Hyperlipidemia
Conditions
Keywords
LDL, hepatic fat
Brief summary
To determine safety and effectiveness of low-dose therapeutic AEGR-733 +/- atorvastatin, ezetimibe or fenofibrate (compared to placebo) on liver fat accumulation measured by Magnetic Resonance Spectroscopy
Detailed description
The goal within the current development program and this study is to investigate whether lower doses of AEGR-733 can result in significant reductions in LDL-C and TGs while providing fewer gastrointestinal adverse events and less hepatic fat accumulation than seen in studies with higher doses. The potential for atorvastatin, ezetimibe or the PPAR-alpha agonist (fenofibrate) to ameliorate any hepatic fat accumulation will also be investigated. The twelve week dosing schedule allows us to demonstrate the longer term effects of lower doses of MTP-I on hepatic fat accumulation.
Interventions
DRUGAEGR-733
3 capsules each evening for each 4-week period
DRUGplacebo
3 capsules each evening for each 4-week period
DRUGAEGR-733 and atorvastatin
3 capsules each evening for each 4-week period
DRUGAEGR-733 and fenofibrate
3 capsules each evening for each 4-week period
DRUGAEGR-733 and ezetimibe
3 capsules each evening for each 4-week period
Sponsors
Aegerion Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
1. LDL-C between 100 and 190 mg/dL 2. Hepatic fat under 6.2% per MRS
Exclusion criteria
1. Pregnant or lactating females 2. Uncontrolled hypertension \>180/95 mmHg 3. Chronic renal insufficiency - serum creatinine \>2.5 mg/dL at screen 4. Liver disease; i.e., hepatitis, cirrhosis 5. Major surgery within 3 months of screen 6. Cardiac insufficiency 7. Hx of malignancy other than basal or squamous cell within past 5 yrs 8. Participation in any investigational drug study within 6 wks of screen 9. Prior exposure to AEGR-733 in past 12 months 10. Serious or unstable medical or psychological conditions 11. More than one alcoholic drink per day 12. Regular consumption of grapefruit juice or meds known to be metabolized by CYP 3A4 13. Currently taking corticosteroids 14. Other lipid-lowering meds (washout permitted) 15. Fish oil, niacin grater than 200 mg/day and herbal weight loss products (washout permitted) 16. Acute CVD or event within previous 6 months 17. Diabetes Mellitus 18. Hepatitis B or C 19. Medicated COPD 20. Idiopathic pulmonary fibrosis 21. G.I. disorders that cause chronic diarrhea 22. Fasting triglycerides =/\> 400 mg/dL 23. Body Mass Index \> 35kg/m2
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Absolute Change From Baseline in Percent Hepatic Fat | Baseline and 12 weeks on study drug | Absolute change from Baseline in percent hepatic fat |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Absolute Change From Baseline in Percent Hepatic Fat | Baseline and 12 weeks on study drug | Absolute change from Baseline in percent hepatic fat |
Countries
United States
Participant flow
Recruitment details
The study was performed from 06 Sept 2007 to 05 Sept 2008. A total of 16 medical clinics participated in the study.
Pre-assignment details
Subjects underwent a 5- to 9-week screening washout period to determine study eligibility and to wash-out patients of all lipid-lowering therapies; patients were required to have low-density lipoprotein cholesterol (LDL-C) between 100 and 190 mg/dL (average of 2 visits during screening) and hepatic fat less than 6.2% for randomization.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Oral placebo every 4 weeks for 12 weeks | 33 |
| AEGR-733 2.5 mg Oral lomitapide 2.5 mg every 4 weeks for 12 weeks | 34 |
| AEGR-733 5 mg Oral lomitapide 5 mg every 4 weeks for 12 weeks | 34 |
| AEGR-733 7.5 mg Oral lomitapide 7.5 mg every 4 weeks for 12 weeks | 34 |
| AEGR-733 10 mg Oral lomitapide 10 mg every 4 weeks for 12 weeks | 35 |
| AEGR-733 5 mg + Atorvastatin 20 mg Oral lomitapide 5 mg + atorvastatin 20 mg every 4 weeks for 12 weeks | 28 |
| AEGR-733 5 mg + Fenofibrate 145 mg Oral lomitapide 5 mg + micronized fenofibrate 145 mg every 4 weeks for 12 weeks | 33 |
| AEGR-733 5 mg + Ezetimibe 10 mg Oral lomitapide 5 mg + ezetimibe 10 mg every 4 weeks for 12 weeks | 29 |
| Total | 260 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 |
|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 7 | 8 | 5 | 11 | 4 | 4 | 2 |
| Overall Study | Inclusion/exclusion criteria not met | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
| Overall Study | Lost to Follow-up | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 1 | 2 | 0 | 3 | 1 | 0 | 2 |
Baseline characteristics
