| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 18.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10003601 |
| E.1.2 | Term | Atherosclerosis |
| E.1.2 | System Organ Class | 100000004866 |
|
| 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). |
|
| 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;
- Hospitalization for unstable angina needing urgent revascularization.
Please refer to protocol section 2.1.2 for additional secondary objectives |
|
| 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.
2. Compliance
Subjects must be willing and able to comply with scheduled visits,
treatment plan, laboratory tests, and other study procedures.
3. Age
For subjects who have had a prior CVD event, or who have a condition of
elevated LDL-C without a prior CVD event (heterozygous familial
hypercholesterolemia [heFH] or an LDL-C≥190 mg/dL [4.9 mmol/L]),
subjects must be men or women age≥ the legal age of majority (legal
adulthood), in the subject's country. For other 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 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 ≥6 weeks prior to the screening
visit:
-atorvastatin, 40 or 80 milligrams (mg) once a day;
- rosuvastatin, 20 or 40 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 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 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, 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.
See Protocol Section 4.1 for inclusion criteria 6-8. |
|
| 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;
-PCI≤ 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
for any length of time; 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; males and females 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
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 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 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.
13. Blood donation
Plans to donate blood 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 criteria 19-23 |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The time from randomization to theto 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:
1. A composite endpoint of CV death, non-fatal MI, and non-fatal stroke;
2.A composite endpoint of all-cause death, non-fatal MI, and non-fatal
stroke, and hospitalization for unstable angina needing urgent
revascularization;
3. 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 all cause death, non-fatal MI, and non-fatal
stroke;
-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
Circulating biomarker endpoints are secondary efficacy endpoints and
include the lipid and nflammatory parameters listed below. Lipid
parameters will be evaluated as percent change from baseline. In
addition, LDL-C will be evaluated as nominal change from baseline. The
inflammatory parameter will be evaluated as the nominal change
(mg/dL) from baseline. To evaluate, 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 ≥130 mg/dL (3.36 mmol/L), bococizumab compared with
placebo, with respect to the following circulating lipid biomarkers, and
their percent change from baseline at 3 months:
- 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).
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. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 |
|
| 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 | No |
| 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 | 40 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 415 |
| 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 |
| Finland |
| France |
| Germany |
| Hungary |
| India |
| Israel |
| Italy |
| Korea, Republic of |
| Mexico |
| Netherlands |
| Peru |
| Philippines |
| Poland |
| Romania |
| Russian Federation |
| Slovakia |
| South Africa |
| Spain |
| Taiwan |
| 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. |
|
| 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 | 1 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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