
Hungary	Research Site	Komarom
Hungary	Research Site	Marcali
Hungary	Research Site	Mosonmagyarovar
Hungary	Research Site	Pecs
Italy	Research Site	Bologna
Italy	Research Site	Cagliari
Italy	Research Site	Chieti
Italy	Research Site	Ferrara
Italy	Research Site	Milano
Italy	Research Site	Napoli
Italy	Research Site	Padova
Italy	Research Site	Perugia
Italy	Research Site	Pisa
Italy	Research Site	Trieste
Korea, Republic of	Research Site	Seoul
Korea, Republic of	Research Site	Seoul
Korea, Republic of	Research Site	Seoul
Korea, Republic of	Research Site	Suwon
Korea, Republic of	Research Site	Suwon-si
Mexico	Research Site	Durango
Mexico	Research Site	Guadalajara	Jalisco
Mexico	Research Site	Guadalajara	Jalisco
Mexico	Research Site	Leon	Guanajuato
Mexico	Research Site	Mexico	Distrito Federal
Mexico	Research Site	Mexico	Distrito Federal
Mexico	Research Site	Monterrey	Nuevo León
Mexico	Research Site	San Luis Potosi	San Luis PotosÃ-
Mexico	Research Site	Tampico	Tamaulipas
Netherlands	Research Site	Amsterdam
Netherlands	Research Site	Amsterdam
Netherlands	Research Site	Den Helder
Netherlands	Research Site	Groningen
Netherlands	Research Site	Hoogeveen
Netherlands	Research Site	Nieuwegein
Netherlands	Research Site	Nijmegen
Netherlands	Research Site	Rotterdam
Netherlands	Research Site	Waalwijk
Netherlands	Research Site	Zwijndrecht
Russian Federation	Research Site	Barnaul
Russian Federation	Research Site	Kemerovo
Russian Federation	Research Site	Moscow
Russian Federation	Research Site	Moscow
Russian Federation	Research Site	Moscow
Russian Federation	Research Site	Novosibirsk
Russian Federation	Research Site	Saint Petersburg
Russian Federation	Research Site	Saint Petersburg
Russian Federation	Research Site	Saint Petersburg
Russian Federation	Research Site	Saint-Petersburg
Russian Federation	Research Site	Saratov
South Africa	Research Site	Alberton	Gauteng
South Africa	Research Site	Bloemfontein
South Africa	Research Site	Cape Town
South Africa	Research Site	Johannesburg	Gauteng
South Africa	Research Site	Kuils River	Western Cape
South Africa	Research Site	Lyttelton	Gauteng
South Africa	Research Site	Pretoria	Gauteng
South Africa	Research Site	Somerset West	Western Cape
Spain	Research Site	AlmerÃ-a	AndalucÃ-a
Spain	Research Site	Almeria	AndalucÃ-a
Spain	Research Site	Barcelona	Cataluña
Spain	Research Site	Barcelona	Cataluña
Spain	Research Site	L'Hospitalet de Llobregat	Cataluña
Spain	Research Site	Madrid
Spain	Research Site	Madrid
Spain	Research Site	Pozuelo De Alarcón	Madrid
Spain	Research Site	Pozuelo de Alarcon	Madrid
Spain	Research Site	Valencia	Comunidad Valenciana
Sweden	Research Site	Ã-rebro
Sweden	Research Site	Göteborg
Sweden	Research Site	Lund
Sweden	Research Site	Lund
Sweden	Research Site	Stockholm
Sweden	Research Site	Uddevalla
Switzerland	Research Site	Bellinzona
Switzerland	Research Site	Geneva 14
Switzerland	Research Site	Lausanne
Switzerland	Research Site	Muensterlingen
Switzerland	Research Site	St. Gallen
Switzerland	Research Site	Zurich
Taiwan	Research Site	Kaohsiung
Taiwan	Research Site	Kaohsiung
Taiwan	Research Site	Taipei
United Kingdom	Research Site	Birmingham
United Kingdom	Research Site	Blackpool
United Kingdom	Research Site	Cardiff
United Kingdom	Research Site	Chesterfield
United Kingdom	Research Site	Chorley
United Kingdom	Research Site	Doncaster
United Kingdom	Research Site	Glasgow
United Kingdom	Research Site	Glasgow
United Kingdom	Research Site	Harrow
United Kingdom	Research Site	Liverpool
United Kingdom	Research Site	Liverpool
United Kingdom	Research Site	Manchester
United Kingdom	Research Site	Manchester
United Kingdom	Research Site	Reading
United Kingdom	Research Site	Reading
United Kingdom	Research Site	Scunthorpe
United Kingdom	Research Site	Wakefield
United Kingdom	Research Site	Whitby
United States	Research Site	Atlanta	Georgia
United States	Research Site	Atlanta	Georgia
United States	Research Site	Auburn	Maine
United States	Research Site	Baltimore	Maryland
United States	Research Site	Bangor	Maine
United States	Research Site	Billings	Montana
United States	Research Site	Birmingham	Alabama
United States	Research Site	Boise	Idaho
United States	Research Site	Cadiz	Ohio
United States	Research Site	Canton	Ohio
United States	Research Site	Carmichael	California
United States	Research Site	Cincinnati	Ohio
United States	Research Site	Cincinnati	Ohio
United States	Research Site	Crestview Hills	Kentucky
United States	Research Site	Dallas	Texas
United States	Research Site	Dayton	Ohio
United States	Research Site	Daytona Beach	Florida
United States	Research Site	Duncansville	Pennsylvania
United States	Research Site	Encino	California
United States	Research Site	Florence	South Carolina
United States	Research Site	Glendale	Arizona
United States	Research Site	Hammond	Indiana
United States	Research Site	Houston	Texas
United States	Research Site	Indianapolis	Indiana
United States	Research Site	Iowa City	Iowa
United States	Research Site	Jackson	Tennessee
United States	Research Site	Jackson	Tennessee
United States	Research Site	Jacksonville	Florida
United States	Research Site	Littleton	Colorado
United States	Research Site	Long Beach	California
United States	Research Site	Manlius	New York
United States	Research Site	Mansfield	Ohio
United States	Research Site	Marion	Ohio
United States	Research Site	Melbourne	Florida
United States	Research Site	Miami	Florida
United States	Research Site	Monroe	Louisiana
United States	Research Site	Newport Beach	California
United States	Research Site	Norman	Oklahoma
United States	Research Site	Pittsburgh	Pennsylvania
United States	Research Site	Port Charlotte	Florida
United States	Research Site	Portland	Maine
United States	Research Site	Rapid City	South Dakota
United States	Research Site	Rochester	New York
United States	Research Site	San Antonio	Texas
United States	Research Site	San Diego	California
United States	Research Site	Sandusky	Ohio
United States	Research Site	Santa Ana	California
United States	Research Site	Santa Rosa	California
United States	Research Site	Suffolk	Virginia
United States	Research Site	Syracuse	New York
United States	Research Site	Tacoma	Washington
United States	Research Site	Thousand Oaks	California
United States	Research Site	Torrance	California
United States	Research Site	Tucson	Arizona
United States	Research Site	Tucson	Arizona
United States	Research Site	Tupelo	Mississippi
United States	Research Site	Tustin	California
United States	Research Site	Valparaiso	Indiana
United States	Research Site	Voorhees	New Jersey
United States	Research Site	Westlake Village	California
United States	Research Site	Williamsville	New York
United States	Research Site	Winchester	Virginia
United States	Research Site	Winston-Salem	North Carolina
United States	Research Site	York	Pennsylvania
United States	Research Site	Ypsilanti	Michigan

