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TIPPS: Thrombophilia in Pregnancy Prophylaxis Study (TIPPS)

Primary Purpose

Pregnancy, Thrombophilia, Pregnancy Complications

Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
dalteparin sodium
Sponsored by
Ottawa Hospital Research Institute
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Pregnancy focused on measuring Pregnancy, Thrombophilia, High-risk pregnancy, LMWH prophylaxis, Placenta mediated pregnancy complications

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)FemaleDoes not accept healthy volunteers

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

Sites / Locations

  • Saint Louis University
  • University of Utah Health Sciences Centre
  • Royal Alexandra Hospital
  • QEII Health Sciences Centre
  • Hamilton Health Sciences Centre
  • The Ottawa Hospital, Civic Campus
  • Mount Sinai Hospital
  • Women's College Health Sciences Centre
  • SMBD Jewish General Hospital
  • St Mary's Hospital Centre
  • Royal University Hospital
  • CHA, Hopital Enfant Jesus

Arms of the Study

Arm 1

Arm 2

Arm Type

No Intervention

Active Comparator

Arm Label

Control

dalteparin sodium

Arm Description

Subjects randomized to control will receive identical obstetrical care and follow-up, but not antenatal dalteparin. 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

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

Outcomes

Primary Outcome Measures

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)

Secondary Outcome Measures

Identify if prophylactic LMWH will reduce rates of pregnancy induced hypertension (PIH), preterm labor and abruptio placenta in pregnant thrombophilic women compared to control
Determine the safety of LMWH use in pregnancy (Specifically rates of bleeding, thrombocytopenia and fractures)
Identify whether prolonged use of LMWH in pregnancy results in decreased bone mineral density (BMD) compared to control

Full Information

First Posted
May 29, 2009
Last Updated
May 16, 2014
Sponsor
Ottawa Hospital Research Institute
Collaborators
Canadian Institutes of Health Research (CIHR)
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1. Study Identification

Unique Protocol Identification Number
NCT00967382
Brief Title
TIPPS: Thrombophilia in Pregnancy Prophylaxis Study
Acronym
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.
Study Type
Interventional

2. Study Status

Record Verification Date
May 2014
Overall Recruitment Status
Completed
Study Start Date
July 2000 (undefined)
Primary Completion Date
March 2014 (Actual)
Study Completion Date
March 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Ottawa Hospital Research Institute
Collaborators
Canadian Institutes of Health Research (CIHR)

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief 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?
Detailed 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Pregnancy, Thrombophilia, Pregnancy Complications
Keywords
Pregnancy, Thrombophilia, High-risk pregnancy, LMWH prophylaxis, Placenta mediated pregnancy complications

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
292 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Control
Arm Type
No Intervention
Arm Description
Subjects randomized to control will receive identical obstetrical care and follow-up, but not antenatal dalteparin. 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
Arm Title
dalteparin sodium
Arm Type
Active Comparator
Arm Description
Subjects randomized to the treatment group will receive daily injections of dalteparin during the antenatal period. They will be taught how to self-administer sub-cutaneous injections of dalteparin 5000 IU once daily (o.d.) until gestational age 20, then twice daily (bid) until 37 weeks gestation or onset of labour. 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
Intervention Type
Drug
Intervention Name(s)
dalteparin sodium
Other Intervention Name(s)
Fragmin
Intervention Description
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
Primary Outcome Measure Information:
Title
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)
Time Frame
6 weeks post-partum
Secondary Outcome Measure Information:
Title
Identify if prophylactic LMWH will reduce rates of pregnancy induced hypertension (PIH), preterm labor and abruptio placenta in pregnant thrombophilic women compared to control
Time Frame
6 weeks post-partum
Title
Determine the safety of LMWH use in pregnancy (Specifically rates of bleeding, thrombocytopenia and fractures)
Time Frame
6 weeks post-partum
Title
Identify whether prolonged use of LMWH in pregnancy results in decreased bone mineral density (BMD) compared to control
Time Frame
6 weeks post-partum

