The objective of the study is to assess the efficacy and safety of Alirocumab in patients with heterozygote familial hypercholesterolemia whose LDL-C level is higher than or equal to 160 mg/dL (4.14 mmol/L) on maximally tolerated statin therapy with…
ID
Source
Brief title
Condition
- Metabolic and nutritional disorders congenital
- Lipid metabolism disorders
- Arteriosclerosis, stenosis, vascular insufficiency and necrosis
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The percent change in calculated LDL-C from baseline to week 24, which is
defined as : 100x (calculated LDL-C value at week 24 - calculated LDL-C value
at baseline) / calculated LDL-C value at baseline.
The baseline calculated LDL-C value will be the last LDL-C level obtained
before the first double-blind IMP injection.
Secondary outcome
The percent change in calculated LDL-C from baseline to week 12.
The percent change in calculated Apo B from baseline to week 24
The percent change in calculated non-HDL-C from baseline to week 24
The percent change in calculated total-C from baseline to week 24
The percent change in calculated Apo B from baseline to week 12
The percent change in calculated non-HDL-c from baseline to week 12
The percent change in calculated total-C from baseline to week 12
The percent change in calculated LDL-C from baseline to week 52
The percent change in Lp(a) from baseline to week 24
The percent change in HDL-C from baseline to week 12
The percent change in Lp(a) from baseline to week 12
The percent change in fasting TG from baseline to week 24
The percent change in fasting TG from baseline to week 12
The percent change in Apo A-1 from baseline to week 24
The percent change in Apo A-1 from baseline to week 12
The percent change in HDL-C from baseline to week 24
The proportion of patients reaching LDL-C goal at week 24, i.e. LDL-C < 70
mg/dL in case of prior cardiovascular disease, or LDL-C < 100 mg/dL for
patients without cardiovascular disease.
The proportion of patients reaching LDL-C goal at week 12, 52 and 78
The percent change in calculated LDL-C from baseline to week 78.
The proportion of patients reaching LDL-C < 100 mg/dL (2.59 mmol/L) at week 24
The proportion of patients reaching LDL-C < 100 mg/dL (2.59 mmol/L) at week 12
The proportion of patients reaching LDL-C < 70 mg/dL (1.81 mmol/L) at week 24
The proportion of patients reaching LDL-C < 70 mg/dL (1.81 mmol/L) at week 12
The absolute change in calculated LDL-C (mg/dL and mmol/L) from baseline to
Weeks 12, 24, 52 and 78
The percent change in Apo B, non-HDL-C, total-C, Lp (a), HDL-C, fasting TG, and
Apo A-1 from baseline to Week 52 and 78
The change in ratio Apo B / Apo A-1 from baseline to weeks 12, 24, 52 and 78
The proportion of patients with Apo B < 80 mg/dL (0.8 mmol/L) at weeks 12, 24,
52 and 78
The proportion of patients with non-HCL-C < 100 mg/dL at weeks 12, 24, 52 and
78.
The proportion of patients with calculated LDL-C < 70 mg/dL (1.81 mmol/L)
and/or > or equal to 50*% reduction in calculated LDL-C (if calculated LDL-C
> or equal to 70 mg/dL (1.81 mmol/L) ) at weeks 12, 24, 52 and 78.
Background summary
The study will include patients with heterozygous familial hypercholesterolemia
(heFH) with or without a history of MI or ischemic stroke. Familial
hypercholesterolemia (FH) is an inherited disorder of lipid metabolism that
predisposes a person to premature severe cardiovascular disease (CVD). Familial
hypercholesterolemia has a high prevalence in Caucasian populations, were
estimated 1 in 500 individuals are affected.
In the heterozygous form of FH, the cumulative risk of experiencing a coronary
event by the age of 60 years without effective treament is at least 50% in men
and approximately 30% in women.
In 4 observational studies, statin therapy was shown to reduce the risk of CVD
by 50% to 80% in patients with FH. Unfortunately, even after treatment, the
risk in heFH can still be almost 2-fold higher than the general population. In
addition only a small fraction of treated heFH patients are able to reach
recommended levels of LDL-C. Thus, the need for more intensive treatment in
heFH patients is clear.
Alirocumab is a fully human monoclonal antibody that binds Propotein Convertase
Subtilisin Kexin type 9 (PCSK9).
