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Trial record 2 of 73 for:    PreVENT AND AMC

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

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ClinicalTrials.gov Identifier: NCT01828697
Recruitment Status : Completed
First Posted : April 11, 2013
Last Update Posted : May 26, 2022
Sponsor:
Collaborators:
Netherlands Organisation for Scientific Research
Aspen Pharma
CHU of Saint Etienne: French Ministry of Health Grant (sponsor of the French part of the study)
Rotunda Hospital: Definitive Interventions and Feasibility Awards (DIFA) 2017 (sponsor of the Irish part of the study))
Information provided by (Responsible Party):
S. Middeldorp, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Tracking Information
First Submitted Date  ICMJE April 5, 2013
First Posted Date  ICMJE April 11, 2013
Last Update Posted Date May 26, 2022
Actual Study Start Date  ICMJE April 24, 2013
Actual Primary Completion Date October 31, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 26, 2014)
  • Symptomatic confirmed deep venous thrombosis [ Time Frame: From date of randomization up to 6 weeks postpartum ]
    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 ]
    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)
Original Primary Outcome Measures  ICMJE
 (submitted: April 8, 2013)
  • Symptomatic deep venous thrombosis [ Time Frame: From date of randomization up to 6 weeks postpartum ]
    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 pulmonary embolism [ Time Frame: From date of randomization up to 6 weeks postpartum ]
    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)
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 26, 2014)
  • Symptomatic confirmed deep venous thrombosis [ Time Frame: From date of randomization up to 3 months postpartum ]
    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 ]
    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)
Original Secondary Outcome Measures  ICMJE
 (submitted: April 8, 2013)
  • Symptomatic deep venous thrombosis [ Time Frame: From date of randomization up to 3 months postpartum ]
    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 pulmonary embolism [ Time Frame: From date of randomization up to 3 months postpartum ]
    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)
Current Other Pre-specified Outcome Measures
 (submitted: May 10, 2013)
  • Major bleeding [ Time Frame: During pregnancy until 3 months postpartum ]
    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 ]
    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 ]
    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 ]
  • Blood transfusion < 24 hours postpartum [ Time Frame: Within 24 hours of delivery ]
  • Late postpartum hemorrhage [ Time Frame: From 24 hours postpartum to 6 weeks postpartum ]
    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 ]
  • Minor bleeding [ Time Frame: During pregnancy until 3 months postpartum ]
    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 ]
    e.g. itching, swelling, pain
  • Easy bruising [ Time Frame: During pregnancy until 3 months postpartum ]
  • Necessity to switch to other LMWH [ Time Frame: During pregnancy until 6 weeks postpartum ]
  • Heparin-induced thrombocytopenia [ Time Frame: During pregnancy until 3 months postpartum ]
    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 ]
Original Other Pre-specified Outcome Measures
 (submitted: April 8, 2013)
  • Major bleeding [ Time Frame: During pregnancy until 3 months postpartum ]
    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 ]
    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
  • Postpartum hemorrhage [ Time Frame: Within 24 hours of delivery ]
    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 ]
  • Blood transfusion < 24 hours postpartum [ Time Frame: Within 24 hours of delivery ]
  • Median peripartum blood loss [ Time Frame: Peripartum ]
  • Mortality [ Time Frame: During pregnancy until 3 months postpartum ]
  • Minor bleeding [ Time Frame: During pregnancy until 3 months postpartum ]
    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 ]
    e.g. itching, swelling, pain
  • Easy bruising [ Time Frame: During pregnancy until 3 months postpartum ]
  • Necessity to switch to other LMWH [ Time Frame: During pregnancy until 6 weeks postpartum ]
  • Heparin-induced thrombocytopenia [ Time Frame: During pregnancy until 3 months postpartum ]
    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 ]
 
Descriptive Information
Brief Title  ICMJE Comparison of Low and Intermediate Dose Low-molecular-weight Heparin to Prevent Recurrent Venous Thromboembolism in Pregnancy
Official Title  ICMJE Low-molecular-weight Heparin to Prevent Recurrent VTE in Pregnancy: a Randomized Controlled Trial of Two Doses
Brief Summary

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.

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Condition  ICMJE
  • Deep Venous Thrombosis
  • Pulmonary Embolism
Intervention  ICMJE
  • 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: 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: 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: 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: 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: 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: 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
  • 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
Study Arms  ICMJE
  • 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.
    Interventions:
    • Drug: Low dose nadroparin
    • Drug: Low dose enoxaparin
    • Drug: Low dose dalteparin
    • Drug: Fixed low dose tinzaparin
  • 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.
    Interventions:
    • Drug: Intermediate dose nadroparin
    • Drug: Intermediate dose enoxaparin
    • Drug: Intermediate dose dalteparin
    • Drug: Intermediate dose tinzaparin
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: May 21, 2022)
1110
Original Estimated Enrollment  ICMJE
 (submitted: April 8, 2013)
1000
Actual Study Completion Date  ICMJE October 31, 2021
Actual Primary Completion Date October 31, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Ages  ICMJE 18 Years to 50 Years   (Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Belgium,   Canada,   Denmark,   France,   Ireland,   Netherlands,   Norway,   Russian Federation,   Spain,   United States
Removed Location Countries Austria
 
Administrative Information
NCT Number  ICMJE NCT01828697
Other Study ID Numbers  ICMJE Highlow study
2012-001505-24 ( EudraCT Number )
NL40326.018.12 ( Other Identifier: CCMO )
NTR3894 ( Registry Identifier: Netherlands Trial Register )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Current Responsible Party S. Middeldorp, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Original Responsible Party Same as current
Current Study Sponsor  ICMJE Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE
  • Netherlands Organisation for Scientific Research
  • Aspen Pharma
  • CHU of Saint Etienne: French Ministry of Health Grant (sponsor of the French part of the study)
  • Rotunda Hospital: Definitive Interventions and Feasibility Awards (DIFA) 2017 (sponsor of the Irish part of the study))
Investigators  ICMJE
Principal Investigator: Saskia Middeldorp, MD PhD Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
PRS Account Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Verification Date May 2022

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP