stirrhs seminar on transdisciplinarity
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STIRRHS Seminar on Transdisciplinarity. Dr William D. Fraser MD, MSc, FRCSC June 2 nd , 2006. Agenda. Oxidative Stress INTAPP Trial MIROS Program. Hypertension and pregnancy. Gestational hypertension Majority high-risk antenatal visits : high BP - PowerPoint PPT PresentationTRANSCRIPT
STIRRHS Seminar on
Transdisciplinarity
Dr William D. Fraser MD, MSc, FRCSC
June 2nd, 2006
Agenda
Oxidative Stress
INTAPP Trial
MIROS Program
• Gestational hypertension– Majority high-risk antenatal visits : high BP
(24% of antenatal hospital admissions) – Ranked first among the direct obstetric causes of
maternal death – Perinatal deaths (preterm delivery & intrauterine growth
restriction) – 10 to 25% of all very low birth weight infants
• Preeclampsia, or proteinuric gestational hypertension – Accounts for 1/3 of maternal deaths in pregnancy
• Eclampsia – 20% occur without antecedent proteinuria
Hypertension and pregnancy
Delivery is the only known cure of Preeclampsia
Prevention of preeclampsia?
• A disturbance in the prooxidant-antioxidant balance in favor of prooxidants leading to potential damage.
Sies, 1991
Definition of Oxidative Stress
Oxidative Stress: Reactive Oxygen and Nitrogen Species
Reactive nitrogen species
Nitric oxide, NO•
Nitrogen dioxide, NO2•
Reactive oxygen speciesSuperoxide, O2•-Hydroxyl, OH•Peroxyl, RO2•Alkoxyl, RO•Hydroperoxyl, HO2•
Antioxidants of Interest
– Carotenoids– Xanthophylls– Metallothionein– Coenzyme Q10– Uric acid– Flavonoids & Polyphenols– Herbal remedies such as
theaflavin, Ginko biloba, etc.
– Vitamin E (Tocopherol)– Vitamin C (Ascorbic Acid)– Vitamin A– Proteins:– Superoxide dismutase– Glutathione peroxidase– Catalase– Ceruloplasmin – Beta-carotene
Oxidative Stress/ Abnormal Lipid Metabolism / Endothelial Dysfunction
/Preeclampsia
AntioxidantsAntioxidants
Antioxidants in the Prevention of Preeclampsia
Primary Outcome MeasurePrimary Outcome MeasureMean PAI-1/PAI-2 during gestation in completed-study cohort
0.50
0.45
0.40
0.35
0.30
0.25
0.20
12 16 20 24 28 32 36 40
Placebo (n = 82)Vitamins (n = 79)
Chappell et coll., Lancet, 1999
Secondary Outcome Measure: Secondary Outcome Measure: Frequency of PreeclampsiaFrequency of Preeclampsia
1512 Women Screened by uterine Doppler 284 Randomised Women with High Risk of Preeclampsia
142 PlaceboTotal
Preeclampsia 24 (17%)
Relative Risk: 0.39; 95% CI 0.17-0.90
141 Vit C & E Total
Preeclampsia11 (8%)
INTAPP Protocol review and study design
Primary Hypotheses
• Oral antenatal supplementation with vitamins C and E reduces the incidence of "Gestational hypertension (with or without proteinuria) and its adverse condition(s)"
Population
• Stratum I: Nulliparous women without additional identified risk factors
• Stratum II: Nulliparous and multiparous women with identified risk factors
Inclusion criteria
• Women between 120/7 and 186/7 weeks of pregnancy– Gestational age of patients will be based on the last
menstrual period and confirmed by early ultrasound examination. (if discrepancy > 7 days, use ultrasound to estimate gestational age)
• At least 18 years old• Speak a language known by the medical staff• Plan to deliver in a participating centre
Definition of the Primary OutcomeGestational hypertension (with or without proteinuria) and its adverse condition(s)
Gestational hypertension• Two or more readings of diastolic blood pressure
90 mmHg taken 4 hours apart within a 24-hour period and occurring after 20 weeks of pregnancy
Severe gestational hypertension • Two recordings of diastolic blood pressure of 110
mmHg or systolic pressure 160 mmHg at least 4 hours apart within a 24 hour period
Proteinuria • Excretion of > 300 mg protein in 24 hours
Based on a modification of Canadian Consensus statement definition and ACOG criteria
Must include 1 or more of the following selected medical
conditions:
• Diastolic pressure ≥ 110 mmHg or systolic pressure ≥ 160 mmHg
• Proteinuria > 3 g/24h urine collection • Convulsion (eclampsia)• Thrombocytopenia • Elevated liver enzyme levels (AST or ALT >70 U/L) • Creatinine > 180 µmol/L• Hematocrit < 24 and blood transfusion• IUGR <3rd centile• Perinatal death
Participant Stratification
Risk Strata Participants
I. Low Risk Group Nulliparous without additional risk factors
II. High Risk Group Nulliparous or multiparous with at least one additional risk factor
• pre-pregnancy chronic hypertension
• pre-pregnancy diabetes
• multiple pregnancy
• a history of preeclampsia in the previous
pregnancy
Treatment Plan
Group Treatment Regimen Low-Risk Stratum
(N)
High-Risk Stratum
(N)
Control
Once daily, 2 capsules, at meals. Each soft gel capsule is a matching placebo of the active treatment.