10. Eligibility

Sex
Female
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Marc A Rodger, MD
Organizational Affiliation
Ottawa Hospital Research Institute, Ottawa, Canada
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
William Hague, MD
Organizational Affiliation
Women's and Children's Hospital, Adelaide, Australia
Official's Role
Principal Investigator
Facility Information:
Facility Name
Saint Louis University
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63117
Country
United States
Facility Name
University of Utah Health Sciences Centre
City
Salt Lake City
State/Province
Utah
ZIP/Postal Code
84132
Country
United States
Facility Name
Royal Alexandra Hospital
City
Edmonton
State/Province
Alberta
Country
Canada
Facility Name
QEII Health Sciences Centre
City
Halifax
State/Province
Nova Scotia
Country
Canada
Facility Name
Hamilton Health Sciences Centre
City
Hamilton
State/Province
Ontario
Country
Canada
Facility Name
The Ottawa Hospital, Civic Campus
City
Ottawa
State/Province
Ontario
Country
Canada
Facility Name
Mount Sinai Hospital
City
Toronto
State/Province
Ontario
Country
Canada
Facility Name
Women's College Health Sciences Centre
City
Toronto
State/Province
Ontario
Country
Canada
Facility Name
SMBD Jewish General Hospital
City
Montreal
State/Province
Quebec
Country
Canada
Facility Name
St Mary's Hospital Centre
City
Montreal
State/Province
Quebec
Country
Canada
Facility Name
Royal University Hospital
City
Saskatoon
State/Province
Saskatchewan
Country
Canada
Facility Name
CHA, Hopital Enfant Jesus
City
Quebec
Country
Canada

12. IPD Sharing Statement

Citations:
PubMed Identifier
33779986
Citation
Middleton P, Shepherd E, Gomersall JC. Venous thromboembolism prophylaxis for women at risk during pregnancy and the early postnatal period. Cochrane Database Syst Rev. 2021 Mar 29;3(3):CD001689. doi: 10.1002/14651858.CD001689.pub4.
Results Reference
derived
PubMed Identifier
25066248
Citation
Rodger MA, Hague WM, Kingdom J, Kahn SR, Karovitch A, Sermer M, Clement AM, Coat S, Chan WS, Said J, Rey E, Robinson S, Khurana R, Demers C, Kovacs MJ, Solymoss S, Hinshaw K, Dwyer J, Smith G, McDonald S, Newstead-Angel J, McLeod A, Khandelwal M, Silver RM, Le Gal G, Greer IA, Keely E, Rosene-Montella K, Walker M, Wells PS; TIPPS Investigators. Antepartum dalteparin versus no antepartum dalteparin for the prevention of pregnancy complications in pregnant women with thrombophilia (TIPPS): a multinational open-label randomised trial. Lancet. 2014 Nov 8;384(9955):1673-83. doi: 10.1016/S0140-6736(14)60793-5. Epub 2014 Jul 24.
Results Reference
derived
PubMed Identifier
22449204
Citation
Bennett SA, Bagot CN, Arya R. Pregnancy loss and thrombophilia: the elusive link. Br J Haematol. 2012 Jun;157(5):529-42. doi: 10.1111/j.1365-2141.2012.09112.x. Epub 2012 Mar 26.
Results Reference
derived
Links:
URL
http://healthypregnancy.ca
Description
Healthy pregnancy is a website designed to provide general information about thrombophilia and placenta mediated pregnancy complications as well as information to help promote the TIPPS study. It is also a resource for site investigators and their team.
URL
http://www.ohri.ca/home.asp
Description
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.
URL
http://cihr-irsc.gc.ca
Description
Site of the Canadian Institutes of Health Research - information regarding the terms of reference related to the TIPPS grant can be found herein.

Learn more about this trial

TIPPS: Thrombophilia in Pregnancy Prophylaxis Study

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