Homozygous Familial Hypercholesterolemia
Conditions
Brief summary
The goal of this trial is to study the effects of AEGR-733 on LDL cholesterol, other lipids as well as measures of safety over the long-term.
Detailed description
Homozygous familial hypercholesterolemia (FH) is a serious life-threatening genetic disease. Total plasma cholesterol levels are generally over 500 mg/dl and markedly premature cardiovascular disease is the major consequence. Untreated, most patients develop atherosclerosis before age 20 and generally do not survive past age 30. The primary goal of therapy involves reducing cholesterol (specifically, LDL cholesterol) and preventing coronary artery disease. Unfortunately, patients with homozygous FH are minimally responsive or unresponsive to available drug therapy and thus there are limited treatment options. The current standard of care is LDL apheresis, a physical method of removing the plasma of LDL cholesterol which can transiently reduce cholesterol by more than 50%. However, there is rapid re-accumulation of LDL cholesterol in plasma, and therefore apheresis has to be repeated frequently (every 1-2 weeks) and requires 2 separate sites for IV access. Although anecdotally this procedure may delay the onset of atherosclerosis, it is laborious, expensive, and not readily available. Furthermore, although it is a procedure that is generally well tolerated, the fact that it needs frequent repetition and IV access can be challenging for many of these young patients. Therefore, there is a tremendous unmet medical need for new medical therapies for this orphan disease. AEGR-733 is a novel oral therapeutic agent for hypercholesterolemia. Its mechanism involves inhibition of microsomal triglyceride transfer protein, resulting in a reduction of LDL cholesterol. Earlier studies in patients with homozygous FH reveal AEGR-733 is highly effective in lowering LDL cholesterol, yet long term safety and efficacy need to be established.
Interventions
DRUGAEGR-733
5-80 mg daily by mouth for 1.5 yrs
Sponsors
FDA Office of Orphan Products Development
Aegerion Pharmaceuticals, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Males and females at least 18 years of age 2. Diagnosis of functional homozygous FH by at least one (a-c) of the following clinical criteria: * documented functional mutation(s) in both LDL receptor alleles or alleles known to affect LDL receptor functionality OR * skin fibroblast LDL receptor activity less than 20% normal OR * untreated TC greater than 500 mg/dL AND TG less then 300 mg/dL AND both parents have documented TC greater than 250 mg/dL 3. Concurrent lipid lowering medication/apheresis must be stable for at least 6 weeks before the baseline visit and must remain stable for the first 26 weeks. 4. Body weight at least 40 kg and less than 136 kg 5. Negative screening pregnancy test if female of child-bearing potential (females of child-bearing potential and all males must be following a medically accepted form of contraception) 6. Subjects must be willing to comply with all study-related procedures
Exclusion criteria
1. Uncontrolled hypertension 2. History of chronic renal insufficiency 3. History of biopsy proven cirrhosis or abnormal LFTs at screening (AST or ALT greater than 2 x upper limit of normal and/or Total Bilirubin greater than or equal to 1.5 mg/dl unless patient has unconjugated hyperbilirubinemia due to Gilbert's syndrome) 4. Chronic hepatitis B or chronic hepatitis C 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 III or Class IV 7. Previous organ transplantation 8. History of a non-skin malignancy within the previous 3 years 9. Male subjects reporting more than 2 drinks per day or females reporting more than 1 drink per day (1 drink= 12 oz beer, 1 oz hard liquor, 5 oz wine). 10. Participation in an investigational drug study within 6 weeks prior to the screening visit 11. Known significant gastrointestinal bowel disease or malabsorption such as inflammatory bowel disease or chronic pancreatitis requiring use of daily pancreatic enzymes. 12. 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. 13. Certain prohibited medications known to be potentially hepatotoxic, especially those that can induce microvesicular or macrovesicular steatosis. These include but are not limited to: accutane, amiodarone, heavy acetaminophen use (4g/day greater than 3 x q week), methotrexate, tetracyclines,and tamoxifen 14. Documented diagnosis of any of the following pulmonary conditions: Asthma, Chronic Obstructive Pulmonary Disease (COPD), Idiopathic pulmonary fibrosis 15. Documented diagnosis of any of the following liver diseases: Nonalcoholic Steatohepatitis, Alcoholic liver disease, Autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, Wilson's disease, hemochromatosis, alpha 1 anti-trypsin deficiency. 16. Current use of corticosteroids or betaine
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C) | Baseline and Week 26 | Percent change from Baseline in LDL-C |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Total Cholesterol (TC) | Baseline and Week 26 | Percent change from Baseline in TC |
| Percent Change From Baseline for Apolipoprotein B (Apo B) | Baseline and Week 26 | Percent change from Baseline for Apo B |
| Percent Change From Baseline in Triglycerides | Baseline and Week 26 | Percent change from Baseline in triglycerides |
| Percent Change From Baseline in High Density Lipoprotein Cholesterol (HDL-C) | Baseline and Week 26 | Percent change from Baseline in HDL-C |
| Percent Change From Baseline in Non-HDL-C | Baseline and Week 26 | Percent change from Baseline in non-HDL-C |
| Percent Change From Baseline in Apolipoprotein AI (Apo AI) | Baseline and Week 26 | Percent change from Baseline in Apo AI |
| Absolute Change From Baseline in Alanine Aminotransferase (ALT) | Baseline and Week 78 | Absolute change from Baseline in ALT |
| Absolute Change From Baseline in Aspartate Aminotransferase (AST) | Baseline and Week 78 | Absolute change from Baseline in AST |
| Absolute Change From Baseline in Total Bilirubin | Baseline and Week 78 | Absolute change from Baseline in total bilirubin |
| Absolute Change From Baseline in Weight | Baseline and Week 78 | Absolute change from Baseline in weight |
| Absolute Change From Baseline in Hepatic Fat Percent | Baseline and Week 78 | Absolute change from Baseline in hepatic fat percent |
Countries
Canada, Italy, South Africa, United States
Participant flow
Recruitment details
The study was performed from 18 Dec 2007 to 13 Oct 2011. A total of 11 medical clinics participated in the study.
