E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with primary hypercholesterolemia and moderate, high or very high cardiovascular (CV) risk who are intolerant to statins |
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E.1.1.1 | Medical condition in easily understood language |
High blood cholesterol level |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10020603 |
E.1.2 | Term | Hypercholesterolaemia |
E.1.2 | System Organ Class | 10027433 - Metabolism and nutrition disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
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 (taken orally once per day) after 24 weeks in patients with primary hypercholesterolaemia (heterozygous familial hypercholesterolemia [heFH] and non-familial hypercholesterolaemia [FH]) who are intolerant to statins. |
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E.2.2 | Secondary objectives of the trial |
- To evaluate the effect of REGN727 75 mg in comparison with EZE on LDL-C after 12 weeks of treatment - To evaluate the effect of REGN727 on other lipid parameters (ie, ApoB, non-HDL-C, total-C, Lp(a), HDL-C, TG levels, and ApoA-1 levels) - To evaluate the safety and tolerability of REGN727, including the characterisation of the incidence rate and treatment withdrawal rate of skeletal muscle-related adverse events (AEs) - To evaluate the development of anti-REGN727 antibodies |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Title: A Randomized, Double-Blind, Double-Dummy, Active-Controlled Study to Evaluate the Efficacy and Safety of REGN727/SAR236553 in Patients with Primary Hypercholesterolemia Who are Intolerant to Statins
Objectives: to identify genetic associations with clinical or biomarker response to PCSK9 inhibition, hyperlipidaemia, or CVD (Cardiovascular Disease) |
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E.3 | Principal 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 |
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E.4 | Principal 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 (hemoglobin A1c [HbA1c] >9%) diabetes 27. Use of systemic corticosteroids, unless used as replacement therapy for pituitary/adrenal disease with a stable regimen for at least 6 weeks prior to randomization Note: Topical, intra-articular, nasal, inhaled and ophthalmic steroid therapies are not considered as ‘systemic’ and are allowed 28. Use of estrogen or testosterone therapy unless the regimen has been stable in the past 6 weeks prior to the screening visit (week -7), and no plans to change the regimen during the study 29. History of undergoing plasmapheresis treatment within 2 months prior to the screening visit (week -7), or plans to undergo plasmapheresis during the study 30. Systolic blood pressure >160 mm Hg or diastolic blood pressure >100 mm Hg at the screening visit (week -7) or time of randomization (week 0/day 1) 31. History of a MI, unstable angina leading to hospitalization, CABG, PCI, uncontrolled cardiac arrhythmia, carotid surgery or stenting, stroke, transient ischemic attack, carotid revascularisation, endovascular procedure or surgical intervention for peripheral vascular disease within 3 months prior to the screening visit (week -7) 32. Patients currently participating in a rehabilitation or exercise program 33. History of New York Heart Association Class III or IV heart failure within the past 12 months 34. Age <18 years or legal age of majority at the screening visit (week -7), whichever is greater 35. Not previously instructed on a cholesterol-lowering diet prior to the screening visit (week -7) 36. Known history of a hemorrhagic stroke 37. History of cancer within the past 5 years, except for adequately treated basal cell skin cancer, squamous cell skin cancer, or in situ cervical cancer. 38. Known history of HIV positivity 39. Use of any active investigational drugs within 1 month or 5 half lives, whichever is longer. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint is the percent change in calculated LDL-C from baseline to week 24. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
From baseline to week 24. |
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E.5.2 | Secondary end point(s) |
- 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.
OTHER ENDPOINTS - Anti-REGN727 antibody status (positive/negative) and titers assessed throughout the study. - The percent change in high sensitivity C-reactive protein (hs-CRP) from baseline toweek 24. - The absolute change in HbA1c (%) from baseline to week 24. - Long-term safety assessments in the open-label treatment period. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
from baseline to weeks 12 and 24 |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
Double-Dummy, Active-Controlled |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 33 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Austria |
Belgium |
Canada |
France |
Ireland |
Israel |
Italy |
Netherlands |
Norway |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 4 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 11 |
E.8.9.2 | In all countries concerned by the trial days | 29 |