The Safety & Efficacy of Combination BMS-201038 (AEGR-733) & Ezetimibe vs. Monotherapy in Moderate Hypercholesterolemia

Condition(s) targeted: Hypercholesterolemia

Intervention: BMS-201038 (AEGR-733) (Drug); Ezetimibe (Drug)

Phase: Phase 2

Status: Completed

Sponsored by: University of Pennsylvania

Official(s) and/or principal investigator(s):
Michael Davidson, MD, Principal Investigator, Affiliation: Radiant Research
Jackson Downey, MD, Principal Investigator, Affiliation: Jacksonville Center for Clinical Research
Paul Grena, MD, Principal Investigator, Affiliation: Cardiology Consultants of Philadelphia
Barry Lubin, MD, Principal Investigator, Affiliation: Hampton Roads Center for Clinical Research
James McKenney, Pharm D, Principal Investigator, Affiliation: National Clinical Research
Eli Roth, MD, Principal Investigator, Affiliation: Sterling Research Group, LTD

The main objectives of this study are to evaluate the efficacy and safety of combination therapy BMS-201038 (AEGR-733) plus ezetimibe vs. each agent given alone on LDL cholesterol and other lipoproteins over 12 weeks of therapy.

Official title: A Randomized, Double-Blind, Active Controlled, Parallel-Group Study to Evaluate the Safety and Efficacy of the Combination BMS-201038 (AEGR-733) and Ezetimibe vs. Monotherapy in Subjects With Moderate Hypercholesterolemia

Study design: Treatment, Randomized, Double-Blind, Placebo Control, Parallel Assignment, Safety/Efficacy Study

Primary outcome: % LDL-C at 12 weeks therapy compared to baseline between treatments

Secondary outcome:

% changes at 12 weeks therapy compared to baseline between treatments for the following parameters:

other baseline serum lipoproteins (TC, non-HDL, VLDL, TG, HDL-C, Lp (a), apolipoproteins AI and B)

high sensitivity C-reactive protein

body weight

markers of safety and overall safety and tolerability.

Additional objectives are to characterize the safety and tolerability of BMS-201038 (AEGR-733) alone and in combination with ezetimibe.

Detailed description: Subjects will participate in this study for approximately 14-17 weeks. This study has 2 periods: 1) a 1-2-week screening period with 2 visits where baseline cholesterol and other characteristics will be evaluated to determine study eligibility. This period also includes a 4-week washout for patients on prior lipid-lowering therapies; and 2) a 12-week treatment period with interim visits at weeks 4 and 8.

Approximately 60 subjects will be randomized into one of 3 treatment arms with equal probability. In treatment arm 1, subjects will receive BMS-201038 (AEGR-733) 5 mg plus ezetimibe placebo. In treatment arm 2, subjects will receive BMS-201038 (AEGR-733) placebo plus 10 mg of ezetimibe. In treatment arm 3, subjects will receive BMS-201038 (AEGR-733) 5 mg plus ezetimibe 10 mg. After 4 weeks of treatment, subjects in arms 1 and 3 will be force-titrated to BMS-201038 (AEGR-733) 7. 5 mg. After another 4 weeks of treatment, subjects in arms 1 and 3 will then be force-titrated to BMS-201038 (AEGR-733) 10 mg for 4 more additional weeks of treatment. Subjects in arm 2 will continue to receive BMS-201038 (AEGR-733) matching placebo for the entire 12 weeks of treatment. Subjects randomized to ezetimibe 10 mg in arms 2 and 3 and ezetimibe placebo in arm 1 will remain on these doses for the entire 12-week treatment period.

Minimum age: 18 Years. Maximum age: 70 Years. Gender(s): Both.

Criteria:

Inclusion Criteria:

1. Men and women between the ages of 18 and 70 years .

2. For subjects with 0 to 1 risk factor (cigarette smoking, hypertension (BP > 140/90 or on antihypertensive medication), low HDL (<40mg/dl), family history of premature CHD (CHD in male first degree relative <55 years; CHD in female first degree relative <65 years), age (men> 45 years; women > 55 years): Baseline mean LDL-C must be >160 and <250 mg/dl as determined by the arithmetic mean of measures taken at visit 1 and 2. Fasting mean TGs should be <400 mg/dl.

3. For subjects with 2 or more risk factors (cigarette smoking, hypertension (BP > 140/90 or on antihypertensive medication), low HDL (<40mg/dl), family history of premature CHD (CHD in male first degree relative <55 years; CHD in female first degree relative <65 years), age (men> 45 years; women > 55 years) or prior stable CHD: Baseline mean LDL-C must be >130 and <250 mg/dl as determined by the arithmetic mean of measures taken at visit 1 and 2. Fasting mean TGs should be <400 mg/dl.

4. Able to understand and willing to comply with all study requirements, particularly the study drug regimen.

5. Able to understand and willing to sign the Informed Consent Form.

Exclusion Criteria:

1. Women who are pregnant or lactating or who are planning to become pregnant or women of child bearing potential who have not successfully been using acceptable contraceptive methods over the previous 3 months (e. g. intrauterine device and barrier method plus spermicide).

2. Uncontrolled hypertension defined as: systolic blood pressure > 180 mmHg, diastolic blood pressure > 95 mmHg

3. History of chronic renal insufficiency (serum creatinine >2. 5 mg/dL)

4. History of liver disease or transaminases above 1. 5 X ULN at screening

5. Any major surgical procedure occurring less than 3 months prior to the screening visit

6. Cardiac insufficiency defined by the NYHA classification as functional Class II-Class IV

7. History of a malignancy (other than basal cell or squamous cell carcinoma of the skin that has been removed) within the previous 5 years

8. Participation in an investigational drug study within 6 weeks prior to the screening visit.

9. Serious or unstable medical or psychological conditions that, in the opinion of the investigator, would compromise the subject’s safety or successful participation in the study.

10. Regular alcohol use > 1 drink per day

11. Regular consumers of grapefruit juice, or currently taking medications known to be metabolized by CYP 3A4 (cyclosporine, itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, and nefazodone)

12. Other lipid-lowering medications (washouts will be permitted)

13. Acute CVD (CVD event within the previous 6 months)

14. Diabetes Mellitus

Pharmanet, Inc, Princeton, New Jersey 08540-6242, United States

Starting date: May 2006
Ending date: January 2007
Last updated: November 28, 2006