Low Molecular Weight Heparin and/or Aspirin in Prevention of Habitual Abortion (HABENOX)

This study has been completed.
Sponsor:
Collaborators:
Oulu University Hospital, Oulu, Finland
Karolinska Hospital, Stockholm, Sweden
Leiden Hospital, Leiden, The Netherlands
Information provided by:
Helsinki University
ClinicalTrials.gov Identifier:
NCT00959621
First received: July 21, 2009
Last updated: August 13, 2009
Last verified: August 2009

July 21, 2009
August 13, 2009
January 2002
December 2004   (final data collection date for primary outcome measure)
Pregnancy outcome: livebirths (>37 weeks of gestation), premature livebirths (> 24, but <37 weeks of gestation) [ Time Frame: gestational weeks >37 and gestational weeks > 24, but <37 ] [ Designated as safety issue: Yes ]
Same as current
Complete list of historical versions of study NCT00959621 on ClinicalTrials.gov Archive Site
Bleeding complications, intrauterine growth retardation (<-2SD), pre-eclampsia, abruption placenta [ Time Frame: gestational weeks > 37 and gestational weeks >24, but <37 ] [ Designated as safety issue: Yes ]
Same as current
Not Provided
Not Provided
 
Low Molecular Weight Heparin and/or Aspirin in Prevention of Habitual Abortion
Role of LMWH (Enoxaparine) With or Without Aspirin in the Prevention of Habitual Abortion; Special Attention to the Thrombophilic Status of the Mother

1 % of all pregnancies end in habitual/recurrent abortion. In about half of women with habitual abortions (HAB) hereditary or acquired (antiphospholipid antibodies) thrombophilia are observed. The investigators wanted to test whether antithrombotic treatment (Low-Molecular Weight Heparin, LMWH, ASA or both combined)would prevent these women from a subsequent abortion. Depending on thrombophilic status the women included in one of the three sub-studies: HABENOX 1 (mild, single thrombophilia), HABENOX 2 (no known thrombophilia), HABENOX 3 (moderate to severe thrombophilia, with combined thrombophilia or moderate to high titer antiphospholipid antibodies).

Study design: Randomised placebo controlled multicenter study.

Number of patients per study: 90 patients per group, 270 altogether.

Timetable: Starting 2/2002, finishing 31.12.2007.

Time frame: >37 weeks of gestation and >24, but <37 weeks of gestation (premature)

Treatment started before 7. gw.

HABENOX 1 and 2:

Study groups:

Group 1 : Enoxaparin 40 mg+ placebo, Group 2: Enoxaparin 40 +ASA 100 mg, Group 3: ASA.

HABENOX 3:

Study groups:

Group 1: Enoxaparin 40 twice daily+ placebo o.d., Group 2: Enoxaparin 40 mg twice daily +ASA 100 mg o.d.

Primary end-points:

Pregnancy outcome: livebirths ( ≥37 weeks of gestation), premature livebirths (≥24, but <37 weeks of gestation)

Secondary end-points: Bleeding complications, intrauterine growth retardation (<-2SD), pre-eclampsia, abruptio placentae,

Ending: In the group of combined medication, tablets will be stopped at 36 weeks of gesta-tion. LMWH will be started in all patients after delivery and continued 6 weeks postpartum.

Background: The prevalence of spontaneous abortions is 1000-1500/10000 pregnancies per year meaning that 10-15% of all pregnancies will end in an abortion; 1/10 of these abortions are recurrent (1 % of all pregnancies). In about half of women with habitual abortions (HAB) hereditary (F V Leiden, F II (prothrombin) mutation, Protein C, S deficiency and anti-thrombin) or acquired (antiphospholipid antibodies) thrombophilia are observed. Efficacy of the medical treatment of patients with a history of HAB has yet to be completely demonstrated. We have recently shown that low-molecular-weight heparin (LMWH) is as effective as unfractionated heparin in prevention of thromboembolic complications in pregnant women and causes less bleeding complications (UFH) and has no osteoporotic effect. LMWH could be safer than UF-heparin during long treatment periods (7-8 months).

Study design: Randomised placebo controlled multicenter study.

Centers: Helsinki (2), Oulu (1), Stockholm (1), Leiden (1)

Number of patients per study: 90 patients per group, 270 altogether

Timetable: Starting 2/2002, finishing 31.12.2007

Drugs:

HABENOX 1 and 2: Study groups Group 1 : Enoxaparin 40 mg+ placebo, Group 2: Enoxaparin 40 +ASA 100 mg, Group 3: ASA.

HABENOX 3: Study groups Group 1: Enoxaparin 40 twice daily+ placebo o.d., Group 2: Enoxaparin 40 mg twice daily +ASA 100 mg o.d.

