| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| primary hyperlipidemia or mixed dyslipidemia |
|
| 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 | 18.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10020667 |
| E.1.2 | Term | Hyperlipidemia |
| E.1.2 | System Organ Class | 100000004861 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10058110 |
| E.1.2 | Term | Dyslipidemia |
| E.1.2 | System Organ Class | 100000004861 |
|
| 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 a superior LDL-C lowering effect of PF-04950615 150 mg administered by the SC route Q2wks compared to placebo, in subjects with primary hyperlipidemia or mixed dyslipidemia at high and very high risk for CV events receiving a maximally tolerated dose of statin therapy. |
|
| E.2.2 | Secondary objectives of the trial |
To demonstrate a superior effect of PF-04950615 150 mg administered by the SC route Q2wks compared to placebo, in subjects with dyslipidemia at risk for CV events receiving maximally tolerated dose of statin therapy and whose LDL-C is ≥70 mg/dL or ≥100 mg/dL on Total cholesterol , HDL-C, Triglycerides (TG), and non HDL-C; other lipid parameters, including Apolipoprotein B, Apolipoprotein A-I, Apolipoprotein A-II, lipoprotein (a)[Lp(a)], very low density lipoprotein cholesterol (VLDL-C).
To demonstrate a superior LDL-C lowering effect of PF-04950615 150 mg administered by the SC route Q2wks compared to placebo:
-In subjects with primary hypercholesterolemia and mixed dyslipidemia (pre-randomization TG ≥200 mg/dL
Additional details provided in the Protocol. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subject eligibility should be reviewed and documented by an appropriately qualified member of the investigator's study team before subjects are included in the study.
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the study:
1. Evidence of a personally signed and dated informed consent document indicating that the subject (or a legally acceptable representative) has been informed of all pertinent aspects of the study.
2. Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
3. Males and females ≥18 years of age where permitted by law.
4. With primary hyperlipidemia or mixed dyslipidemia.
5. Subjects are required to be treated with atorvastatin, simvastatin, or rosuvastatin 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; and no dose should be lower than atorvastatin 20 mg, rosuvastatin 20 mg, or simvastatin 40 mg.
-Subjects on simvastatin 80 mg must have been on this dose for >1 year before
screening.
-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.
-Source records and case report form (CRF) must show documentation of the requirements shown above..
6. Subjects should be at high or very high risk of incurring a CV event, defined as:
a. Known CVD or CVD risk equivalents:
- Known history of CVD.
- Coronary heart disease: (any one of the following conditions): history of acute myocardial infarction or evidence of silent myocardial infarction or myocardial ischemia, or history of unstable angina or stable angina pectoris, or history of coronary procedures (coronary angioplasty and coronary artery surgery), or;
-Other clinical atherosclerotic diseases: peripheral arterial disease, abdominal aortic aneurysm, carotid artery disease (symptomatic [eg, transient ischemic attack or stroke of carotid origin] or >50 percent stenosis on angiography or
ultrasound), and likely other forms of clinical atherosclerotic disease (eg, renal artery disease), or;
-Type 2 or Type 1 diabetes, or;
-Chronic kidney disease (CKD), defined as glomerular filtration rate (GFR) calculated
by Modification of Diet in Renal Disease (MDRD) formula between 30 and 60 mL/min/1.73m2 (inclusive).
b. Presence of multiple risk factors:
Subjects who do not have past CVD disease or CVD risk equivalents but have 3 or more of the risk factors from the list below:
-Current cigarette smoking defined as any smoking for 30 days or more at the time of
screening.
-HDL-C <40 mg/dL (<1.0 mmol/L) at screening or TC/HDL-C ratio of ≥6.
-Family history of premature CHD (CHD in male first-degree relative <55 years; CHD
in female first-degree relative <65 years).
-Age (men ≥55 years; women ≥65 years).
-hs-CRP >2.0 mg/L at screening.
7. Lipids should meet the following criteria on a background treatment with a statin at the 2 screening visits:
a. Subjects with known CVD or CVD risk equivalents (Refer to 6a, above) at the highest approved dose of statins described in 5, above:
-Fasting LDL C ≥70 mg/dL (1.81 mmol/L) at both screening visits and the value at the second screening visit within 7 days of randomization 3 must not be lower or higher than 20% of this initial value, as described in Section 7.1.
-Subjects not at the highest approved dose of statins described in 5, above:
-Fasting LDL C ≥77 mg/dL (1.99 mmol/L) at both screening visits and the value at the second screening visit within 7 days of randomization 3 must not be lower
or higher than 20% of this initial value, as described in Section 7.1 of the protocol.
b. Subjects with multiple risk factors (Refer to 6b, above) at the highest approved dose of statins described in 5, above:
-Fasting LDL C ≥100 mg/dL (2.59 mmol/L) at both screening visits and the value
at the second screening visit within 7 days of randomization 3 must not be lower
or higher than 20% of this initial value, as described in Section 7.1 of the protocol. Subjects not at the highest approved dose of statins described in 5, above:
-Fasting LDL C ≥110 mg/dL (2.85 mmol/L) at both screening visits and the value at the second screening visit within 7 days of randomization 3 must not be lower or higher than 20% of this initial value, as described in Section 7.1.
-Fasting TG ≤400 mg/dL (4.51 mmol/L) at the second screening visit within 7 days of randomization 3.
