E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
Hypercholesterolemia, specifically, elevated low density lipoprotein cholesterol (LDL-C), is one of the major risk factors for the development of coronary heart disease (CHD)
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E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10020604 |
E.1.2 | Term | Hypercholesterolemia |
E.1.2 | System Organ Class | 100000004861 |
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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 |
To evaluate the effect of ALN-PCSSC treatment on LDL-C levels at Day 180. |
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E.2.2 | Secondary objectives of the trial |
To evaluate the effect of ALN-PCSSC on the following: • LDL-C levels at Day 90 •LDL-C levels at other time points •PCSK9 levels over time •Other lipids, lipoproteins, apolipoproteins •The proportion of subjects achieving different global lipid guidelines •Individual responsiveness to different doses •Duration of lipid-lowering effect of different doses •The safety and tolerability profile of ALN-PCSSC
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male or female subjects ≥ 18 years of age . 2.History of ASCVD or ASCVD-risk equivalents (symptomatic atherosclerosis, Type 2 diabetes, familial hypercholesterolemia, including subjects whose 10-year risk of a cardiovascular [CV] event assessed by Framingham Risk Score * or equivalent has a target LDL-C of < 100mg/dL) 3. Serum LDL-C ≥1.8 mmol/L (≥70 mg/dL) for ASCVD subjects or ≥2.6 mmol/L (≥100 mg/dL) for ASCVD-risk equivalent subjects at screening 4. Fasting triglyceride <4.52 mmol/L (<400 mg/dL) at screening 5. Calculated glomerular filtration rate > 30 mL/min by estimated glomerular filtration rate (eGFR) using standardized local clinical methodology. 6. Subjects on statins should be receiving the maximally tolerated dose (investigator’s discretion). 7. Subjects on lipid-lowering therapies (such as statins and/or ezetimibe) should be on a stable dose for ≥30 days before screening with no planned medication or dose change during study participation. 8. Willing and able to give written and informed consent before initiation of any study-related procedures and willing to comply with all required study procedures. *By Framingham Risk Score > 20%
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E.4 | Principal exclusion criteria |
1. Any uncontrolled or serious disease, or any medical or surgical condition, that may either interfere with participation in the clinical study, and/or put the subject at significant risk (according to investigator’s [or delegate] judgment) if he/she participates in the clinical study. 2. An underlying known disease, or surgical, physical, or medical condition that, in the opinion of the investigator (or delegate) might interfere with interpretation of the clinical study results 3. New York Heart Failure Association (NYHA) class II, III or IV heart failure or last known left ventricular ejection fraction <30%. 4. Cardiac arrhythmia within 3 months prior to randomization that is not controlled by medication or via ablation. 5. Any history of hemorrhagic stroke. 6. Major adverse cardiac event within 6 months prior to randomization. 7. Uncontrolled severe hypertension: systolic blood pressure >180 mmHg or diastolic blood pressure >110 mmHg prior to randomization despite anti-hypertensive therapy. 8. Poorly controlled Type II diabetes, ie, glycated hemoglobin A1c (HbA1c) >10.0% prior to randomization. 9. Active liver disease defined as any known current infectious, neoplastic, or metabolic pathology of the liver or unexplained alanine aminotransferase (ALT), aspartate aminotransferase (AST), elevation > 2x the upper limit of normal (ULN), or total bilirubin elevation > 1.5x ULN at screening confirmed by a repeat measurement at least one week apart. 10. Serious comorbid disease in which the life expectancy of the subject is shorter than the duration of the trial (eg, acute systemic infection, cancer, or other serious illnesses). This includes all cancers with the exception of treated basal-cell carcinoma occurring >5 years before screening. 11. Females who are pregnant or nursing, or who are of childbearing potential and unwilling to use at least two methods of contraception (oral contraceptives, barrier methods, approved contraceptive implant, long- term injectable contraception, intrauterine device or tubal ligation)**. Women who are >2 years postmenopausal defined as ≥1 year since last menstrual period AND if < 55 years old with a negative pregnancy test within 24 hours of randomization or surgically sterile are exempt from this exclusion. 12. Males who are unwilling to use an acceptable method of birth control during the entire study period (ie, condom with spermicide). 13. Known history of alcohol and/or drug abuse within the last 5 years. 14. Treatment with other investigational medicinal products or devices within 30 days or five half lives, whichever is longer. 15. Use of other investigational medicinal products or devices during the course of the study. 16. Any condition that according to the investigator could interfere with the conduct of the study, such as but not limited to: a. Inappropriate for this study, including subjects who are unable to communicate or to cooperate with the investigator. b. Unable to understand the protocol requirements, instructions and study-related restrictions, the nature, scope, and possible consequences of the study (including subjects whose cooperation is doubtful due to drug abuse or alcohol dependency). c. Unlikely to comply with the protocol requirements, instructions and study-related restrictions (eg, uncooperative attitude, inability to return for follow-up visits, and improbability of completing the study). d. Have any medical or surgical condition, which in the opinion of the investigator would put the subject at increased risk from participating in the study. e. Involved with, or a relative of, someone directly involved in the conduct of the study. f. Any known cognitive impairment (eg, Alzheimer’s disease). 17. Previous or current treatment (within 90 days of screening) with monoclonal antibodies directed towards PCSK9. **For the entire duration of the study
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary Endpoint: Percentage change in LDL-C from baseline to Day 180.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Included in previous section. |
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E.5.2 | Secondary end point(s) |
Secondary Endpoints: • Percentage change in LDL-C from baseline to Day 90 • Percentage change in LDL-C from baseline to Days 14, 30, 60, 104, 120, 150, and 210 • Proportion of subjects in each group with LDL-C greater than 80% of the baseline value at Day 180 and Day 210 • Duration of time on treatment for subjects to return to 80% of baseline or greater LDL-C or PCSK9 protein • Individual responsiveness defined as the number of subjects reaching on treatment LDL-C levels of <25 mg/dL, <50 mg/dL, <70 mg/dL, and <100 mg/dL at Days 90, 120, and 180 • Proportion of subjects in each group with greater or equal to 50% LDL-C reduction from baseline at Days 90, 120, and 180 • Percentage change in PCSK9 levels from baseline to Days 14, 30, 60, 104, 120, 150, 180 and 210 • Percentage change in other lipids, lipoproteins, apolipoproteins from baseline at each subsequent visit to Day 210 • Proportion Proportion of subjects in each group with greater or equal to 50% LDL-C reduction from baseline at Days 90, 120, and 180
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Included in previous section. |
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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 | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
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 | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 5 |
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 | 15 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 40 |
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 |
Germany |
Netherlands |
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 | 1 |
E.8.9.1 | In the Member State concerned months | 6 |
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 | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |