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    Summary
    EudraCT Number:2007-000284-21
    Sponsor's Protocol Code Number:524E-CVD-9101-004
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2007-07-27
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedUK - MHRA
    A.2EudraCT number2007-000284-21
    A.3Full title of the trial
    A multicentre, multinational randomised control trial of prophylactic low molecular weight heparin(LMWH) in high risk pregnant thrombophilic women
    A.3.2Name or abbreviated title of the trial where available
    Thrombophilia in Pregnancy Prophylaxis Study (TIPPS)
    A.4.1Sponsor's protocol code number524E-CVD-9101-004
    A.5.1ISRCTN (International Standard Randomised Controlled Trial) NumberISRCTN87441504
    A.7Trial is part of a Paediatric Investigation Plan Information not present in EudraCT
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorYork Hospitals NHS Foundation Trust
    B.1.3.4CountryUnited Kingdom
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    B.Sponsor: 2
    B.1.1Name of SponsorUniversity of York
    B.1.3.4CountryUnited Kingdom
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Fragmin 5000IU
    D.2.1.1.2Name of the Marketing Authorisation holderPharmacia Limited
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameDalteparin
    D.3.4Pharmaceutical form Injection
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) Information not present in EudraCT
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product Yes
    D.3.11.9Recombinant medicinal product Information not present in EudraCT
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Thrombophilia in pregnancy. This is a multi-centre, multi-national randomised controlled trial of Low Molecular Weight Heparin to prevent pregnancy complications in high-risk pregnant thrombophilic women.
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.0
    E.1.2Level LLT
    E.1.2Classification code 10057396
    E.1.2Term Thrombophilia
    E.1.2System Organ Class 10005329 - Blood and lymphatic system disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The main research question of this Trial is: Can LMWH prevent blood clots in the leg veins, pulmonary arteries and placental vessels, thereby reducing the risk of deep vein thrombosis (DVT), pulmonary embolism (PE)(blood clot in the lungs), IUGR, preeclampsia, miscarriage and stillbirth?
    E.2.2Secondary objectives of the trial
    This study will also evaluate if LMWH will prevent 1) Pregnancy induced hypertension (high blood pressure during pregnancy), with or without the presence of protein in the urine, 2) Preterm delivery (babies born before 37 weeks estimated gestational age), 3) Abruptio placentae (bleeding behind the placenta), 4) Major and minor bleeding, 5) Thrombocytopenia (low platelet count). Data will be collected looking at the incidence of fractures and significant bone loss associated with long-term use of LMWH.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    The following sub-studies described in the study protocol will be carried out in UK study sites: - Obstetrical Ultrasounds: U/S will be undertaken at gestational week 18 for routine foetal anatomy, and at gestational week 24, 28, 32 and 36 for assessment of foetal growth. In addition, uterine artery Doppler studies will be performed at 24 weeks. Data collected from the ultrasounds will assess the utility of ultrasound monitoring in thrombophilic pregnancies. - Placental Pathology: placentas will be collected from all women and sent to pathology for examination for placental thrombosis. - Bone Mineral Density: a two site bone mineral density will be done at six weeks post-partum on all patients or at early termination if patient has been on study for more than 6 weeks. Results will determine the impact of antenatal LMWH prophylaxis on bone density and risk of fracture. A 1 year follow-up two site bone mineral density will be done to evaluate the long-term impact of antenatal LMWH prophylaxis on bone density and risk of fracture. - 1 Year follow-up: Patients will be mailed a developmental questionnaire one year after delivery and will be called 1 year after delivery to follow-up on infant outcome. This sub-study will assess the impact of adverse pregnancy outcomes on infant development.
