This document summarizes a clinical trial that aims to compare the efficacy and safety of pitavastatin 4 mg once daily versus simvastatin 40 mg once daily in reducing LDL-C concentrations over 12 weeks in patients with primary hypercholesterolemia or combined dyslipidemia. The trial plans to enroll 355 patients across 15 centers in Canada in a randomized, double-blind, controlled trial. The primary endpoint is the percentage change in LDL-C concentrations from baseline to 12 weeks. Secondary endpoints include changes in other lipid variables. The trial procedures, inclusion/exclusion criteria, and safety and efficacy monitoring plans are described.

1. Basim Ibrahim CRA student
Oxford college May 2014
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2. • Coronary artery disease (CAD) is the most common
type of heart disease. It is the leading cause of death
and major disability worldwide.1
• It happens when the arteries that supply blood to
heart muscle become hardened and narrowed
(atherosclerosis).1
• Blood cholesterol levels are a strong predictor of
mortality and morbidity associated with CAD.2
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3. • Statins are used for the secondary prevention of
cardiovascular events in patients with CAD (including a
history of angina or acute myocardial infarction) and
for primary prevention in patients who are at
increased risk of cardiovascular vents because of
factors such as smoking, hypertension and diabetes.3
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4. • statins were shown to reduce the risks of major
vascular events, cardiac mortality, and overall
mortality by 21%, 19%, and 12%, respectively, for
each mmol/L decrease in LDL-C.4
• According to the latest WHO data published in April
2011 Coronary Heart Disease Deaths in Canada
reached 42,043 or 21.84% of total deaths.5
• Heart disease and stroke costs the Canadian economy
more than $20.9 billion every year.6
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7. • Pitavastatin is a potent, orally available inhibitor of
hepatic 3-hydroxy-3-methylglutaryl-coenzyme A
(HMG-CoA) reductase which is the major rate limiting
enzyme in cholesterol synthesis.8
• pitavastatin lowers total serum cholesterol and low
density lipoprotein (LDL) concentrations, thereby
reducing the risk of atherosclerosis and its
complications.8
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8. Product name pitavastatin
Dosage form Tablet form
Dosage available 1,2,4 mg/tablet
Administration Orally, once daily
indication Hyperlipedimia
hypercholesterolemia
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9. • patients experienced musculoskeletal symptom
(Myopathy) and mild creatine kinase (CK) elevation.
• Moderate asymptomatic elevations in hepatic
transaminase .
• Asymptomatic reduced energy and fatigue on
exertion .11
• Sever myopathy, rhabdomyolysis in rare occasion.13
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10. • Statin therapy reduced the incidence of myocardial
infarction, stroke by about one-third in high-risk
patients.12
• pitavastatin decrease cardiovascular mortality and
morbidity .13
• pitavastatin is an effective and well-tolerated statin
therapy.
Risk benefit ratio
• The potential benefits of this clinical trial will far
outweigh the potential risks
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11. • The protocol was approved by local institutional REB
committees at each centre, the trial conducted in
accordance with this protocol, health Canada, TCPS2
statement and GCP.
• All participants provided written informed consent
before inclusion in the study.
• No deviation from the protocol will be implemented
with out prior review and approval of REB except
where it may be necessary to eliminate an immediate
hazard to the patient.
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12. • 355 patient enrolled in the study.
• Men and women at the age of 18-74 years old.
• Meet inclusion criteria.
• 15 trial center involved across Canada.
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13. • The primary objective was to demonstrate
noninferiority of pitavastatin 4 mg once daily
compared with simvastatin 40 mg once daily
in reducing LDL-C concentrations.
• Secondary objectives were to assess the
long-term efficacy of the two drugs in
achieving the LDL-C targets.
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14. Design Method
Phase III
Allocation Randomized
Interventional model Parallel Assignment
Masking Double blind
Comparator controlled Simvistatin
Endpoint Classification Efficacy and safety study
Site Multicenter
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15. Arm Number of
participant
Assigned
intervention
Experimental
group: Pitavastatin
4 once daily
236 started treatment
at a dose of 2 mg,
and the dose was
increased to 4 mg
after 4 weeks.
Active Comparator
group: Simvastatin
40 mg once daily
119 initial dose was 20
mg, which was
increased to 40 mg
after 4 weeks.
