PROLIPOSTAT®: An Introductory study Introduction to the...

PROLIPOSTAT®: An Introductory study

Introduction to the PROLIPOSTAT® Student Practice Study:

Efficacy of the lowering effect of PROLIPOSTAT® on Blood concentrations of low-density lipoprotein cholesterol (LDL-C) in patients with normal and elevated blood concentrations of LDL-C: A Double-blind, controlled Phase II study (Randomized comparative method, multi-center study) It is a truism that the one of the best teachers is experience. Why? It is because we not only learn how to properly function in a job, but we also learn from our mistakes. To help KRC students gain valuable ‘Hands on’ experience without having to be preoccupied with possible errors, ClinProxy has developed an entire simulated practice study. This study has been designed to get the student involved in a practice study that, in all ways, simulates the real clinical environment. The study data are comprehensive and have been designed to demonstrate the same data trends that would occur in a in an actual study of this nature. It is you, the student, however, that must carry out all clinical study tasks, both independently and in teams with others, which determine what those trends are. When you have finished your Practice Study Tasks, you will be able to work on actual studies currently being conducted by ClinProxy. These include, but are not limited to, the following: · EGF03/CT: Phase II Study the Efficacy of the healing effect of recombinant human epidermal growth factor (rhEGF) on diabetic foot ulcers; Double-blind, controlled Phase II study (Randomized comparative method, multi-center study) · ISTA03/CT: Phase I Study the safety and Dose determination of Immuno - Stimulatory Therapy Agent for Bladder cancer, melanoma and colon cancer. · PU CR Survey: Proper Use and Cost Reduction strategies for prescription and non-prescription drugs in Ontario. After completing your assigned tasks with the actual clinical studies you will be able to list these tasks as actual work experience on your resume. The Practice study is a Phase II clinical study based upon the fictitious blood lipid lowering agent PROLIPOSTAT®. PROLIPOSTAT® belongs to a group of drugs called statins. Statins lower the blood cholesterol by a variety of mechanisms. Our Practice Study drug, PROLIPOSTAT®, is a lipid-lowering agent that is derived synthetically from a fermentation product of Aspergillus terreus. After oral ingestion, Prolipostat, which is an inactive lactone, is hydrolyzed to the corresponding β-hydroxyacid form. This is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. This enzyme catalyzes the conversion of HMG-CoA to mevalonate, which is an early and rate-limiting step in the biosynthesis of cholesterol. By this mechanism the amount of blood cholesterol produced is limited.

P R O T O C O L

STAT08/CH

Efficacy of the lowering effect of PROLIPOSTAT® on Blood concentrations of low-density lipoprotein cholesterol (LDL-C) in patients with normal and elevated blood

concentrations of LDL-C

Double-blind, controlled Phase II study (Randomized comparative method, multi-center study)

PROTOCOL NUMBER: 0159

CONFIDENTIAL INFORMATION

CLINPROXY Research Services.

375 N. Stephanie St., Suite 1411

Henderson, Nevada 89014-8909

Phone (702) 446-8458

Version 3: March 27, 2004

GENERAL INFORMATION

STUDY TITLE:

Phase II Study of the Efficacy of the lowering effect of PROLIPOSTAT on Blood concentrations of low-density lipoprotein cholesterol (LDL-C) in patients with normal and elevated blood concentrations of LDL-C. Randomized, Double-Blind, Placebo Control.

INDICATION:

Patients with Hypercholesterolemia Requiring Modifications of Lipid Profiles

OBJECTIVES:

To determine efficacy and optimal dose of PROLIPOSTAT® in lowering LDL-C in patients with hypercholesterolemia

STUDY DESIGN:

Randomized, double-blind, placebo-controlled, parallel group design.

SAMPLE SIZE AND PATIENT SELECTION CRITERIA:

600 patients (n=20 patients per group) from 30 centers in Canada.

Patients with Hypercholesterolemia Requiring Modifications of Lipid Profiles

TABLET FORMULATION:

PROLIPOSTAT® (STAT08/CH )is a lipid-lowering agent that is derived synthetically from a fermentation product of Aspergillus terreus. After oral ingestion, simvastatin, which is an inactive lactone, is hydrolyzed to the corresponding β-hydroxyacid form. This is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. This enzyme catalyzes the conversion of HMG-CoA to mevalonate, which is an early and rate-limiting step in the biosynthesis of cholesterol.

PROLIPOSTAT® (STAT08/CH) is butanoic acid, 2,2-dimethyl-,1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)-ethyl]-1-naphthalenyl ester, [1S-[1α,3α,7β,8β(2S*,4S*),-8aβ]]. The empirical formula of simvastatin is C25H38O5 and its molecular weight is 418.57.

PROLIPOSTAT® (STAT08/CH) is a white to off-white, non-hygroscopic, crystalline powder that is practically insoluble in water, and freely soluble in chloroform, methanol and ethanol.

Tablets of PROLIPOSTAT® (STAT08/CH) for oral administration contain 40 mg of PROLIPOSTAT® (STAT08/CH) and the following inactive ingredients: cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, iron oxides, lactose, magnesium

stearate, starch, talc, titanium dioxide and other ingredients. Butylated hydroxyanisole is added as a preservative.

SAFETY PARAMETERS:

At every visit, adverse events, vital signs, laboratory tests (hematology, blood chemistry, urinalysis, ECG) and physical exams.

Duration of Treatment

Run-in period – 2 weeks, treatment period – 24 weeks

STATISTICAL ANALYSIS:

Complete statistical analyses are fully detailed in the Statistical Analysis portion of the protocol.

A classic intent-to-treat analysis will be utilized after the 24 weeks of treatment from baseline comparing a significant decrease in LDL-C, whereas failure to significantly lower the LDL-C will be defined as ineffectual treatment.

Sponsor:

CLINPROXY Research Services.

375 N. Stephanie St., Suite 1411 Henderson, Nevada 89014-8909 Phone (702) 446-8458

1.0 Background information and Overall Goals

Coronary heart disease (or coronary artery disease) is a narrowing of the small blood vessels that supply blood and oxygen to the heart (coronary arteries). Coronary disease usually results from the build up of fatty material and plaque (atherosclerosis). Atherosclerosis is a common disorder of the arteries. Fat, cholesterol and other substances accumulate in the walls of arteries and form "atheromas" or plaques.

Eventually, this fatty tissue can erode the wall of the artery, diminish its elasticity (stretchiness) and interfere with blood flow. Plaques can also rupture, causing debris to migrate downstream within an artery. This is a common cause of heart attack and stroke.

Clots can also form around the plaque deposits, further interfering with blood flow and posing added danger if they break off and travel to the heart, lungs, or brain. Many physicians now suspect that there is an immune system component to the problem (inflammation may help cause atherosclerosis). As the coronary arteries narrow, the flow of blood to the heart can slow or stop. The disease can cause chest pain (stable angina), shortness of breath, heart attack, or other symptoms.

Cholesterol is an important normal constituent of the body. It is part of the structure of cell membranes, bile acids, and steroid hormones. Since cholesterol is water insoluble, most cholesterol is carried in the blood by lipoproteins (large protein-like molecules, including chylomicrons, very low density lipoprotein (VLDL), low density lipoprotein (LDL), and high density lipoprotein (HDL). Chylomicrons are lipoproteins that are present shortly after a meal, but disappear within about 2 hours in "normal" people.

The main function of LDL seems to be to carry cholesterol to various tissues throughout the body. Laboratory testing measures the cholesterol portion of the LDL molecule, rather than the actual concentration of LDL in the blood. This is also true for high density lipoprotein (HDL) and very low density lipoprotein (VLDL). The total cholesterol level is the sum of LDL, HDL, and VLDL cholesterol.

LDL is formed from very-low-density lipoprotein (VLDL) and is catabolized predominantly by the high-affinity LDL receptor. PROLIPOSTAT® is a specific inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the enzyme that catalyzes the conversion of HMG-CoA to mevalonate, which is an early and rate-limiting step in the biosynthesis of cholesterol. The mechanism of the LDL-lowering effect of PROLIPOSTAT® may involve both reduction of VLDL cholesterol concentration, and induction of the LDL receptor, leading to reduced production and/or increased catabolism of LDL-C. It is postulated that Apolipoprotein B (Apo B) will also fall substantially during treatment with PROLIPOSTAT®. As each LDL particle contains one molecule of Apo B, and

since in patients with predominant elevations in LDL-C (without accompanying elevation in VLDL) little Apo B is found in other lipoproteins, this strongly suggests that PROLIPOSTAT® does not merely cause cholesterol to be lost from LDL, but also reduces the concentration of circulating LDL particles. In addition, PROLIPOSTAT® is thought to reduce VLDL and TG and increase HDL-C. The effects of PROLIPOSTAT® on Lipoprotein(a), fibrinogen, and certain other independent biochemical risk markers for CHD are unknown.

In the current study, we postulated that there would be a lowering of Total-C, LDL-C, VLDL-C, Apo B within the circulating blood with a concomitant increase in the concentration of circulating HDL-C.

1.1 Summary of Pharmacological and Toxicological Studies

MECHANISM OF PROLIPOSTAT® ACTION

PROLIPOSTAT® (STAT08/CH) Lowers blood levels of TG, LDL-C, VLDL-C and Apo B through the down regulation of the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase enzyme, a rate limiting step in cholesterol biosynthesis.

1. Specific Effects

The involvement of low-density lipoprotein cholesterol (LDL-C) in atherogenesis has been well documented in clinical and pathological studies, as well as in many animal experiments.

Epidemiological studies have established that elevated plasma levels of total cholesterol (total-C), LDL-C, and apolipoprotein B (Apo B) promote human atherosclerosis and are risk factors for developing cardiovascular disease, while increased levels of high-density lipoprotein cholesterol (HDL-C) and its transport complex, Apo A-I, are associated with decreased cardiovascular risk. High plasma triglycerides (TG) and cholesterol-enriched TG-rich lipoproteins, including very-low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), and remnants, can also promote atherosclerosis. Elevated plasma TG are frequently found in a triad with low HDL-C and small LDL particles, as well as in association with non-lipid metabolic risk factors for Coronary Heart Disease (CHD). As such, total plasma TG has not consistently been shown to be an independent risk factor for CHD. Furthermore, the independent effect of raising HDL-C or lowering TG on the risk of coronary and cardiovascular morbidity and mortality has not been determined.

PROLIPOSTAT® has been shown to reduce both normal and elevated LDL-C concentrations. LDL is formed from very-low-density lipoprotein (VLDL) and is catabolized predominantly by the high-affinity LDL receptor. The mechanism of the LDL-lowering effect of PROLIPOSTAT® may involve both reduction of VLDL cholesterol concentration, and induction of the LDL receptor, leading to reduced production and/or increased catabolism of LDL-C. Apo B has also been observed to fall substantially during treatment with PROLIPOSTAT®. As each LDL particle contains one molecule of Apo B, and since in patients with predominant elevations in LDL-C (without accompanying elevation in VLDL) little Apo B is found in other lipoproteins, this strongly suggests that PROLIPOSTAT® does not merely cause cholesterol to be lost from LDL, but also reduces the concentration of circulating LDL particles. In addition, PROLIPOSTAT® reduces VLDL and TG

and increases HDL-C. The effects of PROLIPOSTAT® on Lp(a), fibrinogen, and certain other independent biochemical risk markers for CHD are unknown.

PROLIPOSTAT® is a specific inhibitor of HMG-CoA reductase, the enzyme that catalyzes the conversion of HMG-CoA to mevalonate. The conversion of HMG-CoA to mevalonate is an early step in the biosynthetic pathway for cholesterol.

2. General Pharmacology

PROLIPOSTAT® is a lactone that is readily hydrolyzed in vivo to the corresponding -hydroxyacid, a potent inhibitor of HMG-CoA reductase. Inhibition of HMG-CoA reductase is the basis for an assay in pharmacokinetic studies of the -hydroxyacid metabolites (active inhibitors) and, following base hydrolysis, active plus latent inhibitors (total inhibitors) in plasma following administration of PROLIPOSTAT®.

Following an oral dose of 14C-labeled PROLIPOSTAT® in man, 13% of the dose was excreted in urine and 60% in feces. The latter represents absorbed drug equivalents excreted in bile, as well as any unabsorbed drug. Plasma concentrations of total radioactivity (PROLIPOSTAT® plus 14C-metabolites) peaked at 4 hours and declined rapidly to about 10% of peak by 12 hours postdose. Absorption of PROLIPOSTAT®, estimated relative to an intravenous reference dose, in each of two animal species tested, averaged about 85% of an oral dose. In animal studies, after oral dosing, PROLIPOSTAT® achieved substantially higher concentrations in the liver than in non-target tissues. Simvastatin undergoes extensive first-pass extraction in the liver, its primary site of action, with subsequent excretion of drug equivalents in the bile. As a consequence of extensive hepatic extraction of PROLIPOSTAT® (estimated to be > 60% in man), the availability of drug to the general circulation is low. In a single-dose study in nine healthy subjects, it was estimated that less than

5% of an oral dose of PROLIPOSTAT® reaches the general circulation as active inhibitors. Following administration of PROLIPOSTAT® tablets, the coefficient of variation, based on between-subject variability, was approximately 48% for the area under the concentration-time curve (AUC) for total inhibitory activity in the general circulation.

Both PROLIPOSTAT® and its -hydroxyacid metabolite are highly bound (approximately 95%) to human plasma proteins. Animal studies have not been performed to determine whether PROLIPOSTAT® crosses the blood-brain and placental barriers. However, when radiolabeled PROLIPOSTAT® was administered to rats, PROLIPOSTAT®-derived radioactivity crossed the blood-brain barrier.

The major active metabolites of PROLIPOSTAT® present in human plasma are the -hydroxyacid of PROLIPOSTAT® and its 6’-hydroxy, 6’-hydroxymethyl, and 6’-exomethylene derivatives. Peak plasma concentrations of both active and total

inhibitors were attained within 1.3 to 2.4 hours postdose. While the recommended therapeutic dose range is 5 to 80 mg/day, there was no substantial deviation from linearity of AUC of inhibitors in the general circulation with an increase in dose to as high as 120 mg. Relative to the fasting state, the plasma profile of inhibitors was not affected when PROLIPOSTAT® was administered immediately before an American Heart Association recommended low-fat meal.

In a study including 16 elderly patients between 70 and 78 years of age who received PROLIPOSTAT® 40 mg/day, the mean plasma level of HMG-CoA reductase inhibitory activity was increased approximately 45% compared with 18 patients between 18-30 years of age. Clinical study experience in the elderly (n=1522), suggests that there were no overall differences in safety between elderly and younger patients

Kinetic studies with another reductase inhibitor, having a similar principal route of elimination, have suggested that for a given dose level higher systemic exposure may be achieved in patients with severe renal insufficiency (as measured by creatinine clearance).

In a study of 12 healthy volunteers, PROLIPOSTAT® at the 80-mg dose had no effect on the metabolism of the probe cytochrome P450 isoform 3A4 (CYP3A4) substrates midazolam and erythromycin. This indicates that PROLIPOSTAT® is not an inhibitor of CYP3A4, and, therefore, is not expected to affect the plasma levels of other drugs metabolized by CYP3A4.

The risk of myopathy is increased by high levels of HMG-CoA reductase inhibitory activity in plasma. Potent inhibitors of CYP3A4 can raise the plasma levels of HMG-CoA reductase inhibitory activity and increase the risk of myopathy.

PROLIPOSTAT® is a substrate for CYP3A4. Grapefruit juice contains one or more components that inhibit CYP3A4 and can increase the plasma concentrations of drugs metabolized by CYP3A4. In one study2, 10 subjects consumed 200 mL of double-strength grapefruit juice (one can of frozen concentrate diluted with one rather than 3 cans of water) three times daily for 2

days and an additional 200 mL double-strength grapefruit juice together with and 30 and 90 minutes following a single dose of 60 mg PROLIPOSTAT® on the third day. This regimen of grapefruit juice resulted in mean increases in the concentration (as measured by the area under the concentration-time curve) of active and total HMG-CoA reductase inhibitory activity [measured using a radioenzyme inhibition assay both before (for active inhibitors) and after (for total inhibitors) base hydrolysis] of 2.4-fold and 3.6-fold, respectively, and of PROLIPOSTAT® and its -hydroxyacid metabolite [measured using a chemical assay —liquid chromatography/tandem mass spectrometry] of 16-fold and 7-fold, respectively. In a second study, 16 subjects consumed one 8 oz glass of single-strength grapefruit juice (one can of frozen concentrate diluted with 3 cans of water) with breakfast for 3 consecutive days and a single dose of 20 mg simvastatin in the evening of the third day. This regimen of grapefruit juice resulted in a mean increase in the plasma concentration (as measured by the area under the concentration-time curve) of active and total HMG-CoA reductase inhibitory activity [using a validated enzyme inhibition assay different from that used in the first study, both before (for active inhibitors) and after (for total inhibitors) base hydrolysis] of 1.13-fold and 1.18-fold, respectively, and of PROLIPOSTAT® and its -hydroxyacid metabolite [measured using a chemical assay — liquid chromatography/tandem mass spectrometry] of 1.88-fold and 1.31-fold, respectively. The effect of amounts of grapefruit juice between those used in these two studies on PROLIPOSTAT® pharmacokinetics has not been studied.

3. Pharmacokinetics and Toxicology

CNS Toxicity

Optic nerve degeneration was seen in clinically normal dogs treated with PROLIPOSTAT® for 14 weeks at 180 mg/kg/day, a dose that produced mean plasma drug levels about 12 times higher than the mean plasma drug level in humans taking 80 mg/day.

A chemically similar drug in this class also produced optic nerve degeneration (Wallerian degeneration of retinogeniculate fibers) in clinically normal dogs in a dose-dependent fashion starting at 60 mg/kg/day, a dose that produced mean plasma drug levels about 30 times higher than the mean plasma drug level in humans taking the highest recommended dose (as measured by total enzyme inhibitory activity). This same drug also produced vestibulocochlear Wallerian-like degeneration and retinal ganglion cell chromatolysis in dogs treated for 14 weeks at 180 mg/kg/day, a dose that resulted in a mean plasma drug level similar to that seen with the 60 mg/kg/day dose.

CNS vascular lesions, characterized by perivascular hemorrhage and edema, mononuclear cell

Infiltration of perivascular spaces, perivascular fibrin deposits and necrosis of small vessels were seen in dogs treated with PROLIPOSTAT® at a dose of 360 mg/kg/day, a dose that produced mean plasma drug levels that were about 14 times higher than the mean plasma drug levels in humans taking 80 mg/day. Similar CNS vascular lesions have been observed with several other drugs of this class.

There were cataracts in female rats after two years of treatment with 50 and 100 mg/kg/day (22 and 25 times the human AUC at 80 mg/day, respectively) and in dogs after three months at 90 mg/kg/day (19 times) and at two years at 50 mg/kg/day (5 times).

Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 72-week carcinogenicity study, mice were administered daily doses of PROLIPOSTAT® of 25, 100, and 400 mg/kg body weight, which resulted in mean plasma drug levels approximately 1, 4, and 8 times higher than the mean human plasma drug level, respectively (as total inhibitory activity based on AUC) after an 80-mg oral dose. Liver carcinomas were significantly increased in high-dose females and mid- and high-dose males with a maximum incidence of 90% in males. The incidence of adenomas of the liver was significantly increased in mid- and high-dose females. Drug treatment also significantly increased the incidence of lung adenomas in mid- and high-dose males and females. Adenomas of the Harderian gland (a gland of the eye of rodents) were significantly higher in high-dose mice than in controls. No evidence of a tumorigenic effect was observed at 25 mg/kg/day.

In a separate 92-week carcinogenicity study in mice at doses up to 25 mg/kg/day, no evidence of a tumorigenic effect was observed (mean plasma drug levels were 1 times higher than humans given 80 mg PROLIPOSTAT® as measured by AUC).

In a two-year study in rats at 25 mg/kg/day, there was a statistically significant increase in the incidence of thyroid follicular adenomas in female rats exposed to approximately 11 times higher levels of PROLIPOSTAT® than in humans given 80 mg PROLIPOSTAT® (as measured by AUC).

A second two-year rat carcinogenicity study with doses of 50 and 100 mg/kg/day produced hepatocellular adenomas and carcinomas (in female rats at both doses and in males at 100 mg/kg/day).

Thyroid follicular cell adenomas were increased in males and females at both doses; thyroid follicular cell carcinomas were increased in females at 100 mg/kg/day. The increased incidence of thyroid neoplasms appears to be consistent with findings from other HMG-CoA reductase inhibitors. These treatment levels represented plasma drug levels (AUC) of approximately 7 and 15 times (males) and 22 and 25 times (females) the mean human plasma drug exposure after an 80 milligram daily dose.

No evidence of mutagenicity was observed in a microbial mutagenicity (Ames) test with or without rat or mouse liver metabolic activation. In addition, no evidence of damage to genetic material was noted in an in vitro alkaline elution assay using rat hepatocytes, a V-79 mammalian cell forward mutation study, an in vitro chromosome aberration study in CHO cells, or an in vivo chromosomal aberration assay in mouse bone marrow.

There was decreased fertility in male rats treated with PROLIPOSTAT® for 34 weeks at 25 mg/kg body weight (4 times the maximum human exposure level, based on AUC, in patients receiving 80 mg/day); however, this effect was not observed during a subsequent fertility study in which PROLIPOSTAT® was administered at this same dose level to male rats for 11 weeks (the entire cycle of spermatogenesis including epididymal maturation). No microscopic changes were observed in the testes of rats from either study. At 180 mg/kg/day, (which produces exposure levels 22 times higher than those in humans taking 80 mg/day based on surface area, mg/m2), seminiferous tubule degeneration (necrosis and loss of spermatogenic epithelium) was observed. In dogs, there was drug-related testicular atrophy, decreased spermatogenesis, spermatocytic degeneration and giant cell formation at 10 mg/kg/day, (approximately 2 times the human exposure, based on AUC, at 80 mg/day). The clinical significance of these findings is unclear.

Pregnancy

Safety in pregnant women has not been established.

PROLIPOSTAT®(STAT08/CH) was not teratogenic in rats at doses of 25 mg/kg/day or in rabbits at doses up to 10 mg/kg daily. These doses resulted in 3 times (rat) or 3 times (rabbit) the human exposure based on mg/m2 surface area. However, in studies with another structurally-related HMG-CoA reductase inhibitor, skeletal malformations were observed in rats and mice.

Rare reports of congenital anomalies have been received following intrauterine exposure to HMG-CoA reductase inhibitors. In a review of approximately 100 prospectively followed pregnancies in women exposed to other structurally related HMG-CoA reductase inhibitors, the incidences of congenital anomalies, spontaneous abortions and fetal deaths/stillbirths did not exceed what would be expected in the general population. The number of cases is adequate only to

exclude a 3- to 4-fold increase in congenital anomalies over the background incidence. In 89% of the prospectively followed pregnancies, drug treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified. As safety in pregnant women has not been established and there is no apparent benefit to therapy with PROLIPOSTAT® during pregnancy, treatment should be immediately discontinued as soon as pregnancy is recognized. PROLIPOSTAT® should be administered to women of child-bearing potential only when such patients are highly unlikely to conceive and have been informed of the potential hazards.

2.0 Trial Objectives and Purpose

To determine efficacy and optimal dose of PROLIPOSTAT® in the lowering of Total Cholesterol, VLDL Cholesterol, LDL Cholesterol and Apolipoprotein B in the Blood

The criteria to be used in the study for patient selection are:

1) Patients diagnosed with CHD or at high risk of CHD requiring a reduction in risk of CHD Mortality and Cardiovascular Events

2) Patients with Hypercholesterolemia Requiring Modifications of Lipid Profiles

3) Patients who are between 25 and 55 years of Age

The patients will be seen in the designated multidisciplinary heart clinic in our heart center. Throughout the study patients will have their blood drawn and analyzed for LD-C, HDL-C, TG and Apo(B) so that a continuous lipid profile can be developed.

The lipid profile will performed to measure total-C, HDL-C, and TG. For patients with TG less than 400 mg/dL (< 4.5 mmol/L), LDL-C can be estimated using the following equation:

LDL-C = total-C – [(0.20 x TG) + HDL-C]

For TG levels > 400 mg/dL (> 4.5 mmol/L), this equation is less accurate and LDL-C concentrations should be determined by ultracentrifugation. Lipid determinations will be performed at intervals of no less than four weeks and dosage adjusted to the patient's weight.

For VLDL-C:

VLDL = TC - HDL - LDL

2.1 Trial Design

The patients will be seen in the designated multidisciplinary heart clinic in the heart center.

Overall Coronary Heart Disease (CHD) control will be maximized by the study cardiologist. Comprehensive heart and lipid assessment will be carried out by the cardiologist, including the determination of VLDL, LDL-C, HDL-C

2 Study Events Schedule

At the initial consultation, patients will be evaluated with a view to their inclusion in the trial. At the initial consultation, patients whose profiles do not match the Inclusion/ Exclusion criteria will be excluded. Informed consent will be obtained, and randomization will be performed by drawing envelopes. Patients will be randomly assigned into three groups:

group 1 (treated with PROLIPOSTAT®, 40 mg Tablets),

group 2 (treated with PROLIPOSTAT®, 80 mg Tablets),

and group 3 (treated with Placebo)

The study protocol and consent form will be approved by the ethics committee of the United Christian Hospital.

STAT08/CH STUDY EVENT SCHEDULE

The Phase II Clinical Study for the Evaluation of the Efficacy STAT08/CH

A summary of the major events of the Phase II clinical study to determine the efficacy of rhEGF on diabetic foot ulcers is as follows:

Visit 1 2 3 4 5

Screen Baseline 1 month 2

months 3

months Informed Consent X Inclusion/Exclusion X Medical history X Demographics X Vital signs X X X X X ECG X X X Chest X ray X Physical exam X X X X Laboratory Safety Tests X X X X X VLDL-C X X X X X LDL-C X X X X X HDL-C X X X X X

TG X X X X X Apo (B) X X X X X Total-C X X X X X Concomitant therapy X X X X X Dispense Medication X² Medication Compliance X Tablet Accountability X X Adverse events X X X

Screening Visit , Day 1; Week 1:

The first visit is the Screening visit. The following activities should be monitored and the source documents verified and appropriate copies made of reports:

• Validation of all informed consent forms and appropriate copies made, • Check to ensure that all inclusion/exclusion criteria have been applied and

new subjects brought on study as necessary. • Medical history completed. • Chest X-ray, ECG done • Complete Blood Lipid profile (VLDL-C, LDL-C, HDL-C, TG, Apo(B) and

Total-C) • Subjects are checked for use of concomitant medications.

Baseline Visit 1, on or about 14 days of screening ( Day 1, Week 1 of Treatment)

This is the start of the actual treatment regimen. The following activities should be monitored and the source documents verified and appropriate copies made of reports:

• Vital signs and laboratory safety tests done. • Complete Blood Lipid profile (VLDL-C, LDL-C, HDL-C, TG, Apo(B) and

Total-C) • Lipid levels are checked. If lipids lowered >8% with conventional dietary

treatment, subjects will be excluded. • If patients excluded other candidates will need to be brought on study to

adjust for statistical sample. • Changes or additions to concomitant medications are checked. • Patients will be randomly assigned into three groups: group 1 PROSTAT®

(STAT08/CH) 40mg Tablets, group 2 PROSTAT® (STAT08/CH) 80mg Tablets, and group 3 placebo.

• Instruction on the use of medication is given and the medication is dispensed to all study subjects and all data on medication recorded.

• Volunteer Subject drop-outs checked for reasons; new volunteer subjects brought online, if required.

• CRFs checked for completeness • Any IRB/SMB issues reviewed • Remedial action, if any, recorded • Code breakage checked

Study Visit 2, Day 28, Week 4 (1 month of treatment)

Subjects have been receiving treatment for 4 weeks. The following activities should be monitored and the source documents verified and appropriate copies made of reports:

• Vital signs, ECG and laboratory Safety tests done. • Physical examination performed. • Complete Blood Lipid profile (VLDL-C, LDL-C, HDL-C, TG, Apo(B) and

Total-C) • Check done for dropouts and subjects who may have worsening

conditions and may need to be dropped. New subjects brought on study, if required.

• Changes or additions to concomitant medications checked • Adverse events checked • Safety Assessments collected and monitoring staff will conduct SDV • CRFs checked for completeness • Any IRB/SMB issues reviewed • Remedial actions, if any, recorded • Code breakage checked

Study Visit 3, Day 56, Week 8 (2 months of treatment)


• Vital signs, ECG and laboratory Safety tests done.

• Physical examination performed.

• Complete Blood Lipid profile (VLDL-C, LDL-C, HDL-C, TG, Apo(B) and Total-C)

• Check done for dropouts and subjects who may have worsening conditions and may need to be dropped. New subjects brought on study, if required.

• Changes or additions to concomitant medications checked • Subject medication compliance checked (80% compliance required) • Tablet accountability checked • Adverse events checked • Safety Assessments collected and monitoring staff will conduct SDV • CRFs checked for completeness • Any IRB/SMB issues reviewed • Remedial actions, if any, recorded • Code breakage checked

Study Visit 4, Day 82, Week 12 (3 months of treatment)


• Vital signs, ECG and laboratory safety tests done.

• Complete Blood Lipid profile (VLDL-C, LDL-C, HDL-C, TG, Apo(B) and Total-C)

• Check done for dropouts and subjects who may have worsening conditions and may need to be dropped. New subjects brought on study, if required.

• Changes or additions to concomitant medications checked • Adverse events checked • Tablet accountability done • CRFs checked for completeness • Any IRB/SMB issues reviewed • Remedial actions if any, recorded • Code breakage checked

3.0 Study Population/Selection of Patients

600 patients (n=20 patients per group) from 30 centers in Canada.

• Patients diagnosed with CHD or at high risk of CHD requiring a reduction in risk of CHD Mortality and Cardiovascular Events

• Patients with Hypercholesterolemia Requiring Modifications of Lipid Profiles

Evaluation and profiling period – 2 weeks, treatment period – 24 weeks

3.1 Inclusion Criteria

1. Informed consent obtained from the patient and caregiver (and representative or guardian if different from caregiver) prior to entry into the study.

2. Patients diagnosed with CHD or at high risk of CHD requiring a reduction in risk of CHD Mortality and Cardiovascular Events

3. Patients with Hypercholesterolemia Requiring Modifications of Lipid Profiles

4. Patients will be Male and Females aged 25-55 years

3.2 Exclusion Criteria

1. Patients who are pregnant should be excluded. Patients at imminent risk of a major coronary event

2. Patients using itraconazole, ketoconazole, erythromycin, clarithromycin, HIV protease inhibitors, nefazodone, or large quantities of grapefruit juice (>1 quart daily) should be excluded, as should patients Concomitant using other medicines labeled as having a potent inhibitory effect on CYP3A4.

