| 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 |
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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 | 10003601 |
| E.1.2 | Term | Atherosclerosis |
| E.1.2 | System Organ Class | 100000004866 |
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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 demonstrate the superior efficacy of bococizumab compared with placebo in reducing the risk of major CV events, a composite endpoint which includes adjudicated and confirmed CV death, non-fatal MI (myocardial infarction), non-fatal stroke, and hospitalization for unstable angina with urgent
revascularization (as defined in Appendix 4 of the protocol), in subjects at high or very high risk of major CV events who are on background lipid lowering treatment and have an LDL-C ≥100 mg/dL (2.59 mmol/L) or non-HDL-C (non-high density lipoprotein cholesterol)≥130 mg/dL (3.36 mmol/L). |
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| E.2.2 | Secondary objectives of the trial |
The key secondary objectives of this clinical trial are to demonstrate in subjects with high or very high risk of major CV events, who are on background lipid lowering treatment and have an LDL-C≥100 mg/dL (2.59 mmol/L) or non-HDL-C ≥130 mg/dL (3.36 mmol/L), the superior efficacy of bococizumab compared with placebo in reducing the risk of adjudicated and confirmed key secondary endpoints (as defined in Appendix 4 of the protocol) of:
- A composite endpoint of CV death, non-fatal MI, and non-fatal stroke;
- A composite endpoint of all-cause death, non-fatal MI, non-fatal stroke, and hospitalization for unstable angina needing urgent revascularization;
- A composite endpoint of all-cause death, non-fatal MI, and non-fatal stroke;
- Hospitalization for unstable angina needing urgent revascularization.
Please refer to protocol section 2.1.2 for additional secondary objectives |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Informed Consent
There must be evidence of personally signed and dated informed consent documents for both the pre-screening and screening visits, indicating that the subject (or a legal representative) has been informed of all pertinent aspects of the study. The pre-screening visit informed consent form will be limited to study activities up until the screening visit. The screening visit informed consent form will cover all aspects of the study. Subjects should be reconsented if there are modifications to the original informed consent document, at the next available opportunity.
2. Compliance
Subjects must be willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
3. Age
Subjects who have had a prior CVD event must be men or women age≥ the legal age of majority (legal adulthood), in the subject’s country. Subjects who have not had a prior CVD event, must be age ≥50 years if a man, and must be age ≥60 years, if a woman, with the following exceptions:
Subjects who have not had a prior CVD event, but who have a conditions of elevated LDL-C, (heterozygous familial hypercholesterolemia [heFH] or a history of LDL-C ≥190 mg/dL [4.9 mmol/L]) should be ≥ 35 years of age if a man, and ≥ 45 years of age, if a woman.
4. Acceptance of administration of investigational product
Subjects must be willing and able to self-administer or be administered sub-cutaneous injections of IP.
5. Requirements for background lipid lowering treatment
There should be no plans at the time of pre-screening and randomization to modify the dose of statin for the duration of the trial. Unless the background lipid lowering treatment exceptions described below are met, subjects must be treated with one of the following highly effective statins at the specified daily doses for ≥4 weeks prior to the pre-screening visit:
-atorvastatin, at least 40 milligrams (mg) once a day;
- rosuvastatin, at least 20 mg, once a day;
- simvastatin, at least 40 mg, once a day or, if a subject has been on that dose for >1 year, 80 mg, once a day.
Combination medications that contain atorvastatin, rosuvastatin, or simvastatin components described at the aforementioned doses will be permitted.
Background lipid lowering treatment exceptions
The following background lipid lowering treatment exceptions are permitted:
-Lower doses of statins due to partial statin intolerance
Subjects may be on a lower dose of one of the highly effective statins described above if there is documented intolerance to any one of them (atorvastatin, rosuvastatin, or simvastatin) at the aforementioned, or lower, doses. Intolerance to any dose of any statin must be documented as historical adverse events attributed to the statin in question, in the source documentation and case report form (CRF).
- Regulatory limitations
Subjects may be on a lower dose of one of the highly effective statins described above if the highest locally approved dose for one of the stated statins is lower than those doses shown above (eg, in Japan, atorvastatin 20 mg, once a day, is the highest locally approved dose) or due to label restrictions.
- Alternative statins
Subjects may be treated with other statins (pravastatin, fluvastatin, pitavastatin, or lovastatin), different from the highly effective statins listed above, if there is documented intolerance to any two different highly effective statins (atorvastatin, rosuvastatin, simvastatin) at the lowest available daily dose for at least one of those highly effective statins. Intolerance to any statin must be documented as historical adverse events attributed to the statin in question, in the source documentation and CRF.
