| 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 | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10003601 |
| E.1.2 | Term | Atherosclerosis |
| E.1.2 | System Organ Class | 100000022953 |
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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 |
English 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 ≥70 mg/dL (1.81 mmol/L) or non-HDL-C (non-high density lipoprotein cholesterol) ≥100 mg/dL (2.59 mmol/L).
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| E.2.2 | Secondary objectives of the trial |
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 ≥70 mg/dL (1.81 mmol/L) or
non-HDL-C≥ 100 mg/dL (2.59 mmol/L), the superior efficacy of bococizumab compared with placebo in reducing the risk of adjudicated and confirmed key secondary endpoints
(see protocol, Appendix 4) of:
- A composite endpoint of CV death, non-fatal MI, and non-fatal stroke
- 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; - Hospitalization for unstable angina needing urgent
revascularization.
-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 |
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. 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, subjects must be men or women age ≥ the legal age of majority (legal adulthood), in the subject's country. For subjects who have not had a prior CVD event, men must be age ≥50 years and women must be age ≥ 60 years. 4. Acceptance of administration of investigational product Subjects must be willing and able to self-administer or be administered
sub-cutaneous injections of investigational product. 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, 40 once a day; -rosuvastatin, 20 mg, once a day; -simvastatin, 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).
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 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, 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 a single statin, is a documented history of rhabdomyolysis attributed
to that statin. 6. Qualifying cardiovascular disease risk
Qualifying cardiovascular disease (CVD) risk must be documented by
supporting source documentation such as, but not limited to, copies of a hospital discharge summary, copies of medical records, or other
documents that can be used to confirm the qualifying CVD risk event or diagnosis and its approximate date of occurrence or onset. Ideally, this documentation should be acquired before Visit 1. A subject may qualify for inclusion according to the following (see Appendix 10 of protocol):
a. Myocardial infarction OR
b. Ischemic stroke OR
c. Coronary artery revascularizationOR
d. Prior non-coronary arterial revascularization ;OR
e. CVD risk conditions
Subjects may qualify for inclusion if they have two CVD risk conditions;
OR
-one CVD risk condition and two CV risk factors (described below); OR
- any condition of elevated LDL-C as specified below:
7. Qualifying LDL-C lipids level (LDL-C or non-HDL-C)
8. Contraception requirements
See Protocol Section 4.1 for further details of each inclusion criteria.
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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.
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 trial 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 investigational product 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 investigational product 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 females;
breastfeeding females; and male and female subjects who (with their
partners) are of childbearing potential, who 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 investigational product (refer to Section 4.4.2). 6. Latex sensitivity
Latex sensitive individuals (due to potential for exposure to natural dry
rubber in the prefilled syringe cap of investigational product, 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.
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 BP measurement may be
performed within the hour or at the completion of the office visit, to
confirm a reading.
12. Cerebral hemorrhage risk
A prior history of hemorrhagic stroke or lacunar infarct.
13. Tissue donation
Plans to donate any tissue 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).
16. Prior exposure to a PCSK9 inhibitor Subjects with prior exposure to bococizumab or other investigational PCSK9 inhibitor.
17. Intramuscular injections
Subjects who are receiving routine intramuscular (IM) injections or for
whom IM therapy is anticipated during the course of the study.
Elevations of Creatine Kinase (CK) is known to occur with IM injections,
hence the elimination of the use of IM injections with concomitant
medications will minimize the diagnostic uncertainty of CK elevations.
18. Hypersensitivity to monoclonal antibodies History of allergic or anaphylactic reaction to any therapeutic or diagnostic monoclonal antibody (immunoglobulin G [IgG] protein) or
molecules made of components of monoclonal antibodies (eg, Enbrel®
which contains the fragment crystallizable [Fc] portion of an antibody or Lucentis® which is a monoclonal antibody fragment).
(See Protocol Section 4.2 for exclusion criterions 16-23)
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint is defined as the time from randomization to the
first adjudicated and confirmed occurrence of a major CV event, a
composite endpoint that includes CV death, non-fatal MI, non-fatal
stroke, and hospitalization for unstable angina needing urgent
revascularization.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
Key secondary endpoints are defined as the times from randomization to
the first adjudicated and confirmed occurrence 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.
Other Secondary Clinical Endpoints
The times from randomization to the first adjudicated and confirmed
occurrence of the following endpoints:
- A composite endpoint of CV death, non-fatal MI, and 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.
Other Secondary Circulating Biomarker Endpoints
The percent and nominal change from baseline at Week 14 and percent and nominal change from baseline to the last available postbaseline observation in LDLC (direct measurement); The percent change from baseline to Week 14 in:
-Non-HDL-C;
- VLDL-C;
- RLP-C;
-Lp(a);
- Apo-B;
- HDL-C;
- apo-A-I;
- Total cholesterol;
-Triglycerides.
- The nominal change from baseline to 3 months (Visit 8) in hs-CRP.
Friedewald LDL-C will be summarized by treatment group and visit according to sponsor standards.
Inflammatory biomarker endpoint
The sole inflammatory biomarker endpoint is the nominal change from
baseline at Week 14, in levels of hs-CRP.
Health Care Resource Utilization Endpoints
Health care resource utilization endpoints being evaluated 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,
length of stay, and discharge disposition;
- The occurrence of CV hospitalizations within 30 days of a previous
hospitalization, primary and secondary discharge diagnoses, 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 protocol, Section
7.2 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 | 73 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 705 |
| 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 |
| China |
| Colombia |
| Czech Republic |
| Denmark |
| Finland |
| France |
| Germany |
| Hungary |
| Ireland |
| Israel |
| Italy |
| Japan |
| Korea, Republic of |
| Mexico |
| Netherlands |
| New Zealand |
| Peru |
| Philippines |
| Poland |
| Puerto Rico |
| Romania |
| Russian Federation |
| Slovakia |
| South Africa |
| Spain |
| Sweden |
| Switzerland |
| Taiwan |
| Thailand |
| Turkey |
| 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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| End of Trial in a MS of the EU is defined as the time at which it is deemed that sufficient subjects have been recruited and completed the study as stated in the Clinical Trial Application and ethics application in the MS. Poor recruitment (recruiting less than the anticipated number in the CTA) by a MS is not a reason for premature termination but is considered a normal conclusion to the study in that MS. End of Trial in all other participating countries is defined as LSLV. |
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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 | 3 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | 22 |
| 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 | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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