The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT01763918




Registration number
NCT01763918
Ethics application status
Date submitted
7/01/2013
Date registered
9/01/2013
Date last updated
17/06/2019

Titles & IDs
Public title
Reduction of LDL-C With PCSK9 Inhibition in Heterozygous Familial Hypercholesterolemia Disorder Study-2
Scientific 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
Secondary ID [1] 0 0
2012-001365-32
Secondary ID [2] 0 0
20110117
Universal Trial Number (UTN)
Trial acronym
RUTHERFORD-2
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Hyperlipidemia 0 0
Condition category
Condition code
Metabolic and Endocrine 0 0 0 0
Other metabolic disorders
Human Genetics and Inherited Disorders 0 0 0 0
Other human genetics and inherited disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Other interventions - Evolocumab
Treatment: Drugs - Placebo

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

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

Experimental: Evolocumab Q2W - Participants received 140 mg evolocumab by subcutaneous injection once every 2 weeks for up to 12 weeks.

Experimental: Evolocumab QM - Participants received 420 mg evolocumab by subcutaneous injection once a month for up to 12 weeks.


Other interventions: Evolocumab
Administered by subcutaneous injection

Treatment: Drugs: Placebo
Administered by subcutaneous injection

Intervention code [1] 0 0
Other interventions
Intervention code [2] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Percent Change From Baseline in LDL-C at Week 12
Timepoint [1] 0 0
Baseline and Week 12
Primary outcome [2] 0 0
Percent Change From Baseline in LDL-C at the Mean of Weeks 10 and 12
Timepoint [2] 0 0
Baseline and Weeks 10 and 12
Secondary outcome [1] 0 0
Change From Baseline in LDL-C at the Mean of Weeks 10 and 12
Timepoint [1] 0 0
Baseline and Weeks 10 and 12
Secondary outcome [2] 0 0
Change From Baseline in LDL-C at Week 12
Timepoint [2] 0 0
Baseline and Week 12
Secondary outcome [3] 0 0
Percentage of Participants With Mean LDL-C at Weeks 10 and 12 of Less Than 70 mg/dL (1.8 mmol/L)
Timepoint [3] 0 0
Weeks 10 and 12
Secondary outcome [4] 0 0
Percentage of Participants With LDL-C < 70 mg/dL (1.8 mmol/L) at Week 12
Timepoint [4] 0 0
Week 12
Secondary outcome [5] 0 0
Percent Change From Baseline in Non-High-Density Lipoprotein Cholesterol (Non-HDL-C) at the Mean of Weeks 10 and 12
Timepoint [5] 0 0
Baseline and Weeks 10 and 12
Secondary outcome [6] 0 0
Percent Change From Baseline in Non-HDL-C at Week 12
Timepoint [6] 0 0
Baseline and Week 12
Secondary outcome [7] 0 0
Percent Change From Baseline in Apolipoprotein B at the Mean of Weeks 10 and 12
Timepoint [7] 0 0
Baseline and Weeks 10 and 12
Secondary outcome [8] 0 0
Percent Change From Baseline in Apolipoprotein B at Week 12
Timepoint [8] 0 0
Baseline and Week 12
Secondary outcome [9] 0 0
Percent Change From Baseline in the Total Cholesterol/HDL-C Ratio at the Mean of Weeks 10 and 12
Timepoint [9] 0 0
Baseline and Weeks 10 and 12
Secondary outcome [10] 0 0
Percent Change From Baseline in the Total Cholesterol/HDL-C Ratio at Week 12
Timepoint [10] 0 0
Baseline and Week 12
Secondary outcome [11] 0 0
Percent Change From Baseline in Apolipoprotein B/Apolipoprotein A1 Ratio at the Mean of Weeks 10 and 12
Timepoint [11] 0 0
Baseline and Weeks 10 and 12
Secondary outcome [12] 0 0
Percent Change From Baseline in Apolipoprotein B/Apolipoprotein A1 Ratio at Week 12
Timepoint [12] 0 0
Baseline and Week 12
Secondary outcome [13] 0 0
Percent Change From Baseline in Lipoprotein (a) at the Mean of Weeks 10 and 12
Timepoint [13] 0 0
Baseline and Weeks 10 and 12
Secondary outcome [14] 0 0
Percent Change From Baseline in Lipoprotein (a) at Week 12
Timepoint [14] 0 0
Baseline and Week 12
Secondary outcome [15] 0 0
Percent Change From Baseline in Triglycerides at the Mean of Weeks 10 and 12
Timepoint [15] 0 0
Baseline and Weeks 10 and 12
Secondary outcome [16] 0 0
Percent Change From Baseline in Triglycerides at Week 12
Timepoint [16] 0 0
Baseline and Week 12
Secondary outcome [17] 0 0
Percent Change From Baseline in HDL-C at the Mean of Weeks 10 and 12
Timepoint [17] 0 0
Baseline and Weeks 10 and 12
Secondary outcome [18] 0 0
Percent Change From Baseline in HDL-C at Week 12
Timepoint [18] 0 0
Baseline and Week 12
Secondary outcome [19] 0 0
Percent Change From Baseline in Very Low-Density Lipoprotein Cholesterol (VLDL-C) at the Mean of Weeks 10 and 12
Timepoint [19] 0 0
Baseline and Weeks 10 and 12
Secondary outcome [20] 0 0
Percent Change From Baseline in VLDL-C at Week 12
Timepoint [20] 0 0
Baseline and Week 12

