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