The primary objective of the study is to demonstrate the reduction of low-density lipoprotein (LDL) cholesterol (LDL-C) by REGN727 in comparison with ezetimibe (EZE) 10 mg PO QD after 24 weeks in patients with primary hypercholesterolemia (…
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 primary efficacy endpoint is the percent change in calculated LDL-C from
baseline to week 24
Secondary outcome
* The percent change in calculated LDL-C from baseline to week 12
* The percent change in ApoB from baseline to week 24.
* The percent change in non-HDL-C from baseline to week 24.
* The percent change in total-C from baseline to week 24.
* The percent change in ApoB from baseline to week 12.
* The percent change in non-HDL-C from baseline to week 12.
* The percent change in total-C from baseline to week 12.
* The proportion of patients reaching LDL-C goal at week 24, ie, LDL-C <70
mg/dL (1.81 mmol/L) in case of very high CV risk or LDL-C <100 mg/dL (2.59
mmol/L) for patients with moderate or high CV risk.
* The proportion of patients reaching LDL-C <70 mg/dL (1.81 mmol/L) at week 24
* The percent change in Lp(a) from baseline to week 24.
* The percent change in HDL-C 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 ApoA-1 from baseline to week 24.
* The percent change in ApoA-1 from baseline to week 12.
Background summary
REGN727 is a fully human monoclonal antibody that binds proprotein convertase
subtilisin/kexin type 9 (PCSK9). REGN727 is also referred to as SAR236553. In
the context of this clinical study protocol, it will be referred to as REGN727
This study will include patients with primary hypercholesterolemia
(heterozygous familial hypercholesterolemia [heFH] and non-familial
hypercholesterolemia [FH]) with or without a history of documented myocardial
infarction (MI) or ischemic stroke
Current LDL-C lowering medications include statins, ezetimibe (EZE), fibrates,
niacin, and bile acid sequestrants, of which statins are the most commonly
prescribed, as they have shown a great ability to lower LDL-C and reduce CHD
events. However, despite these available treatments, when used alone or in
combination, many high-risk patients fail to reach the ESC/EAS guideline target
level.
Proprotein convertase subtilisin kexin type 9 (PCSK9) belongs to the subtilisin
family of serine proteases and is highly expressed in the liver. PCSK9 is
involved in regulating the levels of the low-density lipoprotein receptor
(LDLR) protein.
Once PCSK9 is secreted into plasma, it directly binds to the LDLR and promotes
its degradation. The increased degradation of LDLRs leads to a decreased
removal of LDL-C and therefore, higher circulating levels of LDL-C.
Blocking PCSK9 from binding to the LDLR can potentially benefit patients with
hypercholesterolemia by decreasing their plasma LDL-C levels. In addition,
PCSK9 messenger RNA and protein levels are increased in response to statins,
potentially attenuating their cholesterol-lowering effect.
Study objective
The primary objective of the study is to demonstrate the reduction of
low-density lipoprotein (LDL) cholesterol (LDL-C) by REGN727 in comparison with
ezetimibe (EZE) 10 mg PO QD after 24 weeks in patients with primary
hypercholesterolemia (heterozygous familial hypercholesterolemia [heFH] and
non-familial hypercholesterolemia [FH]) who are intolerant to statins
Study design
This is a randomized, double-blind, double-dummy, active-controlled,
parallel-group, multi-national, multi-center study in patients with primary
hypercholesterolemia and moderate, high, or very high cardiovascular (CV) risk,
who are intolerant to statins.
The study consists of 5 periods: screening; washout; single-blind placebo
run-in; double-blind treatment; and follow-up.
Treatment groups:
* REGN727 75 mg SC Q2W + placebo voor EZE of atorvastatine PO QD
* EZE 10 mg PO QD + placebo voor REGN727 75 mg SC Q2W
* Atorvastatine 20 mg PO QD + placebo voor REGN727 75 mg SC Q2W
Study Drug schedules:
Study drug: Dose/Route/Schedule: REGN727 75 mg SC Q2W for 24 weeks, or 75 mg SC
Q2W for 12 weeks followed by 150 mg SC Q2W for 12 weeks
Study Drug: Dose/Route/Schedule: Ezetimibe 10 mg PO QD for 24 weeks
Study Drug: Dose/Route/Schedule:Atorvastatin 20 mg PO QD for 24 weeks
Placebo: Dose/Route/Schedule: Placebo matching REGN727/Placebo matching EZE and
atorvastatin SC Q2W for 24 weeks/PO QD for 24 weeks
Placebo Run-in: Route/Schedule: Placebo matching REGN727 and placebo capsule SC
Q2W and PO QD
Intervention
Study drug: Dose/Route/Schedule: REGN727 75 mg SC Q2W for 24 weeks, or 75 mg SC
Q2W for 12 weeks followed by 150 mg SC Q2W for 12 weeks
Study Drug: Dose/Route/Schedule: Ezetimibe 10 mg PO QD for 24 weeks
Study Drug: Dose/Route/Schedule:Atorvastatin 20 mg PO QD for 24 weeks
Placebo: Dose/Route/Schedule: Placebo matching REGN727/Placebo matching EZE and
atorvastatin SC Q2W for 24 weeks/PO QD for 24 weeks
Placebo Run-in: Route/Schedule: Placebo matching REGN727 and placebo capsule SC
Q2W and PO QD
Study burden and risks
Risks: side effects of the study drug
Burden
* 9 study visits + 1 follow-up visit
* come to the hospital in fasting condition almost every study visit (lipid
panel test - bloodtests)
* 8 SC injections(self administration or done by somebody else), subject will
be trained to do this
* physical examination (3x)
* vital signs (bloeddruk, pols): every study visit
* weight: 5x
* ECG: 2x
* diet review: 4x
* bloodtest: every study visit
* urine testing: every study visit (5x urine analysis) + every study visit for
pregnancy test)
* pregnancy test: serum test 1x (screening), urine (elk studiebezoek)
* complete patient diary
Old Saw Mill River Road 777
NY Tarrytown 10591
US
Old Saw Mill River Road 777
NY Tarrytown 10591
US
Listed location countries
Age
Inclusion criteria
Patients with primary hypercholesterolemia (familiaal of niet familiaal) with moderate, high or very high CV risk and a history of statin intolerance
*** Definition of statin intolerance: Inability to tolerate at least 2 previous statins at the lowest approved daily dose due to skeletal muscle-related symptoms, other than those due to strain or trauma, such as pain, aches, weakness, or cramping, that began or increased during statin therapy and stopped when statin therapy was discontinued.
Exclusion criteria
- Calculated serum LDL-C <70 mg/dL (1.81 mmol/L) and very high CV risk (as defined in section 4.2) at the screening visit (week -7)
- Calculated serum LDL-C <100 mg/dL (2.59 mmol/L) and high or moderate CV risk (as defined in section 4.2) at the screening visit (week -7)
- diagnosis of fibromyalgia, history of severe neuropathic pain, history of reumatological disease, history of myalgia or myopathy, history of seizure disorder, history of transplant surgery
- presence of clinically significant uncontrolled endocrine disease known to influence serum lipids
- known loss of function of PCSK9 (genetic mutation)
- known homozygous FH
- < 18 years or legal age
- known HIV positivity
- previous participation in any clinical trial of REGN727 or SAR236553
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 | EUCTR2012-001221-27-NL |
| CCMO | NL42262.068.12 |