TIPPS: Thrombophilia in Pregnancy Prophylaxis Study

TIPPS is a multicentre, multi-national open-label randomized controlled clinical trial.
Three hundred and twelve (312) thrombophilic women at risk for VTE or placenta mediated
pregnancy complications will be recruited. Patients who require anticoagulant prophylaxis
during this pregnancy (as judged by the local investigator) or have participated in TIPPS
before will not be eligible for the trial.

The study consists of five periods: screening, randomization, antenatal follow-up, labour
and delivery, and the post-partum follow-up.

Eligible and consenting patients will be assigned to one of two groups (treatment or
control), stratified by gestational age at randomization: less than 8 weeks, 8 weeks +1 day
to 12 weeks , 12 weeks +1 day to 19 weeks + 6 days.

Treatment Group - Subjects randomized to the treatment group will receive daily injections
of dalteparin during the ante-natal period. They will be taught how to self-administer
sub-cutaneous injections of dalteparin 5000IU once daily (o.d.) until gestational week 20,
then twice daily (bid) until 37 weeks gestation or onset of labour.

Control Group- Subjects randomized to control will receive identical obstetrical care and
follow-up, but no ante-natal dalteparin.

Visit Schedule Subject will be evaluated for study eligibility and once the consent has been
signed a baseline assessment will be completed. Randomization is done within 7 days of the
baseline visit.

All patients will be seen in person for the first follow-up visit 7-9 days after
randomization. Subsequent visits are based on the gestational age of the fetus and will be
as follows:

- Monthly (+/- 1 week) from gestational week 8 to 28 -

- Every 2 weeks (+/- 1 week) from gestational week 28 to 34

- Every week from gestational week 35 until delivery.

The following visits are required in-person at day 7-9 and at gestational weeks 12, 20, 28,
32 and/or 36 and at 6 weeks post-partum to coincide with safety blood draws for hematology
and biochemistry regardless of treatment allocation.

The remaining visits can be done in person or by phone calls: at gestational weeks 8, 16,
24, 30, 34, 35, 37, 38, 39 and 40. If available, results for hematology and biochemistry
done at gestational age 8, 16, 24 and 40 will be recorded.

At each visit, weight and blood pressure measurements will be recorded and all subjects will
be monitored for study progress, study outcomes, adverse events (AEs), and concomitant
medications. Subjects randomized to receive dalteparin will have their compliance assessed
through the monthly visits. Subjects will be required to complete the patient injection
diary and will be asked to bring it with them at all in-person-visits. The diary will be
collected at the completion of study participation.

Labour and delivery: outcomes and AEs will be assessed through a review of subjects'
medical records. If available, results from blood drawn for hematology and biochemistry
will be recorded. Data pertaining to the labour and delivery, as well as foetal weight and
health at birth, will be documented. For those subjects randomized to receive dalteparin,
the date and time of the last injection will be noted.

During the six-week postpartum period, all subjects will receive dalteparin 5,000 IU o.d.
for VTE prophylaxis. Subjects randomized to control will be taught to self-administer the
subcutaneous injections prior to starting their postpartum injections. Subjects will be
asked to complete the patient injection diary and to return it at the final visit. The
final study visit occurs at 6 weeks post-partum (+/- 1week) or at early termination; at this
visit study progress, study outcomes, adverse events, results from blood drawn for
hematology and biochemistry and compliance with study drug will be documented.

Inclusion Criteria:One or more of the following

- Previous preeclampsia

- Previous unexplained intra-uterine growth restriction

- Previous recurrent miscarriage:

- 3 or more unexplained miscarriage at less than 10 weeks gestation

- 2 or more unexplained fetal loss between 10 and 16 weeks gestation

- 1 or more unexplained fetal loss at or greater than 16 weeks gestation

- Previous abruptio placenta

- Women with one or more of the following thrombotic events:

- Previous documented secondary proximal VTE

- Previous documented calf-vein thrombosis (idiopathic or secondary)

- Previous superficial phlebitis

- First degree relative with symptomatic thrombophilia

- Pregnancy - > 4weeks gestation and < 20 weeks gestation

- Thrombophilia:

- Two abnormal tests, and no normal tests

- Protein S

- Protein C

- Antithrombin

- Two positive tests

- Anticardiolipin IgM (>30 U/ml)

- Anticardiolipin IgG (>30 U/ml)

- Anti-b2 glycoprotein IgG (>20 U/ml)

- Anti-b2 glycoprotein IgM (>20 U/ml)

- Lupus anticoagulant

- One positive test

- Factor V Leiden (heterozygous or homozygous)

- Prothrombin gene defect (heterozygous or homozygous)

Exclusion Criteria:

- Less than 4 weeks gestation

- Greater than 19+6 weeks gestation

- Contraindication to heparin therapy

- History of heparin induced thrombocytopenia

- Platelet count less than 100,000 109/L

- History of osteoporosis or steroid use

- Actively bleeding

- Documented peptic ulcer within 6 weeks

- Heparin, bisulfite or fish allergy

- Severe hypertension (SBP >200mmhg and/or DBP >120mmHg)

- Serum creatinine greater than 80 umol/L (1.3mg/dl) and an abnormal 24 hour urine
creatine clearance (<30ml/min)

- Severe hepatic failure (INR >1.8)

- Geographic inaccessibility

- Need for anticoagulants, discretion of the investigator such as but not limited to:

- Recurrent fetal loss and phospholipid antibody syndrome

- Prior idiopathic proximal VTE:

- History of idiopathic DVT or PE treated with anticoagulants (> 1 month of
heparin or warfarin) or IVC interruption;

- Idiopathic is a VTE occurring outside all of the following periods:
antepartum, postpartum, oral contraceptive use, surgery, immobilaztion,
cast, and malignancy

- Mechanical heart valve

- Legal lower age limitations (country specific)

- Prior participation in TIPPS

- Unable/unwilling to provide informed consent