Comment Period Extended to 3/23/2015 for Notice of Proposed Rulemaking (NPRM) for FDAAA 801 and NIH Draft Reporting Policy for NIH-Funded Trials

Comparison of Low and Intermediate Dose Low-molecular-weight Heparin to Prevent Recurrent Venous Thromboembolism in Pregnancy

This study is currently recruiting participants. (see Contacts and Locations)
Verified January 2015 by Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Sponsor:
Collaborators:
Netherlands Organisation for Scientific Research
GlaxoSmithKline
CHU of Saint Etienne (sponsor of the French part of the study)
Information provided by (Responsible Party):
S. Middeldorp, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
ClinicalTrials.gov Identifier:
NCT01828697
First received: April 5, 2013
Last updated: January 5, 2015
Last verified: January 2015
  Purpose

This is a randomized-controlled open-label trial comparing two different doses of low-molecular-weight heparin (LMWH) in pregnant patients with a history of previous venous thromboembolism (VTE). Both doses are recommended doses in the 2012 guidelines of the American College of Chest Physicians (ACCP), but it is not known which dose is more efficacious in preventing recurrent venous thromboembolism in pregnancy.

Patients enter the study and will be randomized as soon as a home test confirms pregnancy. LMWH will be administered until 6 weeks postpartum. Follow-up will continue until 3 months postpartum. Patients will be recruited by their treating physician, either an obstetrician or internist.


Condition Intervention Phase
Deep Venous Thrombosis
Pulmonary Embolism
Drug: Low dose nadroparin
Drug: Intermediate dose nadroparin
Drug: Low dose enoxaparin
Drug: Intermediate dose enoxaparin
Drug: Low dose dalteparin
Drug: Intermediate dose dalteparin
Drug: Fixed low dose tinzaparin
Drug: Intermediate dose tinzaparin
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Prevention
Official Title: Low-molecular-weight Heparin to Prevent Recurrent VTE in Pregnancy: a Randomized Controlled Trial of Two Doses

Resource links provided by NLM:


Further study details as provided by Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA):

Primary Outcome Measures:
  • Symptomatic confirmed deep venous thrombosis [ Time Frame: From date of randomization up to 6 weeks postpartum ] [ Designated as safety issue: No ]

    All events of symptomatic deep venous thrombosis in subjects will be recorded from the the date of randomization up to 6 weeks postpartum.

    Definition of symptomatic deep venous thrombosis (DVT):

    Suspected (recurrent) DVT with one of the following findings:

    If there were no previous DVT investigations:

    • Abnormal compression ultrasound (CUS),
    • An intraluminal filling defect on venography.

    If there was a previous DVT investigation:

    • Abnormal CUS where compression had been normal or, if non-compressible during screening, a substantial increase (4 mm or more) in diameter of the thrombus during full compression,
    • An extension of an intraluminal filling defect, or a new intraluminal filling defect or an extension of non-visualization of veins in the presence of a sudden cut-off on venography.

  • Symptomatic confirmed pulmonary embolism [ Time Frame: From date of randomization up to 6 weeks postpartum ] [ Designated as safety issue: No ]

    All events of symptomatic pulmonary embolism in subjects will be recorded from the the date of randomization up to 6 weeks postpartum.

    Definition of symptomatic pulmonary embolism (PE):

    Suspected PE with one of the following findings:

    • A (new) intraluminal filling defect in subsegmental or more proximal branches on spiral CT scan
    • A (new) intraluminal filling defect or an extension of an existing defect or a new sudden cut-off of vessels more than 2.5 mm in diameter on the pulmonary angiogram
    • A (new) perfusion defect of at least 75% of a segment with a local normal ventilation result (high-probability) on ventilation/perfusion lung scan (VPLS)


Secondary Outcome Measures:
  • Symptomatic confirmed deep venous thrombosis [ Time Frame: From date of randomization up to 3 months postpartum ] [ Designated as safety issue: No ]

    All events of symptomatic deep venous thrombosis in subjects will be recorded from the the date of randomization up to 3 months postpartum.

