Reduction of LDL-C With PCSK9 Inhibition in Heterozygous Familial Hypercholesterolemia Disorder Study-2

Hyperlipidemia Clinical Trial

— RUTHERFORD-2  

Official title:

A Double-blind, Randomized, Placebo-controlled, Multicenter Study to Evaluate Safety, Tolerability and Efficacy of AMG 145 on LDL-C in Subjects With Heterozygous Familial Hypercholesterolemia

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01763918
• Other study ID #: 20110117
• Secondary ID: 2012-001365-32
• Status: Completed
• Phase: Phase 3
• Start date: February 7, 2013
• Est. completion date: December 19, 2013

Study information

• Verified date: June 2019
• 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 subcutaneously once every 2 weeks (Q2W) and once monthly (QM), compared with placebo, on percent change from baseline in low-density lipoprotein cholesterol (LDL-C) in adults with heterozygous familial hypercholesterolemia (HeFH).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 331
• Est. completion date: December 19, 2013
• Est. primary completion date: November 27, 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

• Diagnosis of heterozygous familial hypercholesterolemia

• On a stable dose of an approved statin and lipid regulating medication

• Fasting LDL-C = 100 mg/dL (2.6 mmol/L)

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

Exclusion Criteria:

• Homozygous familial hypercholesterolemia

• LDL or plasma apheresis

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

• Uncontrolled cardiac arrhythmia

• Uncontrolled hypertension

• Type 1 diabetes, poorly controlled type 2 diabetes

• Uncontrolled hypothyroidism or hyperthyroidism

Related Conditions & MeSH terms

• Hypercholesterolemia
• Hyperlipidemia
• Hyperlipidemias
• Hyperlipoproteinemia Type II
• Hyperlipoproteinemias

Intervention

Biological:
• Evolocumab
Administered by subcutaneous injection

Drug:
• Placebo
Administered by subcutaneous injection

Locations

Country	Name	City	State
Australia	Research Site	Camperdown	New South Wales
Australia	Research Site	Perth	Western Australia
Canada	Research Site	Chicoutimi	Quebec
Canada	Research Site	London	Ontario
Canada	Research Site	Montreal	Quebec
Canada	Research Site	Montreal	Quebec
Canada	Research Site	Vancouver	British Columbia
France	Research Site	Bron
France	Research Site	Nantes Cedex 1
France	Research Site	Paris Cedex 13
Germany	Research Site	Köln
Hong Kong	Research Site	New Territories
Netherlands	Research Site	Amersfoort
Netherlands	Research Site	Amsterdam
Netherlands	Research Site	Amsterdam
Netherlands	Research Site	Gouda
Netherlands	Research Site	Groningen
Netherlands	Research Site	Hoorn
Netherlands	Research Site	Tilburg
Netherlands	Research Site	Utrecht
New Zealand	Research Site	Christchurch
Norway	Research Site	Oslo
South Africa	Research Site	Johannesburg	Gauteng
South Africa	Research Site	Midrand	Gauteng
South Africa	Research Site	Observatory	Western Cape
South Africa	Research Site	Parow	Western Cape
Spain	Research Site	Cordoba	Andalucía
Spain	Research Site	Madrid
Spain	Research Site	Reus	Cataluña
Spain	Research Site	Zaragoza	Aragón
Sweden	Research Site	Stockholm
Sweden	Research Site	Stockholm
Switzerland	Research Site	Reinach
United Kingdom	Research Site	Coventry
United Kingdom	Research Site	London
United Kingdom	Research Site	London
United Kingdom	Research Site	Manchester
United States	Research Site	Cincinnati	Ohio
United States	Research Site	Scottsdale	Arizona

Sponsors (1)

Lead Sponsor	Collaborator
Amgen

Countries where clinical trial is conducted

United States,  Australia,  Canada,  France,  Germany,  Hong Kong,  Netherlands,  New Zealand,  Norway,  South Africa,  Spain,  Sweden,  Switzerland,  United Kingdom, 

References & Publications (7)

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

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

Raal FJ, Stein EA, Dufour R, Turner T, Civeira F, Burgess L, Langslet G, Scott R, Olsson AG, Sullivan D, Hovingh GK, Cariou B, Gouni-Berthold I, Somaratne R, Bridges I, Scott R, Wasserman SM, Gaudet D; RUTHERFORD-2 Investigators. PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial. Lancet. 2015 Jan 24;385(9965):331-40. doi: 10.1016/S0140-6736(14)61399-4. Epub 2014 Oct 1. — 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

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

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percent Change From Baseline in 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 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	Percentage of Participants With Mean LDL-C at Weeks 10 and 12 of Less Than 70 mg/dL (1.8 mmol/L)		Weeks 10 and 12
Secondary	Percentage of Participants With LDL-C < 70 mg/dL (1.8 mmol/L) at Week 12		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	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 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
Secondary	Percent Change From Baseline in Very Low-Density Lipoprotein Cholesterol (VLDL-C) at the Mean of Weeks 10 and 12		Baseline and Weeks 10 and 12
Secondary	Percent Change From Baseline in VLDL-C at Week 12		Baseline and Week 12

External Links

•   AmgenTrials clinical trials website