Transcript WP8

EUGIS
European Union Garlic Inflammation
Study in Humans
Background
• No clear indications that ‘garlic’ influences lipid
metabolism
• Indications from cell and animal studies that ‘garlic’
may influence inflammation parameters
• Cardiovascular disease (atherosclerosis) shares
common features with inflammation
• Current treatment strategies for atherosclerosis also
focus on inflammation
Aim
Study the effects of garlic on inflammatory
biomarkers of atherosclerotic disease and on
cancer biomarkers in man
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Primary endpoint: changes in C-reactive protein ( CRP)
Secondary endpoints:
– Indicators of lipid metabolism
– Biochemical markers of inflammation
– Blood pressure / heart rate variability
– Biomarkers for anti-carcinogenic effects
Inclusion criteria
• Able and willing to give informed consent
• 90 subjects of either gender*
• Aged between 40-75 years
• Smoking≥ 10 cigarettes/day and BMI≥ 24.5
kg/m2
* Power calculation to find a reduction of 30%
in plasma CRP levels with = 0.05 and a power
of 80% about 30 subjects per group are needed
Exclusion criteria
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Any major clinical significant abnormality detected
by a general health questionnaire or by blood
sampling
Chronic drug treatment / use of medication
Participation in prior study in the last 3 months or
blood donation
Inadequate use of contraceptives / pregnancy /
lactating women
History of alcohol / drug abuse
Positive test results for HepB/C or HIV
Dislike of garlic
Experimental design
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Double dummy placebo-controlled trial
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3 parallel groups (n=30)
I.C. / screening
-2
0
Intervention period
4-5
Blood and urine collection
11-12 weeks
12-weeks treatment
1. Garlic (from EU-sponsored Printanor 2001)
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Lichtwer capsule preparation (300 mg)
2.1g daily (3 cap - breakfast & 4 cap at dinner)
2. Atorvastatin:
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40 mg/day daily at dinner
3. Placebo:
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garlic and statin placebo daily
Measurements
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Safety:
– Parameters of muscle and liver function
– Haematology
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Clinical:
– Blood pressure
– 12 lead ECG (HR, conduction)
– Heart Rate Variability (HRV)
Measurements
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Biochemical:
– Cholesterol, HDL, and triglycerides;
– CRP, vWF, Fbg, and cytokines after whole blood
stimulation without or with LPS (TNF-α, IL-10);
– Sensitivity of leukocytes to inflammatory stimulus;
– Cancer biomarkers: anti-oxidant enzymes (GPX,
SOD), DNA damage (Comet assay), anti-mutagenic
properties of urine (Ames test);
– Metabolites of garlic compounds in plasma and
urine;
Additional measurements suggested in
the EU proposal
• SAA, and PAI-1
• s-VCAM / s-ICAM / s-Selectine
• MCP-1 and other chemokines
• Endothelin 1 and 3
• Plasma ox-LDL
• Urine isoprostanes
Current study status
•  Subjects at information sessions: >148
•  Subjects signing IC: 142
•  Subjects randomised : 92
–  Subjects completed: 84
–  Subjects withdrawn: 8 (6 non-related AEs)
• Entire clinical study period: < 5 months!
– last samples at Jan 15th
Study population - baseline
• Female
– n = 47
– age: 40-67 yrs
– BMI: 29.6 (SD: 4.1) kg/m2
– BP: 124 (18) / 76 (12) mm Hg
• Male
– n = 37
– age: 40-63 yrs
– BMI: 29.3 (SD: 3.2) kg/m2
– BP: 130 (11) / 82 (10) mm Hg
Baseline lipids
• Female
– Total Cholesterol:
– HDL-Cholesterol:
– LDL-Cholesterol:
– Triglycerides:
5.60 (1.01) mmol/L (3.9-7.3)
1.35 (0.32) mmol/L (>1.16)
3.52 (0.95) mmol/L
1.63 (0.95) mmol/L (0.8-1.94)
– Total Cholesterol:
– HDL-Cholesterol:
– LDL-Cholesterol:
– Triglycerides:
5.71 (1.04) mmol/L (3.9-7.3)
1.11 (0.32) mmol/L (>0.90)
3.54 (0.99) mmol/L
2.35 (1.32) mmol/L (0.8-1.94)
• Male
Adverse Events
• AE’s
– Headache:
• 52 episodes in 41 subjects
– Abdominal discomfort
• 36 episodes in 26 subjects
– Other
• 60 various events (URT infection, ‘pains’, intercurrents)
PLAN
• All samples have been / are being shipped
• Unblinding next week
• Primary parameter laboratory analysis
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completed at Jan 31st
Stats analysis time allocated
Main report around March 1st 2004
• Additional reports: to be discussed
THANKS
• Lichtwer
• LUMC pharmacy
• TNO-PG
• CHDR
• S Striegl
• T Haffner
• P Meijer
• R Kret
• R Streunding
• R Press
• M van Doorn
• I Kamerling
• Nursing staff
• Participants who tolerated 2.1 gram garlic/day