    E.3Principal inclusion criteria
    1 One or more of the following high risk criteria for pregnancy complications (VTE or placenta mediated complications): 1.1 Previous pre-eclampsia. 1.2 Previous unexplained IUGR (Infant birth weight 10th percentile for sex and gestational age). 1.3 Previous recurrent miscarriage defined as: 1.3.1 Three or more unexplained miscarriages under 10 weeks gestation, or 1.3.2 Two or more unexplained foetal losses between 10 and 16 weeks gestation, or 1.3.3 One or more unexplained foetal losses at or greater than 16 weeks gestation. *Examples of explained miscarriage or foetal loss include; loss associated with severe congenital malformations, chromosomal abnormalities, neonatal alloimmune haemolytic anaemia, recent CMV infection, positive foetal or placental Listeria cultures, and women with known abnormal uterine anatomy. 1.4 Women with a history of one or more of the following thromboembolic events: 1.4.2 Previous documented secondary proximal VTE *Secondary includes a VTE that occurs during any of the following periods:surgery, immobilisation, cast, and/or malignancy. Any VTE that occurs outside of these periods is considered idiopathic. Women with idiopathic proximal VTE are ineligible (see section 6.2, exclusion criterion 5.2). ** Proximal VTE includes pulmonary embolism or deep vein thrombosis occurring above the trifurcation of the popliteal vein. 1.4.2 Previous documented primary (idiopathic) calf-vein thrombosis or secondary calf-vein thrombosis. * Calf-vein thrombosis is a DVT that occurs below the trifurcation of the popliteal vein. 1.4.3 Previous superficial phlebitis * Superficial phlebitis (also known as thrombophlebitis) refers to thrombosis in a superficial vein. 1.5 Previous major abruptio placenta, defined as an abruption associated with: vaginal bleeding or concealed hemorrhage, and uterine tenderness, and foetal distress, maternal shock, or maternal coagulopathy 1.6 A first degree relative (FDR) with symptomatic thrombophilia (a history of PE or DVT treated with anticoagulants (over one month with heparin or warfarin)). 2. Pregnancy confirmed by a positive serum or urine ßHcG. 3. Thrombophilia confirmed by one or more thrombophilia: Two abnormal tests, and no normal tests, for one or more of the following: 3.1 Protein C deficiency 3.2 Protein S deficiency (outside the normal range for gestational age, see Appendix V), so long as: At least one test is done outside pregnancy or the 6 week post partum period, or In addition to the two abnormal tests in pregnancy, one abnormal test (and no normal tests) is obtained in a first degree relative (FDR). 3.3 Antithrombin deficiency OR Two positive tests for one or more of the following: 3.4 Anticardiolipin IgG (>30 U/ml) 3.5 Anticardiolipin IgM (>30 U/ml) 3.6 Anti-β2 glycoprotein IgG (>20 U/ml) 3.7 Anti-β2 glycoprotein IgM (>20 U/ml) 3.8 Lupus anticoagulant OR One positive test for: 3.9 Factor V Leiden One positive PCR result for Factor V Leiden, or Documented activated protein C resistance and a FDR testing once for Factor V Leiden (PCR positive) 3.10 Prothrombin gene defect 4. Signed Informed Consent.
    E.4Principal exclusion criteria
    1. Less than 4weeks +1 day and greater than 19 weeks +6 days gestational age at time of randomisation. 2. Contraindication to heparin therapy including 2.1 History of heparin induced thrombocytopenia 2.2 Platelet count of less than 100,000 x 106/L 2.3 History of osteoporosis or steroid use (potential increased risk of osteoporosis and osteoporotic fracture with heparin therapy) 2.4 Actively bleeding 2.5 Documented peptic ulcer within 6 weeks (contraindication to anticoagulation) 2.6 Heparin, bisulfite or fish allergy 2.7 Severe hypertension (SBP>200 and/or DBP>120 - contraindication to anticoagulation) 2.8 Severe hepatic failure (INR>1.8) (increased likelihood of bleeding) 3. Women with serum creatinines greater than 80 and an abnormal 24 hour creatinine clearance. * Women with serum creatinines less than 80 do not require a normal 24hr creatinine clearance to be eligible. 4. Geographic inaccessibility (less likely to comply with required follow-up visits and care). 5. Need for anticoagulants as judged by the local investigator such as but not limited to: 5.1 Women with recurrent foetal loss with antiphospholipid antibody syndrome 5.2 Women with prior idiopathic proximal VTE * History of PE or DVT treated with anticoagulants (over one month of heparin or warfarin) or IVC interruption * Idiopathic refers to a VTE that occurs outside all of the following periods: antepartum, postpartum, oral contraceptive use, surgery, immobilisation, cast, and/or malignancy. * Proximal refers to a VTE that occurs above the bifurcation of the popliteal vein. 5.4 Women with mechanical heart valves 6. Women <18 years of age 7. Prior participation in TIPPS 8. Women unable/unwilling to providing informed consent. Subjects currently receiving ASA 80mg daily are eligible for the study
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is a composite outcome that includes any of the following events: 1. Objectively documented VTEs 2. Development of severe or early onset pre-eclampsia 3. IUGR 4. Foetal loss, which includes: Miscarriage:foetal loss prior to 20 weeks estimated gestational age Stillbirth: foetal loss at or over 20 weeks estimated gestational age
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis Yes
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Identical obstetic care and follow-up; no drug intervention
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned8
    E.8.5The trial involves multiple Member States No
    E.8.5.1Number of sites anticipated in the EEA8
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    The last visit of the last subject undergoing the trial.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male No
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women Yes
    F.3.3.4Nursing women Yes
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state60
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 60
    F.4.2.2In the whole clinical trial 385
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2007-08-10
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2007-11-08
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2014-03-30
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