3. Patients using gemfibrozil should be excluded. Other lipid-lowering drugs (other fibrates or lipid-lowering doses (≥1 g/day) of niacin) can cause myopathy even when given alone.

4. Patients receiving cyclosporine should be excluded.

5. Patient with Diabetes mellitus should be excluded

6. Patients undergoing treatment with cholesterol-lowering statins within the past 6 months.

All patients starting clinical testing with STAT08/CH should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness or weakness. STAT08/CH therapy should be discontinued immediately if myopathy is diagnosed or suspected. The presence of these symptoms, and/or a CK level >10 times the ULN indicates myopathy. In most cases, when patients were promptly discontinued from treatment, muscle symptoms and CK should resolve themselves. Periodic CK determinations may be considered if any patients complain of tenderness.

Persistent increases (to more than 3X the ULN) in serum transaminases have occurred in 3 patients who received STAT08/CH in clinical studies. When drug treatment was interrupted or discontinued in these patients, the transaminase levels usually fell slowly to pretreatment levels. The increases were not associated with jaundice or other clinical signs or symptoms. There was no evidence of hypersensitivity.

3.2 Withdrawal of Patients

Reasonable efforts to keep each patient in the study should be made and must be documented by the investigator. The patient and the caregiver have the right to withdraw from the study at any time for any reason. The investigator has the right to withdraw a patient from the study in the event of an intercurrent illness, adverse event, protocol violation, etc.

If the investigator removes a patient from treatment or if a patient declines further participation, a study termination visit should be performed at the time of study withdrawal. The study termination visit includes all procedures normally performed at the 24 weeks (final study visit).

4.0 Ethics and Regulatory Considerations

This study will be conducted according to Good Clinical Practice, the Declaration of Helsinki (Protocol Appendix A), and ICH Consolidated Guideline as adopted by the TPD, Part 50 Protection of Human Subjects, and Part 56 - Institutional Review Boards. Written informed consent for the study must be obtained from all subjects and caregivers prior to protocol-specific procedures, including cognitive testing, are carried out. Patients will be informed of their right to withdraw from the study at any time.

Institutional Review Board (IRB) must be constituted according to the applicable requirements of each participating location and have in place written procedures and adequate membership.

All required documents (protocol, amendments, informed consent document, investigator brochure etc) will be submitted to all applicable IRBs and written unconditional approval obtained and submitted to Contract Research Organization prior to tablet shipment and start of any study procedures.

Informed Consent will encompass all the elements required by ICH and the Declaration of Helsinki (Protocol Appendix A). Informed consent documents and information must be provided in both oral and written form whenever possible. Only IRB approved consents and information can be utilized. It must be clearly demonstrated and understood that ample opportunity to inquire about details of the study be given to patients, caregivers etc during the consent process.

5.0 STUDY PROCEDURES

Case report forms will be provided by the sponsor/CRO, as well as all materials (including investigational agent and placebo), laboratory collection kits and shipment packaging, etc required to conduct the study.

5.1 VISIT 1: Screening Visit

Patients who are considered potential candidates for the study (as per the inclusion and exclusion criteria) and their responsible caregivers will sign an informed consent form and provide the patient's medical history and for the withdrawal of blood for establishing reference data. Potential study participants will undergo a physical examination (including vital signs). A Comprehensive Heart and lipid assessment will be carried out by the cardiologist including all routine safety tests to assist in the establishment of baseline values. Lipid Baseline data will include the determination of VLDL-C, LDL-C, HDL-C, TG, Total C and Apo(B).

All concomitant medications will be recorded on the case report form (CRF). It will be expected that the supporting raw data for Visit 1 will be available in the source document for review by the monitoring staff.

5.2 VISIT 2: Baseline Visit

The baseline visit should be scheduled on or about 14 days post screening visit. In the second consultation, we will exclude patients whose Total C has decreased >8% with conventional dietary strategies. Informed consent will be obtained, and randomization will be performed by drawing envelopes. Patients will be randomly assigned into three groups:

Group 1: STAT08/CH 80 mg/tablet,

Group 2: STAT08/CH 40mg/tablet

Group 3: Placebo.

Dosing Begins.

5.3 Visit 3

This visit will take place 56 days (+-week) after the baseline visit (Visit 2). The schedules of events for this visit are identified in the study events calendar. Adverse events, changes in concomitant therapy, safety assessments will also be collected. Monitoring staff will conduct SDV for this visit.

5.4 Visit 4

This visit will take place 110 days (+ - week) days after the baseline visit (Visit 2). The schedules of events for this visit are identified in the study events calendar. Adverse events, changes in concomitant therapy, safety assessments will also be collected. Monitoring staff will conduct SDV for this visit.

5.5 Visit 5

This visit will take place 150 days (+ - week) days after the baseline visit (Visit 2). The schedules of events for this visit are identified in the study events calendar. Adverse events, changes in concomitant therapy, safety assessments will also be collected. At this visit a 12 lead ECG will be performed and compared to the screening ECG to assess what if any change has occurred. This is the final study visit.

6.0 Investigational Product

PROLIPOSTAT® (STAT08/CH), 40 & 80 Mg tablets, to be administered orally.

6.1 Allocation, Randomization and Description

Each patient who successfully completes the screening visit and continues to the baseline visit will be randomized to a unique double-blind patient randomization number.

Patients will be randomly assigned into three groups:

Group 1: STAT08/CH 80 mg/tablet,

Group 2: STAT08/CH 40mg/tablet

Group 3: Placebo.

Randomizations are recorded in the source document and the appropriate CRF. Randomization numbers will be allocated using a block format and the numbers will be provided for each site (medication, medication logs and blinded codes will be included).

6.2 Breaking the Code

Scratch off labels will be provided for all investigational product/placebo. In the event of an emergency and after discussion with the sponsor/CRO the investigator can determine the treatment allocation of the patient. The sponsor/CRO will also have identical scratch off labels for all study medication should the need to unblind a patient in the absence of an investigator (i.e. emergency room visit) occur.

6.3 Storage

Investigational agent/placebo must be stored in a locked cabinet with limited access. The tablets are not light or heat sensitive and can be stored at room temperature.

6.4 Tablet Accountability

Shipment of tablets to sites will be accompanied by a tablet shipment form which must be signed and dated upon receipt and faxed back to the sponsor/CRO. This form must be filed in the investigator binder. Tablet accountability, per patient, will be performed by the monitor after Visit 3 and again at the end of the study prior to tablet return.

6.5 Assessment of Compliance

Compliance will be recorded by the study coordinator or investigator during Visit 3 and must be documented in the source document and appropriate CRF. Patients must have greater than 80% compliance or they will be deemed in protocol violation; however they would remain in study for the gathering of safety data.

7.0 STUDY METHODS

7.1 Safety Assessment

A complete patient history and physical examinations will be performed at the screening visit. The complete Physical Examinations will be repeated at visits 3, 4 & 5.

7.3 Efficacy Parameters

Change form baseline (Visit 2) will be measured to assess the primary efficacy measure. Efficacy Measurements will include:

• Downward trends in VLDL-C and LD-C

• Downward trends in triglycerides

• Upward trends in HDL-C

Downward trend in Total-C

7.4 Reasons for Early Treatment Discontinuation

Reasonable efforts to keep each patient in the study should be made and must be documented by the investigator. The patient and the caregiver have the right to withdraw from the study at any time for any reason. The investigator has the right to withdraw a patient from the study in the event of an intercurrent illness, adverse event, protocol violation, etc. If the investigator removes a patient from treatment or if a patient declines further participation, a study termination visit should be performed at the time of study withdrawal. The study termination visit includes all procedures normally performed at the 12 week (3 month) final study visit.

The primary reason for treatment discontinuation should be noted on the study termination form using the following categories:

1. Safety Risk and/or Adverse event. The patient has experienced an adverse event, which, in the opinion of the investigator, requires early termination

2. Death.

3. Protocol Violation.

4. Noncompliance in returning for visits and/or in administration of study medication.

5. In the investigator's judgment, it is in the patient's best interest.

6. Consent is withdrawn. The patient wishes to withdraw from the study in the absence of a medical need to withdraw as determined by the investigator.