For Inclusion Criteria 8 please refer to the Protocol |
|
| E.4 | Principal exclusion criteria |
Subjects presenting with any of the following will not be included in the study:
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. Participation in other studies involving small molecule investigational drug(s) (Phases 1-4) within 1 month or 5 half-lives except for cholesteryl ester transfer protein (CETP) inhibitors (indefinitely), or biological agents within 6 months or 5 half lives, whichever is longer before the current study begins and/or during study participation (the investigator should refer to documents provided by the subject on the other study to determine the investigational product half life). If the blind has been broken and the Investigator knows (with documentation) that the subject received placebo, he/she can be included.
3. Subjects with prior exposure to PF-04950615 or other investigational PCSK9 inhibitor.
4. Subjects who are unable to receive injections, as either a self-injection, or administered by a family member, health care assistant, or health care provider.
5. History of a cardiovascular or cerebrovascular event or procedure (eg, Myocardial infarction, stroke, transient ischemic attack, angioplasty) during the past 30 days.
6. Congestive heart failure, New York Heart Association functional class IV, or Left
Ventricular Ejection Fraction measured by imaging <25%.
7. Poorly controlled hypertension at any screening visit or at randomization (defined as the average of two systolic blood pressure measurements greater than 160 mm Hg or the average of two diastolic blood pressure 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.
An additional Blood pressure (BP) measurement may be performed within the hour or at the completion of the office visit, to confirm a reading.
8. Any history of hemorrhagic stroke or lacunar infarct.
9. Current untreated hypothyroidism or thyroid stimulating hormone (TSH) >1 X upper limit of normal (ULN) at screening. Subjects who are treated and well controlled should be on a stable dose of thryoid hormone for at least 6 months.
10. Current history of alcoholism or drug addiction according to the 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.
11. History of cancer within the last 5 years (except for cutaneous basal cell or squamous cell cancer resolved by excision).
12. Medical history of positive testing for Human immunodeficiency virus (HIV).
13. Any disease or condition that might compromise the, hematological, renal, hepatic, pulmonary, endocrine, central nervous, immune, or gastrointestinal systems (unless deemed not clinically significant by the Investigator and/or the Sponsor) or confound the interpretation of the study results. Examples of such conditions include but are not limited to nephrotic syndrome, uncontrolled diabetes, excessive alcohol consumption, cholestatic liver disease.
14. Use of statins other than atorvastatin, rosuvastatin, simvastatin or red yeast rice.
15. Undergoing apheresis or have planned start of apheresis.
16. Initiation of, or change in, non lipid lowering prescription drugs, herbal medicine or supplements (including foods with added plant sterols and stanols) within 6 weeks of screening (exception: initiation or change in multivitamins used for general health purposes are acceptable). Short term use of medications to treat acute conditions, and vaccines are allowed (e.g. antibiotics or allergy medication).
17. Subjects on systemic corticosteroids at screening (ie, oral, intravenous (IV), intramuscular (IM), or intra-articular. The use of topical, inhaled or opthalmic corticosteroids by inhalation is permitted.
18. Subjects taking prescription medications that are contraindicated with the use of statins at screening. Refer to statin product labels for these medications.
19. History of allergic or anaphylactic reaction to any therapeutic or diagnostic monoclonal antibody (IgG protein) or molecules made of components of monoclonal antibodies (eg, Enbrel which contains the Fc portion of an antibody or Lucentis which is a Fab).
20. Subjects who are latex-sensitive (due to potential for exposure to latex or dry rubber in the pre-filled syringe cap during self administration).
For exclusion conditions 21-30 please refer to the protocol |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Percent change from baseline in fasting LDL-C at week 12 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
-Percent change from baseline in fasting TC, ApoB, and non HDL-C at week 12;
-Percent change from baseline in fasting LDL-C at week 12 in subjects with primary
hyperlipidemia (pre-randomization TG <200 mg/dL;
- Percent change from baseline in fasting LDL-C at week 12 in subjects with mixed
dyslipidemia (pre-randomization TG <200 mg/dL;
- Percent change from baseline in fasting Lp(a) at week 12;
- Percent change from baseline in fasting HDL-C at week 12.
Secondary Endpoints
-Percent change from baseline in fasting LDL-C at week 24 and week 52;
-Percent change from baseline in fasting LDL-C at week 24 and week 52 by TG cut-off of < or ≥200 mg/dL (2.26 mmol/L);
-Percent change from baseline in fasting TC, non HDL-C, ApoB, Lp(a) and HDL-C at week 24 and week 52;
-Percent change from baseline in fasting, TG, ApoA-I, ApoA-II, VLDL-C at week 12, week 24 and week 52;
-Absolute change from baseline in fasting LDL-C at week 12, week 24 and week 52 by TG cut-off of < or ≥200 mg/dL (2.26 mmol/L);
-Absolute change from baseline in fasting LDL-C, TC, non HDL-C, Apo B, Lp(a) and HDL-C at week 12;
Absolute change from baseline in fasting TC/HDL-C ratio and ApoB/ApoA-I ratio at week 12, week 24 and week 52;
-Proportion of subjects achieving fasting LDL-C ≤100 mg/dL (2.59 mmol/L) at week 12, week 24 and week 52;
-Proportion of subjects achieving fasting LDL-C ≤70 mg/dL (1.81 mmol/L) at week 12, week 24 and week 52;
- Plasma PF-04950615 concentrations at week 12, week 24 and week 52.
Safety endpoints are:
-Adverse events (including Type 1 and 3 hypersensitivity reactions and injection site reactions);
-Incidence of anti-drug-antibodies. |
|
| 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 | 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) | 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 44 |
| 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 |
| Colombia |
| France |
| Hungary |
| Latvia |
| Lithuania |
| Mexico |
| Romania |
| Russian Federation |
| 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 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 regulatory application 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 MS. For all other participating countries it 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 | 2 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | 5 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| 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 | 5 |
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