-No background statin therapy
Subjects may be enrolled who are only on non-statin lipid lowering therapy (drug and/or preventive cardiology lifestyle change guidance), if complete statin intolerance has been documented. Subjects with complete statin intolerance must be unable to tolerate at least two statins: one statin at the lowest available daily dose AND another statin at any dose. Intolerance to any statin must be documented as historical adverse events attributed to the statin in question, in the source documentation and CRF. The sole exception, for which a subject may participate in the study with documentation of intolerance to only one statin, is a documented history of rhabdomyolysis attributed to that statin or a history of
documented statin allergy, precluding challenge with an alternative statin.
See Protocol Section 4.1 for inclusion criteria 6-8. |
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| E.4 | Principal exclusion criteria |
1. Personnel involved in the conduct of the study
Subjects who are investigational site staff members directly involved in the conduct of the trial and their family members, site staff members otherwise supervised by the Investigator, or subjects who are Pfizer employees directly involved in the conduct of the trial.
2. Exclusionary prior CV events or planned revascularization procedures
-A planned coronary (PCI or CABG) or other arterial revascularization;
-Myocardial infarction, stroke, or any non-coronary arterial revascularization≤ 30 days prior to screening;
-Coronary revascularization≤ 90 days prior to screening;
- Subjects with SAEs that would have potentially met the criteria for a CVD event (as defined in Appendix 4), between Visit 0 and Visit 5, should be excluded. Such subjects may be rescreened at a later date.
3. Participation in prior clinical research studies
Participation in other studies involving small molecule investigational drug(s) (Phases 1-4) within 1 month, or five half-lives, of Visit 1, whichever is longer; any participation in a cholesteryl ester transfer protein (CETP) inhibitor within 1 year of Visit 1; or any biological agents within 6 months or 5 half-lives, of Visit 1, whichever is longer (the investigator should refer to documents provided by the subject on the other study to determine the IP half-life). If the blind of the prior study has been broken and the investigator provides documentation that the subject received placebo, the potential subject can be included, regardless of when participation occurred.
4. Other exclusionary conditions
Other severe, acute, or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or IP administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for entry into this study.
5. Childbearing potential and/or breast feeding
Pregnant female subjects; breastfeeding female subjects; male subjects with partners currently pregnant who are sexually active; male subjects able to father children and female subjects of childbearing potential, who are at risk of pregnancy with their partners and are unwilling or unable to use a highly effective method of contraception as outlined in this protocol for the duration of the study and for 63 days after last dose of IP.
6. Latex sensitivity
Latex sensitive individuals (due to potential for exposure to natural dry rubber in the prefilled syringe cap of IP, during administration).
7. Apheresis
Undergoing lipid apheresis, within 6 weeks of pre-screening, or planned start of lipid apheresis.
8. Severe congestive heart failure
Congestive heart failure of New York Heart Association (NYHA) Class IV, or if there is prior documentation of left ventricular ejection fraction (LVEF) of <25%, measured by imaging. For subjects who have had serial assessments of LVEF, only the most recent study is used for the purposes of this exclusion requirement.
9. Dialysis
Potential subjects with end stage renal disease on dialysis.
10. Chronic renal insufficiency
Potential subjects with an eGFR of <30 ml/min/1.73m2 by MDRD formula at Visit 1.
11. Hypertension
Poorly controlled hypertension at any screening visit or at randomization, defined as the average of two systolic blood pressure (BP) measurements >180 mmHg or the average of two diastolic BP measurements >110 mmHg even with treatment. Subjects who have hypertension and are controlled on stable doses of anti-hypertensive medications may be included. An additional set of BP measurements may be performed within the hour or at the completion of the office visit, to determine if a subject may be included in the study, given the potential for “white coat hypertension.” The final set of measurements will be the measurements of record.
12. Cerebral hemorrhage risk
A prior history of hemorrhagic stroke or lacunar infarct resulting in a stroke (a lacunar infarct which was seen with cerebral imaging is not exclusionary in the absence of a clinical stroke). A prior ischemic stroke which resulted in hemorrhagic transformation is not exclusionary.
13. Tissue donation
Plans to donate any tissues (eg, blood, sperm, or other tissues, including participating in in vitro fertilization) during the study.
14. Substance abuse
Current history of alcoholism or drug addiction according to diagnostic and statistical manual of mental disorders (DSM) IV criteria within 12 months prior to screening. Use of any recreational drugs within 12 months prior to screening.
15. Human immunodeficiency virus
Medical history of positive testing for human immunodeficiency virus (HIV).
