| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Heterozygous Familial Hypercholesterolemia |
|
| 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 | 10020604 |
| E.1.2 | Term | Hypercholesterolemia |
| 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 heterozygous familial hypercholesterolemia (HeFH) and at high and very high risk of CV events receiving a maximally tolerated dose of statin therapy and whose LDL-C is ≥70 mg/dL (1.81mmol/L) |
|
| 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 HeFH and at high and very high risk of CV events receiving maximally tolerated dose of statin therapy and whose LDL-C is ≥70 mg/dL(1.81 mmol/L) on:
- Total cholesterol (TC), HDL-C, Triglycerides (TG), and non HDL-C;
-Other lipid parameters, including Apolipoprotein B (ApoB), Apolipoprotein A-I (ApoAI), Apolipoprotein A-II (ApoA-II), lipoprotein (a)[Lp(a)], very low density lipoprotein cholesterol (VLDL-C);
- To compare the safety and tolerability of PF-04950615 150mg administered by the SC
route Q2wks to placebo, in subjects with HeFH and at high and very high risk of CV
events receiving maximally tolerated dose of statin therapy and whose LDL-C is ≥70
mg/dL (1.81 mmol/L);
-To assess the immunogenicity of PF-04950615;
-To assess the exposure of PF-04950615. |
|
| 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 legal 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.
4.With previously diagnosed HeFH phenotype as defined according to the Simon Broome criteria, described in Appendix 2 or a genetic diagnosis of HeFH.
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 without known history of CVD or diabetes or chronic kidney
disease (definition below) who are on the highest approved statin dose
must have a LDL-C ≥100 mg/dL (2.59 mmol/L)( or LDL-C ≥ 110 mg/dL [2.84 mmol/L]if at the maximally tolerated statin dose). Subjects with known history of CVD or diabetes or CKD (definition below) who are on the highest approved statin dose must have a LDL-C ≥ 70 mg/dL (1.81 mmol/L) dose ( or ≥ 77 mg [1.99 mmol/L] if at the maximally tolerated statin dose.)
Detailed criteria:
Subjects must meet the following fasting LCL-C minimum levels based on their history of CVD or risk equivalent and statin dose.
*LDL-C must meet these values at both screening visits and the value at
the second screening visit within 7 days of randomization 1 must not be
lower or higher than 20% of this initial value, as described in Section
7.1. If the fasting LDL-C at the second screening visit is lower or higher
than 20% of the initial value, LDL-C can be repeated once (within 7 days
of randomization), and the subject is eligible if the value of this repeat
test is within 20% (inclusive) of the value for the second screening
visit.
• Subjects must also have fasting TG ≤ 400 mg/dL (4.5 mmol/L) at the
second screening visit.
Known history of CVD or risk equivalent is based on any one of the
below:
• Coronary heart disease (any of the following conditions): history of
acute myocardial infarction, or evidence of silent myocardial infarction
or myocardial ischemia, or history of unstable angina and stable angina
pectoris, or history of coronary procedures (coronary angioplasty
orand coronary artery surgery);
• Other clinical atherosclerotic diseases (any one of the following
conditions): peripheral arterial disease, or abdominal aortic aneurysm,
or carotid artery disease (symptomatic [eg, transient ischemic attack or
stroke of carotid origin] or >50 percent stenosis on angiography or
ultrasound), and or 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).
7. 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 (Section 4.4.2).
Female subjects who are not of childbearing potential (ie, meet at least
one of the following criteria):
• Have undergone a documented hysterectomy or bilateral
oophorectomy;
• Have medically confirmed ovarian failure; or
• 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 |
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 (RN316) or other investigational PCSK9 inhibitors.
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 erebrovascular event or procedure (eg, Myocardial infarction, stroke, transient ischemic attack, angioplasty) during the past 30 days.
6. Congestive heart failure, New York Heart Association (NYHA) 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. 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) >1X Upper Limit of Normal (ULN) at screening. Subjects who are treated and well controlled should be on a stable dose of thyroid 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 and cholestatic liver disease.
14. Use of statins other than atorvastatin, rosuvastatin, simvastatin or use of red yeast rice.
15. Undergoing apheresis or have planned to start 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 (ie, oral, intravenous (IV), intramuscular [IM], or intra-articular) at screening. The use of corticosteroids topical, inhaled or ophthalmic 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 Week12. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Key secondary Endpoints
-Percent change from baseline in fasting TC, non HDL-C, and ApoB at Week 12;
- Percent change from baseline in 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 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 and ApoA-II at Week 12, Week 24 and Week 52.
- Absolute change from baseline in fasting LDL-C, TC, HDL-C, non HDL-C,
TG, ApoB, ApoA-I, ApoA-II and Lp(a) at Week 12, Week 24 and Week 52.
- 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 | 10 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 50 |
| 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 |
| Bulgaria |
| Canada |
| Finland |
| Italy |
| Netherlands |
| Norway |
| Poland |
| South Africa |
| Spain |
| 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 Member State. 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 | 5 |
| E.8.9.1 | In the Member State concerned days | 25 |
| 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 | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 25 |
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