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

Primary Purpose

Hyperlipidemia

Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Evolocumab
Placebo
Sponsored by
Amgen
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Hyperlipidemia focused on measuring High cholesterol, Treatment for high cholesterol, Lowering cholesterol, Lowering high cholesterol, Hypercholesterolemia

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

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Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Placebo Comparator

Placebo Comparator

Experimental

Experimental

Arm Label

Placebo Q2W

Placebo QM

Evolocumab Q2W

Evolocumab QM

Arm Description

Participants received placebo subcutaneous injection once every 2 weeks (Q2W) for up to 12 weeks.

Participants received placebo subcutaneous injection once every month (QM) for up to 12 weeks.

Participants received 140 mg evolocumab by subcutaneous injection once every 2 weeks for up to 12 weeks.

Participants received 420 mg evolocumab by subcutaneous injection once a month for up to 12 weeks.

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

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

Full Information

First Posted
January 7, 2013
Last Updated
June 3, 2019
Sponsor
Amgen
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1. Study Identification

Unique Protocol Identification Number
NCT01763918
Brief Title
Reduction of LDL-C With PCSK9 Inhibition in Heterozygous Familial Hypercholesterolemia Disorder Study-2
Acronym
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
Study Type
Interventional

2. Study Status

Record Verification Date
June 2019
Overall Recruitment Status
Completed
Study Start Date
February 7, 2013 (Actual)
Primary Completion Date
November 27, 2013 (Actual)
Study Completion Date
December 19, 2013 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Amgen

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief 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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hyperlipidemia
Keywords
High cholesterol, Treatment for high cholesterol, Lowering cholesterol, Lowering high cholesterol, Hypercholesterolemia

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
331 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Placebo Q2W
Arm Type
Placebo Comparator
Arm Description
Participants received placebo subcutaneous injection once every 2 weeks (Q2W) for up to 12 weeks.
Arm Title
Placebo QM
Arm Type
Placebo Comparator
Arm Description
Participants received placebo subcutaneous injection once every month (QM) for up to 12 weeks.
Arm Title
Evolocumab Q2W
Arm Type
Experimental
Arm Description
Participants received 140 mg evolocumab by subcutaneous injection once every 2 weeks for up to 12 weeks.
Arm Title
Evolocumab QM
Arm Type
Experimental
Arm Description
Participants received 420 mg evolocumab by subcutaneous injection once a month for up to 12 weeks.
Intervention Type
Biological
Intervention Name(s)
Evolocumab
Other Intervention Name(s)
AMG 145, Repatha
Intervention Description
Administered by subcutaneous injection
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Administered by subcutaneous injection
Primary Outcome Measure Information:
Title
Percent Change From Baseline in LDL-C at Week 12
Time Frame
Baseline and Week 12
Title
Percent Change From Baseline in LDL-C at the Mean of Weeks 10 and 12
Time Frame
Baseline and Weeks 10 and 12
Secondary Outcome Measure Information:
Title
Change From Baseline in LDL-C at the Mean of Weeks 10 and 12
Time Frame
Baseline and Weeks 10 and 12
Title
Change From Baseline in LDL-C at Week 12
Time Frame
Baseline and Week 12
Title
Percentage of Participants With Mean LDL-C at Weeks 10 and 12 of Less Than 70 mg/dL (1.8 mmol/L)
Time Frame
Weeks 10 and 12
Title
Percentage of Participants With LDL-C < 70 mg/dL (1.8 mmol/L) at Week 12
Time Frame
Week 12
Title
Percent Change From Baseline in Non-High-Density Lipoprotein Cholesterol (Non-HDL-C) at the Mean of Weeks 10 and 12
Time Frame
Baseline and Weeks 10 and 12
Title
Percent Change From Baseline in Non-HDL-C at Week 12
Time Frame
Baseline and Week 12
Title
Percent Change From Baseline in Apolipoprotein B at the Mean of Weeks 10 and 12
Time Frame
Baseline and Weeks 10 and 12
Title
Percent Change From Baseline in Apolipoprotein B at Week 12
Time Frame
Baseline and Week 12
Title
Percent Change From Baseline in the Total Cholesterol/HDL-C Ratio at the Mean of Weeks 10 and 12
Time Frame
Baseline and Weeks 10 and 12
Title
Percent Change From Baseline in the Total Cholesterol/HDL-C Ratio at Week 12
Time Frame
Baseline and Week 12
Title
Percent Change From Baseline in Apolipoprotein B/Apolipoprotein A1 Ratio at the Mean of Weeks 10 and 12
Time Frame
Baseline and Weeks 10 and 12
Title
Percent Change From Baseline in Apolipoprotein B/Apolipoprotein A1 Ratio at Week 12
Time Frame
Baseline and Week 12
Title
Percent Change From Baseline in Lipoprotein (a) at the Mean of Weeks 10 and 12
Time Frame
Baseline and Weeks 10 and 12
Title
Percent Change From Baseline in Lipoprotein (a) at Week 12
Time Frame
Baseline and Week 12
Title
Percent Change From Baseline in Triglycerides at the Mean of Weeks 10 and 12
Time Frame
Baseline and Weeks 10 and 12
Title
Percent Change From Baseline in Triglycerides at Week 12
Time Frame
Baseline and Week 12
Title
Percent Change From Baseline in HDL-C at the Mean of Weeks 10 and 12
Time Frame
Baseline and Weeks 10 and 12
Title
Percent Change From Baseline in HDL-C at Week 12
Time Frame
Baseline and Week 12
Title
Percent Change From Baseline in Very Low-Density Lipoprotein Cholesterol (VLDL-C) at the Mean of Weeks 10 and 12
Time Frame
Baseline and Weeks 10 and 12
Title
Percent Change From Baseline in VLDL-C at Week 12
Time Frame
Baseline and Week 12