(see Protocol Section 4.2 for exclusion criteria 16-23)
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The time from randomization to the first occurrence of the adjudicated and confirmed occurrence of a major CV event, a composite endpoint which includes CV death, non-fatal MI, non-fatal stroke, and hospitalization for unstable angina needing urgent revascularization. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
The times from randomization to the first adjudicated and confirmed occurrence of the endpoints below:
- A composite endpoint of CV death, non-fatal MI, and non-fatal stroke;
- A composite endpoint of all-cause death, non-fatal MI, and non-fatal stroke, and hospitalization for unstable angina needing urgent revascularization;
- A composite endpoint of all-cause death, non-fatal MI, non-fatal stroke;
- Hospitalization for unstable angina needing urgent revascularization.
Other Secondary Clinical Endpoints
The times from randomization to the first adjudicated and confirmed occurrence of the endpoints below (as defined in Appendix 4):
-A composite endpoint of CV death, non-fatal MI, non-fatal stroke, and hospitalization for unstable angina;
-CV death;
-Any MI (fatal and non-fatal);
-Fatal MI;
-Non-fatal MI;
-Any stroke (fatal and non-fatal);
-Any stroke (fatal and non-fatal), of any etiology;
-Fatal stroke;
-Non-fatal stroke;
-Hospitalization for unstable angina;
-Hospitalization for congestive heart failure (CHF);
-Any coronary revascularization procedure;
-CABG;
-PCI;
-Any arterial revascularizations;
-All cause death.
Circulating Biomarker Endpoints
LDL-C
The percent change and nominal change, from baseline at Week 14 (Visit -8) and percent change from baseline to the last available post-randomization value, in LDL-C (direct measurement).
Other circulating lipid biomarker endpoints
The percent change from baseline at Week 14 (Visit 8) in levels of:
- Non-HDL-C;
- Total cholesterol;
-Very low density lipoprotein cholesterol (VLDL-C);
-Remnant lipoprotein cholesterol (RLP-C);
- Apolipoprotein B (apo B);
- Lipoprotein(a) (Lp(a));
- Triglycerides;
- HDL-C;
- Apolipoprotein A-I (apo A-I).
Inflammatory Circulating Biomarker
The percent change from baseline at Week 14 (Visit 8), in levels of hs-CRP.
Health Care Resource Utilization Endpoints
The HCRU endpoints include:
- The occurrence, primary and secondary discharge diagnoses, overall length of stay, duration of stay in different medical care units, and discharge disposition, of all-cause hospitalizations;
- The occurrence, primary and secondary discharge diagnoses, overall length of stay, duration of stay in different medical care units, and discharge disposition, of CV hospitalizations;
- The occurrence of emergency room visits;
- The occurrence of physician office visits;
- The occurrence of outpatient rehabilitation visits;
- The occurrence of all-cause hospitalizations within 30 days of a previous hospitalization, primary and secondary discharge diagnoses, time to hospitalization within 30 days of a previous hospitalization, length of stay, and discharge disposition;
- The occurrence of CV hospitalizations within 30 days of a previous hospitalization, primary and secondary discharge diagnoses, time to hospitalization within 30 days of a previous hospitalization, length of stay, and discharge disposition.
Safety Endpoints
Safety endpoints include investigator reported adverse events, (including Type 1 and 3 hypersensitivity reactions and injection site reactions), serious adverse events, vital signs, examination observations (physical and neurological examinations and cognitive testing), 12-lead ECG recordings, and safety laboratory tests, including hematology, blood chemistry studies (including liver function tests and creatine kinase tests), urinalysis studies, and ADA assessments. See Section 7.2 of the protocol for details. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | No |
| 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 | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Reduction of the occurrence of major CV events |
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| 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 | 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 | 2 |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 696 |
| 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 |
| Argentina |
| Australia |
| Belgium |
| Brazil |
| Canada |
| Chile |
| China |
| Colombia |
| Czech Republic |
| Denmark |
| Finland |
| France |
| Germany |
| Hungary |
| Ireland |
| Israel |
| Italy |
| Japan |
| Korea, Republic of |
| Mexico |
| Netherlands |
| New Zealand |
| Peru |
| Poland |
| Puerto Rico |
| Romania |
| Russian Federation |
| Slovakia |
| South Africa |
| Spain |
| Sweden |
| Switzerland |
| Taiwan |
| Thailand |
| 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
|
| End of Trial in a Member State (MS) of the European Union is defined as the time at which it is deemed that sufficient subjects have been recruited and completed the study as stated in the regulatory application CTA and ethics application in the (MS). Poor recruitment by a (MS) is not a reason for premature termination but is considered a normal conclusion to the study in that Member State. End of Trial in all other participating countries is defined as Last Subject Last Visit. |
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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 | 2 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| 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 | 0 |
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