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

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

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).

Study Overview

• Status: Completed
• Conditions: Hyperlipidemia
• Intervention / Treatment: Drug: Placebo; Biological: Evolocumab

• Study Type: Interventional
• Enrollment (Actual): 331
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Camperdown, New South Wales, Australia, 2015
      • Research Site
  • Western Australia
    • Perth, Western Australia, Australia, 6000
      • Research Site
• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V6Z 1Y6
      • Research Site
  • Ontario
    • London, Ontario, Canada, N6A 5K8
      • Research Site
  • Quebec
    • Chicoutimi, Quebec, Canada, G7H 7K9
      • Research Site
    • Montreal, Quebec, Canada, H3A 1A1
      • Research Site
    • Montreal, Quebec, Canada, H2W 1R7
      • Research Site
• France
  • Bron, France, 69677
    • Research Site
  • Nantes Cedex 1, France, 44093
    • Research Site
  • Paris Cedex 13, France, 75651
    • Research Site
• Germany
  • Köln, Germany, 50937
    • Research Site
• Hong Kong
  • New Territories, Hong Kong
    • Research Site
• Netherlands
  • Amersfoort, Netherlands, 3813 TZ
    • Research Site
  • Amsterdam, Netherlands, 1091 AC
    • Research Site
  • Amsterdam, Netherlands, 1105 AZ
    • Research Site
  • Gouda, Netherlands, 2803 HH
    • Research Site
  • Groningen, Netherlands, 9713 GZ
    • Research Site
  • Hoorn, Netherlands, 1625 HV
    • Research Site
  • Tilburg, Netherlands, 5022 GC
    • Research Site
  • Utrecht, Netherlands, 3584 CX
    • Research Site
• New Zealand
  • Christchurch, New Zealand, 8011
    • Research Site
• Norway
  • Oslo, Norway, 0373
    • Research Site
• South Africa
  • Gauteng
    • Johannesburg, Gauteng, South Africa, 2193
      • Research Site
    • Midrand, Gauteng, South Africa, 1685
      • Research Site
  • Western Cape
    • Observatory, Western Cape, South Africa, 7925
      • Research Site
    • Parow, Western Cape, South Africa, 7505
      • Research Site
• Spain
  • Madrid, Spain, 28040
    • Research Site
  • Andalucía
    • Cordoba, Andalucía, Spain, 14004
      • Research Site
  • Aragón
    • Zaragoza, Aragón, Spain, 50009
      • Research Site
  • Cataluña
    • Reus, Cataluña, Spain, 43204
      • Research Site
• Sweden
  • Stockholm, Sweden, 141 86
    • Research Site
  • Stockholm, Sweden, 111 35
    • Research Site
• Switzerland
  • Reinach, Switzerland, 4153
    • Research Site
• United Kingdom
  • Coventry, United Kingdom, CV2 2DX
    • Research Site
  • London, United Kingdom, W6 8RF
    • Research Site
  • London, United Kingdom, SE1 7EH
    • Research Site
  • Manchester, United Kingdom, M13 9WL
    • Research Site
• United States
  • Arizona
    • Scottsdale, Arizona, United States, 85258
      • Research Site
  • Ohio
    • Cincinnati, Ohio, United States, 45227
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo Q2W; Participants received placebo subcutaneous injection once every 2 weeks (Q2W) for up to 12 weeks.	Drug: Placebo; Administered by subcutaneous injection
Placebo Comparator: Placebo QM; Participants received placebo subcutaneous injection once every month (QM) for up to 12 weeks.	Drug: Placebo; Administered by subcutaneous injection
Experimental: Evolocumab Q2W; Participants received 140 mg evolocumab by subcutaneous injection once every 2 weeks for up to 12 weeks.	Biological: Evolocumab; Administered by subcutaneous injection; Other Names: Repatha; AMG 145
Experimental: Evolocumab QM; Participants received 420 mg evolocumab by subcutaneous injection once a month for up to 12 weeks.	Biological: Evolocumab; Administered by subcutaneous injection; Other Names: Repatha; AMG 145

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Percent Change From Baseline in LDL-C at the Mean of Weeks 10 and 12	Baseline and Weeks 10 and 12
Percent Change From Baseline in LDL-C at Week 12	Baseline and Week 12

Secondary Outcome Measures

Outcome Measure	Time Frame
Change From Baseline in LDL-C at the Mean of Weeks 10 and 12	Baseline and Weeks 10 and 12
Change From Baseline in LDL-C at Week 12	Baseline and Week 12
Percent Change From Baseline in Non-HDL-C at Week 12	Baseline and Week 12
Percent Change From Baseline in Apolipoprotein B at the Mean of Weeks 10 and 12	Baseline and Weeks 10 and 12
Percent Change From Baseline in Apolipoprotein B at Week 12	Baseline and Week 12
Percent Change From Baseline in Apolipoprotein B/Apolipoprotein A1 Ratio at the Mean of Weeks 10 and 12	Baseline and Weeks 10 and 12
Percent Change From Baseline in Apolipoprotein B/Apolipoprotein A1 Ratio at Week 12	Baseline and Week 12
Percent Change From Baseline in Lipoprotein (a) at the Mean of Weeks 10 and 12	Baseline and Weeks 10 and 12
Percent Change From Baseline in Lipoprotein (a) at Week 12	Baseline and Week 12
Percent Change From Baseline in Triglycerides at the Mean of Weeks 10 and 12	Baseline and Weeks 10 and 12
Percent Change From Baseline in Triglycerides at Week 12	Baseline and Week 12
Percent Change From Baseline in VLDL-C at Week 12	Baseline and Week 12
Percent Change From Baseline in HDL-C at Week 12	Baseline and Week 12
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
Percentage of Participants With LDL-C < 70 mg/dL (1.8 mmol/L) at Week 12	Week 12
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
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
Percent Change From Baseline in the Total Cholesterol/HDL-C Ratio at Week 12	Baseline and Week 12
Percent Change From Baseline in HDL-C at the Mean of Weeks 10 and 12	Baseline and Weeks 10 and 12
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

Collaborators and Investigators

• Sponsor: Amgen

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Helpful Links

• AmgenTrials clinical trials website

Study record dates

Study Major Dates

• Study Start (Actual): February 7, 2013
• Primary Completion (Actual): November 27, 2013
• Study Completion (Actual): December 19, 2013

Study Registration Dates

• First Submitted: January 7, 2013
• First Submitted That Met QC Criteria: January 8, 2013
• First Posted (Estimate): January 9, 2013

Study Record Updates

• Last Update Posted (Actual): June 17, 2019
• Last Update Submitted That Met QC Criteria: June 3, 2019
• Last Verified: June 1, 2019

More Information

Terms related to this study

• Keywords: High cholesterol, Treatment for high cholesterol, Lowering cholesterol, Lowering high cholesterol, Hypercholesterolemia
• Additional Relevant MeSH Terms: Metabolic Diseases; Genetic Diseases, Inborn; Metabolism, Inborn Errors; Lipid Metabolism Disorders; Dyslipidemias; Lipid Metabolism, Inborn Errors; Hyperlipoproteinemias; Hypercholesterolemia; Hyperlipidemias; Hyperlipoproteinemia Type II; Molecular Mechanisms of Pharmacological Action; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Evolocumab
• Other Study ID Numbers: 20110117; 2012-001365-32 (EudraCT Number)