Clinical trial NCT01274637: PROSPER: PostpaRtum PrOphylaxiS for PE Randomized Control Trial Pilot
Official title: Postpartum Prophylaxis for PE Randomized Control Trial Pilot: A Pilot Study Assessing Feasibility of a Randomized, Open-label Trial of Low-Molecular-Weight-Heparin for Postpartum Prophylaxis in Women at Risk of Developing Venous Thromboembolism
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Venous Thromboembolism
Postpartum
Keywords: postpartum
low molecular weight heparin
venous thromboembolism
prophylaxis
Dalteparin Sodium
Lead sponsor: Ottawa Hospital Research Institute
Sponsor class: OTHER
Collaborators: name: Canadian Institutes of Health Research (CIHR)
First posted: 2011-01-11
Enrollment: 62
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: The purpose of this study is to determine if it is feasible to conduct a multi-center randomized trial to determine whether a blood thinner, low-molecular-weight-heparin (LMWH), is effective at preventing blood clots, thromboembolism (VTE), in postpartum women at risk.

Detailed description: The PROPSER pilot is a randomized, open-label pilot study comparing prophylactic low molecular weight heparin (LMWH) to saline placebo. The PROSPER pilot study will assess the feasibility of conducting a full trial as measured by the number of subjects recruited per center per month. In addition, clinical data will be collected to determine an estimate of the primary outcome event rate (symptomatic VTE or asymptomatic proximal deep vein thrombosis (DVT) and major bleeding event rate for the full trial in LMWH and control groups. If our pilot results indicate that no substantial changes are needed to the study design, we will include the pilot data in the primary and secondary outcome analyses for the full trial (i.e. a "Vanguard trial" or internal pilot trial).

Eligible consenting women at risk of postpartum thrombosis will be randomized within 36 hours after delivery of the placenta and will be equally allocated to 2 trial arms, either the treatment group: prophylactic-dose LMWH, subcutaneously once daily for 10 days (+/-3 days), or the control group.

At 10 days (+/- 3 days), all women will have a study visit to assess for study outcomes, including bilateral leg ultrasound screening for VTE and a D-dimer test. A final telephone follow-up will occur at 90 days for outcome assessment of subsequent VTE, bleeding or other adverse events.

Eligibility criteria: Inclusion Criteria:

Women must be at high risk for thromboembolism for one of the following reasons:

1. Known low risk thrombophilia (Known = diagnosed prior to enrollment and low risk thrombophilia includes heterozygous factor V Leiden or prothrombin gene variant or protein C deficiency or protein S deficiency. If not previously tested then assumed not to have thrombophilia).
2. Immobilization (defined as \>90% of waking hours in bed, of a week or more at any point in the antepartum period).

OR any two of the following reasons:

1. Postpartum infection (fever (temperature\>38.5oC) and clinical signs/symptoms of infection and elevated neutrophil count (higher than local lab normal))
2. Postpartum hemorrhage (Estimated blood loss \>1000 ml during delivery and postpartum)
3. Pre-pregnancy BMI \>25 kg/m2
4. Emergency cesarean birth (emergency = not planned prior to onset of labour)
5. Smoking \>5 cigarettes per day prior to pregnancy
6. Preeclampsia (blood pressure ≥ 140mmHG systolic and/or ≥90 mmHg diastolic on at least one occasion and proteinuria (1+ on urine dipstick or 300mg/dl or total excretion of 300mg/24 hours) or typical end-organ dysfunction.
7. Infant birth weight (adjusted for sex and gestational age) \<3rd percentile (i.e., small for gestational age).

Exclusion Criteria:

1. Less than 6 hours or more than 36 hours since delivery at the time of randomization
2. Need for anticoagulation as judged by the local investigator, may include but not limited to:

   1. Personal history of previous provoked or unprovoked VTE (DVT or PE)
   2. Continuation of LMWH that was started in the antenatal period for VTE prophylaxis
   3. Mechanical heart valve
   4. Known high-risk thrombophilia (Known = diagnosed prior to enrolment and high-risk thrombophilia includes deficiency of antithrombin (at least 1 abnormal lab result), persistently positive anticardiolipin antibodies (\> 30U/ml on two measurements a minimum of six weeks apart), persistently positive Anti B2 glycoprotein antibodies (\> 20U/ml on two measurements a minimum of six weeks apart), persistently positive lupus anticoagulant (positive on two measurements a minimum of six weeks apart), homozygous factor V Leiden (FVL), homozygous prothrombin gene mutation (PGM), compound heterozygosity factor V Leiden (FVL) and prothrombin gene mutations (PGM), more than 1 thrombophilia (any combination of 2 or more: FVL, PGM, protein C deficiency, protein S deficiency). If not previously tested then assumed not to have thrombophilia).
3. Contraindication to heparin therapy, including:

   1. History of heparin induced thrombocytopenia (HIT)
   2. Platelet count of less than 80,000 x 106/L on postpartum Complete Blood Count(CBC)
   3. Hemoglobin ≤ 75 g/L on postpartum CBC
   4. Active bleeding at any site (not resolved prior to randomization)
   5. Excessive postpartum vaginal bleeding (\>1 pad per hour prior to randomization).
   6. Documented gastrointestinal ulcer within 6 weeks prior to randomization
   7. History of heparin or LMWH allergy
   8. Severe postpartum hypertension (systolic blood pressure (SBP) \> 200mm/hg and/or diastolic blood pressure (DBP) \> 120mm/hg)
   9. Severe hepatic failure (INR \>1.8 if liver disease suspected)
4. Have received more than one dose of heparin or LMWH since delivery
5. \< age of legal majority in local jurisdiction (age \<18 in Canada)
6. Prior participation in PROSPER
7. Unable or refused to consent

Primary outcomes:
measure: Feasibility of Recruitment and Trial Operations.
timeFrame: 4 months
Secondary outcomes:
measure: Venous Thromboembolism in the Early Postpartum Period.
timeFrame: From randomization to Day 10
measure: Late Symptomatic Venous Thromboembolism
timeFrame: From Day 10 to Day 90
measure: Death From Venous Thromboembolism
timeFrame: From Randomization to Day 90
measure: Major Bleeding or Clinically Relevant Non-major Bleeding
timeFrame: From Randomization to Day 90
measure: Heparin Induced Thrombocytopenia
timeFrame: From Randomization to Day 90
Other outcomes:
Locations:
city: Charlottesville
country: United States
facility: University of Virginia Medical Center
state: Virginia
city: Seattle
country: United States
facility: Puget Sound Blood Center
state: Washington
city: Edmonton
country: Canada
facility: Royal Alexandra Hospital
state: Alberta
city: Hamilton
country: Canada
facility: McMaster University Medical Centre
state: Ontario
city: Ottawa
country: Canada
facility: Ottawa Hospital General Campus & Civic Campus
state: Ontario
city: Toronto
country: Canada
facility: Sunnybrook Health Sciences Centre
state: Ontario
city: Montreal
country: Canada
facility: SMBD Jewish General Hospital
state: Quebec
Study officials:
affiliation: Ottawa Hospital Research Institute
name: Marc A Rodger, M.D., MSc.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Rodger MA, Phillips P, Kahn SR, Bates S, McDonald S, Khurana R, James AH, Konkle BA; PROSPER Investigators: Tim Ramsay, Dean Fergusson, Anne McLeod, Wee Shian Chan, Rshmi Khurana, Kara Narenberg, Haim Abenhaim, John Heit, Ghada Bourjeilly, Paul Gibson, Kent Bailey. Low molecular weight heparin to prevent postpartum venous thromboembolism: A pilot study to assess the feasibility of a randomized, open-label trial. Thromb Res. 2016 Jun;142:17-20. doi: 10.1016/j.thromres.2016.04.004. Epub 2016 Apr 9. No abstract available.
citation: Rodger MA, Phillips P, Kahn SR, James AH, Konkle BA; PROSPER Investigators. Low-molecular-weight heparin to prevent postpartum venous thromboembolism. A pilot randomised placebo-controlled trial. Thromb Haemost. 2015 Jan;113(1):212-6. doi: 10.1160/TH14-06-0485. Epub 2014 Nov 6.
citation: Middleton P, Shepherd E, Gomersall JC. Venous thromboembolism prophylaxis for women at risk during pregnancy and the early postnatal period. Cochrane Database Syst Rev. 2021 Mar 29;3(3):CD001689. doi: 10.1002/14651858.CD001689.pub4.