Hypercholesterolemia
Conditions
Keywords
Cholesterol
Brief summary
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.
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. 85 subjects were 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.
Interventions
DRUGBMS-201038 (AEGR-733)
DRUGEzetimibe
Sponsors
Aegerion Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Percent Change in LDL-C at 12 Weeks Therapy Compared to Baseline Between Treatments | Baseline and 12 weeks of treatment |
Secondary
| Measure | Time frame |
|---|---|
| Percent Change in HDL-C at 12 Weeks Compared to Baseline | Baseline and 12 weeks of treatment |
| Percent Change in Lipoprotein(a)[Lp(a)]at 12 Weeks as Compared to Baseline | Baseline and 12 weeks of treatment |
| Percent Change in Apolipoprotein A1 (Apo A1) at 12 Weeks as Compared to Baseline | baseline and 12 weeks of treatment |
| Percent Change in Apolipoprotein B (Apo B) at 12 Weeks as Compared to Baseline | Baseline and 12 weeks of treatment |
| Percent Change in Body Weight at 12 Weeks as Compared to Baseline | Baseline and 12 weeks of treatment |
| Percent of Change at 12 Weeks Therapy Compared to Baseline Between Treatments for the Following Parameters: Total Cholesterol (TC) | Baseline and 12 weeks of treatment |
| Percent Change in Non-high-density Lipoprotein Cholesterol (Non-HDL-C) at 12 Weeks as Compared to Baseline. | Baseline and 12 weeks of treatment |
| Percent Change in Tryglycerides (TGs) at 12 Weeks Compared to Baseline | Baseline and 12 weeks of treatment |
| Percent Change in High-sensitivity C-reactive Protein (Hs-CRP) at 12 Weeks as Compared to Baseline | Baseline and 12 weeks of treatment |
Countries
United States
Participant flow
Recruitment details
The study was performed from 30 Jun 2006 to 27 Dec 2006. A total of 6 medical clinics participated in the study.
Pre-assignment details
Patients who were previously on a lipid lowering therapy underwent a 4-week washout period.
Participants by arm
| Arm | Count |
|---|---|
| Combination Therapy Oral ezetimibe 10 mg and lomitapide escalated with an initial oral dose of 5 mg for 4 weeks and then escalated through 2 additional dose levels (7.5 mg and 10 mg) every 4 weeks over an 8-week period. | 28 |
| Lomitapide Monotherapy Oral ezetimibe placebo and lomitapide escalated with an initial oral dose of 5 mg for 4 weeks and then escalated through 2 additional dose levels (7.5 mg and 10 mg) every 4 weeks over an 8-week period. | 28 |
| Ezetimibe Monotherapy Oral ezetimibe 10 mg and lomitapide placebo for 12 weeks. | 29 |
| Total | 85 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 4 | 9 | 4 |
| Overall Study | Lost to Follow-up | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Combination Therapy | Total | Ezetimibe Monotherapy | Lomitapide Monotherapy |
|---|---|---|---|---|
| Age, Continuous | 55.1 years STANDARD_DEVIATION 5.7 | 55.7 years STANDARD_DEVIATION 7.48 | 54.7 years STANDARD_DEVIATION 9 | 57.5 years STANDARD_DEVIATION 7.2 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 9 Participants | 22 Participants | 7 Participants | 6 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 18 Participants | 62 Participants | 22 Participants | 22 Participants |
| Region of Enrollment United States | 28 participants | 85 participants | 29 participants | 28 participants |
| Sex: Female, Male Female | 14 Participants | 45 Participants | 18 Participants | 13 Participants |
| Sex: Female, Male Male | 14 Participants | 40 Participants | 11 Participants | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 24 / 28 | 24 / 28 | 15 / 29 |
| serious Total, serious adverse events | 0 / 28 | 1 / 28 | 0 / 29 |
Outcome results
Primary
Percent Change in LDL-C at 12 Weeks Therapy Compared to Baseline Between Treatments
Time frame: Baseline and 12 weeks of treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Combination Therapy | Percent Change in LDL-C at 12 Weeks Therapy Compared to Baseline Between Treatments | -46.2 Percent Change | Standard Deviation 23.8 |
| Lomitapide Monotherapy | Percent Change in LDL-C at 12 Weeks Therapy Compared to Baseline Between Treatments | -29.9 Percent Change | Standard Deviation 15.3 |
| Ezetimibe Monotherapy | Percent Change in LDL-C at 12 Weeks Therapy Compared to Baseline Between Treatments | -19.6 Percent Change | Standard Deviation 9.9 |
Secondary
Percent Change in Apolipoprotein A1 (Apo A1) at 12 Weeks as Compared to Baseline
Time frame: baseline and 12 weeks of treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Combination Therapy | Percent Change in Apolipoprotein A1 (Apo A1) at 12 Weeks as Compared to Baseline | -10.7 Percent Change | Standard Deviation 15.8 |
| Lomitapide Monotherapy | Percent Change in Apolipoprotein A1 (Apo A1) at 12 Weeks as Compared to Baseline | -8.0 Percent Change | Standard Deviation 12.3 |
| Ezetimibe Monotherapy | Percent Change in Apolipoprotein A1 (Apo A1) at 12 Weeks as Compared to Baseline | 2.3 Percent Change | Standard Deviation 9.5 |
Secondary
Percent Change in Apolipoprotein B (Apo B) at 12 Weeks as Compared to Baseline
