Study designed to evaluate the safety and efficacy of AMG 145 compared with Ezetimibe treatment, in people with high cholesterol who have experienced side effects whilst taking existing statin treatment

• Register: EUCTR
• Last refreshed on: 22 January 2018
• Main ID: EUCTR2013-000935-29-NO
• Date of registration: 17/03/2014
• Prospective Registration: Yes
• Primary sponsor: Amgen Inc.
• Public title: Study designed to evaluate the safety and efficacy of AMG 145 compared with Ezetimibe treatment, in people with high cholesterol who have experienced side effects whilst taking existing statin treatment
• Scientific title: A Double-blind, Randomized, Multicenter Study to Evaluate the Safety and Efficacy of AMG 145, Compared With Ezetimibe, in Hypercholesterolemic Subjects Unable to Tolerate an Effective Dose of a HMG-CoA Reductase Inhibitor Due to Muscle Related Side Effects - GAUSS-3
• Date of first enrolment: 15/04/2014
• Target sample size: 500
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2013-000935-29
• 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: yes; Other: yes; Other trial design description: This a 3 part study: please refer to the protocol for the design of parts A to C; If controlled, specify comparator, Other Medicinial Product: yes; Placebo: yes; Other: no; Number of treatment arms in the trial: 5
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Australia, Canada, Czech Republic, Denmark, France, Germany, Italy, Netherlands, New Zealand, Norway, South Africa, 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:
1) Subject who has provided informed consent/assent prior to initiation of any study-specific activities/procedures.
2) Male or female = 18 to = 80 years of age at signing of informed consent
3) Subject who is not at LDL-C goal as evidenced by their NCEP ATP III risk category and the following LDL-C levels by central laboratory at screening:
a) Fasting LDL-C = 100 mg/dL (2.59 mmol/L) for subjects with diagnosed CHD or are CHD risk equivalent or
b) Fasting LDL-C = 130 mg/dL (3.37 mmol/L) for subjects without diagnosed CHD or risk equivalent and 2 or more risk factors or
c) Fasting LDL-C = 160 mg/dL (4.14 mmol/L) for subjects without diagnosed CHD or risk equivalent and with 1 or more risk factors or
d) Fasting LDL-C = 190 mg/dL (4.9 mmol/L) for subjects without diagnosed CHD or risk equivalent and with no risk factors
4) Subject who has a history of statin intolerance as evidenced by the following:
a) Unable to tolerate atorvastatin at an average daily dose of 10 mg AND unable to tolerate any other statin at any dose due to skeletal muscle related symptoms (e.g., pain, aches, weakness or cramping)
OR
b) Unable to tolerate at least three statins: one statin at the lowest starting average daily dose (defined below) AND any other two statins at any dose, due to skeletal muscle related symptoms (e.g., pain, aches, weakness or cramping)
- atorvastatin - 5 mg
- simvastatin - 10 mg
- pravastatin - 40 mg
- lovastatin - 20 mg
- fluvastatin - 40 mg
- pitavastatin - 2 mg
OR
c) A documented history of CK elevation > 10 x ULN accompanied by muscle symptoms while on statin therapy and documented resolution of both CK elevation and muscle symptoms upon discontinuation of statin therapy;
AND
d) Symptoms resolved or improved when statin dose was decreased or discontinued
5) Lipid lowering therapy has been stable prior to LDL-C screening for at least 4 weeks if currently on a bile-acid sequestering resin and/or stanol; if subject is on statin or ezetimibe at start of screening, statin or ezetimibe must be discontinued for = 4 weeks before LDL-C screening
6) Fasting triglycerides = 400 mg/dL (4.52 mmol/L) 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 400
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 100

Exclusion criteria:
1) History of haemorrahagic stroke
2) Personal or family history of hereditary muscular disorders
3) NYHA III or IV heart failure, or last known left ventricular ejection fraction (LVEF) < 30%
4) 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
5) Myocardial infarction, unstable angina, percutaneous coronary intervention (PCI), coronary artery bypass graft (CABG) or stroke within 3 months prior to randomization
6) Planned cardiac surgery or revascularization
7) Type 1 diabetes, poorly controlled type 2 diabetes (HbA1c > 8.5%), newly diagnosed type 2 diabetes (within 6 months of randomization), or laboratory evidence of diabetes during screening (fasting serum glucose = 126 mg/dL [7.0 mmol/L] or HbA1c = 6.5%) without prior diagnosis of diabetes
8) Uncontrolled hypertension defined as sitting systolic blood pressure (SBP) > 160 mmHg or diastolic BP (DBP) > 100 mmHg
9) Subject who has taken in the last 4 weeks prior to LDL C screening red yeast rice, > 200 mg/day niacin, or prescription lipid-regulating drugs (eg, fibrates and derivatives, statins or, ezetimibe) other than bile-acid sequestering resin, or stanols and stanol esters
10) Subject who has taken a cholesterylester transfer protein (CETP) inhibitor in the last 12 months prior to LDL-C screening, such as: anacetrapib, dalcetrapib or evacetrapib.
11) Treatment in the last 3 months prior to LDL-C screening with any of the following drugs: systemic cyclosporine, systemic steroids (eg, IV, intramuscular [IM], or PO) (Note: hormone replacement therapy is permitted), vitamin A derivatives and retinol derivatives for the treatment of dermatologic conditions (eg, Accutane); (Note: vitamin A in a multivitamin preparation is permitted)
12) Uncontrolled hypothyroidism or hyperthyroidism as defined by thyroid stimulating hormone (TSH) < 1.0 time the lower limit of normal or >1.5 times the ULN, respectively, at screening. Potential subjects with TSH < 1.0 time the lower limit of normal due to thyroid replacement therapy is not considered an exclusion
13) Moderate to severe renal dysfunction, defined as an estimated glomerular filtration rate (eGFR) < 30 ml/min/1.73m2 at screening
14) 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
15) Known active infection or major hematologic, renal, metabolic, gastrointestinal or endocrine dysfunction in the judgment of the investigator
16) Diagnosis of deep vein thrombosis or pulmonary embolism within 3 months prior to randomization
17) 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)
18) 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)
19) Female subject who has either (1) not used at least 1 highly effective method of contraception for at least 1 month prior to screening or (2) is not willing to use such a method during treatment and for an additional 15 weeks af

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

Health Condition(s) or Problem(s) studied

Hypercholesterolemia
MedDRA version: 16.1 Level: LLT Classification code 10020604 Term: Hypercholesterolemia System Organ Class: 100000004861

Therapeutic area: Diseases [C] - Cardiovascular Diseases [C14]

Intervention(s)

Product Name: AMG 145
Pharmaceutical Form: Solution for injection in pre-filled pen
Current Sponsor code: AMG 145
Other descriptive name: AMG 145
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 140-
Pharmaceutical form of the placebo: Solution for injection in pre-filled pen
Route of administration of the placebo: Subcutaneous use

Trade Name: Atorvastatin calcium
Product Name: Atorvastatin
Product Code: C10AA05
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: ATORVASTATIN
CAS Number: 134523-00-5
Other descriptive name: atorvastatin
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 20-
Pharmaceutical form of the placebo: Tablet
Route of administration of the placebo: Oral use

Trade Name: ZETIA® (ezetimibe) Tablets
Product Name: ezetimibe
Product Code: C10A X09
Pharmaceutical Form: Tablet
CAS Number: 163222-33-1
Current Sponsor code: EZETIMIBE
Other descriptive name: EZETIMIBE
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 10-
Pharmaceutical form of the placebo: Tablet
Route of administration of the placebo: Oral use

Product Name: AMG 145
Pharmaceutical Form: Solution for injection in cartridge
Current Sponsor code: AMG 145
Other descriptive name: AMG 145
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 120-

Primary Outcome(s)

Main Objective: To evaluate the effect of AMG 145 administered subcutaneously (SC) once every month (QM) compared with ezetimibe (Part B), on percent change from baseline in low-density lipoprotein cholesterol (LDL-C) in hypercholesterolemic subjects who are unable to
tolerate an effective dose of a statin due to muscle related side effects (MRSE).

Timepoint(s) of evaluation of this end point: 1) Week 22 and Week 24 of Part B of the study design
2) Week 24 of Part B

Primary end point(s): Coprimary endpoints are:
1) Mean percent change from baseline in LDL-C at Weeks 22 and 24 of Part B
2) Percent change from baseline in LDL-C at Weeks 24 of Part B

Secondary Objective: • To evaluate the safety and tolerability of SC AMG 145 QM, compared with ezetimibe, in hypercholesterolemic subjects unable to tolerate an effective dose of a statin
• To assess the effect of 24 weeks of SC AMG 145 QM, compared with ezetimibe, on change from baseline in LDL-C, and percent change from baseline in total
cholesterol, non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (ApoB), total cholesterol/HDL-C ratio, ApoB/Apolipoprotein A1 (ApoA1) ratio, lipoprotein(a) [Lp(a)], triglycerides, HDL-C, and VLDL-C in hypercholesterolemic subjects unable to tolerate an effective dose of a statin
• To assess the effect of 24 weeks of SC AMG 145 QM, compared with ezetimibe, on percent of subjects attaining LDL-C < 70 mg/dL (1.81 mmol/L) in hypercholesterolemic subjects unable to tolerate an effective dose of a statin

Secondary Outcome(s)

Secondary end point(s): Co-secondary endpoints of the means at Weeks 22 and 24 of Part B and at Week 24 of Part B for:
Tier 1 endpoints
• Change from baseline in LDL-C
• LDL-C response (LDL-C < 70 mg/dL [1.81 mmol/L])
• Percent change from baseline in total cholesterol
• Percent change from baseline in non-HDL-C
• Percent change from baseline in ApoB
• Percent change from baseline in the total cholesterol/HDL-C ratio
• Percent change from baseline in ApoB/ApoA1 ratio

Tier 2 endpoints
• Percent change from baseline in Lp(a)
• Percent change from baseline in triglycerides
• Percent change from baseline in HDL-C
• Percent change from baseline in VLDL-C

Timepoint(s) of evaluation of this end point: The means at Weeks 22 and 24 of Part B and at Week 24 of Part B

Secondary ID(s)

2013-000935-29-CZ

20120332

Source(s) of Monetary Support

Amgen Inc.