Basim Ibrahim CRA student

Oxford college May 2014

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• 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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• 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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• 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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• 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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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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• 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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• 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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• 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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• 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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• 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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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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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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Trial design (SOP)

screeningInformed consent Washout period

RandomizationStart of

treatmentFollow

uptermination

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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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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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• 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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• 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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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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• 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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• 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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• 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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• 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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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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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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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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• 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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• 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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• 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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