7. The study is terminated by the sponsor.

8. Loss of caregiver. The patient no longer has a responsible caregiver to oversee patient visits and administration of medication.

8.0 ADVERSE EVENT

8.1 Collecting and Documenting Adverse events

It is the responsibility of-the investigator to document all adverse events, which occur during the investigation. An adverse event includes any pathological or unintended change in anatomical, physiological or metabolic functions as indicated by physical signs, symptoms and/or laboratory changes occurring in any phase of the clinical study, whether associated with the study tablets or placebo and whether or not considered tablet related. This includes an exacerbation of pre-existing conditions or events, intercurrent illness, treatment interaction or the significant worsening of the disease under study.

All adverse events occurring after the baseline visit (Visit 2) must be reported at each visit. Adverse events will be recorded and evaluated by the investigator. Adverse events not previously documented in the study will be recorded in the adverse event section in the case report form. The nature of each individual experience, date and time of onset, duration, severity, and relationship to treatment should be established by the individual investigator. Details of change to the dosing schedule or any corrective treatment must be recorded on the appropriate pages of the case report form.

Adverse events already documented in the CRF, at a previous visit, and designated as 'continuing' should be reviewed at each visit. If an adverse event is resolved, the documentation in the CRF must be completed to that effect. NB: If an adverse event changes in frequency or severity during a study period, a NEW record of that experience will be initiated.

Soliciting of adverse events should be non-specific and subjects should be asked the question: "Do you feel different in any way since starting the new treatment?"

8.2 Assessment of Severity If any adverse events have occurred they will be recorded on the adverse event report page and their intensity will be graded. Symptoms should be graded as follows:

MILD: An adverse event, which is easily tolerated by the patient, causing minimal

discomfort and not interfering in daily activities.

MODERATE: An adverse event, which is sufficiently discomforting to interfere with normal everyday activities.

SEVERE: An adverse event, which prevents normal everyday activities. Hospitalization of greater than 24 hours.

8.3 Assessment of Relationship

Every effort should be made by investigators to explain each adverse event and assess its relationship, if any, to study cream treatment. Causality should be assessed using the following categories: definite, probable, possible, unknown, not related.

The degree of certainty with which an adverse event is attributed to treatment (or alternative causes, e.g., natural history of the underlying diseases or concomitant therapy) will be determined by how well the event can be understood in terms of one or more of the following:

1. Time of the experience between dose and the onset of the adverse event;

2. Remaining tablet levels and evidence, if any, of overdosage;

3. A known or expected response pattern to the test substance;

This includes:

a. Previous experience with the test substance or vehicle and whether the adverse event is known to have occurred with the test substance or vehicle;

b. Physiological effect of the cream;

c. Is the adverse event known as an adverse event related to other creams, which belong to the same or to a similar class?

d. Can the experience be explained by the pharmacological action or with regards to findings in animal studies?

e. Has the patient a specific genetic disposition (e.g. slow acetylizer)?

4. Alternative explanations for the adverse event, such as the use of other treatments, illness, non-oral therapies, diagnostic tests, procedures, or other confounding effects. This includes:

a. Did the adverse event also happen with placebo?

Definitions are given below for a five-category system that will be used to classify the relationship between adverse event and vehicle. Assessment will be made by the investigator first. The Sponsor will give its clinical judgment after having evaluated all accessible data and, if necessary, will re-evaluate the case as new information becomes available.

Definite

An adverse event that follows a reasonable temporal sequence from administration of the oral tablets (including the course after withdrawal of the tablets) and that satisfies any of the following:

• Reappearance of a similar reaction by repeated exposure (Rechallenge)

• Toxic level of the treatment substance in body fluids

Probable

An adverse event that follows a reasonable temporal sequence from administration of the oral tablets (including the course after withdrawal of the tablets), and that can exclude the possibilities of other factors, such as underlying disease, complications, concomitant creams or concurrent treatment, than the test substance.

Possible

An adverse event that follows a reasonable temporal sequence from administration of the oral tablets (including the course after withdrawal of the tablets), that cannot exclude the possibilities of the oral tablets themselves (*), although other factors such as underlying disease, complications, concomitant creams or concurrent treatment are presumable.

*e.g., existence of similar reports attribute to the test treatment and/or its analogues.

*Reactions attributable to the pharmacological effect.

Unknown

This category should be reserved for an adverse event that lacks data sufficient for assessment (Judgment withheld). Investigators should avoid assignment to this category if at all possible.

Not related

An adverse event that does not follow a reasonable temporal sequent from administration of the cream, or that can be reasonably explained by other factors, including underlying disease, complications, concomitant creams or concurrent treatment.

The investigator will make a judgment regarding whether or not, in his/her opinion; the adverse event will be related to the test treatment. However, even if the investigator feels there is no relationship to the test treatment, the adverse event should be reported.

8.4 Laboratory Values

The investigator will also evaluate any change in laboratory values; make a determination as to whether the change is clinically or not clinically significant and whether or not the change will be related to the investigational agent.

8.4 Following-Up Adverse events The investigator will follow-up patients who experience an adverse events until the event has subsided, the condition is considered medically stable, or the patient is no longer available for follow-up. Patients who discontinue the study treament due to adverse events (clinical or laboratory) will be treated and followed according to established acceptable medical practice—all pertinent information concerning the outcome of such treatment will be entered on the Case Report Forms. Reports relative to a subject's subsequent course must be submitted to the clinical study monitor.

8.6 Serious Adverse events A serious adverse event is any event which is fatal, life threatening, disabling or incapacitating or results in hospitalization, prolongs a hospital stay or is associated with congenital abnormality, cancer, overdose. In addition any experience which the investigator regards as serious or which would suggest any significant hazard, contraindication, side effect or precaution that may be associated with the use of the cream should be reported as a serious experience.

Because of the need to report to health authorities all serious adverse events in a timely manner, it is vitally important that an investigator report immediately any adverse events which by the above definition would be considered serious, even if the investigator does not consider the adverse event to be clinically significant or cream-related.

An adverse event is life-threatening if the patient will be at immediate risk of death from the event as it occurred; i.e. it does not include a reaction that, if it had occurred in a more serious form, might have caused death.

An adverse event in incapacitating or disabling if the experience results in a substantial and/or permanent disruption of the subject's ability to carry out normal life functions.

Reporting Serious Adverse events

ANY SERIOUS ADVERSE EVENT (INCLUDING DEATH) DUE TO ANY CAUSE, WHICH OCCURS DURING THE COURSE OF THIS INVESTIGATION, WHETHER OR NOT RELATED TO THE INVESTIGATIONAL SPRAY, MUST BE REPORTED IMMEDIATELY TO CLINPROXY Research Services. BY TELEPHONE OR FAX. IF THE EXPERIENCE IS REPORTED BY PHONE, A FAX SHOULD IMMEDIATELY FOLLOW. IT IS IMPERATIVE THAT CLINPROXY Research Services. BE INFORMED WITHIN 24 HOURS OF A SERIOUS ADVERSE EVENT SO THAT REPORTING REQUIREMENTS TO THE FDA CAN BE MET WITHIN THE REQUIRED TIME FRAME (3 OR 10 DAYS).

The Contract Research Organization will be collecting and compiling serious adverse event information from the sites. As the CLINPROXY Research Services., is the agent for the IND, the Contract Research Organization is required by regulatory bodies to report all serious and unexpected adverse events that are associated with the use of the Test Treatment in clinical trials. Once the investigator has determined that an adverse event has occurred which meets the regulatory authority definition of serious, this should be reported immediately to CLINPROXY Research Services. A determination will then be made as to whether the serious adverse event will be also unexpected and associated with the use of the test treatment.