PCSK9 which is highly expressed in the liver, is involved in regulating the
levels of Low-density lipoportein receptor (LDL-R) protein. Once secreted into
plasma, PCSK9 binds to the LDL-R and promotes its degeneration, which leads to
reduced LDL-C removal or higher LDL-C circulating levels.
Therefor blocking PCSK9 can potentially benefit patients by decreasing their
plasma LDL-C levels. In addition, PCSK9 messenger ribonucleic acid (mRNA) and
protein levels are increased in response to statins, potentially attenuating
their cholesterol-lowering effect.
Study objective
The objective of the study is to assess the efficacy and safety of Alirocumab
in patients with heterozygote familial hypercholesterolemia whose LDL-C level
is higher than or equal to 160 mg/dL (4.14 mmol/L) on maximally tolerated
statin therapy with or without additional lipd modifying therapy.
Study design
This is a randomized, double-blind, placebo-controlled, parallel-group,
unbalanced (2:1, Alirocumab:placebo), multi-center, multi-national study.
Randomization will be stratified according to prior history of myocardial
infarction (MI) or ischemic stroke (yes/no), and statin treatment (atorvastatin
40 to 80 mg dialy or rosuvastatin 20 to 40 mg dialy vs. simvastatin whatever
the dialy dose, atorvastatin below 40 mg dialy or rosuvastatin below 20 mg
daily). After randomization, patients will receive double-blind study
treatment (either Alirocumab or placebo) every 2 weeks over period of 78 weeks
on top of stable maximally tolerated dialy statin therapy +/- other lipid
modifying therapy. After completion of the 18 month double blind treatment
period (DBTP), patients may be offered to consent for another study (open-label
extension study). Patients who consent to participate in the open-label
extension study will not undergo the follow up period. Patients will undergo
the follow-up period if not consenting to participate in the open-label
extension study or if prematurely discontinuing study treatment. The follow-up
period for such patients will be 8 weeks after the last visit of the DBTP.
Intervention
Biweekly subcutenous injections with study drug/placebo
Study burden and risks
This study consists of 3 periods:
1)screening period up to 2 weeks including an intermediate visit during which
the patient will be trained to self-inject of the study medication.
2)Double-blind treatment period of 18 months with 10 visits. During each visit
there will be a fasting bloodsampling, every two visits a urine sample will be
asked except for the women of childbearing potential, they will give more urine
samples for pregnancy testing. During each visit bloodpressure and heartrate
will be monitored . During the complete treatment period the patient will
receive three ECG and six questionnaires. Between the visits the patient will
keep a diary and follow a diet to decrease the cholesterol.
3) Follow-up period of 8 weeks after the end of the previous period for
patients not consenting to participate in the opn-label extension study or if
prematurely discontinuing study treatment
Alirocumab was well tolerated in all completed Phase 2 studies throughout the
treatmentperiod and for all treatment groups. Injection site reactions were
reported in patients including placebo-treated patients. These events were
generally transient with no dose relationship. Rare cases of hypersensitivity
reactions were reported. Among all SAEs reported for all Alirocumab studies,
only one case leucocytoclastic vasculitis (angiitis) was reported as being
related te Alirocumab. No particular signal noted for "treament emergent
adverse events" related to musculoskeletal or connective tissue disorders as
well as no elevations in liver enzymes.
As with any experimental drug, there may be side effects that are unknown and
that could occur when the drug is taken alone or in combination with other
drugs.
The effect of Alirocumab on pregnancy or breast feeding mothers is not known at
this time.
Avenue Pierre Brossolette 1
Chilly Mazarin 91385
FR
Avenue Pierre Brossolette 1
Chilly Mazarin 91385
FR
Listed location countries
Age
Inclusion criteria
Patients with heterozygous familial hypercholesterolemia who are not adequately controlled with their lipid-modifying therapy.
Exclusion criteria
- Age < 18 years;- LDL-C < 160 mg/dL (< 4.14 mmol/L) at the screening visit (Week-2).;- Fasting serum triglycerides > 400 mg/dL (> 4.52 mmol/L) during the screening period.;- Known history of homozygous familial hypercholesterolemia.
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 | EUCTR2012-001096-37-NL |
| Other | IND NUMMER 105574 |
| CCMO | NL41092.018.12 |