| 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 |
|
| E.1.1.1 | Medical condition in easily understood language |
| High blood cholesterol level |
|
| 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 |
|
| 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 after 24 weeks in patients with primary hypercholesterolemia (heterozygous familial hypercholesterolemia [heFH] and non-familial hypercholesterolemia [FH]) who are intolerant to statins. |
|
| 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 characterization of the incidence rate and treatment withdrawal rate of skeletal muscle-related adverse events (AEs)
- To evaluate the development of anti-REGN727 antibodies |
|
| 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, hyperlipidemia, or CVD. |
|
| E.3 | Principal inclusion criteria |
1. Patients with primary hypercholesterolemia (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 may be based on either the Simon Broome criteria or the WHO/Dutch Lipid Network criteria.
** Moderate, high, and very high CV risk as defined in section 4.2.
*** 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.
2. Provide signed informed consent |
|
| 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
2. Calculated serum LDL-C <100 mg/dL (2.59 mmol/L) and high or moderate CV risk at the screening visit
3. A 10-year fatal CVD risk SCORE < 1% at the screening visit
4. Use of a statin that is at or above the lowest approved daily dose within 4 weeks prior to the screening visit
5. Experienced skeletal muscle-related adverse event(s), other than those due to strain or trauma during the 4-week single-blind placebo run-in
6. Experiencing a skeletal muscle-related adverse event(s), other than those due to strain or trauma at the time of screening, start of single-blind placebo run-in period, or 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 or from screening to randomization, as applicable
8. Use of fibrates, other than fenofibrate, within 6 weeks of the screening visit
9. Use of nutraceuticals or over-the-counter (OTC) therapies known to affect lipids, at a dose/amount that has not been stable for at least 4 weeks prior to the screening visit or between the screening and randomization visits
10. Use of red yeast rice from the screening visit 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 the end-of-study visit
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, e.g., rheumatoid arthritis
15. History of myalgia or myopathy that began or increased during treatment with lipid modifying therapy (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 (CK) > 10,000 IU/L)
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The percent change in calculated LDL-C. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| From baseline to week 24. |
|
| E.5.2 | Secondary end point(s) |
- The percent change in calculated LDL-C from baseline to week 24 in the modified intent-to-treat (mITT) population, using all LDL-C values during the efficacy treatment period (on-treatment estimand).
- The percent change in calculated LDL-C from baseline to week 12 (ITT estimand).
- The percent change in calculated LDL-C from baseline to week 12 (on-treatment estimand).
- The percent change in Apo B from baseline to week 24 (ITT estimand).
- The percent change in Apo B from baseline to week 24 (on-treatment estimand).
- The percent change in non-HDL-C from baseline to week 24 (ITT estimand).
- The percent change in non-HDL-C from baseline to week 24 (on-treatment estimand).
- The percent change in total-C from baseline to week 24 (ITT estimand).
- The percent change in Apo B from baseline to week 12 (ITT estimand).
- The percent change in non-HDL-C from baseline to week 12 (ITT estimand).
- The percent change in total-C from baseline to week 12 (ITT estimand).
- The proportion of very high CV risk patients reaching calculated LDL-C <70 mg/dL (1.81 mmol/L) or moderate or high CV risk patients reaching calculated LDL-C <100 mg/dL (2.59 mmol/L) at week 24 (ITT estimand).
- The proportion of very high CV risk patients reaching calculated LDL-C <70 mg/dL (1.81 mmol/L) or moderate or high CV risk patients reaching calculated LDL-C <100 mg/dL (2.59 mmol/L) at week 24 (on-treatment estimand).
- The proportion of patients reaching calculated LDL-C <70 mg/dL (1.81 mmol/L) at week 24 (ITT estimand).
- The proportion of patients reaching calculated LDL-C <70 mg/dL (1.81 mmol/L) at week 24 (on-treatment estimand).
- The percent change in Lp(a) from baseline to week 24 (ITT estimand).
- The percent change in HDL-C from baseline to week 24 (ITT estimand).
- The percent change in fasting TGs from baseline to week 24 (ITT estimand).
- The percent change in Apo A-1 from baseline to week 24 (ITT estimand).
- The percent change in Lp(a) from baseline to week 12 (ITT estimand).
- The percent change in HDL-C from baseline to week 12 (ITT estimand).
- The percent change in fasting TGs from baseline to week 12 (ITT estimand).
- The percent change in Apo A-1 from baseline to week 12 (ITT estimand). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| from baseline to weeks 12 and 24 |
|
| 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 |
|
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 18 |
| 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 |
| Canada |
| France |
| Germany |
| Italy |
| Netherlands |
| Norway |
| United States |
|
| 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
|
|
| 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 | |
| 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 | 4 |
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