With respect to the timeliness of the reporting of serious adverse events for investigational drugs, regulations require that all serious adverse events that are both unexpected and associated with the use of the test treatment must be reported in writing within 10 working days of notification of Contract Research Organization of the serious adverse event. If the serious adverse event is fatal or immediately life-threatening, there is an additional obligation of Contract Research Organization to notify the regulatory authorities by telephone within 3 working days, with a follow-up written report in 10 working days.

There can be serious consequences including, ultimately, criminal and/or civil penalties for sponsors who fail to comply with the regulations governing the reporting of serious adverse experiences to the regulatory authorities. Each investigator in this study has the responsibility of promptly informing Contract Research Organization of all serious adverse events so that Contract Research Organization can comply with these regulations.

Any serious adverse event which occurs during the clinical study or within 30 days (or five half- lives whichever is longer) of receiving the last dose of study medication, whether or not related to the test treatment, must be reported by the investigator to the study monitor by telephone or fax within 24 hours. Investigators should not wait to receive additional information to fully document the event before notifying Contract Research Organization or its designee of a serious adverse event. The telephone report should be followed by a full written summary detailing all relevant aspects of the adverse event in question.

Instances of death, cancer or congenital abnormality, if brought to the attention of the investigator AT ANY TIME after cessation of the study medication and linked by the investigator to a previous clinical trial MUST be reported to the study monitor.

9.0 DATA ANALYSIS

9.1 Analytical Plan Analysis will be based on intention to treat. A t test for continuous data and a Kruskal-Wallis test and a test for categorical data will be used for comparison of baseline characteristics among the three groups. A Kaplan-Meier plot will be used to examine the time to maximum treatment effect in each group. Data will be censored at 12 weeks. A log-rank test will be used to compare the time to maximum treatment effect among the different groups.

Exact test.

9.2 Safety Monitoring Board (SMB)

An Independent Safety Monitoring Board will be established by CLINPROXY Research Services. to review the safety of all patients enrolled in the trial on an ongoing basis. No CLINPROXY Research Services. employee or investigator involved in the trial will be a voting member of the SMB. The SMB will periodically review the safety of the data collected. The SMB will be regularly informed of the occurrence of any serious adverse events and immediately notified of any fatal or life-threatening events. The SMB will initially be provided with data blinded to treatment arm. The SMB can request and unblinding of the treatment groups if there is a safety concern. After reviewing the emerging safety data, the SMB will make recommendations regarding the conduct of the study. These recommendations include amending the safety monitoring procedures, modifying the protocol or consent, performing additional analyses, terminating the study, or continuing the study as designed. The discussions and recommendations of the SMB will be summarized in a written report following each SMB meeting and forwarded to CLINPROXY Research Services..

10.0 CASE REPORT FORMS

All patient data generated by the study will be recorded on the case report forms provided by the sponsor.

The forms consist of three-part NCR paper and should be filled out with a black ballpoint pen or typewriter. The top two sheets (original and first copy) are the property of CLINPROXY Research Services. and will be collected by CLINPROXY Research Services. The prink copy is for the investigator's files and must be made available for review by CLINPROXY Research Services'S medical director, CLINPROXY Research Services'S monitors and appropriate representatives of regulatory agencies.

Documents relevant to the conduct of the study and distribution of the investigational treatment (e.g., Case Report Forms, consent forms, laboratory test results, medication inventory records and other pertinent information) must be retained by the investigator for a period of at least 2 years following the date that a New Drug Application (NDA) is approved for the indication being investigated or, if no application is filed or approved for such indication, until 2 years after the investigation is discontinued.

Sample:

ClinProxy Center, Inc. – Protocol STAT08/CH – CRF Version 1 27 March/04

VISIT VISIT DATE PT. INITIALS SCREEN NUMBER

SCREEN – Visit 1 ____/____/____ ___ ___ ___ ___ ___ - ___ ___

Exclusion Criteria – Any Yes answer excludes patient

YES NO

Patients who are pregnant should be excluded Patients at imminent risk of a major coronary event Patients using itraconazole, ketoconazole, erythromycin, clarithromycin, HIV protease inhibitors,

nefazodone, or large quantities of grapefruit juice (>1 quart daily) should be excluded, as should patients Concomitant using other medicines labelled as having a potent inhibitory effect on CYP3A4. Patients using gemfibrozil should be excluded. Other lipid-lowering drugs (other fibrates or lipid-lowering doses (≥1 g/day) of niacin) can cause myopathy even when given alone

Patients receiving cyclosporine should be excluded Patient with Diabetes mellitus should be excluded Patients undergoing treatment with cholesterol-lowering statins within the past 6 months.

Patients whose Total C has decreased >8% from screening (visit 1) values with conventional dietary strategies (Visit 2 only)

Demographics Sex: Male Female Date of Birth

_____/_____/_____ Race:

Caucasian

Black

Oriental

Other: _______________

specify

Marital Status:

Married

Divorced

Separated

Widowed

Other: _______________

specifiy Domiciliary Status: Lives with spouse

Lives with child(ren)

Lives with friend

Lives on own

Other: ______________

specify

Medical History

* If any current medication is indicated above, please complete Concomitant Med page

Condition

Active In-Active Date of Diagnosis

Current Treatment*

Yes

No

___/___/___

Yes No

Yes

No

___/___/___

Yes No

Yes

No

___/___/___

Yes No

Yes

No

___/___/___

Yes No

Yes

No

___/___/___

Yes No

Yes

No

___/___/___

Yes No

Yes

No

___/___/___

Yes No

Vital Signs

Heart rate (bpm): _____________ Respiration: __________

(breaths/minute)

Sitting blood pressure (mmHg): ______/______ Oral temperature: ________ºC

Height (cm): _____.___ Weight (kg): _____.___

Physical Exam

Norm Abnormal Not Done Comment (only if abnormal) Head/neck

Ears, nose, throat

Eyes (funduscopy)

Lymph nodes

Thorax

Lungs

Abdomen

Skin

Heart and blood vessels

Musculoskeletal

General appearance

VLDL-C LDL-C HDL-C TG Apo (B) Total-C

Result Clinically Significant* Not Clinically Significant

TFTs

B12 /

VDRL /

ECG

Chest x-ray

* for any clinically significant result exclude patient

CURRENT MEDICATIONS (include all medications taken within 3 months of screen visit.

UNITS ROUTE

MCG Microgram u

Units IH Inhaled PR Rectal MG Milligram CA Capsules ID Intradermal PV Vaginal GM Gram TB Tablets IL Intralesional sc Subcutaneous

ML Milliliter GT Drops IM Intramuscular SL Sublingual ME Milliequivalent OT Other IV Intravenous TP Topical IU International PO Oral OT Other

Units

Drug Name Dose Unit Route Start Date DD/MM/YY

Stop Date DD/MM/YY

Ongoing circle

Yes/No

Indication

/ / / / Yes No

/ / / / Yes No

/ / / / Yes No

/ / / / Yes No

/ / / / Yes No

/ / / / Yes No

/ / / / Yes No

/ / / / Yes No

/ / / / Yes No

/ / / / Yes No

/ / / / Yes No

/ / / / Yes No

/ / / / Yes No

/ / / / Yes No

/ / / / Yes No

Medication Compliance:

Bottle Number*

# Dispensed Date Dispensed

# Returned Date Returned

Compliance %

*Bottle Number must match Randomization Number

11.0 PATIENT CONFIDENTIALITY

The Contract Research Organization and CLINPROXY Research Services affirm and uphold the principle of the patient's right to protection against invasion of privacy. Throughout this study, all data will only be identified in the Case Report Forms by an identification number and patient initials. The data will be blinded correspondingly in all data analyses.

