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Trial registered on ANZCTR


Registration number
ACTRN12608000446369
Ethics application status
Approved
Date submitted
15/08/2008
Date registered
8/09/2008
Date last updated
12/01/2010
Type of registration
Retrospectively registered

Titles & IDs
Public title
Thrombophilia in Pregnancy Prophylaxis Study: a multicentre, multinational, randomised controlled trial of prophylactic low molecular weight heparin in high-risk pregnant thrombophilic women.
Scientific title
Thrombophilia in Pregnancy Prophylaxis Study: a multicentre, multinational, randomised controlled trial of prophylactic low molecular weight heparin for the prevention of placenta mediated complications in high-risk pregnant thrombophilic women.
Secondary ID [1] 649 0
International Standard Randomised Controlled Trial Number Register ISRCTN87441504
Universal Trial Number (UTN)
Trial acronym
TIPPS
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Venous thromboembolism (VTE) and placenta mediated pregnancy complications in thrombophilic women. 3540 0
Condition category
Condition code
Reproductive Health and Childbirth 3620 3620 0 0
Fetal medicine and complications of pregnancy

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Dalteparin sodium 5000U given subcutaneously (s.c., under the skin) once daily up to 20 weeks gestation, then 5000U s.c. twice daily from 20 weeks gestation to 37 weeks gestation or delivery. All participants will receive Fragmin 5000U s.c. daily from post-partum day 1 for 6 weeks.
Intervention code [1] 3189 0
Prevention
Comparator / control treatment
Control - standard care. Standard care, depending on practitioner/physician preference, may include anti-platelet treatment with low dose aspirin (100mg daily), more frequent fetal ultrasound to monitor fetal health and growth, more frequent monitoring of mothers' blood pressure, blood biochemistry and haematology and more frequent urinalysis.
Control group
Active

Outcomes
Primary outcome [1] 4513 0
Severe or early onset (defined as prior to 32 weeks gestation) pre-eclampsia.
Timepoint [1] 4513 0
Any stage of gestation. As the pregnancy progresses the practitioner/physician will monitor the mother's blood pressure, analyse urine sample for presence of protein, monitor blood biochemistry and haematology for markers of developing pre-eclampsia. This would be done at the visits at 12, 20, 28 and 32 or 36 weeks and as necessary.
Primary outcome [2] 4514 0
Objectively documented venous thromboembolic events including:
1.1 Deep vein thrombosis - as assessed by pain, swelling and diagnosed by ultrasound visualisation.
1.2 Pulmonary embolism - assessed by presence of chest pain, difficulty breathing and confirmation by lung perfusion scan.
1.3 Sudden death.
Timepoint [2] 4514 0
Any stage of gestation, puerperium and post partum. These outcome events will be assessed as necessary.
Primary outcome [3] 4515 0
Intrauterine Growth Restriction (IUGR) fetal growth will be assessed by fetal ultrasound, fetal loss (miscarriage or stillbrith).
Timepoint [3] 4515 0
At any point of gestation if the obstetrician/physician has a concern that the fetus is not growing adequately
Secondary outcome [1] 7633 0
Pregnancy induced hypertension
Timepoint [1] 7633 0
Pregnancy induced hypertension will be assessed by monitoring the mother's blood pressure. The blood pressure will be measured at each visit at 20, 24, 28 and 32 or 36 weeks of gestation. If the participant is being cared for by both an Obstetrician and a Physician, she may have additional measures taken as part of routine clinical management.
Secondary outcome [2] 7634 0
Pre-term delivery.
Timepoint [2] 7634 0
Any time before 37 weeks gestation.
Secondary outcome [3] 7635 0
Abruptio-placentae, major and minor haemorrhage.
Timepoint [3] 7635 0
Any time during gestation, for haemorrhage any time during gestation, puerperium, post-partum.
Secondary outcome [4] 7636 0
Side effects of low molecular weight heparin - fractures, thrombocytopenia, reduction in bone mineral density.
Timepoint [4] 7636 0
If a participant has a "minimal trauma" fracture event at any stage of pregnancy or the 6 week post partum period this will be recorded. Thrombocytopenia is the decrease in the number of platelets in a persons blood. In TIPPS, thrombocytopenia is defined as a 50% drop from baseline in the number of platelets in the blood. Safety monitoring for thrombocytopenia will be conducted at baseline, randomisation, one week after joining the study, 12, 20, 28, at 32 or 36 weeks and 6 weeks after the birth. Bone mineral density for all particpants will be assessed 6 weeks after the birth by Dual energy X-ray absorptiometry (DXA) scan.

