| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with Non-familial hypercholesterolemia or heterozygous familial hypercholesterolemia (heFH) at high CV risk who are not adequately controlled with atorvastatin (20mg or 40mg) with or without other lipid-modifying therapy (LMT) (excluding EZE) |
|
| 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 | 14.1 |
| 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 |
| To evaluate the reduction of low-density lipoprotein cholesterol (LDL-C) by REGN727 as add-on therapy to atorvastatin in comparison with ezetimibe (EZE) as add-on therapy to atorvastatin, in comparison with doubling the atorvastatin dose, or in comparison with a therapy switch from atorvastatin to rosuvastatin, after 24 weeks of treatment |
|
| E.2.2 | Secondary objectives of the trial |
-To evaluate the reduction of LDL-C by REGN727 75 mg as add-on therapy to atorvastatin in comparison with EZE as add-on therapy to atorvastatin, in comparison with doubling of the atorvastatin dose, or in comparison with a switch from atorvastatin to rosuvastatin after 12 weeks of treatment.
-To evaluate the effect of REGN727 on other lipid parameters eg, apolipoprotein (Apo) B, non-high-density lipoprotein cholesterol (HDL-C), total-cholesterol (C), lipoprotein a (Lp[a]), HDL-C, triglycerides (TG) levels, and ApoA-1 levels.
-To evaluate the safety and tolerability of REGN727.
-To evaluate the development of anti-REGN727 drug antibodies (ADA).
|
|
| 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 Study of the Efficacy and Safety of REGN727 Added-on to Atorvastatin versus Ezetimibe Added-on to Atorvastatin versus Atorvastatin Dose Increase versus Switch to Rosuvastatin in Patients Who are Not Controlled on Atorvastatin.
Objectives: to identify genetic associations with clinical or biomarker response to PCSK9 inhibition, hyperlipidemia, or CVD. If needed, samples may also be used to identify markers associated with toxicity. |
|
| E.3 | Principal inclusion criteria |
1. A patient must meet either 1a or 1b to be eligible for inclusion in the study:
a. Patients with screening (visit 1) LDL-C ≥70 mg/dL (1.81 mmol/L) who are not adequately controlled with a 20 mg or 40 mg stable daily dose of atorvastatin for at least 4 weeks before the screening visit (visit 1), with or without other LMT (excluding EZE). Patients with heFH* or non-FH must also have a history of documented CHD (defined below), or non-CHD CVD (defined below), or diabetes mellitus with target organ damage.
OR
b. Patients with screening (visit 1) LDL-C ≥100 mg/dL (2.59 mmol/L) who are not adequately controlled with a 20 mg or 40 mg daily dose of atorvastatin for at least 4 weeks before the screening visit (visit 1), with or without other LMT (excluding EZE). Patients must also have heFH*, or have non-FH, without CHD or non-CHD CVD, but with a calculated 10-year fatal CVD risk SCORE ≥5%, or with moderate CKD, or with diabetes mellitus but no target organ damage.
Note: Details for the inclusion criteria are provided below.
2. Provide signed informed consent |
|
| E.4 | Principal exclusion criteria |
LDL-C <70 mg/dL (<1.81 mmol/L) in patients with CVD
LDL-C <100 mg/dL (<2.59 mmol/L) in patients without CVD, but with other risk factors
LDL-C >250 mg/dL or TG >400 mg/dL
Homozygous FH or patients receiving plasmapheresis
CV event within 3 months prior to screening
NYHA Class III or IV heart failure
History of hemorrhagic stroke
Uncontrolled endocrine disease known to influence serum lipids
Any clinically significant abnormality that in the judgment of the investigator would preclude safe completion of the study or constrain endpoints assessment such as major systemic diseases, patients with short life expectancy, patients who cannottolerate subcutaneous injections.
Use of ezetimibe or red yeast rice products within 4 weeks of screening
Use of systemic corticosteroids or use of fibrates, other than fenofibrate within 6 weeks of the screening
eGFR <30 mL/min/1.73m2
ALT or AST aminotransferase >3 x upper limit of normal (ULN)
CPK >3 x ULN
TSH < lower limit of normal (LLN) or >ULN
Known hypersensitivity to any component of the drug product
Pregnant or breast-feeding women
Women of childbearing potential not protected by highly-effective contraceptive method(s) of birth control
|
|
| 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, which is defined as: 100x (calculated LDL-C value at week 24 - calculated LDL-C value at baseline)/calculated LDL-C value at baseline. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| 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
- 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. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| From baseline to week 12 or week 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 |
|
| 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 | 7 |
| 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 | 26 |
| 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 |
| Australia |
| Brazil |
| Canada |
| France |
| Germany |
| Italy |
| Spain |
| Mexico |
| United Kingdom |
| 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 | 1 |
| 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 | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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