| 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 | 16.1 |
| 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 PF-04950615 compared with placebo in reducing the risk of major CV events, a composite endpoint which includes adjudicated and confirmed CV death, non-fatal MI, non-fatal stroke, and hospitalization for unstable angina with urgent revascularization in subjects at high or very high risk of major CV events who are on maximally tolerated background lipid lowering treatment but have an LDL-C ≥ 70 mg/dL (1.8 mmol/L) and < 100 mg/dL (2.6 mmol/L) or non-HDL-C ≥ 100 mg/dL (2.6 mmol/L) and < 130 mg/dL (3.4 mmol/L). |
|
| E.2.2 | Secondary objectives of the trial |
To demonstrate in subjects with high or very high risk of major CV events on maximally tolerated background lipid lowering treatment with LDL-C≥70 mg/dL and <100 mg/dL or non-HDL-C ≥100 mg/dL and <130 mg/dL, the superior efficacy of PF-04950615
compared with placebo in reducing the risk of adjudicated and confirmed key secondary endpoints of: (please refer to protocol section 2.1.2)
To evaluate in subjects with high or very high risk of major CV events on maximally tolerated background lipid lowering treatment with LDL-C ≥70 mg/dL and <100 mg/dL or non-HDL-C ≥100 mg/dL and < 130 mg/dL, the efficacy of PF-04950615 compared with placebo in reducing the risk of other adjudicated and confirmed secondary endpoints (please refer to protocol section 2.1.2) |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Evidence of a personally signed and dated informed consent document indicating that the subject (or a legal representative) has been informed of all pertinent aspects of the study.
2. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
3. Age: men or women aged ≥ 18 years for those with a confirmed prior CVD event; or men aged ≥ 55 years, or women, aged ≥ 65 years with a CVD risk equivalent.
4. Willing and able to self-administer or be administered sub-cutaneous injections of investigational product.
5. Must be treated with atorvastatin, rosuvastatin, or simvastatin, at the highest locally approved dose. If at a lower dose, there must be documentation that the subject is receiving a maximally tolerated dose of the aforementioned statins, or that the subject is at his or her LDL-C or non-HDL-C target; and no dose should be lower than atorvastatin 20 mg, rosuvastatin 20 mg, or simvastatin 40 mg, once a day.
a. Subjects on simvastatin 80 mg must have been on this dose for > 1 year before screening.
b. All subjects must be on a stable dose at least 6 weeks prior to screening. There should be no plans at the time of screening and randomization to modify the dose of statin for the duration of the trial.
c. Source records and case report form (CRF) documentation of the above, must be shown.
6. Qualifying CV risk factor: prior CVD event.
A prior CVD event must be documented by source documentation that includes an anonymized hospital discharge summary describing the qualifying index CVD event diagnosis or surgical event and that includes documentation of the event’s date of occurrence.
Qualifying prior CVD event:
a. greater than thirty days but no more than five years post prior myocardial infarction as defined by the universal definition of MI excluding those with MI due to cocaine abuse or vasospasm) or ischemic stroke, as documented by hospital discharge summary and brain imaging scan
b. greater than one year but no more than five years post previous cardiac revascularization including PCI or CABG, as documented by hospital discharge summary c. pre-existing arterial revascularization, documented as a carotid, or peripheral artery revascularization, as defined as surgery or stent placement and documented by hospital discharge summary (at least one month [30 days] but no more than five years prior to screening)
7. Qualifying CV risk factor: CVD risk equivalent with two additional risk factors: Type I or Type II diabetes mellitus, as defined per local diabetes guidelines (eg, American Diabetes Association [ADA] in the U.S.A, European Association for the Study of Diabetes [EASD] in the European Union [E.U.]) heterozygous familial hypercholesterolemia (heFH), subjects with symptomatic peripheral vascular disease
or chronic kidney disease (with a glomerular filtration rate of ≥30 and ≤60 mL/min/1.73m2, based on the screening visit measurement of creatinine, as calculated by Modification of Diet in Renal Disease [MDRD] formula, and not on dialysis) and ≥55 years of age for men and ≥65 years of age for women, with at least two of the following additional risk factors for CVD:
a. Evidence of coronary artery stenoses of > 50% narrowing in at least two major coronary arteries as documented by coronary artery imaging;
b. Current cigarette smoking, defined as smoking for 30 days or more (any number
of cigarettes) at the time of screening;
c. HDL-C < 40 mg/dL (< 1.0 mmol/L) as measured at the screening visit;
d. hs-CRP > 2.0 mg/L documented within one year of the screening visit;
e. A glomerular filtration rate (GFR) ≥30 and ≤60 mL/min/1.73m2 (based on the
creatinine measured at the screening visit, and as calculated by the MDRD formula).
8. Subject must have an LDL-C ≥70 mg/dL (1.8 mmol/L) and < 100 mg/dL (2.6 mmol/L) or non-HDL-C ≥100 mg/dL (2.6 mmol/L) and < 130 mg/dL (3.4 mmol/L) at Visit 3.
9. Male and female subjects of childbearing potential must agree to use a highly
effective method of contraception throughout the study and for at least 63 days after the last dose of assigned treatment. A subject is of childbearing potential if, in the opinion of the investigator, he/she is biologically capable of having children and is sexually active.
