Clinical trial NCT00954824: Inflammation and the Metabolic Syndrome in Humans
Official title: Inflammation and the Metabolic Syndrome in Humans
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Metabolic Syndrome X
Lead sponsor: University of Pennsylvania
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
First posted: 2009-08-07
Enrollment: 50
Sex: ALL
Minimum age (years): 18
Maximum age (years): 40
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: HEALTH_SERVICES_RESEARCH

Brief summary: People who are overweight are at increased risk of heart disease. Being overweight and having heart disease are linked in that both involve inflammation. Inflammation refers to the body's first line of defense against infection and injury. Metabolic changes in cholesterol, triglycerides (fat in the blood) and sugar in the blood caused by inflammation are similar to that in some people who are overweight. The investigators wish to examine the effects of inflammation on these metabolic changes that may lead to heart disease.

Detailed description: This study is a single site, open-label, "baseline-controlled" (pre LPS saline period) study examining the pro-atherosclerotic metabolic responses and safety responses to a single administration low-dose (3 ng/kg) endotoxin (LPS) in 20 additional non-metabolic syndrome participants: 10 healthy overweight and 10 healthy lean counterparts (20 non-metabolic syndrome participants were studies in first phase), and 40 subjects with the metabolic syndrome. We are continuing to use an approach whereby "metabolic syndrome" subjects will be recruited to have key metabolic syndrome abnormalities that are sensitive to insulin resistance compared to the non-metabolic syndrome groups, although all of these "metabolic syndrome" subjects may not fulfill traditional NCEP criteria for the syndrome.

Eligibility criteria: Inclusion Criteria:

1. Men and non-pregnant/lactating women between the ages of 18 and 40
2. Subjects must be able to give written informed consent and willing to comply with all study-related procedures.
3. BMI \>18 and \< 24 and BIA \< 15% fat for men, \< 25% fat for women, and do not have diagnosis of NCEP metabolic syndrome as defined below, OR
4. BMI \> 26 but \< 30 and BIA \> 15% fat for men, \> 25% fat for women, do not have diagnosis of NCEP metabolic syndrome, OR
5. BMI \>18 and \< 30 and have metabolic syndrome abnormalities as defined below. The modified NCEP Metabolic Syndrome criteria are as follows

   * abdominal obesity, waist circumference: men \>= 37 in (94 cm), women \>= 31 in (80 cm)
   * fasting triglycerides \> 150 mg/dL
   * HDL cholesterol \< 40 mg/dL for men; HDL cholesterol \< 50 mg/dL for women
   * Blood pressure \> 130/ \>85 mmHg in untreated patients
   * Fasting glucose \> 100 mg/dL, but less than 126 mg/dL
6. For inclusion in "metabolic syndrome" group, the following additional criteria must be fulfilled:

   * Three or more of the NCEP criteria defined above. OR
   * Two or more of the NCEP criteria AND TG/HDL ratio \> 3.0.

Exclusion Criteria:

1. Known atherosclerotic cardiovascular disease, including coronary disease, cerebrovascular disease, or peripheral vascular disease.
2. History of diabetes mellitus.
3. A plasma glucose greater than 200 mg/dL at the 2 hour blood draw of the oral glucose tolerance test.
4. History of a non-skin malignancy within the previous 5 years.
5. Renal insufficiency as defined by creatinine \>= 1.5 mg/dl at visit 1 (grade 1 of NIH's Common Toxicity Criteria (CTC), version 2.0, 4/30/99).
6. History of liver disease or ALT, AST, ALK Phosphatase or Gamma GT above normal limits as defined by HUP William Pepper Clinical Laboratory at visit 1.
7. Elevated (\> 1.5x ULN; grade 1, CTC, 4/30/99) Total Bilirubin or LDH at visit 1.
8. Men who consume \> 14 alcoholic drinks per week or \> 4 alcoholic drinks per occasion (AMA/NIAAA criteria for "at risk" usage levels).
9. Women who consume \> 7 alcoholic drinks per week or \> 3 alcoholic drinks per occasion (AMA/NIAAA criteria for "at risk" usage levels).
10. Total white blood cell count below normal limits as defined at HUP William Pepper Clinical Laboratory prior to the baseline visit.
11. Hemoglobin below normal limits (gender specific) as defined at HUP William Pepper Clinical Laboratory prior to the baseline visit.
12. Any medical condition or abnormal laboratory value that is judged clinically significant by an investigator.
13. Any major active rheumatologic, pulmonary, or dermatologic disease or inflammatory condition or minor active infection.
14. History of HIV positive.
15. 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).
16. Patients who have undergone any organ transplant.
17. Individuals who currently use tobacco products or have done so in the previous 30 days.
18. Treatment with aspirin, NSAIDs, COX-2 inhibitors, steroids or other immunomodulatory therapy 2 weeks prior to the screening visit
19. Treatment with statins, fibrates or niacin 4 weeks prior to the screening visit.
20. Current daily use of Vitamin C \> 1000 mg, Beta carotene \> 1000 IU, vitamin A \> 5000 IU, vitamin E \> 400 IU, and selenium \> 200 mcg.
21. Positive urine pregnancy at the screening visit.
22. Participation in another clinical trial within the previous 6 weeks prior to the screening visit.
23. Poorly controlled blood pressure (BP \> 160/100) or on any anti-hypertensive medications.
24. For subjects in non-metabolic syndrome groups; a diagnosis of metabolic syndrome using NCEP ATPIII criteria.
25. For subjects in "metabolic syndrome" group; an abnormal Bruce protocol cardiac exercise stress test.