Eligibility
Key inclusion criteria
High-risk pregnant women with a confirmed thrombophilia, who have had any of the following pregnancy complications: recurrent miscarriages, stillbirth, pre-eclampsia, very small birth weight baby (IUGR), bleeding in the placenta before delivery (called abruptio placentae) or previous VTE or first degree relative with a history of VTE and confirmed thrombophilia. To be eligible women must give informed consent and be over 18 years of age.
Minimum age
18 Years
Maximum age
No limit
Sex
Females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Less than 4 weeks or greater than 20 weeks pregnant. No confirmed thrombophilia. Unwilling or unable to give informed consent. Contraindication to heparin therapy, including: previous heparin induced thrombocytopenia, platelet count of less than 100,000x10^6/L, history of osteoporosis or steroid use, actively bleeding, documented peptic ulcer. Sensitivity or allergy to pork products. Severe hypertension, severe liver or kidney failure. Need for anticoagulation - i.e. women with recurrent fetal loss and known Anti-Phospholipid Antibody Syndrome, women with prior history of idiopathic VTE and mechanical heart valves.

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Eligible women are informed about the study. They are encouraged to discuss their participation with a family member, friend or health professional. They sign a consent form. Randomisation is web based - the woman's initials, stage of gestation and confirmed thrombophilia are entered into the web randomisation form. This is submitted electronically and the woman is immediately randomised to intervention (dalteparin sodium injections) or control (observation).
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Women are randomised using a web- based randomisation tool. Randomisation is statified by gestation (less than 8 weeks, 8 weeks plus one day to 12 weeks, 12 weeks plus one day to 19 weeks plus 6 days) and by continent (Australia, North America or Europe)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 4
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/07/2000
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
385
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
Recruitment postcode(s) [1] 1021 0
5006
Recruitment postcode(s) [2] 1022 0
6008
Recruitment postcode(s) [3] 1023 0
3052
Recruitment postcode(s) [4] 1024 0
4814
Recruitment postcode(s) [5] 1025 0
4029
Recruitment postcode(s) [6] 1026 0
2065
Recruitment postcode(s) [7] 1027 0
2750
Recruitment outside Australia
Country [1] 1058 0
New Zealand
State/province [1] 1058 0
Auckland
Country [2] 1059 0
United Kingdom
State/province [2] 1059 0
York
Country [3] 1060 0
United Kingdom
State/province [3] 1060 0
Bristol
Country [4] 1061 0
United Kingdom
State/province [4] 1061 0
Hull
Country [5] 1062 0
United Kingdom
State/province [5] 1062 0
Surrey
Country [6] 1063 0
United Kingdom
State/province [6] 1063 0
Manchester
Country [7] 1064 0
United Kingdom
State/province [7] 1064 0
Birmingham
Country [8] 1065 0
United Kingdom
State/province [8] 1065 0
London
Country [9] 1066 0
United Kingdom
State/province [9] 1066 0
Leicester
Country [10] 1067 0
United Kingdom
State/province [10] 1067 0
Leeds
Country [11] 1068 0
United Kingdom
State/province [11] 1068 0
Newcastle
Country [12] 1069 0
United Kingdom
State/province [12] 1069 0
Sunderland
Country [13] 1070 0
Canada
State/province [13] 1070 0
Ontario
Country [14] 1071 0
Canada
State/province [14] 1071 0
Nova Scotia
Country [15] 1072 0
Canada
State/province [15] 1072 0
Quebec
Country [16] 1073 0
Canada
State/province [16] 1073 0
British Columbia
Country [17] 1074 0
Canada
State/province [17] 1074 0
Saskatchewan
Country [18] 1075 0
Canada
State/province [18] 1075 0
Alberta
Country [19] 1076 0
United States of America
State/province [19] 1076 0
Rhode Island
Country [20] 1077 0
United States of America
State/province [20] 1077 0
Connecticut
Country [21] 1078 0
United States of America
State/province [21] 1078 0
Ohio
Country [22] 1079 0
United States of America
State/province [22] 1079 0
Minnesota
Country [23] 1080 0
United States of America
State/province [23] 1080 0
North Carolina
Country [24] 1081 0
United States of America
State/province [24] 1081 0
Illinois
Country [25] 1082 0
United States of America
State/province [25] 1082 0
Utah
Country [26] 1083 0
United States of America
State/province [26] 1083 0
Missouri
Country [27] 1084 0
United States of America
State/province [27] 1084 0
Texas
Country [28] 1085 0
United States of America
State/province [28] 1085 0
New Jersey
Country [29] 1086 0
United States of America
State/province [29] 1086 0
Tennessee
Country [30] 1087 0
United States of America
State/province [30] 1087 0
Maryland
Country [31] 1088 0
United Kingdom
State/province [31] 1088 0
Sheffield
Country [32] 1089 0
United Kingdom
State/province [32] 1089 0
Coventry and Warwickshire

