Dyslipidemia
Conditions
Brief summary
The objectives of the study are: 1. To evaluate the effect of ABT-335 (choline fenofibrate) on several parameters of RCT (reverse cholesterol transport) in men and post-menopausal women diagnosed with dyslipidemia (i.e., low high-density lipoprotein \[HDL\] cholesterol levels and elevated triglyceride \[TG\] concentrations). 2. To evaluate longitudinal changes in several parameters of RCT in subjects with low HDL. 3. To obtain pilot data for power calculations for subsequent comparative study.
Detailed description
This trial assesses the effects of ABT-335 on RCT as measured by cholesterol efflux or rate of appearance of cholesterol (Ra in mg/kg/hr), cholesterol excretion (%/day), RCT efflux (mg/kg/day) and de novo cholesterol synthesis (%) during a baseline period (7 days) and during a treatment period (94 days). The goal of using RCT to reverse atherosclerosis is to increase the rate of cholesterol export or efflux from the tissues and plaques. An increase in this cholesterol efflux rate should shrink arterial plaques by decreasing their static accumulation of cholesterol. While some currently marketed drugs have a positive impact on RCT by increasing the rate of cholesterol excretion from the body, no drug has yet been approved to increase the rate of cholesterol efflux from the tissues
Interventions
135 mg choline fenofibrate daily(oral, capsule)
Sponsors
Radiant Research
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
21 Years to 75 Years
Healthy volunteers
Yes
Inclusion criteria
1. Male, non-smoker, 21 - 75 years of age inclusive. 2. Female, non-smoker, 40 - 75 years of age inclusive. 3. Post-menopausal women, as defined by lack of menses for at least 2 years and age \> 55, OR history of documented bilateral surgical oophorectomy, confirmed with an elevated follicle-stimulating hormone (FSH) at screening. 4. HDL concentration (≤ 50 mg/dl women, ≤ 40mg/dl men) 5. TG concentration 150-500 mg/dl, inclusive 6. Ability to give informed consent
Exclusion criteria
1. Subject has history of diabetes mellitus, active hepatitis, gall bladder disease, gastric bypass surgery, or clinically significant abnormalities on screening (prestudy) physical examination or laboratory tests. 2. Screening laboratory tests with hematocrit \<30%, aspartate aminotransferase (AST)/alanine aminotransferase (ALT) \> 2X upper limit of normal, abnormal thyroid-stimulating hormone (TSH), fasting glucose ≥126 mg/dl. 3. Renal impairment with creatinine clearance \< 80 ml/min. 4. Treatment within the last 6 months with drugs known to alter lipid metabolism including beta blockers, thiazide diuretics, bile acid resins, ezetimibe, fibrates, niacin, and fish oils (see Appendix 1). Washout of fibrates is not permitted. 5. Treatment with drugs known to interact with ABT-335, e.g., warfarin (see Appendix 1). 6. Treatment with HMG CoA reductase inhibitors (statins) within the past 4 weeks (see Appendix 1). 7. History of allergy to egg or soy products. 8. History of coronary heart disease (CHD), stroke or revascularization procedure in the six months prior to Visit 1. 9. Current or recent history (past 12 months) of drug abuse or alcohol abuse. Alcohol abuse will be defined as \>14 drinks per week (1 drink = 12 oz beer, 5 oz wine, or 1.5 oz hard liquor). 10. Participation in another clinical trial or exposure to any investigational agent within 30 days before visit 1. 11. Individual has a condition the Principal Investigator believes would interfere with his/her ability to provide informed consent, comply with study instructions, or which might confound the interpretation of the study results or put the subject at undue risk.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change in Calculated Low Density Lipoprotein Cholesterol | baseline to 12 weeks | Mean change in calculated LDL, baseline (average Day 0, 1 10) to end-of-treatment (12 weeks treatment,average Day 95) |
| Mean Change in Plasma Triglycerides | baseline to 12 weeks | Change in plasma triglyceride, baseline (average Day 0, 1 10) to end-of-treatment (12 weeks treatment,Day 95) |
| Mean Change in High Density Lipoprotein Cholesterol | Baseline to 12 weeks | Mean change in plasma high density plasma lipoprotein cholesterol (HDL-C)baseline (average Day 0, 1 10) to end-of-treatment (12 weeks treatment,Day 95) |
| Total Cholesterol | 12 weeks | Mean Change in total cholesterol from baseline to End-of-treatment (Day 95) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Bile Acid Excretion | Baseline to 12 weeks | Change in bile acid excretion from baseline to end-of-treatment |
| Plasma Cholesterol Efflux | 12 weeks | Change in efflux rate from baseline to end-of-treatment. The efflux rate of cholesterol from peripheral tissues into the plasma was measured as mg/kg/hr. An IV infusion of \[13C2\] cholesterol mixed in 10% Intralipid® or Liposyn® and 10 % ethanol was given piggy-backed into normal saline over 24 hours. This was used to determine rate of appearance (Ra) cholesterol, measured by dilution of infused \[13C2\] cholesterol during the plateau phase of plasma enrichment (approximately the last 4 hours of the infusion), as well as to provide the plasma cholesterol traced into biliary sterols. |
