A clinical study to assess the safety and efficacy of AMG 145 on low density cholesterol in subjects with Severe Familial Hypercholesterolemia

• Register: EUCTR
• Last refreshed on: 18 June 2018
• Main ID: EUCTR2011-005400-15-ES
• Date of registration: 09/04/2013
• Prospective Registration: Yes
• Primary sponsor: Amgen Inc
• Public title: A clinical study to assess the safety and efficacy of AMG 145 on low density cholesterol in subjects with Severe Familial Hypercholesterolemia
• Scientific title: A Multicenter, Open-label Study to Assess the Long-term Safety, Tolerability, and Efficacy of AMG 145 on LDL-C in Subjects With Severe Familial Hypercholesterolemia - TAUSSIG - Trial Assessing long term USe of PCSK9 Inhibition in Subjects wIth Genetic LDL
• Date of first enrolment: 18/06/2013
• Target sample size: 125
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2011-005400-15
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no Randomised: no Open: yes Single blind: no Double blind: no Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: Placebo: Other: Number of treatment arms in the trial: 3
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Australia, Austria, Belgium, Brazil, Canada, Czech Republic, France, Greece, Hong Kong, Israel, Italy, Japan, Malaysia, Netherlands, New Zealand, Norway, Poland, South Africa, Spain, Turkey, 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:
Subjects will be eligible for the study if they:
- Completed study 20110233 or another qualifying Amgen parent protocol, did not experience a treatment related serious adverse event that led to IP discontinuation, and are still taking investigational product at the end of the study, or
- Have severe familial hypercholesterolemia due to genetic causes (beyond LDL receptor mutations), such as PCSK9 gain of function mutations, as evidenced by genetic or functional evidence and have not participated in a parent protocol. Eligibility must be approved by Amgen?s medical monitor, or
- Have a diagnosis of homozygous familial hypercholesterolemia and are ineligible to meet inclusion criteria for another AMG 145 protocol (for example, patients actively receiving apheresis). Eligibility must be approved by Amgen?s medical monitor, or
- Have a diagnosis of homozygous familial hypercholesterolemiaand are eligible to participate in study 20110233 but study 20110233 has closed. As stated in protocol 20110233, the diagnosis of homozygous familial hypercholesterolemia will be based on genetic confirmation or a clinical diagnosis based on a history of an untreated LDL cholesterol concentration greater than 500 mg/dL (13 mmol/L) together with either xanthoma before 10 years of age or evidence of heterozygous familial hypercholesterolemia in both parents.
Non-parent study subjects that meet inclusion criteria 4.1.2, 4.1.3, or 4.1.4 must also meet all of the following inclusion criteria:
- Are male or female ? 12 to ? 80 years of age
- Are on a stable low-fat diet and taking pre-existing lipid-lowering therapies (such as statins, cholesterol-absorption inhibitors, bile-acid sequestrants or nicotinic acid, or combinations thereof) for at least 4 weeks, with fasting central lab LDL cholesterol concentration and meet the following LDL-C values based on risk factor status (NCEP ATPIII risk categories Grundy et al, 2004):
- > 100 mg/dL (2.6 mmol/L) for subjects with diagnosed CHD or CHD risk equivalent (includes clinical manifestations of noncoronary forms of atherosclerotic disease [peripheral arterial disease, abdominal aortic aneurysm, and carotid artery disease], diabetes, and 2+ risk factors with 10-year risk for hard CHD >20%). Risk factors include cigarette smoking, hypertension (BP ? 140/90 mm Hg or on antihypertensive medication), low HDL cholesterol (< 40 mg/dL), family history of premature CHD (CHD in male first-degree relative < 55 years of age; CHD in female first-degree relative < 65 years of age), and age (men ? 45 years; women ? 55 years) or
- > 130 mg/dL (3.4 mmol/L) for subjects without diagnosed CHD or CHD risk equivalent or
- There is No LDL-C entry requirement for apheresis patients - because their LDL-C values fluctuate and may not be representative of their overall LDL-C burden.
- Fasting triglycerides ? 400 mg/dL (4.5 mmol/L) by central laboratory at screening
- Bodyweight of 40 kg or greater at screening
Are the trial subjects under 18? yes
Number of subjects for this age range: 15
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 80
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 30

