TIPPS: Thrombophilia in Pregnancy Prophylaxis Study

Pregnancy Clinical Trial

— TIPPS  

Official title:

TIPPS - Thrombophilia in Pregnancy Prophylaxis Study: A Multicentre, Multinational, Randomized Control Trial of Prophylaxis Low Molecular Weight Heparin (LMWH) in High-risk Thrombophilic Women.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00967382
• Other study ID #: 1999210-01H
• Secondary ID: IND 72,350ISRCTN
• Status: Completed
• Phase: Phase 3
• First received: May 29, 2009
• Last updated: May 16, 2014
• Start date: July 2000
• Est. completion date: March 2014

Study information

• Verified date: May 2014
• Source: Ottawa Hospital Research Institute
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationAustralia: Department of Health and Ageing Therapeutic Goods AdministrationCanada: Health Canada
• Study type: Interventional

Clinical Trial Summary

The TIPPS trial seeks to determine the safety and effectiveness of low-molecular-weight heparin (LMWH), an anticoagulant, in preventing placenta mediated pregnancy complications and venous thromboembolism (VTE) in women with thrombophilia. Thus, the principal research question is: can LMWH prevent thrombosis in the leg veins, pulmonary arteries and placental vessels, thereby reducing the risk of deep vein thrombosis, pulmonary embolism (PE), intrauterine growth restriction (IUGR), preeclampsia, miscarriage and stillbirth?

Description:

TIPPS is a multicentre, multi-national open-label randomized controlled clinical trial. Two hundred and eighty-four 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 5000 International units (IU) 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 292
• Est. completion date: March 2014
• Est. primary completion date: March 2014
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

One or more of the following:

• Previous preeclampsia

• Previous unexplained intra-uterine growth restriction

• Previous recurrent miscarriage:

• three(3) or more unexplained miscarriage at less than 10 weeks gestation;

• two (2) or more unexplained fetal loss between 10 and 16 weeks gestation;

• one (1) or more unexplained fetal loss at or greater than 16 weeks gestation

• Previous abruptio placenta

• Previous personal history of VTE:

• 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

• 3.1 Protein S

• 3.2 Protein C

• 3.3 Antithrombin

• Two positive tests

• 3.4 Anticardiolipin immunoglobulin M (IgM) (>30 U/ml)

• 3.5 Anticardiolipin immunoglobulin G (IgG) (>30 U/ml)

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

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

• 3.8 Lupus anticoagulant

• One positive test

• 3.9 Factor V Leiden (heterozygous or homozygous)

• 3.10Prothrombin gene defect (heterozygous or homozygous)

Exclusion Criteria:

• Less than 4 weeks gestation or greater than 20 weeks gestation

• No confirmed thrombophilia

• 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 (Systolic Blood Pressure >200mmhg and/or Diastolic Blood Pressure >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 deep venous thrombosis (DVT) or pulmonary embolism (PE) treated with anticoagulants (> 1 month of heparin or warfarin) or inferior vena cava (IVC) interruption;

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

• Mechanical heart valve

• Legal lower age limitations (country specific)

• Prior participation in TIPPS

• Unable/unwilling to provide informed consent

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Pregnancy
• Pregnancy Complications
• Thrombophilia

Intervention

Drug:
• dalteparin sodium
Subject's randomize to treatment arm will receive dalteparin sodium 5,000 IU s.c. daily starting on randomization day until 20 weeks gestational age then; dalteparin sodium 5,000 IU s.c. bid from 20 weeks to onset of labour or 37 weeks gestation (discontinued at the discretion of the investigator/obstetrician) Within 24 hours of delivery, all subject's, regardless of randomization allocation will receive dalteparin sodium 5,000 IU s.c. daily for 6 weeks post-partum

Locations

Country	Name	City	State
Canada	Royal Alexandra Hospital	Edmonton	Alberta
Canada	QEII Health Sciences Centre	Halifax	Nova Scotia
Canada	Hamilton Health Sciences Centre	Hamilton	Ontario
Canada	SMBD Jewish General Hospital	Montreal	Quebec
Canada	St Mary's Hospital Centre	Montreal	Quebec
Canada	The Ottawa Hospital, Civic Campus	Ottawa	Ontario
Canada	CHA, Hopital Enfant Jesus	Quebec
Canada	Royal University Hospital	Saskatoon	Saskatchewan
Canada	Mount Sinai Hospital	Toronto	Ontario
Canada	Women's College Health Sciences Centre	Toronto	Ontario
United States	Saint Louis University	Saint Louis	Missouri
United States	University of Utah Health Sciences Centre	Salt Lake City	Utah

Sponsors (2)

Lead Sponsor	Collaborator
Ottawa Hospital Research Institute	Canadian Institutes of Health Research (CIHR)

Countries where clinical trial is conducted

United States,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	The primary objective of the study is to identify if LMWH prophylaxis in thrombophilic pregnant women results in a greater than 33% relative risk reduction in the composite outcome measure (VTE, pre-eclampsia, IUGR and fetal loss)		6 weeks post-partum	No
Secondary	Identify if prophylactic LMWH will reduce rates of pregnancy induced hypertension (PIH), preterm labor and abruptio placenta in pregnant thrombophilic women compared to control		6 weeks post-partum	No
Secondary	Determine the safety of LMWH use in pregnancy (Specifically rates of bleeding, thrombocytopenia and fractures)		6 weeks post-partum	Yes
Secondary	Identify whether prolonged use of LMWH in pregnancy results in decreased bone mineral density (BMD) compared to control		6 weeks post-partum	Yes

External Links

•   Site of the Canadian Institutes of Health Research - information regarding the terms of reference related to the TIPPS grant can be found herein.
•   The Ottawa Hospital Research Institute is the sponsor for TIPPS. This site provides information about the lead institution and provides a link the to coordinating centre located within the thrombosis program.