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
MD
Organizational Affiliation
Amgen
Official's Role
Study Director
Facility Information:
Facility Name
Research Site
City
Scottsdale
State/Province
Arizona
ZIP/Postal Code
85258
Country
United States
Facility Name
Research Site
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45227
Country
United States
Facility Name
Research Site
City
Camperdown
State/Province
New South Wales
ZIP/Postal Code
2015
Country
Australia
Facility Name
Research Site
City
Perth
State/Province
Western Australia
ZIP/Postal Code
6000
Country
Australia
Facility Name
Research Site
City
Vancouver
State/Province
British Columbia
ZIP/Postal Code
V6Z 1Y6
Country
Canada
Facility Name
Research Site
City
London
State/Province
Ontario
ZIP/Postal Code
N6A 5K8
Country
Canada
Facility Name
Research Site
City
Chicoutimi
State/Province
Quebec
ZIP/Postal Code
G7H 7K9
Country
Canada
Facility Name
Research Site
City
Montreal
State/Province
Quebec
ZIP/Postal Code
H2W 1R7
Country
Canada
Facility Name
Research Site
City
Montreal
State/Province
Quebec
ZIP/Postal Code
H3A 1A1
Country
Canada
Facility Name
Research Site
City
Bron
ZIP/Postal Code
69677
Country
France
Facility Name
Research Site
City
Nantes Cedex 1
ZIP/Postal Code
44093
Country
France
Facility Name
Research Site
City
Paris Cedex 13
ZIP/Postal Code
75651
Country
France
Facility Name
Research Site
City
Köln
ZIP/Postal Code
50937
Country
Germany
Facility Name
Research Site
City
New Territories
Country
Hong Kong
Facility Name
Research Site
City
Amersfoort
ZIP/Postal Code
3813 TZ
Country
Netherlands
Facility Name
Research Site
City
Amsterdam
ZIP/Postal Code
1091 AC
Country
Netherlands
Facility Name
Research Site
City
Amsterdam
ZIP/Postal Code
1105 AZ
Country
Netherlands
Facility Name
Research Site
City
Gouda
ZIP/Postal Code
2803 HH
Country
Netherlands
Facility Name
Research Site
City
Groningen
ZIP/Postal Code
9713 GZ
Country
Netherlands
Facility Name
Research Site
City
Hoorn
ZIP/Postal Code
1625 HV
Country
Netherlands
Facility Name
Research Site
City
Tilburg
ZIP/Postal Code
5022 GC
Country
Netherlands
Facility Name
Research Site
City
Utrecht
ZIP/Postal Code
3584 CX
Country
Netherlands
Facility Name
Research Site
City
Christchurch
ZIP/Postal Code
8011
Country
New Zealand
Facility Name
Research Site
City
Oslo
ZIP/Postal Code
0373
Country
Norway
Facility Name
Research Site
City
Johannesburg
State/Province
Gauteng
ZIP/Postal Code
2193
Country
South Africa
Facility Name
Research Site
City
Midrand
State/Province
Gauteng
ZIP/Postal Code
1685
Country
South Africa
Facility Name
Research Site
City
Observatory
State/Province
Western Cape
ZIP/Postal Code
7925
Country
South Africa
Facility Name
Research Site
City
Parow
State/Province
Western Cape
ZIP/Postal Code
7505
Country
South Africa
Facility Name
Research Site
City
Cordoba
State/Province
Andalucía
ZIP/Postal Code
14004
Country
Spain
Facility Name
Research Site
City
Zaragoza
State/Province
Aragón
ZIP/Postal Code
50009
Country
Spain
Facility Name
Research Site
City
Reus
State/Province
Cataluña
ZIP/Postal Code
43204
Country
Spain
Facility Name
Research Site
City
Madrid
ZIP/Postal Code
28040
Country
Spain
Facility Name
Research Site
City
Stockholm
ZIP/Postal Code
111 35
Country
Sweden
Facility Name
Research Site
City
Stockholm
ZIP/Postal Code
141 86
Country
Sweden
Facility Name
Research Site
City
Reinach
ZIP/Postal Code
4153
Country
Switzerland
Facility Name
Research Site
City
Coventry
ZIP/Postal Code
CV2 2DX
Country
United Kingdom
Facility Name
Research Site
City
London
ZIP/Postal Code
SE1 7EH
Country
United Kingdom
Facility Name
Research Site
City
London
ZIP/Postal Code
W6 8RF
Country
United Kingdom
Facility Name
Research Site
City
Manchester
ZIP/Postal Code
M13 9WL
Country
United Kingdom

12. IPD Sharing Statement

Citations:
PubMed Identifier
28249876
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.
Results Reference
background
PubMed Identifier
29736889
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.
Results Reference
background
PubMed Identifier
29353350
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.
Results Reference
background
PubMed Identifier
29768954
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.
Results Reference
background
PubMed Identifier
25282519
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.
Results Reference
background
PubMed Identifier
30755061
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.
Results Reference
background
PubMed Identifier
30120772
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.
Results Reference
background
Links:
URL
http://www.amgentrials.com
Description
AmgenTrials clinical trials website

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

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