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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/ct2/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
Sex
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
7/02/2013
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
19/12/2013
Sample size
Target
Accrual to date
Final
331
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/ct2/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.
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

For IPD and results data, please see https://clinicaltrials.gov/ct2/show/NCT01763918