PrimaryTo describe the safety and tolerability of 80 weeks of SC evolocumab when added to standard of care in pediatric subjects 10 to 17 years of age with HeFH or HoFH. Secondary Efficacy* To describe percent change and change from baseline in LDL-…
ID
Source
Brief title
Condition
- Metabolic and nutritional disorders congenital
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary clinical hypothesis is that SC evolocumab will be well tolerated
when added to standard of care in pediatric subjects 10 to 17 years of age with
HeFH or HoFH.
Primary Endpoint: Treatment emergent adverse events
Secondary outcome
Secondary Efficacy Endpoints:
* Percent change from baseline at week 80 in:
* LDL-C
* non-HDL-C
* ApoB
* total cholesterol/HDL-C ratio
* ApoB/ApoA1 ratio
* Change from baseline in LDL-C at week 80
Secondary Safety Endpoints:
* Change from baseline in steroid hormones (estradiol in females, testosterone
in males; follicle-stimulating hormone [FSH], luteinizing hormone [LH],
adenocorticotropic hormone [ACTH], dehydroepiandrosterone sulfate [DHEA-S],
cortisol in all subjects) at week 80
* Abnormal muscle and liver enzyme levels (creatine kinase [CK], aspartate
aminotransferase [AST], or alanine aminotransferase [ALT]) at week 80
* Change in cIMT from baseline at week 80
* Change from baseline in growth (height and weight) and pubertal development
(Tanner staging) at weeks 24, 48, and 80
Background summary
Hypercholesterolemia (elevated serum low-density lipoprotein cholesterol
[LDL-C]) is an established risk factor for coronary heart disease (CHD) in
humans (Grundy et al, 2004), and more than 50 million patients are treated for
hypercholesterolemia in the United States and Europe (Kuklina et al, 2011;
Kotseva et al, 2009; Tolonen et al, 2005). Cholesterol elevations requiring
pharmacologic therapy are uncommon in children. However, patients with familial
hypercholesterolemia (FH), an almost exclusively autosomal dominant condition
most often resulting from deficient or defective LDLR function (Rader et al,
2003), have elevated LDL-C beginning in childhood. Since FH is a genetic
condition, the prevalence among children is very similar to the prevalence
among younger adults.
In the pediatric population, FH may be identified by the combination of
elevated LDL-C and a positive family history of hypercholesterolemia and/or
premature cardiovascular disease. HeFH affects approximately one out of every
200 to 500 people worldwide (National Collaborating Centre, 2008; Nordestgaard
et al, 2013; Rader et al, 2003). By comparison, HoFH is present in
approximately 1 in 1,000,000 individuals (Goldstein et al, 2001). Without
treatment, these patients have severe hypercholesterolemia, develop premature
coronary artery disease, and are at increased risk for premature cardiovascular
death (Rader et al, 2003). Because premature atherosclerosis and especially
coronary artery disease are part of the natural history of FH, events related
to coronary artery disease and its complications (eg., manifestations of
myocardial ischemia such as chest pain and myocardial infarction; percutaneous
and surgical revascularization procedures, etc.) are expected to occur in this
population at some frequency regardless of drug exposure.
In the adult population, hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase
inhibitors (statins) are currently the treatment of choice for patients with
HeFH and HoFH patients (Grundy et al, 2004). Although statins reduce mortality
in this patient population (Raal et al, 2011), cholesterol levels may remain
elevated in FH patients despite therapy with diet, exercise, and medications.
Pediatric guidelines in the United States (Daniels and Greer, 2008; McCrindle
et al, 2007; Kavey et al, 2006) recommend considering pharmacologic treatment
after initial treatment with lifestyle modification has failed in patients >= 10
years of age with LDL-C that is:
* >= 130 mg/dL (3.4 mmol/L) for the highest risk (eg, diabetes mellitus)
* >= 160 mg/dL (4.1 mmol/L) for intermediate risk (eg, >= 2 other CHD risk
factors, family history of premature coronary artery disease [CAD])
* >= 190 mg/dL (4.9 mmol/L) for the lowest risk (no cardiovascular risk factors)
Similarly, treatment guidelines from the European Society of Cardiology and
European Atherosclerosis Society (ESC/EAS; Reiner et al, 2011) and from the
National Institute for Health and Clinical Excellence (NICE; National
Collaborating Centre, 2008) recommend statin treatment in patients who are >= 10
years of age and have HeFH or HoFH, and consider pharmacologic treatment for
subjects with HoFH at earlier ages
(Reiner et al, 2011). When a child with FH has exceptionally high LDL-C and/or
cardiovascular risk, bile acid sequestrants and ezetimibe are also indicated
and may be used in combination. Thus, while currently available therapies can
reduce LDL-C levels, novel therapies that can be used alone or in combination
with existing agents to more effectively reduce LDL-C would be valuable for
both adults and pediatric patients with severely elevated cholesterol levels.