    Definition of symptomatic deep venous thrombosis (DVT):

    Suspected (recurrent) DVT with one of the following findings:

    If there were no previous DVT investigations:

    • Abnormal compression ultrasound (CUS),
    • An intraluminal filling defect on venography.

    If there was a previous DVT investigation:

    • Abnormal CUS where compression had been normal or, if non-compressible during screening, a substantial increase (4 mm or more) in diameter of the thrombus during full compression,
    • An extension of an intraluminal filling defect, or a new intraluminal filling defect or an extension of non-visualization of veins in the presence of a sudden cut-off on venography.

  • Symptomatic confirmed pulmonary embolism [ Time Frame: From date of randomization up to 3 months postpartum ] [ Designated as safety issue: No ]

    All events of symptomatic pulmonary embolism in subjects will be recorded from the the date of randomization up to 3 months postpartum.

    Definition of symptomatic pulmonary embolism (PE):

    Suspected PE with one of the following findings:

    • A (new) intraluminal filling defect in subsegmental or more proximal branches on spiral CT scan
    • A (new) intraluminal filling defect or an extension of an existing defect or a new sudden cut-off of vessels more than 2.5 mm in diameter on the pulmonary angiogram
    • A (new) perfusion defect of at least 75% of a segment with a local normal ventilation result (high-probability) on ventilation/perfusion lung scan (VPLS)


Other Outcome Measures:
  • Major bleeding [ Time Frame: During pregnancy until 3 months postpartum ] [ Designated as safety issue: Yes ]

    Major bleeding is defined as overt bleeding and:

    • Associated with a fall in hemoglobin of 2 g/dL or more, or
    • Leading to a transfusion of 2 or more units of packed red blood cells or whole blood, or
    • Occurring in a critical site: intracranial, intraspinal, intraocular, pericardial, intra-articular, intramuscular with compartment syndrome, retro-peritoneal, or
    • Contributing to death

  • Composite of major bleeding and clinically relevant non-major bleeding [ Time Frame: During pregnancy until 3 months postpartum ] [ Designated as safety issue: Yes ]

    See 'Major bleeding' for the definition.

    Clinically relevant non-major bleeding is defined as overt bleeding not meeting the criteria for major bleeding but associated with medical intervention, unscheduled contact (visit or telephone call) with a physician, (temporary) cessation of study treatment, or associated with discomfort such as pain, or impairment of activities of daily life.

    • Hematuria if it is macroscopic, and either spontaneous or lasts for more than 24 hours after instrumentation (e.g. catheter placement or surgery) of the urogenital tract, or
    • Macroscopic gastro-intestinal haemorrhage: at least one episode of melena/hematemesis, if clinically apparent, or
    • Rectal blood loss, if more than a few spots, or
    • Hemoptysis, if more than a few speckles in the sputum, or
    • Intramuscular hematoma, or
    • Subcutaneous hematoma if the size is larger than 25 cm2, or larger than 100 cm2 if provoked, or
    • Multiple source bleeding

  • Early postpartum hemorrhage [ Time Frame: Within 24 hours of delivery ] [ Designated as safety issue: Yes ]
    Postpartum haemorrhage is defined as blood loss of more than 500 mL within 24 hours of delivery (WHO-criteria). Severe postpartum haemorrhage is defined as blood loss of more than 1000 mL within 24 hours of delivery.

  • Blood transfusion < 6 weeks after delivery [ Time Frame: Within 6 weeks of delivery ] [ Designated as safety issue: Yes ]
  • Blood transfusion < 24 hours postpartum [ Time Frame: Within 24 hours of delivery ] [ Designated as safety issue: Yes ]
  • Late postpartum hemorrhage [ Time Frame: From 24 hours postpartum to 6 weeks postpartum ] [ Designated as safety issue: Yes ]
    Postpartum haemorrhage is defined as blood loss of more than 500 mL within 24 hours of delivery (WHO-criteria). Severe postpartum haemorrhage is defined as blood loss of more than 1000 mL within 24 hours of delivery.