Primary outcomes:
measure: The Primary Outcome Measure is Plasma Levels of TNF Alpha.
timeFrame: 24 hours
Secondary outcomes:
Other outcomes:
Locations:
city: Philadelphia
country: United States
facility: Clinical and Translational Research Center, Hospital of the University of Pennsylvania
state: Pennsylvania
Study officials:
affiliation: University of Pennsylvania
name: Muredach P. Reilly, MB, MSCE
role: PRINCIPAL_INVESTIGATOR
References:
citation: Anderson PD, Mehta NN, Wolfe ML, Hinkle CC, Pruscino L, Comiskey LL, Tabita-Martinez J, Sellers KF, Rickels MR, Ahima RS, Reilly MP. Innate immunity modulates adipokines in humans. J Clin Endocrinol Metab. 2007 Jun;92(6):2272-9. doi: 10.1210/jc.2006-2545. Epub 2007 Mar 20.
citation: Heffron SP, Parastatidis I, Cuchel M, Wolfe ML, Tadesse MG, Mohler ER 3rd, Ischiropoulos H, Rader DJ, Reilly MP. Inflammation induces fibrinogen nitration in experimental human endotoxemia. Free Radic Biol Med. 2009 Oct 15;47(8):1140-6. doi: 10.1016/j.freeradbiomed.2009.07.025. Epub 2009 Jul 22.
citation: Shah R, Lu Y, Hinkle CC, McGillicuddy FC, Kim R, Hannenhalli S, Cappola TP, Heffron S, Wang X, Mehta NN, Putt M, Reilly MP. Gene profiling of human adipose tissue during evoked inflammation in vivo. Diabetes. 2009 Oct;58(10):2211-9. doi: 10.2337/db09-0256. Epub 2009 Jul 6.
citation: McGillicuddy FC, de la Llera Moya M, Hinkle CC, Joshi MR, Chiquoine EH, Billheimer JT, Rothblat GH, Reilly MP. Inflammation impairs reverse cholesterol transport in vivo. Circulation. 2009 Mar 3;119(8):1135-45. doi: 10.1161/CIRCULATIONAHA.108.810721. Epub 2009 Feb 16.
citation: Badellino KO, Wolfe ML, Reilly MP, Rader DJ. Endothelial lipase is increased in vivo by inflammation in humans. Circulation. 2008 Feb 5;117(5):678-85. doi: 10.1161/CIRCULATIONAHA.107.707349. Epub 2008 Jan 22.
citation: Song WL, Wang M, Ricciotti E, Fries S, Yu Y, Grosser T, Reilly M, Lawson JA, FitzGerald GA. Tetranor PGDM, an abundant urinary metabolite reflects biosynthesis of prostaglandin D2 in mice and humans. J Biol Chem. 2008 Jan 11;283(2):1179-88. doi: 10.1074/jbc.M706839200. Epub 2007 Nov 8.
citation: Lehrke M, Millington SC, Lefterova M, Cumaranatunge RG, Szapary P, Wilensky R, Rader DJ, Lazar MA, Reilly MP. CXCL16 is a marker of inflammation, atherosclerosis, and acute coronary syndromes in humans. J Am Coll Cardiol. 2007 Jan 30;49(4):442-9. doi: 10.1016/j.jacc.2006.09.034. Epub 2007 Jan 12.
citation: Reilly MP, Lehrke M, Wolfe ML, Rohatgi A, Lazar MA, Rader DJ. Resistin is an inflammatory marker of atherosclerosis in humans. Circulation. 2005 Feb 22;111(7):932-9. doi: 10.1161/01.CIR.0000155620.10387.43. Epub 2005 Feb 14.
citation: Lehrke M, Reilly MP, Millington SC, Iqbal N, Rader DJ, Lazar MA. An inflammatory cascade leading to hyperresistinemia in humans. PLoS Med. 2004 Nov;1(2):e45. doi: 10.1371/journal.pmed.0010045. Epub 2004 Nov 30.