Funding & Sponsors
Funding source category [1] 3653 0
Government body
Name [1] 3653 0
Canadian Institute for Health Research
Country [1] 3653 0
Canada
Primary sponsor type
Government body
Name
The Ottawa Health Research Institute
Address
The Ottawa Hospital
General Campus
501 Smyth Road
Room 1812
OTTAWA K1H 8L6
Country
Canada
Secondary sponsor category [1] 3281 0
Government body
Name [1] 3281 0
The Children's, Youth and Women's Health Service
Address [1] 3281 0
72 King William St.,
NORTH ADELAIDE SA 5006
Country [1] 3281 0
Australia
Other collaborator category [1] 345 0
Other Collaborative groups
Name [1] 345 0
Dr Marc Rodger -Chief Principal Investigator and Principal Investigator, Canada
Address [1] 345 0
The Ottawa Hospital, General Campus
501 Smyth Road, Room W6120
OTTAWA ON K1H 8L6
Country [1] 345 0
Canada
Other collaborator category [2] 346 0
Other Collaborative groups
Name [2] 346 0
Dr W. M. Hague - Australian Principal Investigator
Address [2] 346 0
72 King William St.,
NORTH ADELAIDE SA 5006
Country [2] 346 0
Australia
Other collaborator category [3] 347 0
Other Collaborative groups
Name [3] 347 0
Prof. Ian Greer -Europe Principal Investigator
Address [3] 347 0
Hull York Medical School,
University of York,
Heslington YORK YO10 5DD
Country [3] 347 0
United Kingdom
Other collaborator category [4] 348 0
Other Collaborative groups
Name [4] 348 0
Dr Karen Rosene-Montella, USA Principal Investigator
Address [4] 348 0
Women' and Infant's Hospital of Rhode Island,
101 Dudley Street,
Providence Rhode Island 02905
Country [4] 348 0
United States of America

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 5703 0
Women's and Children's Hospital Research Ethics Committee
Ethics committee address [1] 5703 0
72 King William Street,
NORTH ADELAIDE SA 5006
Ethics committee country [1] 5703 0
Australia
Date submitted for ethics approval [1] 5703 0
26/03/2004
Approval date [1] 5703 0
26/05/2004
Ethics approval number [1] 5703 0
EC00197
Ethics committee name [2] 5800 0
The Royal Women's Hospital Human Ethics Committees
Ethics committee address [2] 5800 0
The Royal Women's Hospital
Locked Bag 300
Grattan St & Flemington Rd
Parkville VIC 3052
Ethics committee country [2] 5800 0
Australia
Date submitted for ethics approval [2] 5800 0
23/03/2005
Approval date [2] 5800 0
02/02/2006
Ethics approval number [2] 5800 0
EC00259
Ethics committee name [3] 5801 0
Northern Sydney Health Hurman Research Ethics Committee
Ethics committee address [3] 5801 0
Level 4, Vindin House
Royal North Shore Hospital
St Leonards NSW 2065
Ethics committee country [3] 5801 0
Australia
Date submitted for ethics approval [3] 5801 0
07/07/2008
Approval date [3] 5801 0
08/08/2008
Ethics approval number [3] 5801 0
EC00333
Ethics committee name [4] 5802 0
King Edward Memorial Hospital for Women Ethics Committee
Ethics committee address [4] 5802 0
GPO Box D184
Perth WA 6840
Ethics committee country [4] 5802 0
Australia
Date submitted for ethics approval [4] 5802 0
10/03/2008
Approval date [4] 5802 0
03/06/2008
Ethics approval number [4] 5802 0
EC00350
Ethics committee name [5] 5803 0
Ethics Committee of each site
Ethics committee address [5] 5803 0
Relevant to each site.
Each site will have the appropriate approvals in place prior to commencing recruiitment.
Ethics committee country [5] 5803 0
Canada
Date submitted for ethics approval [5] 5803 0
Approval date [5] 5803 0
Ethics approval number [5] 5803 0

