Study to assess the tolerability and efficacy of AMG 145 in patients with heterozygous familial hypercholesterolemia

• Register: EUCTR
• Last refreshed on: 5 November 2012
• Main ID: EUCTR2011-001528-39-SE
• Date of registration: 17/06/2011
• Prospective Registration: Yes
• Primary sponsor: Amgen Inc
• Public title: Study to assess the tolerability and efficacy of AMG 145 in patients with heterozygous familial hypercholesterolemia
• Scientific title: A Double-blind, Randomized, Placebo-controlled, Multicenter Study to Evaluate Tolerability and Efficacy of AMG 145 on LDL-C in Subjects with Heterozygous Familial Hypercholesterolemia - Reduction of LDL-C with PCSK9 inhibition in HeFH Disorder Study [RUTHERFORD]
• Date of first enrolment: 20/07/2011
• Target sample size: 150
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2011-001528-39
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no Number of treatment arms in the trial: 3

Countries of recruitment

Canada, Germany, Hong Kong, Netherlands, Norway, Singapore, South Africa, Spain, Sweden, United Kingdom, United States

Contacts

• Name: IHQ Medical Info - Clinical Trials
• Affiliation: Amgen (EUROPE) GmbH

• Name: IHQ Medical Info - Clinical Trials
• Affiliation: Amgen (EUROPE) GmbH

Key inclusion & exclusion criteria

Inclusion criteria:
- Subject has provided informed consent
- Male or female = 18 to = 75 years of age
- Diagnosis of heterozygous familial hypercholesterolemia by having met the diagnostic criteria outlined by the Simon Broome Register Group (Scientific Steering Committee 1991) as defined by the documentation of one of the following in the patient’s past medical record:
1. A total cholesterol concentration > 290 mg/dL (> 7.5 mmol/liter) in
adulthood or a total cholesterol concentration > 260 mg/dL
(> 6.7 mmol/liter) in childhood at an age of less than 16 years, or a
LDL-C concentration > 190 mg/dL (> 4.9 mmol/liter) in adulthood or
> 155 mg/dL (> 4.0 mmol/liter) in childhood AND Tendinous
xanthomas in the patient or first- or second-degree relative
2. Deoxyribonucleic acid (DNA)-based evidence of mutation in the
LDLR, ApoB, or PCSK9 gene
3. A total cholesterol concentration > 290 mg/dL (> 7.5 mmol/liter) in
adulthood or a total cholesterol concentration > 260 mg/dL
(> 6.7 mmol/liter) in childhood at an age of less than 16 years, or a
LDL-C concentration > 190 mg/dL (> 4.9 mmol/liter) in adulthood or
> 155 mg/dL (> 4.0 mmol/liter) in childhood AND family history of
myocardial infarction before age 50 years in a second-degree
relative or before age 60 years in a first-degree relative
4. A total cholesterol concentration > 290 mg/dL (> 7.5 mmol/liter) in
adulthood or a total cholesterol concentration > 260 mg/dL
(> 6.7 mmol/liter) in childhood at an age of less than 16 years, or a LDL-C concentration > 190 mg/dL (> 4.9 mmol/liter) in adulthood or
> 155 mg/dL (> 4.0 mmol/liter) in childhood AND family history of
raised total cholesterol concentration > 290 mg/dL (> 7.5 mmol/liter)
in a first or second-degree adult relative or > 260 mg/dL
(> 6.7 mmol/liter) in child, brother, or sister aged younger than
16 years
- On an approved statin, with stable dose(s) for all allowed (eg, ezetimibe,
bile-acid sequestering resin, stanols, or regulatory-approved and
marketed niacin (eg, Niaspan or Niacor)) lipid-regulating drugs for at least 4 weeks before LDL-C screening, and in the opinion of the
investigator, not requiring uptitration
- Fasting LDL-C = 100 mg/dL (2.6 mmol/liter) by central laboratory at screening
- Fasting triglycerides = 400 mg/dL (4.5 mmol/liter)by central laboratory at screening
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 90
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 60