Sponsors (1)

Lead Sponsor	Collaborator
Amgen

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Canada,  Czechia,  Denmark,  France,  Germany,  Hong Kong,  Hungary,  Italy,  Korea, Republic of,  Mexico,  Netherlands,  Russian Federation,  South Africa,  Spain,  Sweden,  Switzerland,  Taiwan,  United Kingdom, 

References & Publications (12)

Daviglus ML, Ferdinand KC, López 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. — View 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. Review. — View Citation

Koren MJ, Jones PH, Robinson JG, Sullivan D, Cho L, Hucko T, Lopez JAG, Fleishman AN, Somaratne R, Stroes E. A Comparison of Ezetimibe and Evolocumab for Atherogenic Lipid Reduction in Four Patient Populations: A Pooled Efficacy and Safety Analysis of Three Phase 3 Studies. Cardiol Ther. 2020 Dec;9(2):447-465. doi: 10.1007/s40119-020-00181-8. Epub 2020 Jun 20. — View 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. — View Citation

May HT, Muhlestein JB, Ma Y, López JAG, Coll B, Nelson J. Effects of Evolocumab on the ApoA1 Remnant Ratio: A Pooled Analysis of Phase 3 Studies. Cardiol Ther. 2019 Jun;8(1):91-102. doi: 10.1007/s40119-019-0133-6. Epub 2019 Mar 9. — View Citation

Robinson JG, Nedergaard BS, Rogers WJ, Fialkow J, Neutel JM, Ramstad D, Somaratne R, Legg JC, Nelson P, Scott R, Wasserman SM, Weiss R; LAPLACE-2 Investigators. Effect of evolocumab or ezetimibe added to moderate- or high-intensity statin therapy on LDL-C lowering in patients with hypercholesterolemia: the LAPLACE-2 randomized clinical trial. JAMA. 2014 May 14;311(18):1870-82. doi: 10.1001/jama.2014.4030. — View Citation