  • Mortality [ Time Frame: During pregnancy until 3 months postpartum ] [ Designated as safety issue: Yes ]
  • Minor bleeding [ Time Frame: During pregnancy until 3 months postpartum ] [ Designated as safety issue: Yes ]
    Minor bleeding is defined as all other overt bleeding episodes not meeting the criteria for major or clinically relevant bleeding or postpartum haemorrhage.

  • Skin complications [ Time Frame: During pregnancy until 3 months postpartum ] [ Designated as safety issue: Yes ]
    e.g. itching, swelling, pain

  • Easy bruising [ Time Frame: During pregnancy until 3 months postpartum ] [ Designated as safety issue: Yes ]
  • Necessity to switch to other LMWH [ Time Frame: During pregnancy until 6 weeks postpartum ] [ Designated as safety issue: Yes ]
  • Heparin-induced thrombocytopenia [ Time Frame: During pregnancy until 3 months postpartum ] [ Designated as safety issue: Yes ]
    Heparin-induced thrombocytopenia is defined according to the criteria of the ACCP guidelines.

  • Congenital anomalies or birth defects [ Time Frame: During pregnancy until 3 months postpartum ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 1000
Study Start Date: April 2013
Estimated Primary Completion Date: April 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Low dose LMWH

Fixed low dose low-molecular-weight heparin:

  • Fixed low dose nadroparin, or;
  • Fixed low dose enoxaparin, or;
  • Fixed low dose dalteparin, or;
  • Fixed low dose tinzaparin.
Drug: Low dose nadroparin

Fixed low dose nadroparin:

  • < 100 kg: 2850 IU subcutaneously once-daily
  • 100 kg and above: 3800 IU subcutaneously once-daily
Other Names:
  • nadroparin
  • Fraxiparin
Drug: Low dose enoxaparin

Fixed low dose enoxaparin:

  • < 100 kg: 40 mg subcutaneously once-daily
  • 100 kg and above: 60 mg subcutaneously once-daily
Other Names:
  • enoxaparin
  • Clexane
Drug: Low dose dalteparin

Fixed low dose dalteparin:

  • < 100 kg: 5000 IU subcutaneously once-daily
  • 100 kg and above: 7500 IU subcutaneously once-daily
Other Names:
  • dalteparin
  • Fragmin
Drug: Fixed low dose tinzaparin

Fixed low dose tinzaparin:

  • < 100 kg: 3500 IU subcutaneously once-daily
  • 100 kg and above: 4500 IU subcutaneously once-daily
Other Names:
  • tinzaparin
  • Innohep
Active Comparator: Intermediate dose LMWH

Intermediate dose low-molecular-weight heparin. Dosing is weight-adjusted according to the protocol.

  • Intermediate dose nadroparin, or;
  • Intermediate dose enoxaparin, or;
  • Intermediate dose dalteparin, or;
  • Intermediate dose tinzaparin.
Drug: Intermediate dose nadroparin

Intermediate weight-adjusted dose nadroparin:

  • < 50 kg: 3800 IU subcutaneously once-daily;
  • 50 to < 70 kg: 5700 IU subcutaneously once-daily;
  • 70 to < 100 kg: 7600 IU subcutaneously once-daily;
  • 100 kg or above: 9500 IU subcutaneously once-daily.
Other Names:
  • nadroparin
  • Fraxiparin
Drug: Intermediate dose enoxaparin

Intermediate weight-adjusted dose enoxaparin:

  • < 50 kg: 60 mg subcutaneously once-daily, or;
  • 50 kg to < 70 kg: 80 mg subcutaneously once-daily, or;
  • 70 kg to < 100 kg: 100 mg subcutaneously once-daily, or;
  • 100 kg or above: 120 mg subcutaneously once-daily.
Other Names:
  • enoxaparin
  • Clexane
Drug: Intermediate dose dalteparin

Intermediate weight-adjusted dose dalteparin:

  • < 50 kg: 7500 IU subcutaneously once-daily, or;
  • 50 kg to < 70 kg: 10000 IU subcutaneously once-daily, or;
  • 70 kg to < 100 kg: 12500 IU subcutaneously once-daily, or;
  • 100 kg or above: 15000 IU subcutaneously once-daily.
Other Names:
  • dalteparin
  • Fragmin
Drug: Intermediate dose tinzaparin