5 000 1 250
Antioxidant Once daily, 2 capsules, at meals. Each soft gel capsule contains:
500 mg of vitamin C 100 IU of vitamin E (d-alpha-tocopherol) 100 IU of vitamin E (d-alpha-tocopheryl acetate)
5 000 1 250
Total per stratum 10 000 2 500 Total 12 500
INTAPP Schematic design
High Risk N=2 500
Low Risk N=10 000
Antioxidant Group (N=5 000)
Antioxidant group (N=1 250)
Placebo Group (N=5 000)
Placebo Group (N=1 250)
D E L I V E R Y
Gestational Age 120/7-186/7 240/7-266/7 320/7-346/7 ≈40
Visits 1 2 3 4 5
Pregnant Women
Hospital discharge
30 days post-
discharge
Chart review questionnaire
Procedures
Visit 1 Visit 2 Visit 3 Visit 4post-
discharge30 days post-
discharge
120/7-186/7 Weeks240/7 – 266/7
Weeks320/7 – 346/7
Weeks post-partum (any moment)
Eligibility Checklist ●Consent Form ●Questionnaire ● ● ● ●Blood Pressure Measurement ● ● ●Blood Sample ● ● ● ●Urine sample for proteinuria test ● ● ●Weight measurement ● ● ● ●Food Frequency Questionnaire ● ●Randomization ●Treatment Medication Dispensing ● Bottles 1, 2, 3
Participation Medication Diary ● ● ● ● Chart Review Questionnaire ●Adverse Events Screening ● ● ● ● ●
Procedures/Tests
INTAPP INTAPP a multidisciplinary teama multidisciplinary team
Organisation of sites
Research CentresVarious hospitalsAcross Canada
MGS (Management System)University of Sherbrooke
Ctr for Research and Evaluation in DiagnosticsDr Andrew Grant, Director
Central LaboratoryCHUL, Québec
Dr Pierre Julien, DirectorDr François Cadelis, Res Assoc.
GEREQManagement of Clinical Data
MontréalDr Jean-Paul Collet, Director
TCC (Trial Coordinating Center)Ste-Justine, Montréal
Dr William Fraser, Principal Investigator
Aim of this procedure• Ensure appropriate processing, storing and
shipping of blood samples in order to be able to perform sensitive analyses of vitamin C & E
• Ensure an efficient system of communication between study sites, CL, GEREQ and the Center for Research and Evaluation in Diagnostics. – Testing of Vitamins C & E– Biological Specimen Bank
Central Laboratory
• At reception of your samples, CL will make an inventory of the samples, using a bar code scanner to ensure that content match the Inventory log
• This will automatically creates a record in the MGS system at CL.
• MGS will then store the following information:– Date and time of reception– Volume of samples– Quality of samples (intact and frozen)
Central Laboratory
Specimen management system (PIERCE SYSTEM)
• Andrew Grant Centre for Research & Evaluation in Diagnostics (CRED)
Specimen Management SystemUniversité de Sherbrooke
Management of blood specimens and vitamin E & C testing
Food Frequency Questionnaire (FFQ)
• CanadaBryna Shatenstein, PhDMontreal Geriatric Institute
• MexicoMaria-Soccoro Parra, PhDNational Institute of Public Health
• ChinaBaoquing Mo, PhDNanjing Medical University
J.R. Carlson Laboratories inc
Timothy JohaneckRobert Meyer
• Study medication kit preparation• Shipment to study sites
42 study sites- Canada 21 - Mexico 10
- China 4 - Argentina 7
Study sites
Canada
China
Argentina
Mexico
Belgium
Maternal and Infant Research
on Oxidative Stress
INTAPP-MIROS Synergy
MIROS Synergy among projects
MIROS-INTAPP Parallel Structures
MIROS Organizational Structure
Committees Members
Communication Strategy