Summary
Brief summary
Study rationale:
Thrombophilias are disorders that result in a predisposition to develop Venous Thromboembolic Events (VTEs). Thrombophilias are common in the general population. Recent evidence indicates that women with thrombophilia not only have an increased risk of VTEs during pregnancy, but also increased risk of pre-eclampsia, intrauterine growth restriction (IUGR), abruptio placentae and foetal loss. The management of thrombophilic women in pregnancy is controversial and antithrombotic prophylaxis may reduce the rate of complications in pregnancy and the rate of VTEs.

Phase II studies with low molecular weight heparin (LMWH) in pregnant women, for a variety of indications, suggest that there may be a benefit to their use in this high-risk group. However, to date there have been no controlled clinical trials using LMWH to prevent pre-eclampsia, IUGR or foetal loss.
The purpose of this study is to determine the safety and efficacy of LMWH in preventing VTE, pre-eclampsia, IUGR and foetal loss in pregnant thrombophilic women.

Study design:
This study is a multi-centre, open-label, randomised controlled clinical trial based in a maximum of 30 centres. Three hundred and eighty-five(385) pregnant women with confirmed thrombophilia and at high risk for pregnancy complications will be randomised to prophylactic dose dalteparin or control (identical follow-up and care, but no drug intervention).

The study will consist of five periods: a screening period, randomisation, antenatal follow-up, labour and delivery, and postpartum follow-up. Maximum time on study will vary between 26 and 46 weeks.

The primary objective of this 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 foetal loss) compared to control.

Secondary objectives will be to:
1. Identify if prophylactic LMWH will reduce rates of PIH, pre-term labour and abruptio placentae in pregnant thrombophilic women compared to control.
2. Determine safety of LMWH use in pregnancy (specifically rates of bleeding, thrombocytopenia and fractures).
3. Identify whether prolonged LMWH use in pregnancy results in decreased BMD compared to control
Trial website
http://healthypregnancy.ca
Trial related presentations / publications
The effect of dalteparin on coagulation activation during pregnancy in women with thrombophilia: a randomised trial. Thromb Haemost 2007 Jul; 98(1):163-71.

Long-term dalteparin in pregnancy not associated with a decrease in bone mineral density: a substudy of a randomized controlled trial. J Thromb Haemost 2007, 5:1600-1606
Public notes

Contacts
Principal investigator
Name 28780 0
Address 28780 0
Country 28780 0
Phone 28780 0
Fax 28780 0
Email 28780 0
Contact person for public queries
Name 11937 0
Anne Marie Clement
Address 11937 0
The Ottawa Hospital, Civic Campus
Civic Parkdale Clinic
463-737 Parkdale Ave
Ottawa, Ontario K1Y 4E9
Country 11937 0
Canada
Phone 11937 0
0011 1 613-798-5555 ext 19841
Fax 11937 0
0011 1 613-761-4840
Email 11937 0
[email protected]
Contact person for scientific queries
Name 2865 0
Dr Marc Rodger
Address 2865 0
The Ottawa Hospital, General Campus
501 Smyth Road, Room W6120
OTTAWA ON K1H 8L6
Country 2865 0
Canada
Phone 2865 0
0011 1-613-737-8899 ext74641
Fax 2865 0
0011 1-613-739-6102
Email 2865 0
[email protected]

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