A clinical study to assess the safety and efficacy of AMG 145 on low density cholesterol in subjects with homozygous familial hypercholesterolemia or PCSK9 mutations
- Conditions
- Homozygous Familial HypercholesterolemiaMedDRA version: 14.1Level: LLTClassification code 10057100Term: Homozygous familial hypercholesterolaemiaSystem Organ Class: 10010331 - Congenital, familial and genetic disordersTherapeutic area: Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]
- Registration Number
- EUCTR2011-005400-15-GR
- Lead Sponsor
- Amgen Inc
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Not Recruiting
- Sex
- All
- Target Recruitment
- 75
Subjects have completed study 20110233 or another qualifying Amgen protocol (all scheduled visits) and are still taking investigational product at the end of the study
Or
If the subjects did not complete study 20110233 or another qualifying Amgen protocol they will be eligible if they:
- Have severe familial hypercholesterolemia due to genetic causes (beyond LDL receptor mutations) which were not studied in 20110233, such as PCSK9 gain of function mutations, as evidenced by genetic or functional evidence.
- Have a diagnosis of homozygous familial hypercholesterolemia and are interested in enrolling after 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.
- Are male or female = 12 to = 65 years of age
- Are on a stable on a 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 >130 (3.4 mmol/L)
- 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 50
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 10
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 in the parent study
- 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)
If the subjects did not complete study 20110233 or another qualifying Amgen protocol they will be ineligible for this 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 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
- 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
- Diagnosis of d
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method 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<br>ApoB/Apolipoprotein A-1 (ApoA1) ratio in subjects with severe familial hypercholesterolemia;Primary end point(s): Subject incidence of treatment emergent adverse events.;Timepoint(s) of evaluation of this end point: From baseline to week 26 Q4W; quaterly after week 26 until EoS;Main Objective: To characterize the safety and tolerability of long-term administration of AMG 145 among patients with severe familial hypercholesterolemia
- Secondary Outcome Measures
Name Time Method Secondary end point(s): • Percent change in LDL-C from Day 1 OL at each 3 month visit<br>• Percent change in non-HDL-C from Day 1 OL at each 3 month visit<br>• Percent change in ApoB from Day 1 OL at each 3 month visit<br>• Percent change in total cholesterol/HDL-C ratio from Day 1 OL at each 3 month visit<br>• Percent change in ApoB/ApoA1 ratio from Day 1 OL at each 3 month visit;Timepoint(s) of evaluation of this end point: • Percent change in LDL-C from Day 1 OL at each 3 month visit<br>• Percent change in non-HDL-C from Day 1 OL at each 3 month visit<br>• Percent change in ApoB from Day 1 OL at each 3 month visit<br>• Percent change in total cholesterol/HDL-C ratio from Day 1 OL at each 3 month visit<br>• Percent change in ApoB/ApoA1 ratio from Day 1 OL at each 3 month visit