Robinson JG, Rogers WJ, Nedergaard BS, Fialkow J, Neutel JM, Ramstad D, Somaratne R, Legg JC, Nelson P, Scott R, Wasserman SM, Weiss R. Rationale and design of LAPLACE-2: a phase 3, randomized, double-blind, placebo- and ezetimibe-controlled trial evaluating the efficacy and safety of evolocumab in subjects with hypercholesterolemia on background statin therapy. Clin Cardiol. 2014 Apr;37(4):195-203. doi: 10.1002/clc.22252. Epub 2014 Jan 30. — View Citation

Shapiro MD, Minnier J, Tavori H, Kassahun H, Flower A, Somaratne R, Fazio S. Relationship Between Low-Density Lipoprotein Cholesterol and Lipoprotein(a) Lowering in Response to PCSK9 Inhibition With Evolocumab. J Am Heart Assoc. 2019 Feb 19;8(4):e010932. doi: 10.1161/JAHA.118.010932. — View Citation

Stroes E, Robinson JG, Raal FJ, Dufour R, Sullivan D, Kassahun H, Ma Y, Wasserman SM, Koren MJ. Consistent LDL-C response with evolocumab among patient subgroups in PROFICIO: A pooled analysis of 3146 patients from phase 3 studies. Clin Cardiol. 2018 Oct;41(10):1328-1335. doi: 10.1002/clc.23049. Epub 2018 Oct 21. — View 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. — View Citation

Toth PP, Jones SR, Monsalvo ML, Elliott-Davey M, López 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. — View 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. — View Citation

* Note: There are 12 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percent Change From Baseline in Low-Density Lipoprotein Cholesterol (LDL-C) at Week 12		Baseline and Week 12
Primary	Percent Change From Baseline in LDL-C at the Mean of Weeks 10 and 12		Baseline and Weeks 10 and 12
Secondary	Change From Baseline in LDL-C at at the Mean of Weeks 10 and 12		Baseline and Weeks 10 and 12
Secondary	Change From Baseline in LDL-C at Week 12		Baseline and Week 12
Secondary	Percent Change From Baseline in Non-High-Density Lipoprotein Cholesterol (Non-HDL-C) at the Mean of Weeks 10 and 12		Baseline and Weeks 10 and 12
Secondary	Percent Change From Baseline in Non-HDL-C at Week 12		Baseline and Week 12
Secondary	Percent Change From Baseline in Apolipoprotein B at the Mean of Weeks 10 and 12		Baseline and Weeks 10 and 12
Secondary	Percent Change From Baseline in Apolipoprotein B at Week 12		Baseline and Week 12
Secondary	Percent Change From Baseline in the Total Cholesterol/HDL-C Ratio at the Mean of Weeks 10 and 12		Baseline and Weeks 10 and 12
Secondary	Percent Change From Baseline in the Total Cholesterol/HDL-C Ratio at Week 12		Baseline and Week 12
Secondary	Percent Change From Baseline in Apolipoprotein B/Apolipoprotein A1 Ratio at the Mean of Weeks 10 and 12		Baseline and Weeks 10 and 12
Secondary	Percent Change From Baseline in Apolipoprotein B/Apolipoprotein A1 Ratio at Week 12		Baseline and Week 12
Secondary	Percentage of Participants Who Achieved a Mean LDL-C at Weeks 10 and 12 of Less Than 70 mg/dL		Weeks 10 and 12
Secondary	Percentage of Participants Who Achieved LDL-C < 70 mg/dL at Week 12		Week 12
Secondary	Percent Change From Baseline in Lipoprotein(a) at the Mean of Weeks 10 and 12		Baseline and Weeks 10 and 12
Secondary	Percent Change From Baseline in Lipoprotein(a) at Week 12		Baseline and Week 12
Secondary	Percent Change From Baseline in Triglycerides at the Mean of Weeks 10 and 12		Baseline and Weeks 10 and 12
Secondary	Percent Change From Baseline in Triglycerides at Week 12		Baseline and Week 12
Secondary	Percent Change From Baseline in Very Low-Density Cholesterol (VLDL-C) at the Mean of Weeks 10 and 12		Baseline and Weeks 10 and 12
Secondary	Percent Change From Baseline in Very Low-Density Cholesterol (VLDL-C) at Week 12		Baseline and Week 12
Secondary	Percent Change From Baseline in HDL-C at the Mean of Weeks 10 and 12		Baseline and Weeks 10 and 12
Secondary	Percent Change From Baseline in HDL-C at Week 12		Baseline and Week 12

External Links

•   AmgenTrials clinical trials website