Time frame: one year since entering the study with primary end-points:livebirths (> 37 weeks of gestation) and premature livebirths (> 24, but <37 weeks of gestation)

Primary end-points: Pregnancy outcome: livebirths (>37 weeks of gestation), premature livebirths (> 24, but <37 weeks of gestation) Secondary end-points: Bleeding complications, intrauterine growth retardation (<-2SD), pre-eclampsia, abruptio placentae,

Inclusion criteria: Three or more consecutive abortions of first trimester (ad h 12+6 wks) or two second trimester abortions (ad h 13 wks-23+6 wks) or one third trimester abortion (24 weeks or more) with one first-second trimester abortions. Depending on the thrombophiliatest (tested before pregnancy) result the patients will included in one of the three sub-studies:

  1. HABENOX 1: those who have one thrombophiliatest positive: F V Leiden (heterozygote) or protein C or S deficiency, or anticardiolipin antibodies (low to moderate level), prothrombin gene mutation, or high level of F VIII.
  2. HABENOX 2: those with thrombophilia test negative
  3. HABENOX 3:those with "high risk" thrombophilia: positive combined thrombophilia, F V Leiden (homozygote), anticardiolipin antibodies (high level >40) , lupusanticoagulant, or AT III deficiency.

During next pregnancy the patient, with inclusion criteria fulfilled, will be asked to sign informed consent and she will be allocated into one of the three treatment groups. The treatment will be started before 7 weeks of gestation. At baseline and follow-up visits plasma, serum and 20 ml morning urine will be frozen (analysed later for antithrombin, protein S, C, APC ratio, PAI1, PAI2, U-PAR, D-dimer, thrombin-antithrombin (TAT) complex, CRP, TNFalpha(+ receptor), ICAM, VEGF(+receptor), urinary stabile metabolites of thromboxane and prostacyclin.

Follow-up: US/Doppler + obstetric check-up at 8, 10, 14, 18, 24, 28, 32 and 36 weeks of gestation Ending: In the group of combined medication, tablets will be stopped at 36 weeks of gesta-tion. LMWH will be started in all patients after delivery and continued 6 weeks postpartum.

Interventional
Phase 3
Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Prevention
Habitual Abortion
  • Drug: Aspirin
    ASA 100 mg once daily per os
  • Drug: Klexane
    Klexane 40 mg sc once daily (HABENOX 1 and 2), Klexane 40 mg twice daily in HABENOX 3
  • Drug: Klexane and ASA
    Klexane 40 mgx 1 sc and ASA 100 mg po
  • Active Comparator: ASA
    The patients received either Enoxaparine+placebo, Enoxaparine+ASA (Aspirin 100 mg) or ASA alone.ASA or placebo were blinded in the two first groups.
    Intervention: Drug: Aspirin
  • Active Comparator: Klexane
    Clexane (enoxaparine) 40 mg sc
    Intervention: Drug: Klexane
  • Active Comparator: Aspirin and Enoxaparine
    Intervention: Drug: Klexane and ASA
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
220
December 2008
December 2004   (final data collection date for primary outcome measure)

Inclusion Criteria:

  • Habenox 1: Three or more consecutive abortions of first trimester (ad h 12+6 wks) or two second trimester abortions (ad h 13 wks-23+6 wks) or one third trimester abortion (24 weeks or more) with one first-second trimester abortions and one thrombophiliatest positive: F V Leiden (heterozygote) or protein C or S deficiency, or anticardiolipin antibodies (low to moderate level), prothrombin gene mutation, or high level of F VIII.
  • HABENOX 2: The thrombophilic tests above are negative.
  • HABENOX 3:positive combined thrombophilia, F V Leiden (homozygote), anticardiolipin antibodies (high level >40) , lupusanticoagulant, or AT III deficiency.

Exclusion Criteria:

  • History of DVT or pulmonary embolism.
  • Significant bleeding history.
Female
Not Provided
Yes
Contact information is only displayed when the study is recruiting subjects
Finland
 
NCT00959621
HABENOX
No
Professor Risto Kaaja, Helsinki University Hospital
Helsinki University
  • Oulu University Hospital, Oulu, Finland
  • Karolinska Hospital, Stockholm, Sweden
  • Leiden Hospital, Leiden, The Netherlands
Principal Investigator: Veli-Matti Ulander, MD Helsinki University Hospital, Finland
Study Chair: Laure Morin-Papunen, MD Oulu University Hospital, Oulu, Finland
Study Chair: Katja Lampinen, MD Karolinska Hospital, Stockholm, Sweden
Study Chair: Kitty Bloemenkamp, MD Leiden University Hospital, Leiden, The Netherlands
Study Chair: Janvier Visser, MD Leiden University Hospital, Leiden, The Netherlands
Helsinki University
August 2009

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