Healthy Volunteers
Conditions
Brief summary
The purpose of this study is to determine genetic factors that affect responses to niacin therapy and endotoxemia in healthy volunteers.
Detailed description
Niacin is a vitamin that has beneficial effects on cholesterol (a type of fat in the blood) when used in high doses. Different people respond differently to cholesterol lowering doses of niacin, some people have a side effect termed flushing (similar to a hot flash) while others do not and some people have more pronounced effects on cholesterol. Endotoxin or lipopolysaccharide (LPS) is a small part of bacteria (that is no longer living) that can cause many of the effects similar to bacterial infections in humans. However, it can be administered in very small amounts to produce a mild inflammatory response much the same as a 'flu-like illness. Within 1 ½ -3 hours after giving LPS by vein, a response consisting of fever, chills, headache, nausea and vomiting and generalized aches and pains will occur which lasts up to 6-8 hours. In addition to the flu like symptoms, the inflammation causes changes in cholesterol, triglycerides and glucose clearance. Different people respond differently to endotoxin and inflammation. We are performing this study to see if there are genetic factors that predict how people will respond to niacin and to endotoxin and its inflammatory response.
Interventions
DRUGImmediate Release Niacin, Extended Release Niacin, Endotoxin
Subjects receive a one-time 1000mg dose of immediate release Niacin (Niacor pills), a one-time 1000mg dose of extended release Niacin (Niaspan pill) and one-time 1ng/kg injection of endotoxin (LPS).
Sponsors
University of Pennsylvania
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
1. Men and non-pregnant/lactating women between the ages of 18 and 45. 2. Self reported African American or Caucasian racial-ethnic background. 3. Body Mass Index (BMI) of ≥ 18 and ≤ 30. 4. Participants who are able to give written informed consent and willing to comply with all study-related procedures.
Exclusion criteria
1. Known clinically manifest atherosclerotic cardiovascular disease, including coronary disease, cerebrovascular disease, or peripheral vascular disease. 2. History of diabetes mellitus. 3. Fasting glucose \> 126 mg/dL. 4. History of a non-skin malignancy within the previous 5 years. 5. Renal insufficiency as defined by creatinine \> 1.5 mg/dl at Screening Visit. 6. History of liver disease or abnormal liver function tests (LFTs) (AST, ALT, Alk. Phos., GGT \> 1.5x upper limit of normal (ULN); bilirubin \> 2x ULN) at Screening Visit. 7. Men who are unwilling to limit alcohol consumption to \<14 alcoholic drinks per week or \< 4 alcoholic drinks per occasion (AMA / NIAAA criteria for at risk usage levels) while participating in the study. 8. Women who are unwilling to limit alcohol consumption to \< 7 alcoholic drinks per week or \< 3 alcoholic drinks per occasion (AMA / NIAAA criteria for at risk usage levels) while participating in the study. 9. Total white blood cell count less than or equal to 3.0 THO/uL. 10. Hemoglobin below 11.0 g/dL. 11. Any major active rheumatologic, pulmonary, or dermatologic disease or inflammatory condition or minor active infection. 12. History of HIV positive. 13. First degree family history of premature cardiovascular disease event (father or brother if diagnosed at before 55 years of age; mother or sister if diagnosed before 65 years of age). 14. Patients who have undergone any organ transplant. 15. Individuals who currently use tobacco products or have done so in the previous 30 days. 16. Treatment with aspirin, non-steroidal anti-inflammatory drugs (NSAIDs), COX-2 inhibitors, steroids or any immunomodulatory therapy 2 weeks prior to the Screening Visit. 17. Treatment with statins, fibrates or niacin 4 weeks prior to the Screening Visit. 18. Current daily use of Vitamin C \> 1000 mg, Beta carotene \> 1000 IU, vitamin A \> 5000 IU, vitamin E \> 400 IU, and selenium \> 200 mcg. 19. Positive urine pregnancy at the Screening Visit. 20. Participation in another clinical trial within the previous 6 weeks prior to the Screening Visit. 21. Poorly controlled blood pressure (BP \> 160/110) or on any anti-hypertensive medications. 22. A diagnosis of metabolic syndrome using updated 2004 NCEP ATPIII criteria. 23. A history of severe lactose intolerance (e.g., intolerance of any milk intake). 24. Any medical condition or abnormal laboratory value that is judged clinically significant by an investigator.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Baseline and Peak TNF-alpha Values as Categorized by Race and Gender | Baseline (-15 min, -5 min), and 1, 2, 4, 6, 12, 18, and 24 hours post LPS |
Secondary
| Measure | Time frame |
|---|---|
| Baseline and Peak C-Reactive Protein (CRP) Values as Categorized by Race and Gender | Baseline ( -15 min, -5 min), and 1, 2, 4, 6, 12, 18, and 24 hours post LPS |
Countries
United States
Participant flow
Recruitment details
400 subjects were enrolled over an approximate 3.5 year period in order to reach target of about 300 subjects completing all visits. Study ended with 277 subjects completing all visits.