| Characteristic | AEGR-733 5 mg + Ezetimibe 10 mg | Total | Placebo | AEGR-733 2.5 mg | AEGR-733 5 mg | AEGR-733 7.5 mg | AEGR-733 10 mg | AEGR-733 5 mg + Atorvastatin 20 mg | AEGR-733 5 mg + Fenofibrate 145 mg |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 52.7 years STANDARD_DEVIATION 9.36 | 51.3 years STANDARD_DEVIATION 11.44 | 47.8 years STANDARD_DEVIATION 12.53 | 51.5 years STANDARD_DEVIATION 12.99 | 48.6 years STANDARD_DEVIATION 11.3 | 49.0 years STANDARD_DEVIATION 10.24 | 52.9 years STANDARD_DEVIATION 11.97 | 53.9 years STANDARD_DEVIATION 8.92 | 54.0 years STANDARD_DEVIATION 11.95 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 3 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 55 Participants | 5 Participants | 9 Participants | 8 Participants | 9 Participants | 8 Participants | 4 Participants | 7 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 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 | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 20 Participants | 3 Participants | 4 Participants | 2 Participants | 1 Participants | 5 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) White | 22 Participants | 182 Participants | 24 Participants | 21 Participants | 24 Participants | 23 Participants | 22 Participants | 22 Participants | 24 Participants |
| Region of Enrollment United States | 29 participants | 260 participants | 33 participants | 34 participants | 34 participants | 34 participants | 35 participants | 28 participants | 33 participants |
| Sex: Female, Male Female | 12 Participants | 136 Participants | 19 Participants | 18 Participants | 16 Participants | 17 Participants | 20 Participants | 17 Participants | 17 Participants |
| Sex: Female, Male Male | 17 Participants | 124 Participants | 14 Participants | 16 Participants | 18 Participants | 17 Participants | 15 Participants | 11 Participants | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 20 / 33 | 31 / 34 | 30 / 34 | 29 / 34 | 32 / 35 | 24 / 28 | 29 / 33 | 25 / 29 |
| serious Total, serious adverse events | 0 / 33 | 1 / 34 | 0 / 34 | 0 / 34 | 2 / 35 | 0 / 28 | 0 / 33 | 0 / 29 |
Outcome results
Primary
Absolute Change From Baseline in Percent Hepatic Fat
Absolute change from Baseline in percent hepatic fat
Time frame: Baseline and 12 weeks on study drug
Population: ITT
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Absolute Change From Baseline in Percent Hepatic Fat | 0.03 Percent of Hepatic Fat | Standard Deviation 1.814 |
| AEGR-733 5 mg | Absolute Change From Baseline in Percent Hepatic Fat | 4.72 Percent of Hepatic Fat | Standard Deviation 6.297 |
Comparison: One-way analysis of variance (ANOVA) to compare the absolute change from baseline to Week 12 in percent hepatic fat between AEGR-755 5 mg and placebo.p-value: <0.00195% CI: [2.3, 7.07]ANOVA
Secondary
Absolute Change From Baseline in Percent Hepatic Fat
Absolute change from Baseline in percent hepatic fat
Time frame: Baseline and 12 weeks on study drug
Population: ITT
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Absolute Change From Baseline in Percent Hepatic Fat | 0.03 Percent of Hepatic Fat | Standard Deviation 1.814 |
| AEGR-733 5 mg | Absolute Change From Baseline in Percent Hepatic Fat | 4.95 Percent of Hepatic Fat | Standard Deviation 7.122 |
| AEGR-733 5 mg | Absolute Change From Baseline in Percent Hepatic Fat | 4.72 Percent of Hepatic Fat | Standard Deviation 6.297 |
| AEGR-733 7.5 mg | Absolute Change From Baseline in Percent Hepatic Fat | 3.94 Percent of Hepatic Fat | Standard Deviation 5.763 |
| AEGR-733 10 mg | Absolute Change From Baseline in Percent Hepatic Fat | 7.86 Percent of Hepatic Fat | Standard Deviation 9.515 |
| AEGR-733 5 mg + Atorvastatin 20 mg | Absolute Change From Baseline in Percent Hepatic Fat | 3.68 Percent of Hepatic Fat | Standard Deviation 5.365 |
| AEGR-733 5 mg + Fenofibrate 145 mg | Absolute Change From Baseline in Percent Hepatic Fat | 7.70 Percent of Hepatic Fat | Standard Deviation 9.39 |
| AEGR-733 5 mg + Ezetimibe 10 mg | Absolute Change From Baseline in Percent Hepatic Fat | 7.55 Percent of Hepatic Fat | Standard Deviation 6.23 |
Comparison: One-way ANOVA to compare the absolute change from baseline to Week 12 in percent hepatic fat between active treatment groups and placebop-value: <0.00195% CI: [2.27, 7.57]ANOVA
p-value: <0.00195% CI: [2.3, 7.07]ANOVA
Comparison: One-way ANOVA to compare the absolute change from baseline to Week 12 in percent hepatic fat between active treatment groups and placebop-value: <0.00195% CI: [1.73, 6.1]ANOVA
p-value: <0.00195% CI: [4.31, 11.33]ANOVA
Comparison: One-way ANOVA to compare the absolute change from baseline to Week 12 in percent hepatic fat between active treatment groups and placebop-value: <0.00195% CI: [1.58, 5.72]ANOVA
Comparison: One-way ANOVA to compare the absolute change from baseline to Week 12 in percent hepatic fat between active treatment groups and placebop-value: <0.00195% CI: [4.22, 11.11]ANOVA
Comparison: One-way ANOVA to compare the absolute change from baseline to Week 12 in percent hepatic fat between active treatment groups and placebop-value: <0.00195% CI: [5.16, 9.86]ANOVA