Intermediate weight-adjusted dose tinzaparin:

  • < 50 kg: 4500 IU subcutaneously once-daily, or;
  • 50 kg to < 70 kg: 7000 IU subcutaneously once-daily, or;
  • 70 kg to < 100 kg: 10000 IU subcutaneously once-daily, or;
  • 100 kg or above: 12000 IU subcutaneously once-daily.
Other Names:
  • tinzaparin
  • Innohep

  Eligibility

Ages Eligible for Study:   18 Years to 50 Years
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Age: 18 years or older, and;
  • Pregnancy confirmed by urinary pregnancy test, and;
  • Gestational age < 14 weeks, and;
  • Previous objectively confirmed VTE, either unprovoked, in the presence of use of oral contraceptives or estrogen/progestagen use, or related to pregnancy or the postpartum period, or minor risk factors (e.g. long distance travel, minor trauma).

Exclusion Criteria:

  • Previous VTE related to a major provoking risk factor (e.g. surgery, major trauma or plaster cast immobilisation in the 3 months prior to VTE) as the sole risk factor, or;
  • Indication for treatment with therapeutic dose anticoagulant therapy (e.g. treatment of acute VTE; permanent use of therapeutic anticoagulants outside of pregnancy), or;
  • Inability to provide informed consent, or;
  • Any contraindication listed in the local labelling of LMWH.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01828697

Contacts
Contact: S. M. Bleker, MD s.m.bleker@amc.nl
Contact: N. van Es, MD n.vanes@amc.nl