Time frame: Baseline and 12 weeks of treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Combination Therapy | Percent Change in Apolipoprotein B (Apo B) at 12 Weeks as Compared to Baseline | -36.6 Percent Change | Standard Deviation 21.7 |
| Lomitapide Monotherapy | Percent Change in Apolipoprotein B (Apo B) at 12 Weeks as Compared to Baseline | -23.7 Percent Change | Standard Deviation 14.2 |
| Ezetimibe Monotherapy | Percent Change in Apolipoprotein B (Apo B) at 12 Weeks as Compared to Baseline | -14.5 Percent Change | Standard Deviation 10.6 |
Secondary
Percent Change in Body Weight at 12 Weeks as Compared to Baseline
Time frame: Baseline and 12 weeks of treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Combination Therapy | Percent Change in Body Weight at 12 Weeks as Compared to Baseline | -1.4 Percent Change | Standard Deviation 2.9 |
| Lomitapide Monotherapy | Percent Change in Body Weight at 12 Weeks as Compared to Baseline | -1.0 Percent Change | Standard Deviation 2.2 |
| Ezetimibe Monotherapy | Percent Change in Body Weight at 12 Weeks as Compared to Baseline | -0.1 Percent Change | Standard Deviation 2.3 |
Secondary
Percent Change in HDL-C at 12 Weeks Compared to Baseline
Time frame: Baseline and 12 weeks of treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Combination Therapy | Percent Change in HDL-C at 12 Weeks Compared to Baseline | -9.2 Percent Change | Standard Deviation 14.4 |
| Lomitapide Monotherapy | Percent Change in HDL-C at 12 Weeks Compared to Baseline | -6.2 Percent Change | Standard Deviation 10.8 |
| Ezetimibe Monotherapy | Percent Change in HDL-C at 12 Weeks Compared to Baseline | 5.9 Percent Change | Standard Deviation 9.6 |
Secondary
Percent Change in High-sensitivity C-reactive Protein (Hs-CRP) at 12 Weeks as Compared to Baseline
Time frame: Baseline and 12 weeks of treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Combination Therapy | Percent Change in High-sensitivity C-reactive Protein (Hs-CRP) at 12 Weeks as Compared to Baseline | 40.4 Percent Change | Standard Deviation 80.7 |
| Lomitapide Monotherapy | Percent Change in High-sensitivity C-reactive Protein (Hs-CRP) at 12 Weeks as Compared to Baseline | 81.3 Percent Change | Standard Deviation 337.6 |
| Ezetimibe Monotherapy | Percent Change in High-sensitivity C-reactive Protein (Hs-CRP) at 12 Weeks as Compared to Baseline | 233.3 Percent Change | Standard Deviation 874.9 |
Secondary
Percent Change in Lipoprotein(a)[Lp(a)]at 12 Weeks as Compared to Baseline
Time frame: Baseline and 12 weeks of treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Combination Therapy | Percent Change in Lipoprotein(a)[Lp(a)]at 12 Weeks as Compared to Baseline | -12.0 Percent Change | Standard Deviation 23.7 |
| Lomitapide Monotherapy | Percent Change in Lipoprotein(a)[Lp(a)]at 12 Weeks as Compared to Baseline | -11.4 Percent Change | Standard Deviation 29.1 |
| Ezetimibe Monotherapy | Percent Change in Lipoprotein(a)[Lp(a)]at 12 Weeks as Compared to Baseline | 7.5 Percent Change | Standard Deviation 24.1 |
Secondary
Percent Change in Non-high-density Lipoprotein Cholesterol (Non-HDL-C) at 12 Weeks as Compared to Baseline.
Time frame: Baseline and 12 weeks of treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Combination Therapy | Percent Change in Non-high-density Lipoprotein Cholesterol (Non-HDL-C) at 12 Weeks as Compared to Baseline. | -41.3 Percent Change | Standard Deviation 22.7 |
| Lomitapide Monotherapy | Percent Change in Non-high-density Lipoprotein Cholesterol (Non-HDL-C) at 12 Weeks as Compared to Baseline. | -26.9 Percent Change | Standard Deviation 14.6 |
| Ezetimibe Monotherapy | Percent Change in Non-high-density Lipoprotein Cholesterol (Non-HDL-C) at 12 Weeks as Compared to Baseline. | -17.0 Percent Change | Standard Deviation 10.5 |
Secondary
Percent Change in Tryglycerides (TGs) at 12 Weeks Compared to Baseline
Time frame: Baseline and 12 weeks of treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Combination Therapy | Percent Change in Tryglycerides (TGs) at 12 Weeks Compared to Baseline | -7.0 Percent Change | Standard Deviation 36 |
| Lomitapide Monotherapy | Percent Change in Tryglycerides (TGs) at 12 Weeks Compared to Baseline | -5.8 Percent Change | Standard Deviation 33.6 |
| Ezetimibe Monotherapy | Percent Change in Tryglycerides (TGs) at 12 Weeks Compared to Baseline | 2.7 Percent Change | Standard Deviation 35.1 |
Secondary
Percent of Change at 12 Weeks Therapy Compared to Baseline Between Treatments for the Following Parameters: Total Cholesterol (TC)
Time frame: Baseline and 12 weeks of treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Combination Therapy | Percent of Change at 12 Weeks Therapy Compared to Baseline Between Treatments for the Following Parameters: Total Cholesterol (TC) | -34.4 Percent Change | Standard Deviation 18.8 |
| Lomitapide Monotherapy | Percent of Change at 12 Weeks Therapy Compared to Baseline Between Treatments for the Following Parameters: Total Cholesterol (TC) | -22.8 Percent Change | Standard Deviation 12.3 |
| Ezetimibe Monotherapy | Percent of Change at 12 Weeks Therapy Compared to Baseline Between Treatments for the Following Parameters: Total Cholesterol (TC) | -12.0 Percent Change | Standard Deviation 8.7 |