10. Female subjects who are not of childbearing potential should meet at least one of the following criteria:
a. Have undergone a documented hysterectomy and/or bilateral oophorectomy;
b. Have medically confirmed ovarian failure, or
c. Achieved post-menopausal status, defined as: cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause; and have a serum follicle stimulating hormone (FSH) level within the laboratory’s reference range for postmenopausal females. |
|
| E.4 | Principal exclusion criteria |
1. 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. A planned coronary (PCI or CABG) or other arterial revascularization.
3. Participation in other studies involving molecule investigational drug(s) (Phases 1-4) within 1 month, any participation in a cholesteryl ester transfer protein inhibitor trial for any length of time, or biological agents within 6 months or 5 half lives, whichever is longer before the current study begins and/or during study participation. If the blind has been broken and the investigator knows (with documentation) that the subject received placebo, he/she can be included.
4. 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. 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 sensitive individuals (due to potential for exposure to natural dry rubber in the prefilled syringe cap of investigational product, during administration).
7.Potential subjects with an LDL-C < 70 mg/dL (< 1.8 mmol/L) or ≥ 100 mg/dL (2.6 mmol/L or non-HDL-C < 100 mg/dL (2.6 mmol/L) or ≥ 130 mg/dL (3.4 mmol/L) at Visit 1 or Visit 3.
8. Undergoing lipid apheresis or planned start of lipid apheresis.
9. Congestive heart failure of New York Heart Association (NYHA) Class IV, or left ventricular ejection fraction (LVEF) of <25%, measured by imaging.
10. Potential subjects with end stage renal disease on dialysis.
11. Potential subjects with chronic renal insufficiency and a creatinine clearance of < 30 ml/min/1.73m2 by MDRD formula.
12. Poorly controlled hypertension (defined as the average of two systolic blood pressure (BP) measurements greater than 160 mm Hg or diastolic BP measurements greater than 100 mm Hg, even with treatment). Subjects who have hypertension and are controlled on stable dosages of anti-hypertensive medications can be included. Subjects may be permitted into the study if in the Principal Investigator’s opinion the assessment(s) are not clinically significant. BP measurement may be repeated up to three times within the hour or at the completion of the office visit, to confirm a reading.
11. A prior history of hemorrhagic stroke.
12. Plans to donate blood during the study.
13. 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.
14. Medical history of positive testing for human immunodeficiency virus.
15. Subjects with prior exposure to PF-04950615 (RN316) or other investigational PCSK9 inhibitor.
16. Subjects who are receiving routine intramuscular(IM) injections or for whom IM therapy is anticipated during the course of the study. Elevations of Creatinine 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.
17. History of allergic or anaphylactic reaction to any therapeutic or diagnostic monoclonal antibody (immunoglobulin G 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).
18. Positive hepatitis B surface antigen hepatitis B core antibody, or hepatitis C antibody tests indicative of present or prior infection. NOTE: If a subject tests negative for HBsAg, but positive for HBcAb, the subject would be considered eligible if the subject tests positive for antibody to HB surface antigen (HBsAb or anti HBsAg) reflex testing.
19. Creatinine kinase >3.0x upper limit of normal (ULN). A measurement >3.0xULN may be repeated once during screening, and if <3.0 xULN the subject is eligible.
20. Alanine amino transferase (ALT) or aspartate amino transferase (AST)>2xULN.
21. Direct bilirubin>1.5xULN.
22. Subjects with cancer who are actively receiving chemotherapy. Potential subjects with a prior history of malignancy should have thorough documentation of the malignancy type and the extent of disease. Potential subjects considered at high risk of recurrence or the development of metastatic disease within the time frame of the conduct of the CT should be excluded. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The time from randomisation to confirmed 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) |
Time from randomisation to confirmed:
1. Hospitalization for unstable angina needing urgent revascularization;
2. Composite endpoint of CV death, non-fatal MI, and non-fatal stroke;
3. Composite endpoint of all cause death, non-fatal MI, non-fatal stroke, and hospitalization for unstable angina needing urgent coronary revascularization.
Other Secondary Clinical Endpoints
The times from randomization to the first adjudicated and confirmed occurrence of the following endpoints (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);
- 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
The percent change and nominal change from baseline at 3 months (Visit 8) and nominal change to the last post-randomization value of:
- LDL-C;
- Non-HDL-C;
- Total cholesterol;
VLDL-C;
- Apo B;
- Lp(a);
- Triglycerides;
- HDL-C;
- Apo A-I;
- hs-CRP;
Safety Endpoints
Safety endpoints include clinical safety data from investigator reported observations,
including adverse events, (including Type 1 and 3 hypersensitivity reactions and injection site reactions), serious adverse events, vital signs, examinations (physical and neurological examinations and cognitive testing), including 12-lead ECG recordings, and safety laboratory tests, hematology, blood chemistry studies (including liver function tests and creatine kinase tests), urinalysis studies, and anti-drug antibody (ADA) assessments. |
|
| 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 | 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 | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 186 |
| 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 |
| Belgium |
| Canada |
| China |
| Denmark |
| France |
| Italy |
| Japan |
| Netherlands |
| New Zealand |
| Romania |
| Slovakia |
| Sweden |
| Argentina |
| Australia |
| Brazil |
| Colombia |
| Czech Republic |
| Finland |
| Germany |
| Hungary |
| India |
| Korea, Republic of |
| Puerto Rico |
| Spain |
| Thailand |
| Israel |
| Mexico |
| Peru |
| Poland |
| Russian Federation |
| South Africa |
| Switzerland |
| Taiwan |
| Turkey |
| 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 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. |
|
| 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 | 12 |
| 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 | 8 |
| E.8.9.2 | In all countries concerned by the trial days | 12 |
Print