Pre-assignment details
All subjects received niacin and LPS doses. There were no separate arms.
Participants by arm
| Arm | Count |
|---|---|
| Niacin and Endotoxin Immediate Release Niacin, Extended Release Niacin, Endotoxin: Subjects receive a one-time 1000mg dose of immediate release Niacin (Niacor pills), a one-time 1000mg dose of extended release Niacin (Niaspan pill) and one-time 1ng/kg injection of endotoxin (LPS). | 400 |
| Total | 400 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 10 |
| Overall Study | Lost to Follow-up | 11 |
| Overall Study | Physician Decision | 35 |
| Overall Study | poor venous access,unable to draw blood | 4 |
| Overall Study | Withdrawal by Subject | 63 |
Baseline characteristics
| Characteristic | Niacin and Endotoxin |
|---|---|
| Age, Continuous | 25.42 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 143 Participants |
| Race (NIH/OMB) More than one race | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 255 Participants |
| Sex: Female, Male Female | 198 Participants |
| Sex: Female, Male Male | 202 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 86 / 400 |
| serious Total, serious adverse events | 0 / 400 |
Outcome results
Primary
Baseline and Peak TNF-alpha Values as Categorized by Race and Gender
Time frame: Baseline (-15 min, -5 min), and 1, 2, 4, 6, 12, 18, and 24 hours post LPS
Population: This analysis population was categorized by race and gender as follows: European American (EA) male n=102, African American (AA) male n=41, EU female n=91, and AA female n=60. Results include measurements at baseline and peak levels of Tumor Necrosis Factor- alpha (TNF-alpha).
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Niacin/Endotoxin | Baseline and Peak TNF-alpha Values as Categorized by Race and Gender | Baseline TNF-alpha in EA males (n=102) | 1.08 pg/ml |
| Niacin/Endotoxin | Baseline and Peak TNF-alpha Values as Categorized by Race and Gender | Peak TNF-alpha in EA males (n=102) | 43.48 pg/ml |
| Niacin/Endotoxin | Baseline and Peak TNF-alpha Values as Categorized by Race and Gender | Baseline TNF-alpha in AA males (n=41) | 1.03 pg/ml |
| Niacin/Endotoxin | Baseline and Peak TNF-alpha Values as Categorized by Race and Gender | Peak TNF-alpha in AA males (n=41) | 37.28 pg/ml |
| Niacin/Endotoxin | Baseline and Peak TNF-alpha Values as Categorized by Race and Gender | Baseline TNF-alpha in EA females (n=91) | 1.06 pg/ml |
| Niacin/Endotoxin | Baseline and Peak TNF-alpha Values as Categorized by Race and Gender | Peak TNF-alpha in EA females (n=91) | 43.23 pg/ml |
| Niacin/Endotoxin | Baseline and Peak TNF-alpha Values as Categorized by Race and Gender | Baseline TNF-alpha in AA females (n=60) | 1.13 pg/ml |
| Niacin/Endotoxin | Baseline and Peak TNF-alpha Values as Categorized by Race and Gender | Peak TNF-alpha in AA females (n=60) | 34.01 pg/ml |
Secondary
Baseline and Peak C-Reactive Protein (CRP) Values as Categorized by Race and Gender
Time frame: Baseline ( -15 min, -5 min), and 1, 2, 4, 6, 12, 18, and 24 hours post LPS
Population: This analysis population was categorized by race and gender as follows: European American (EA) male n=102, African American (AA) male n=41, EU female n=91, and AA female n=60. Results include measurements at baseline and peak levels of C-Reactive Protein (CRP).
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Niacin/Endotoxin | Baseline and Peak C-Reactive Protein (CRP) Values as Categorized by Race and Gender | Peak CRP in AA males | 14.25 mg/L |
| Niacin/Endotoxin | Baseline and Peak C-Reactive Protein (CRP) Values as Categorized by Race and Gender | Baseline CRP in EA males | 0.34 mg/L |
| Niacin/Endotoxin | Baseline and Peak C-Reactive Protein (CRP) Values as Categorized by Race and Gender | Peak CRP in EA males | 17.8 mg/L |
| Niacin/Endotoxin | Baseline and Peak C-Reactive Protein (CRP) Values as Categorized by Race and Gender | Baseline CRP in AA males | 0.54 mg/L |
| Niacin/Endotoxin | Baseline and Peak C-Reactive Protein (CRP) Values as Categorized by Race and Gender | Baseline CRP in EA females | 0.62 mg/L |
| Niacin/Endotoxin | Baseline and Peak C-Reactive Protein (CRP) Values as Categorized by Race and Gender | Peak CRP in EA females | 15.9 mg/L |
| Niacin/Endotoxin | Baseline and Peak C-Reactive Protein (CRP) Values as Categorized by Race and Gender | Baseline CRP in AA females | 0.71 mg/L |
| Niacin/Endotoxin | Baseline and Peak C-Reactive Protein (CRP) Values as Categorized by Race and Gender | Peak CRP in AA females | 10.8 mg/L |