Locations
Austria
Medizinische Universitaet Wien - Universitaetsklinik fuer Innere Medizin I Not yet recruiting
Vienna, Austria
Contact: Ingrid Pabinger       ingrid.pabinger@meduniwien.ac.at   
Belgium
KU Leuven Not yet recruiting
Leuven, Belgium
Contact: Peter Verhamme       peter.verhamme@uzleuven.be   
France
Hopital Nord, CHU de Saint Etienne Not yet recruiting
Saint Etienne, France
Contact: Andréa Buchmuller       andrea.buchmuller@chu-st-etienne.fr   
Contact: Hervé Decousus       herve.decousus@chu-st-etienne.fr   
Ireland
Mater Misericordiae Hospital Not yet recruiting
Dublin, Ireland
Contact: Fionnuala Ni Ainle, MD PhD       fniainle@mater.ie   
Netherlands
Academic Medical Center Recruiting
Amsterdam, Noord-Holland, Netherlands, 1105 AZ
Contact: S. M. Bleker, MD       s.m.bleker@amc.nl   
Contact: N. van Es, MD       n.vanes@amc.nl   
Jeroen Bosch Ziekenhuis Recruiting
's-Hertogenbosch, Netherlands
Contact: Robert Rijnders       r.rijnders@jbz.nl   
Flevoziekenhuis Not yet recruiting
Almere, Netherlands
Contact: Gunilla Kleiverda       gkleiverda@flevoziekenhuis.nl   
VU medical center Recruiting
Amsterdam, Netherlands
Contact: Marion van Hoorn       m.vanhoorn@vumc.nl   
SLAZ Not yet recruiting
Amsterdam, Netherlands
Contact: Brenda Hermsen       b.hermsen@slaz.nl   
Contact: Reinhard Maas       r.maas@slaz.nl   
OLVG Recruiting
Amsterdam, Netherlands
Contact: E.S.A. van den Akker       e.s.a.vandenakker@olvg.nl   
Gelre Ziekenhuizen Recruiting
Apeldoorn, Netherlands
Contact: Thomas van Bemmel       t.van.bemmel@gelre.nl   
Rijnstate hospital Not yet recruiting
Arnhem, Netherlands
Contact: Marcel Hovens       mhovens@rijnstate.nl   
Wilhelmina Ziekenhuis Recruiting
Assen, Netherlands
Contact: A. Koops       j.h.m.keurentjes@umcg.nl   
Amphia ziekenhuis Recruiting
Breda, Netherlands
Contact: D Papatsonis       dpapatsonis@amphia.nl   
Reinier de Graaf Groep Recruiting
Delft, Netherlands
Contact: H Bremer       bremer@rdgg.nl   
Bronovo ziekenhuis Recruiting
Den Haag, Netherlands
Contact: Wim van Wijngaarden       wvwijngaarden@bronovo.nl   
HAGA ziekenhuis Recruiting
Den Haag, Netherlands
Contact: Paula Ypma       p.ypma@hagaziekenhuis.nl   
Deventer Ziekenhuis Recruiting
Deventer, Netherlands
Contact: Joost Zwart       j.zwart@dz.nl   
Slingeland Active, not recruiting
Doetinchem, Netherlands
Albert Schweitzer Not yet recruiting
Dordrecht, Netherlands
Contact: Sabina Rombout-de Weerd       s.rombout-de.weerd@asz.nl   
Contact: Peter Westerweel       p.e.westerweel@asz.nl   
Groene Hart Ziekenhuis Not yet recruiting
Gouda, Netherlands
Contact: Claudia van Meir       claudia.van.meir@ghz.nl   
Contact: Bea Tanis       bea.tanis@ghz.nl   
Martini Ziekenhuis Active, not recruiting
Groningen, Netherlands
UMCG Recruiting
Groningen, Netherlands
Contact: Maureen Franssen       m.t.m.franssen@umcg.nl   
Kennemer Gasthuis Not yet recruiting
Haarlem, Netherlands
Contact: Paula Pernet       pernet@kg.nl   
Atrium MC Recruiting
Heerlen, Netherlands
Contact: J Langenveld       j.langenveld@atriummc.nl   
MC Leeuwarden Not yet recruiting
Leeuwarden, Netherlands
LUMC Active, not recruiting
Leiden, Netherlands
MUMC Active, not recruiting
Maastricht, Netherlands
Canisius-Wilhelmina Ziekenhuis Not yet recruiting
Nijmegen, Netherlands
Contact: D.H. Schippers       gerard.zijderveld@radboudumc.nl   
St. Radboud UMC Recruiting
Nijmegen, Netherlands
Contact: M Woiski       m.woiski@obgyn.umcn.nl   
Erasmus MC Not yet recruiting
Rotterdam, Netherlands
Contact: Marieke Kruip       m.kruip@erasmusmc.nl   
TweeSteden Active, not recruiting
Tilburg, Netherlands
Diakonessen Utrecht Not yet recruiting
Utrecht, Netherlands
Contact: Nico Schuitemaker       nschuite@diakhuis.nl   
UMCU Recruiting
Utrecht, Netherlands
Contact: Martijn Oudijk       m.a.oudijk@umcutrecht.nl   
Máxima MC Active, not recruiting
Veldhoven, Netherlands
Sponsors and Collaborators
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Netherlands Organisation for Scientific Research
GlaxoSmithKline
CHU of Saint Etienne (sponsor of the French part of the study)
Investigators
Principal Investigator: S. Middeldorp, MD PhD Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
  More Information

Additional Information:
Publications:

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: S. Middeldorp, prof.dr. S. Middeldorp, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
ClinicalTrials.gov Identifier: NCT01828697     History of Changes
Other Study ID Numbers: Highlow, 2012-001505-24, NL40326.018.12, NTR3894
Study First Received: April 5, 2013
Last Updated: January 5, 2015
Health Authority: Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)

Keywords provided by Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA):
Low-molecular-weight heparin
Pregnancy
Venous thrombosis

Additional relevant MeSH terms:
Pulmonary Embolism
Venous Thromboembolism
Venous Thrombosis
Cardiovascular Diseases
Embolism
Embolism and Thrombosis
Lung Diseases
Respiratory Tract Diseases
Thromboembolism
Thrombosis
Vascular Diseases
Dalteparin
Heparin
Heparin, Low-Molecular-Weight
Nadroparin
Tinzaparin
Anticoagulants
Cardiovascular Agents
Fibrin Modulating Agents
Fibrinolytic Agents
Hematologic Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Therapeutic Uses

ClinicalTrials.gov processed this record on March 03, 2015