Exclusion criteria:
- Homozygous familial hypercholesterolemia
- LDL or plasma apheresis within 12 months prior to randomization
- NYHA III or IV heart failure, or last known left ventricular ejection fraction < 30%
- Uncontrolled serious cardiac arrhythmia defined as recurrent and highly
symptomatic ventricular tachycardia, atrial fibrillation with rapid ventricular response, or supraventricular tachycardia that are not controlled by medications, in the past 3 months prior to randomization
- Myocardial infarction, unstable angina, percutaneous coronary
intervention (PCI), coronary artery bypass graft (CABG) or stroke within 3 months prior to randomization
- Planned cardiac surgery or revascularization within 20 weeks of
screening
- Type 1 diabetes or newly diagnosed (within 3 months of randomization) type 2 diabetes, or poorly controlled type 2 diabetes (HbA1c > 8.5%)
- Uncontrolled hypertension defined as sitting systolic blood pressure
(SBP) > 160 mmHg or diastolic BP (DBP) > 100 mmHg, confirmed with
repeat measurement
- Subject requires uptitration of their current statin dose (these subjects can be uptitrated and rescreened one month later).
- Subject has taken in the last 6 weeks prior to LDL-C screening red
yeast rice, omega-3 fatty acids ([eg, DHA and EPA] [> 1000 mg/day])
or prescription lipid-regulating drugs (eg, fibrates and derivatives)
other than statins, ezetimibe, bile-acid sequestering resin, stanols,
or regulatory approved and marketed niacin (eg, Niaspan or Niacor)
- Treatment in the last 3 months prior to LDL-C screening with any of the following drugs: systemic cyclosporine, systemic steroids (IV, intramuscular [IM], or PO), vitamin A derivatives and retinol derivatives for the treatment of dermatologic conditions (eg, Accutane); (Note: vitamin A in a multivitamin preparation is permitted)
- Hyperthyroidism or hypothyroidism as defined by thyroid stimulating
hormone (TSH) below the lower
limit of normal (LLN) or >1.5 times the upper limit of normal (ULN),
respectively, at screening
- Moderate to severe renal dysfunction, defined as an estimated glomerular filtration rate (eGFR) < 30 ml/min/1.73m2 at screening
- Active liver disease or hepatic dysfunction, defined as aspartate
aminotransferase (AST) or alanine aminotransferase (ALT) > 2 times the ULN as determined by central laboratory analysis at screening
- CK > 3 times the ULN at screening, confirmed by a repeat measurement at least 1 week apart
- Known active infection or major hematologic, renal, metabolic,
gastrointestinal or endocrine dysfunction in the judgment of the
investigator
- Diagnosis of deep vein thrombosis or pulmonary embolism within
3 months prior to randomization
- Current therapeutic anticoagulation with vitamin K antagonist (eg,
warfarin), heparin, low-molecular weight heparin, direct thrombin inhibitor, or Factor Xa inhibitor (Note: anti-platelet agents [eg, aspirin, clopidogrel, prasugrel, ticagrelor, dipyridamole] are permitted).
- Unreliability as a study participant based on the investigator's (or
designee’s) knowledge of the subject (eg, alcohol or other drug abuse,
inability or unwillingness to adhere to the protocol, or psychosis)
- Currently enrolled in another investigational device or drug study, or less than 30 days since ending another investigational device or drug study(s), or receiving other investigational agent(s)
- Female subject who is not willing to use at least one highly effective method of birth contr

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]

Heterozygous familial hypercholesterolaemia
MedDRA version: 14.0 Level: LLT Classification code 10057099 Term: Heterozygous familial hypercholesterolaemia System Organ Class: 10010331 - Congenital, familial and genetic disorders

Intervention(s)

Product Name: AMG 145
Product Code: AMG 145
Pharmaceutical Form: Solution for injection
Current Sponsor code: AMG 145
Other descriptive name: AMG 145
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 70-
Pharmaceutical form of the placebo: Solution for injection
Route of administration of the placebo: Subcutaneous use

Primary Outcome(s)

Secondary Objective: - To evaluate the safety and tolerability of 2 doses of AMG 145 SC, compared with placebo SC, in subjects with heterozygous familial hypercholesterolemia
- To assess the effects of 12 weeks of AMG 145 SC, compared with placebo SC, on absolute change in LDL-C, and percent change in non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (ApoB), total cholesterol/HDL-C ratio, and ApoB/Apolipoprotein A-1 (ApoA1) ratio in subjects with heterozygous familial hypercholesterolemia
- To characterize pharmacokinetics of AMG 145 following SC injection in subjects with heterozygous familial hypercholesterolemia

Primary end point(s): The percent change from baseline in LDL-C at week 12.

Main Objective: To evaluate the effect of 12 weeks of subcutaneous (SC) AMG 145,
compared with placebo SC, on percent change from baseline in low-density lipoprotein cholesterol (LDL-C) in subjects with heterozygous familial hypercholesterolemia.

Timepoint(s) of evaluation of this end point: From baseline to week 12

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: - Absolute change from baseline in LDL-C at week 12: from baseline to week 12
- Percent change from baseline in non-HDL-C at week 12: from baseline to week 12
- Percent change from baseline in ApoB at week 12: from baseline to week 12
- Percent change from baseline in the total cholesterol/HDL-C ratio at week 12: from baseline to week 12
- Percent change from baseline in ApoB/ApoA1 ratio at week 12: from baseline to week 12

Secondary end point(s): - Absolute change from baseline in LDL-C at week 12
- Percent change from baseline in non-HDL-C at week 12
- Percent change from baseline in ApoB at week 12
- Percent change from baseline in the total cholesterol/HDL-C ratio at week 12
- Percent change from baseline in ApoB/ApoA1 ratio at week 12

Secondary ID(s)

20090158

2011-001528-39-ES

Source(s) of Monetary Support

Amgen Inc