Pre-assignment details
6-week Run-in Phase. Following screening, patients entered a 6-week Run-in Phase to stabilize their regimen of current lipid-lowering therapy(ies) and to be placed on a low-fat diet containing \<20% energy from fat.
Participants by arm
| Arm | Count |
|---|---|
| Lomitapide Escalated Lomitapide escalated with an initial oral dose of 5 mg/day for 2 weeks and then escalated at 4 week intervals to 60 mg/day. In rare situations (1 patient)who met strict safety and efficacy criteria could have their dose escalated to 80 mg/day. | 29 |
| Total | 29 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 4 |
| Overall Study | Non-compliance | 1 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Lomitapide Escalated |
|---|---|
| Age, Continuous | 30.7 years STANDARD_DEVIATION 10.64 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 25 Participants |
| Region of Enrollment Canada | 5 participants |
| Region of Enrollment Italy | 6 participants |
| Region of Enrollment South Africa | 11 participants |
| Region of Enrollment United States | 7 participants |
| Sex: Female, Male Female | 13 Participants |
| Sex: Female, Male Male | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 23 / 29 |
| serious Total, serious adverse events | 3 / 29 |
Outcome results
Primary
Percent Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C)
Percent change from Baseline in LDL-C
Time frame: Baseline and Week 26
Population: Intention To Treat (ITT) Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lomitapide Escalated | Percent Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C) | -40.1 Percent Change | Standard Deviation 31.25 |
Secondary
Absolute Change From Baseline in Alanine Aminotransferase (ALT)
Absolute change from Baseline in ALT
Time frame: Baseline and Week 78
Population: All patients treated
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lomitapide Escalated | Absolute Change From Baseline in Alanine Aminotransferase (ALT) | 15.0 U/L | Standard Deviation 29.05 |
Secondary
Absolute Change From Baseline in Aspartate Aminotransferase (AST)
Absolute change from Baseline in AST
Time frame: Baseline and Week 78
Population: All patients treated
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lomitapide Escalated | Absolute Change From Baseline in Aspartate Aminotransferase (AST) | 8.9 U/L | Standard Deviation 20.22 |
Secondary
Absolute Change From Baseline in Hepatic Fat Percent
Absolute change from Baseline in hepatic fat percent
Time frame: Baseline and Week 78
Population: All patients treated
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lomitapide Escalated | Absolute Change From Baseline in Hepatic Fat Percent | 6.9 Percent Hepatic Fat | Standard Deviation 5.03 |
Secondary
Absolute Change From Baseline in Total Bilirubin
Absolute change from Baseline in total bilirubin
Time frame: Baseline and Week 78
Population: All patients treated
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lomitapide Escalated | Absolute Change From Baseline in Total Bilirubin | 0.1 mg/dL | Standard Deviation 0.3 |
Secondary
Absolute Change From Baseline in Weight
Absolute change from Baseline in weight
Time frame: Baseline and Week 78
Population: All patients treated
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lomitapide Escalated | Absolute Change From Baseline in Weight | -2.3 kg | Standard Deviation 3.46 |
Secondary
Percent Change From Baseline for Apolipoprotein B (Apo B)
Percent change from Baseline for Apo B
Time frame: Baseline and Week 26
Population: ITT Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lomitapide Escalated | Percent Change From Baseline for Apolipoprotein B (Apo B) | -39.4 Percent Change | Standard Deviation 30.01 |
Secondary
Percent Change From Baseline in Apolipoprotein AI (Apo AI)
Percent change from Baseline in Apo AI
Time frame: Baseline and Week 26
Population: ITT Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lomitapide Escalated | Percent Change From Baseline in Apolipoprotein AI (Apo AI) | -6.5 Percent Change | Standard Deviation 16.12 |
Secondary
Percent Change From Baseline in High Density Lipoprotein Cholesterol (HDL-C)
Percent change from Baseline in HDL-C
Time frame: Baseline and Week 26
Population: ITT Population
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Lomitapide Escalated | Percent Change From Baseline in High Density Lipoprotein Cholesterol (HDL-C) | -6.9 Percent Change | Standard Deviation 19.76 |
Secondary
Percent Change From Baseline in Non-HDL-C
Percent change from Baseline in non-HDL-C
Time frame: Baseline and Week 26
Population: ITT Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lomitapide Escalated | Percent Change From Baseline in Non-HDL-C | -40.0 Percent Change | Standard Deviation 29.66 |
Secondary
Percent Change From Baseline in Total Cholesterol (TC)
Percent change from Baseline in TC
Time frame: Baseline and Week 26
Population: ITT Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lomitapide Escalated | Percent Change From Baseline in Total Cholesterol (TC) | -36.4 Percent Change | Standard Deviation 28.2 |
Secondary
Percent Change From Baseline in Triglycerides
Percent change from Baseline in triglycerides
Time frame: Baseline and Week 26
Population: ITT Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lomitapide Escalated | Percent Change From Baseline in Triglycerides | -29.0 Percent Change | Standard Deviation 55.72 |