Efficacy and Safety of REGN727/SAR236553 in patients with primary hypercholesterolemia who are intolerant to statins

Phase 1

Conditions: Patients with primary hypercholesterolemia and moderate, high or very high cardiovascular (CV) risk who are intolerant to statins
MedDRA version: 19.0 Level: PT Classification code 10020603 Term: Hypercholesterolaemia System Organ Class: 10027433 - Metabolism and nutrition disorders
Therapeutic area: Diseases [C] - Nutritional and Metabolic Diseases [C18]

Registration Number: EUCTR2012-001221-27-GB

Lead Sponsor: Regeneron Pharmaceuticals, Inc.

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: ot Recruiting

Sex: Not specified

Target Recruitment: 314

Inclusion Criteria

A patient must meet the following criteria to be eligible for inclusion in the study:
1. Patients with primary hypercholesterolaemia (heFH* or non-FH) with moderate, high or very high CV risk** and a history of statin intolerance***
* Diagnosis of heFH must be made either by genotyping or by clinical criteria. For patients who are not genotyped, the clinical diagnosis must be a certain/definite diagnosis and maybe based on either the Simon Broome criteria or the WHO/Dutch Lipid Network criteria.
** Moderate, high, and very high CV risk.
*** Definition of statin intolerance: The inability to tolerate at least 2 statins: 1 statin at the lowest daily starting dose (defined as rosuvastatin 5 mg, atorvastatin 10 mg, simvastatin 10 mg, lovastatin 20 mg, pravastatin 40 mg, fluvastatin 40 mg or pitavastatin 2 mg), AND another statin at any 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.

NOTE: Patients not receiving a daily regimen of a statin (eg, 1 to 3 time weekly) will also be considered as not able to tolerate a daily dose and will be eligible to enroll in the study if they cannot tolerate a cumulative weekly statin dose of 7 times the lowest approved tablet size and the criteria outlined above are also met.

2. Provide signed informed consent
Are the trial subjects under 18? no
Number of subjects for this age range: 0
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 250
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 50

Exclusion Criteria

1. Calculated serum LDL-C <70 mg/dL (1.81 mmol/L) and very high CV risk at the screening visit (week -7)
2. Calculated serum LDL-C <100 mg/dL (2.59 mmol/L) and high or moderate CV risk at the screening visit (week -7)
3. A 10-year fatal CVD risk SCORE <1% (ESC/EAS 2011) at the screening visit (week 7)
4. Use of a statin that is at or above the lowest approved daily dose within 4 weeks prior to the screening visit (week -7)
5. Experienced skeletal muscle-related AE(s), other than those due to strain or trauma during the 4-week single-blind placebo run-in
6. Experiencing a skeletal muscle-related AE(s), other than those due to strain or trauma at the time of screening (week -7), start of single-blind placebo run-in period (week -4), or baseline (day 1/week 0)
7. Not on a stable dose of LMT for at least 4 weeks and/or fenofibrate for at least 6 weeks, as applicable, prior to the screening visit (week -7) or from screening to randomisation, as applicable
8. Use of fibrates, other than fenofibrate, within 6 weeks of the screening visit(week -7)
9. Use of nutraceuticals or over-the-counter therapies known to affect lipids, at a dose/amount that has not been stable for at least 4 weeks prior to the screening visit (week -7) or between the screening and randomisation visits
10. Use of red yeast rice from the screening visit (week -7) to the end of study visit
11. Use of analgesics for which the dose is not planned to be stable from the screening visit to week 32
12. Diagnosis of fibromyalgia
13. History of severe neuropathic pain
14. History of rheumatological disease associated with symptoms that may be confounded with symptoms of statin intolerance, eg, rheumatoid arthritis
15. History of myalgia or myopathy that began or increased during treatment with LMT, other than statin therapy, and stopped when the LMT was discontinued
16. Known history of seizure disorder
17. History of previous transplant surgery
18. Use of medications that require intramuscular administration, or planned intramuscular injections during the study
19. Known history of myopathy, other than statin-associated myopathy
20. History of rhabdomyolysis (defined as evidence of organ damage with creatine kinase >10,000 IU/L)
21. Presence of any clinically significant uncontrolled endocrine disease known to influence serum lipids or lipoproteins
Note: Patients on thyroid replacement therapy can be included if the dosage of thyroxine has been stable for at least 12 weeks prior to screening and the thyroid-stimulating hormone (TSH) level is within the normal range of the central laboratory at the screening visit (week - 7)
22. History of bariatric surgery within 12 months prior to the screening visit(week -7)
23. Unstable weight (variation >5 kg) within 2 months prior to the screening visit (week -7)
24. Known history of loss of function of PCSK9 (ie, genetic mutation or sequence variation)
25. Known history of homozygous FH
26. Newly diagnosed (within 3 calendar months prior to randomization visit [week 0/day 1]) diabetes mellitus or poorly controlled (he

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method

Secondary Outcome Measures

Name	Time	Method

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