However, in compliance with regulatory guidelines concerning the acceptance of clinical studies in support of a New Treatment Application and in fulfillment of its obligations to CLINPROXY Research Services to verify compliance with this protocol, the Contract Research Organization requires that the investigator permit it’s monitor and/or CLINPROXY Research Services'S monitor and representatives from regulatory authorities to review that portion of the patient's primary medical records which directly concerns this study (including, but not limited to laboratory test result reports, ECG reports, admission / discharge summaries for hospital admissions occurring during a patient's study participation and autopsy reports for deaths occurring during the study).

Should access to such medical records require a waiver or authorization separate from the statement of informed consent, the investigator will obtain such permission in writing from the patient before the patient is entered into the study.

12.0 PUBLICATION POLICY

It is CLINPROXY Research Services.'S policy that the study will be published by the study investigators. Any data analysis conducted independently by an investigator resulting in manuscripts (including abstracts) must be submitted to the Contract Research Organization and CLINPROXY Research Services for review and comments. CLINPROXY Research Services has the right to review the submitted manuscript/abstract for 30 days prior to submission.

13.0 Investigator Agreement:

SPONSOR: CLINPROXY Research Services..

TITLE: Efficacy of the lowering effect of PROLIPOSTAT® (STAT08/CH) on Blood concentrations of low-density lipoprotein cholesterol (LDL-C) in patients with normal and elevated blood concentrations of LDL-C

Protocol Number 0159

Version 1: March 23, 2004

I have read the above noted protocol, and agree to conduct this study in accordance with all stipulations of the protocol and in accordance with the Declaration of Helsinki and Good Clinical Practice.

----------------------------------- --------------------------------------

Investigator Date

======================================

PROTOCOL APPENDIX A

World Medical Association Declaration of Helsinki

Recommendations guiding investigators in

biomedical research involving human subjects

Adopted By the 18th World Medical Assembly, Helsinki, Finland, June 1964,

Amended By the 29th World Medical Assembly,

Venice, Italy, October 1983

And The 41st World Medical Assembly Hong Kong, September 1989

INTRODUCTION

It is the mission of the investigator to safeguard the health of the people. His or her knowledge and conscience are dedicated to the fulfillment of this mission.

The Declaration of Geneva of the World Medical Association binds the investigator with the words, 'The health of my patient will be my first consideration", and the International Code of Medical Ethics declares that, "An investigator shall act only in the patient's interest when providing medical care which might have the effect of weakening the physical and mental condition of the patient."

The purpose of biomedical research involving human subjects must be to improve diagnostic, therapeutic and prophylactic procedures and the understanding of the etiology and pathogenesis of disease.

In current medical practice most diagnostic, therapeutic or prophylactic procedures involve hazards. This applies especially to biomedical research.

Medical progress is based on research, which ultimately must rest in part of experimentation involving human subjects.

In the field of biomedical research a fundamental distinction must be recognized between medical research in which the aim is essentially diagnostic or therapeutic for a patient, and medical research, the essential object of which is purely scientific and

without implying direct diagnostic or therapeutic value to the person subjected to the research.

Special caution must be exercised in the conduct of research which may affect that

environment, and the welfare of animals used for research must be respected.

Because it is essential that the results of laboratory experiments be applied to human beings for further scientific knowledge and to help suffering humanity, the World Medical Association has prepared the following recommendations as a guide to every investigator in biomedical research involving human subjects. They should be kept under review in the future. It must be stressed that the standards as drafted are only a guide to investigators all over the world. Investigators are not relieved from criminal, civil and ethical responsibilities under the laws of their own countries.

I. BASIC PRINCIPLES

1. Biomedical research involving human subjects must conform to generally accepted scientific principles and should be based on adequately performed laboratory and animal experimentation and on a thorough knowledge of the scientific literature.

2. The design and performance of each experimental procedure involving human subjects should be clearly formulated in an experimental protocol which should be transmitted for consideration, comment and guidance to a specially appointed committee independent of the investigator and CLINPROXY Research Services provided that this independent committee is in conformity with the laws and regulations of the country in which the research experiment is performed.

3. Biomedical research involving human subjects should be conducted only be scientifically qualified persons under the supervision of a clinically competent medical person. The responsibility for the human subject must always rest with a medically qualified person and never rest on the subject of the research, even though the subject has given his or her consent.

4. Biomedical research involving human subjects cannot legitimately be carried out unless the importance of the objective is in proportion to the inherent risk to the subject.

5. Every biomedical research project involving human subjects should be preceded with careful assessment of predictable risks in comparison with foreseeable benefits to the subject or to others. Concern for the interests of the subject must always prevail over the interests of science and society.

6. The right of the research subject to safeguard his or her integrity must always be respected. Every precaution should be taken to respect the privacy of the subject and to minimize the impact of the study on the subject's physical and mental integrity and on the personality of the subject.

7. Investigators should abstain from engaging in research projects involving human subjects unless they are satisfied that the hazards involved are believed to be predictable. Investigators should cease any investigation if the hazards are found to outweigh the potential benefits.

8. In publication of the results of his or her research, the investigator is obliged to preserve the accuracy of the results. Reports of experimentation not in accordance with the principles laid down in this Declaration should not be accepted for publication.

9. In any research on human beings, each potential subject must be adequately informed of the aims methods, anticipated benefits and potential hazards of the study and the discomfort it may entail. He or she should be informed that he or she is at liberty to abstain from participation in the study and that he or she is free to withdraw his or her consent to participation at any time. The investigator should then obtain the subject's freely-given informed consent, preferably in writing.

10. When obtaining informed consent for the research project, the investigator should be particularly cautious if the subject is in a dependent relationship to him or her or may consent under duress. In that case the informed consent should be obtained by an investigator who is not engaged in the investigation and who is completely independent of this official relationship.

11. In case of legal incompetence, informed consent should be obtained from the legal guardian in accordance with national legislation. Where physical or mental incapacity makes it impossible to obtain informed consent, or when the subject is a minor, permission from the responsible relative replaces that of the subject in accordance with national legislation. Whenever the minor child is in fact able to give consent, the minor's consent must be obtained in addition to the consent of the minor's legal guardian.

12. The research protocol should always contain a statement of ethical considerations involved and should indicate that the principles enunciated in the present Declaration are complied with.

II. MEDICAL RESEARCH COMBINED WITH PROFESSIONAL CARE (Clinical Research)

1. 1. In the treatment of the sick person, the investigator must be free to use a new diagnostic and therapeutic measure, if in his or her judgment it offers hope of saving life, re-establishing health or alleviating suffering.

2. 2. The potential benefits, hazards and discomfort of a new method should be weighed against the advantages of the best current diagnostic and therapeutic methods.

3. 3. In any medical study, every patient including those of a control group, if any, should be assured of the best proven diagnostic and therapeutic method.

4. 4. The refusal of the patient to participate in a study must never interfere with the investigator-patient relationship.

5. 5. If the investigator considers it essential not to obtain informed consent, the specific reasons for this proposal should be stated in the experimental protocol for transmission to the independent committee (1,2).

6. 6. The investigator can combine medical research with professional care, the objective being the acquisition of new medical knowledge, only to the extent that medical research is justified by its potential diagnostic or therapeutic value for the patient.

III. NON-THERAPEUTIC BIOMEDICAL RESEARCH INVOLVING HUMAN SUBJECTS

(Non-clinical biomedical research)

1. In the purely scientific application of medical research carried out on a human being, it is the duty of the investigator to remain the protector of the life and health of that person on whom biomedical research is being carried out.

2. The subjects should be volunteers - either healthy persons or patients for whom the experimental design is not related to the patient's illness.

3. The investigator or the investigating team should discontinue the research if in his/her or their judgment it may, if continued, be harmful to the individual.

4. In research on man, the interest of science and society should never take precedence over considerations related to the well-being of the subject.

CONCOMITANT MEDICATIONS:

Has patient experiences and changes in concomitant medication:

Yes* No

*if yes please add to concomitant medications CRF.

Has patient experienced any adverse events:

Yes* No

*if yes please add to adverse event CRF.

PROLIPOSTAT®: An Introductory study Introduction to the...

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