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16. Trial design (SOP)
screening
Informed
consent Washout period
Randomization Start of
treatment
Follow
up
termination
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17. Primary end point Secondary end point
percentage change in LDL-C
concentrations at 12 weeks
compared with baseline
percentage changes from
baseline in concentrations of
triglycerides, total cholesterol,
HDL-C, non-HDL-C,
apolipoprotein B (Apo-B) and
apolipoprotein A1 (Apo-A1),
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18. After initial screening and assessment for criteria,
eligible patient will be given the informed consent.
• Upon receiving the completed informed consent
patients entered a lead-in and washout phase of 8
weeks if they had previously received lipid-modifying
therapy or 6 weeks if they had not previously received
such therapy.
• Patients randomized to pitavastatin started treatment
at a dose of 2 mg, and the dose was increased to 4
mg after 4 weeks.
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19. • In patients randomized to simvastatin, the initial dose
was 20 mg, which was increased to 40 mg after 4
weeks.
• Treatment was given once daily in the evening, and all
other lipid-modifying therapies were prohibited for the
duration of the study.
• All participant followed a fat- and cholesterol
restricted diet according to CAS guidelines.
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20. • Blood samples for lipid analyses were obtained
after a 12-hour fast on three occasions during
the run-in period and at weeks 0, 2, 4, 8, and 12
of the study.
• The study consisted of a 12-week initial
treatment period (the core study) followed by a
44-week extension.
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21. The clinical trial are planed to run through a full
course, however this trial will be terminated
earlier if:
• The sponsor (health Canada and/or heart and
stroke foundation determined to terminate the
present trial.
• Required by regulatory body or REB concerning
the safety and welfare of the patient .
• If sever and unexpected adverse event such as
death and permanent organ damage occur with
the patient.
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22. • Male and female aged 18-75 years.
• Primary hypercholesterolemia or combined
dyslipidemia.
• patients were required to have at least two of the
following cardiovascular risk factors.
• Patients who were receiving lipid-modifying therapies.
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23. • homozygous familial hypercholesterolemia.
• unstable medical conditions.
• significant cardiovascular disease, or symptomatic
heart failure (left ventricular ejection fraction <0.25)
or cerebrovascular disease, uncontrolled or poorly
controlled hypertension, uncontrolled diabetes.
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24. • Patient not compliant with medication for more than
one month and/or failure to attend 2 consecutive
follow up visit.
• impaired liver or kidney function, or other serious
medical conditions.
• Pregnant women.
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25. • Voluntary withdrawal.10
• Serious adverse drug event (myositis).
• Pregnant immediately withdrawal .
• Compromised liver function .
• Development and deterioration of any other clinical
status needed hospitalization.
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26. efficacy parameters included
• LDL-C Concentrations.
• Attainment of (CAS)Lipid Targets.9
• secondary lipid variables (concentrations of
triglycerides, total cholesterol, HDL-C, non-HDL-C,
triglycerides, Apo-B, and Apo-A1).
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27. safety parameters included
• routine blood chemistry.
• haematology.
• Urinalysis.
• liver enzymes (alanine aminotransferase and
aspartate aminotransferase).
• and creatine kinase (CK).
• Other safety evaluations included physical
examination, 12-lead electrocardiogram (ECG), and
vital signs.
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28. Only the following person will be granted the direct
access these confidential source data
• Principle investigator.
• Inspectors from health Canada.
• Auditor from REB.
• Patient and her/his legally acceptable representative.
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29. • This trial conducted in compliance with this protocol,
TCPS2 statement and GCP.
• Clinical research coordinator CRC will appointed as a
monitor to ensure such compliance.
• The CRC/monitor will also to be ensured to have
access to all study related information and facilities.
• The principle investigator will permit and accept any
audit or inspection by sponsor, health Canada and REB
• The term of adverse events according to CTCAE.
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30. • Source data will be enter into the e-CRF.
• All data will be enter into the secure
database on site with backup on the
hospital main server.
• The investigator and statistician will have
direct access to the data.
• All records will be kept for 25 years.
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31. • This trial is supported by health Canada, heart
and stroke foundation and Funded by CIHR.
• Researchers awarded funding from CIHR are
required to ensure that all research papers
generated from CIHR funded projects are freely
accessible through the Publisher's website or
online within 12 months of publication.14
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32. END
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