| Endogenous Bile Acid Excretion | 12 weeks | Change in endogenous bile acid excretion from baseline to end-of-treatment |
| Neutral Sterol Endogenous Excretion | 12 weeks | Change in neutral sterol endogenous excretion from baseline to end-of-treatment |
| Change in Plasma Cholesterol Ester Fractional Catabolic Rate (FCR) | Baseline to 12 weeks | Change in FCR from baseline to end-of-treatment (12 weeks) |
| Percent Change in de Novo Cholesterol Synthesis | Baseline to 12 weeks | Plasma DNC was measured three times from blood draws on the 3 visits in the 10 day period following the isotope infusion at baseline and again at end-of-treatment at 12 weeks, and expressed in percent. Change from baseline to end-of-treatment expressed as percent. |
| Change in Neutral Sterol Excretion | baseline to 12 weeks | The excretion rate of fecal neutral and acidic sterols was measured as mg/day, for each individual three times during the 10 day period following the isotope infusions at baseline and end-of-treatment. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| ABT 335 choline fenofibrate, 135 mg/day,orally, 12 weeks | 25 |
| Total | 25 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | ABT 335 |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 2 Participants |
| Age, Categorical Between 18 and 65 years | 23 Participants |
| High Density Lipoprotein Cholesterol (HDL) | 34 mg/dL STANDARD_DEVIATION 8.2 |
| Low density lipoprotein cholesterol (LDL) | 144 mg/dL STANDARD_DEVIATION 40 |
| Region of Enrollment United States | 25 participants |
| Sex: Female, Male Female | 7 Participants |
| Sex: Female, Male Male | 18 Participants |
| Total cholesterol (TC) | 221 mg/dL STANDARD_DEVIATION 45 |
| Triglycerides (TG) | 241 mg/dL STANDARD_DEVIATION 122 |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 14 / 25 |
| serious Total, serious adverse events | 0 / 25 |
Outcome results
Primary
Mean Change in Calculated Low Density Lipoprotein Cholesterol
Mean change in calculated LDL, baseline (average Day 0, 1 10) to end-of-treatment (12 weeks treatment,average Day 95)
Time frame: baseline to 12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ABT 335 | Mean Change in Calculated Low Density Lipoprotein Cholesterol | -22.7 mg/dL | Standard Deviation 34.2 |
p-value: 0.0042t-test, 2 sided
Primary
Mean Change in High Density Lipoprotein Cholesterol
Mean change in plasma high density plasma lipoprotein cholesterol (HDL-C)baseline (average Day 0, 1 10) to end-of-treatment (12 weeks treatment,Day 95)
Time frame: Baseline to 12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ABT 335 | Mean Change in High Density Lipoprotein Cholesterol | -1.6 mg/dL | Standard Deviation 6 |
Comparison: Comparison from baseline to end-of-treatmentp-value: NS0t-test, 2 sided
Primary
Mean Change in Plasma Triglycerides
Change in plasma triglyceride, baseline (average Day 0, 1 10) to end-of-treatment (12 weeks treatment,Day 95)
Time frame: baseline to 12 weeks
Population: per protocol
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ABT 335 | Mean Change in Plasma Triglycerides | -138.0 mg/dL | Standard Deviation 150.5 |
Comparison: Comparison baseline to end-of-treatmentp-value: 0.0002t-test, 2 sided
Primary
Total Cholesterol
Mean Change in total cholesterol from baseline to End-of-treatment (Day 95)
Time frame: 12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ABT 335 | Total Cholesterol | -54.0 mg/dL | Standard Deviation 34.4 |
p-value: <0.0001t-test, 2 sided
Secondary
Change in Bile Acid Excretion
Change in bile acid excretion from baseline to end-of-treatment
Time frame: Baseline to 12 weeks
Secondary
Change in Neutral Sterol Excretion
The excretion rate of fecal neutral and acidic sterols was measured as mg/day, for each individual three times during the 10 day period following the isotope infusions at baseline and end-of-treatment.
Time frame: baseline to 12 weeks
Secondary
Change in Plasma Cholesterol Ester Fractional Catabolic Rate (FCR)
Change in FCR from baseline to end-of-treatment (12 weeks)
Time frame: Baseline to 12 weeks
Secondary
Endogenous Bile Acid Excretion
Change in endogenous bile acid excretion from baseline to end-of-treatment
Time frame: 12 weeks
Secondary
Neutral Sterol Endogenous Excretion
Change in neutral sterol endogenous excretion from baseline to end-of-treatment
Time frame: 12 weeks
Secondary
Percent Change in de Novo Cholesterol Synthesis
Plasma DNC was measured three times from blood draws on the 3 visits in the 10 day period following the isotope infusion at baseline and again at end-of-treatment at 12 weeks, and expressed in percent. Change from baseline to end-of-treatment expressed as percent.
Time frame: Baseline to 12 weeks
Secondary
Plasma Cholesterol Efflux
Change in efflux rate from baseline to end-of-treatment. The efflux rate of cholesterol from peripheral tissues into the plasma was measured as mg/kg/hr. An IV infusion of \[13C2\] cholesterol mixed in 10% Intralipid® or Liposyn® and 10 % ethanol was given piggy-backed into normal saline over 24 hours. This was used to determine rate of appearance (Ra) cholesterol, measured by dilution of infused \[13C2\] cholesterol during the plateau phase of plasma enrichment (approximately the last 4 hours of the infusion), as well as to provide the plasma cholesterol traced into biliary sterols.
Time frame: 12 weeks