Eligibility
Key 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)
Minimum age
18 Years
Maximum age
80 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key 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 design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,WA
Recruitment hospital [1] 0 0
Research Site - Camperdown
Recruitment hospital [2] 0 0
Research Site - Perth
Recruitment postcode(s) [1] 0 0
2015 - Camperdown
Recruitment postcode(s) [2] 0 0
6000 - Perth
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Arizona
Country [2] 0 0
United States of America
State/province [2] 0 0
Ohio
Country [3] 0 0
Canada
State/province [3] 0 0
British Columbia
Country [4] 0 0
Canada
State/province [4] 0 0
Ontario
Country [5] 0 0
Canada
State/province [5] 0 0
Quebec
Country [6] 0 0
France
State/province [6] 0 0
Bron
Country [7] 0 0
France
State/province [7] 0 0
Nantes Cedex 1
Country [8] 0 0
France
State/province [8] 0 0
Paris Cedex 13
Country [9] 0 0
Germany
State/province [9] 0 0
Köln
Country [10] 0 0
Hong Kong
State/province [10] 0 0
New Territories
Country [11] 0 0
Netherlands
State/province [11] 0 0
Amersfoort
Country [12] 0 0
Netherlands
State/province [12] 0 0
Amsterdam
Country [13] 0 0
Netherlands
State/province [13] 0 0
Gouda
Country [14] 0 0
Netherlands
State/province [14] 0 0
Groningen
Country [15] 0 0
Netherlands
State/province [15] 0 0
Hoorn
Country [16] 0 0
Netherlands
State/province [16] 0 0
Tilburg
Country [17] 0 0
Netherlands
State/province [17] 0 0
Utrecht
Country [18] 0 0
New Zealand
State/province [18] 0 0
Christchurch
Country [19] 0 0
Norway
State/province [19] 0 0
Oslo
Country [20] 0 0
South Africa
State/province [20] 0 0
Gauteng
Country [21] 0 0
South Africa
State/province [21] 0 0
Western Cape
Country [22] 0 0
Spain
State/province [22] 0 0
Andalucía
Country [23] 0 0
Spain
State/province [23] 0 0
Aragón
Country [24] 0 0
Spain
State/province [24] 0 0
Cataluña
Country [25] 0 0
Spain
State/province [25] 0 0
Madrid
Country [26] 0 0
Sweden
State/province [26] 0 0
Stockholm
Country [27] 0 0
Switzerland
State/province [27] 0 0
Reinach
Country [28] 0 0
United Kingdom
State/province [28] 0 0
Coventry
Country [29] 0 0
United Kingdom
State/province [29] 0 0
London
Country [30] 0 0
United Kingdom
State/province [30] 0 0
Manchester

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Amgen
Address
Country

Ethics approval
Ethics application status

Summary
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).
Trial website
https://clinicaltrials.gov/show/NCT01763918
Trial related presentations / publications
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.
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. Review.
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.
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.
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.
Public notes

Contacts
Principal investigator
Name 0 0
MD
Address 0 0
Amgen
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Summary results
Other publications