Exclusion criteria:
All subjects will be ineligible for the study if they fulfill any of the following criteria:
- Female subject is not willing to use at least one highly effective method of birth control during treatment and for an additional 15 weeks after the end of treatment unless subject is sterilized or postmenopausal;
- Menopause is defined as 12 months of spontaneous and continuous amenorrhea in a female ? 55 years old or 12 months of spontaneous and continuous amenorrhea with a follicle-stimulating hormone level > 40 IU/L (or according to the definition of "postmenopausal range" for the laboratory involved) in a female < 55 years old unless the subject has undergone bilateral oophorectomy?
-Highly effective methods of birth control include abstinence, birth control pills, shots, implants, or patches, intrauterine devices (IUDs), sexual activity with a male partner who has had a vasectomy, condom or occlusive cap (diaphragm or cervical/vault caps) used with spermicide.
- Subject is pregnant or breast feeding, or might become pregnant during treatment and/or within 15 weeks after the end of treatment
- Unreliability as a study participant based on the investigator's (or designee?s) knowledge of the subject (eg, inability or unwillingness to adhere to the protocol)
- Experienced a treatment related serious adverse event that led to IP discontinuation in the AMG 145 parent protocol
- Disorder that would interfere with understanding and giving informed consent or compliance with protocol requirements
- Have an unstable medical condition, in the judgment of the investigator.
- 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).
In addition, all subjects that undergo screening procedures will be ineligible for the study if they fulfill any of the following criteria:
- Use of Mipomersen within 5 months of screening
- 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 screening
- Myocardial infarction, unstable angina, percutaneous coronary intervention (PCI), coronary artery bypass graft (CABG) or stroke within 3 months prior to screening
- Planned cardiac surgery or revascularization within 20 weeks of screening
- Uncontrolled hypertension defined as sitting systolic blood pressure (SBP) > 180 mmHg or diastolic BP (DBP) > 110 mmHg, confirmed with repeat measurement
- Subject requires uptitration of their current statin dose within 4 weeks of screening (these subjects can be uptitrated and rescreened one month later)
- 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) > 3 times the ULN as determined by central laboratory analysis at screening
- Unexplained CK > 5 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
-

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

Health Condition(s) or Problem(s) studied

Homozygous Familial Hypercholesterolemia
MedDRA version: 14.1 Level: LLT Classification code 10057100 Term: Homozygous familial hypercholesterolaemia System Organ Class: 100000004850

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

Intervention(s)

Product Name: AMG 145
Product Code: AMG 145
Pharmaceutical Form: Solution for injection
INN or Proposed INN: n/a
CAS Number: n/a
Current Sponsor code: AMG 145
Other descriptive name: AMG 145
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 70-

Primary Outcome(s)

Primary end point(s): Subject incidence of treatment emergent adverse events.

Secondary Objective: To characterize the durable efficacy of long-term administration of AMG 145 as assessed by low density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (ApoB), total cholesterol/HDL-C ratio, and
ApoB/Apolipoprotein A-1 (ApoA1) ratio and response of LDL-C reduction (15% or greater) in subjects with severe familial hypercholesterolemia

Main Objective: To characterize the safety and tolerability of long-term administration of AMG 145 among patients with severe familial hypercholesterolemia

Timepoint(s) of evaluation of this end point: From baseline to week 24 Q4W, at interval visits (week 16 and 20) and quaterly after week 24 until EoS

Secondary Outcome(s)

Secondary end point(s): ? Percent change in LDL-C from baseline at each scheduled visit
? Percent change in non-HDL-C from baseline at each scheduled visit
? Percent change in ApoB from baseline at each scheduled visit
? Percent change in total cholesterol/HDL-C ratio from baseline at each scheduled visit
? Percent change in ApoB/ApoA1 ratio from baseline at each scheduled visit
? Response of LDL-C reduction of 15% or greater from baseline at each scheduled visit

Timepoint(s) of evaluation of this end point: ? Percent change in LDL-C from baseline at each scheduled visit
? Percent change in non-HDL-C from baseline at each scheduled visit
? Percent change in ApoB from baseline at each scheduled visit
? Percent change in total cholesterol/HDL-C ratio from baseline at each scheduled visit
? Percent change in ApoB/ApoA1 ratio from baseline at each scheduled visit

Secondary ID(s)

2011-005400-15-BE

20110271

Source(s) of Monetary Support

Amgen Inc