Study objective
Primary
To describe the safety and tolerability of 80 weeks of SC evolocumab when added
to standard of care in pediatric subjects 10 to 17 years of age with HeFH or
HoFH.
Secondary Efficacy
* To describe percent change and change from baseline in LDL-C, and on percent
change from baseline 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 pediatric subjects 10 to 17 years of age with HeFH or
HoFH after 80 weeks of SC evolocumab, added to standard of care in pediatric
subjects 10 to 17 years of age with HeFH or HoFH
Secondary Safety
* To describe change from baseline in steroid hormones and the subject
incidence of abnormal muscle and liver enzyme levels after 80 weeks of SC
evolocumab, added to standard of care in pediatric subjects 10 to 17 years of
age with HeFH or HoFH
* To describe changes from baseline in carotid intima-media thickness (cIMT)
after 80 weeks of SC evolocumab, added to standard of care in pediatric
subjects 10 to 17 years of age with HeFH or HoFH
* To describe change from baseline in growth and pubertal development
parameters at measured timepoints with 80 weeks of SC evolocumab, added to
standard of care in pediatric subjects 10 to 17 years of age with HeFH or HoFH
Other Safety
* To evaluate the incidence of abnormal neurological examination findings after
80 weeks of SC evolocumab added to standard of care in pediatric subjects 10 to
17 years of age with HeFH or HoFH
* To assess cognitive function, assessed using the change from baseline in the
components of the Cogstate battery at each scheduled administration, after 80
weeks of SC evolocumab added to standard of care in pediatric subjects 10 to 17
years of age with HeFH or HoFH
Exploratory
* To describe change and percent change at measured timepoints in LDL-C, total
cholesterol, non-HDL-C, ApoB, total cholesterol/HDL-C ratio, ApoB/ApoA1 ratio,
triglycerides, VLDL-C, HDL-C, ApoA1, lipoprotein(a) [Lp(a)], with 80 weeks of
SC evolocumab, added to standard of care in pediatric subjects 10 to 17 years
of age with HeFH or HoFH
* To describe change at measured timepoints in proprotein convertase
subtilisin/kexin type 9 (PCSK9) and high sensitivity C-reactive protein (hsCRP)
with 80 weeks of SC evolocumab, added to standard of care in pediatric subjects
10 to 17 years of age with HeFH or HoFH
* To describe the incidence of abnormal neurological examination findings with
80 weeks of SC evolocumab, added to standard of care in pediatric subjects 10
to 17 years of age with HeFH or HoFH
* To investigate the relationship between novel and established biochemical
cardiovascular and lipid biomarkers and effects of evolocumab in pediatric
subjects 10 to 17 years of age with HeFH
* In subjects consenting to the optional pharmacogenetics analysis, to
investigate potential correlations of study data including the subject response
to evolocumab with genetic variation in markers of (PCSK9) signaling,
low-density lipoprotein receptor (LDLR) turnover, cholesterol metabolism,
inflammation, and plaque stability
Study design
This is an open-label, single-arm, multicenter study. Subjects are eligible for
screening if they have completed Study 20120123 or if they are 10 to 17 years
of age at time of enrollment and have HoFH. The minimum expected enrollment of
HeFH (rollover) subjects is approximately 70% of subjects enrolled in Study
20120123 or approximately 111 subjects. In addition, approximately 10 subjects
with HoFH (and without prior
participation in an evolocumab study) will be enrolled for an expected total
enrollment of approximately 124 subjects. Depending on willingness of 20120123
subjects to continue evolocumab administration, final enrollment may be smaller
or greater. The study includes collection of biomarker development samples.
Where permitted by local regulations, subjects will be invited to
consent/assent to pharmacogenetic analyses
Intervention
The subjects will be enrolled to receive monthly Evolocumab for the period of
80 weeks, by means of 3 subcutane injections.
Study burden and risks
Patients will have more visits to the hospital; risks associated with
participation are the one linked to the investigational product.
Minervum 7061
Breda 4817 LK
NL
Minervum 7061
Breda 4817 LK
NL
Listed location countries
Age
Inclusion criteria
All Subjects:
• Subject has provided written informed consent or subject assent prior to
initiation of any study-specific activities/procedures.
and/or
• Subject*s legally acceptable representative has provided informed consent
when the subject is legally too young to provide informed consent and the
subject has provided written subject assent based on local regulations and/or
guidelines prior to any study-specific activities/procedures being initiated.
Subjects with HeFH:
• Completed Study 20120123 while still on assigned investigational product.
Subjects with HoFH:
• Male or female, >= 10 to <= 17 years of age at time of enrollment (includes the
year after the subject completes the 17th year after birth but not the day of
completing the 18th year after birth).
• Diagnosis of HoFH by genetic confirmation or a clinical diagnosis based on a
history of an untreated LDL cholesterol concentration > 500 mg/dL (13 mmol/L)
together with either xanthoma before 10 years of age or evidence of
heterozygous familial hypercholesterolemia in both parents.
• Subject must be on a low-fat diet and receiving background lipid-lowering
therapy (such as statins, cholesterol absorption inhibitors, bile acid
sequestrants, nicotinic acid, or combinations thereof).
• Lipid-lowering therapy, including statin dose, must be unchanged for >= 4
weeks prior to LDL-C screening; fibrates must be stable for at least 6 weeks
prior to screening.
• Fasting LDL-C at screening >= 130 mg/dL (3.4 mmol/L) as determined by central
laboratory.
• Fasting triglycerides <= 400 mg/dL (4.5 mmol/L) by central laboratory at
screening.
Exclusion criteria
All Subjects:
• Currently receiving treatment in another investigational device or drug
study, or less than 30 days since ending treatment on another investigational
device or drug study(s). Other investigational procedures or treatments while
participating in this study are excluded.
• Female subject who has experienced menarche and unwilling to use acceptable
method(s) of effective birth control during treatment with evolocumab and for
an additional 15 weeks after the end of treatment with evolocumab. A female who
has experienced menarche is considered of childbearing potential.
• Female subject is pregnant or breast feeding, or planning to become pregnant
or planning to breastfeed during screening, during treatment with evolocumab,
and within 15 weeks after the end of treatment with evolocumab.
• Unreliability as a study participant based on the investigator's (or
designee*s) knowledge of the subject (eg, alcohol or other drug abuse in the
past year, inability or unwillingness to adhere to the protocol, or psychosis).
• Subject will not be available for or likely not to comply with
protocol-required study visits or procedures, to the best of the subject and
investigator*s knowledge (Note: Day 1 and week 80 visits must be scheduled at
approximately the same time of day, and should be performed as close as
possible to 8 am as the hormones measured have diurnal variation).
• Known sensitivity to any of the active substances or their excipients to be
administered during dosing, eg, carboxymethylcellulose.
Subjects with HoFH:
• Moderate to severe renal dysfunction, defined as an estimated glomerular
filtration rate (eGFR) < 30 ml/min/1.73m2 at screening, confirmed by a repeat
measurement at least 1 week apart. Note: eGFR will be calculated by the central
laboratory and will be provided to the site for eligibility determination.
• Persistent 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, confirmed by a repeat
measurement at least 1 week apart.
• 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.
• Subject has taken a cholesterylester transfer protein (CETP) inhibitor such
as anacetrapib, dalcetrapib or evacetrapib in the last 12 months, or mipomersen
or lomitapide in the last 5 months prior to LDL-C screening.
• Subject has received evolocumab or any other therapy to inhibit PCSK9 within
12 weeks of screening.
• History or evidence of any other clinically significant disorder, condition
or disease, or planned or expected procedure that, in the opinion of the
Investigator or Amgen physician, if consulted, would pose a risk to subject
safety or interfere with the study evaluation, procedures or completion.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2015-002276-25-NL |
| ClinicalTrials.gov | NCT02624869 |
| CCMO | NL56501.018.16 |