PROSPER: PostpaRtum PrOphylaxiS for PE Randomized Control Trial Pilot

Venous Thromboembolism Clinical Trial

— PROSPER  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01274637
• Other study ID #: 2010303-01H
• Status: Completed
• Phase: Phase 3
• First received: January 10, 2011
• Last updated: October 6, 2014
• Start date: March 2011
• Est. completion date: January 2014

Study information

• Verified date: October 2014
• Source: Ottawa Hospital Research Institute
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationCanada: Health CanadaCanada: Ethics Review Committee
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 37
• Est. completion date: January 2014
• Est. primary completion date: January 2014
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Prevention

Related Conditions & MeSH terms

• Postpartum
• Thromboembolism
• Venous Thromboembolism

Intervention

Drug:
• Dalteparin Sodium
5,000 IU/0.2ml (anti-Xa) administered once daily in prefilled glass syringes.

Locations

Country	Name	City	State
Canada	Royal Alexandra Hospital	Edmonton	Alberta
Canada	McMaster University Medical Centre	Hamilton	Ontario
Canada	SMBD Jewish General Hospital	Montreal	Quebec
Canada	Ottawa Hospital General Campus & Civic Campus	Ottawa	Ontario
Canada	Sunnybrook Health Sciences Centre	Toronto	Ontario
United States	University of Virginia Medical Center	Charlottesville	Virginia
United States	Puget Sound Blood Center	Seattle	Washington

Sponsors (2)

Lead Sponsor	Collaborator
Ottawa Hospital Research Institute	Canadian Institutes of Health Research (CIHR)

Countries where clinical trial is conducted

United States,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Feasibility of recruitment and trial operations.	The number of subjects that are recruited per site per month during a 4 month active recruitment phase at each site.; Secondary measures of feasibility will include: Consent rate for eligible women and reasons for non-consent; Rates of compliance with study drug administration; Rates of compliance with primary outcome assessment; Rates of withdrawal or loss to follow-up within 90 days; Length of time required to obtain ethics approval and institutional approvals for conducting the study at Canadian and US sites.	4 months	No
Secondary	Venous Thromboembolism in the early postpartum period.	This includes symptomatic Deep Vein Thrombosis (DVT) or pulmonary embolism (PE) in the interval between randomization and the last dose of study drug (10 days +/- 3 days) OR asymptomatic proximal DVT detected by compression ultrasound of both legs done within 24hrs of the last dose of study drug (10 days (+/- 3 days) postpartum). Compressed and non-compressed images will be obtained from the calf trifurcation to the inguinal ligament. All suspected outcomes will be adjudicated by a blinded expert adjudication committee.	From randomization to Day 10	No
Secondary	Late symptomatic Venous Thromboembolism	This includes symptomatic Deep Vein Thrombosis or Pulmonary Embolism. Suspected outcomes will be adjudicated by a blinded adjudication committee.	From Day 10 to Day 90	No
Secondary	Death From Venous Thromboembolism	If a subject dies between randomization and late postpartum follow up (Day 90 +/- 7 days) the death will be adjudicated as certain, highly probable, probable, or unlikely due to Pulmonary Embolism (PE) using the following criteria.; Certain: hypotension, hypoxia, cardiac arrest with no other explanation other than PE and autopsy or radiographic confirmation Highly probable: criteria for certain but another disease could have caused the death Probable: other cause suspected based on clinical evidence but 100% certainty not available Unlikely: all other cases.	From Randomization to Day 90	No
Secondary	Major Bleeding or clinically relevant non-major bleeding	Major bleeding meets at least one of the following: Fatal bleeding; Symptomatic bleeding in a critical area or organ (intracranial, intraspinal, retroperitoneal, etc.); Bleeding causing a fall in hemoglobin level of 20 g L-1 (1.24 mmol L-1) or more, or leading to transfusion of two or more units of whole blood or red cells .; Clinically Relevant Non-major Bleeding does not meet the criteria for major bleeding but meets at least one of the following: Hospitalization; Medical intervention; Unscheduled contact with a physician; Discomfort (pain, or impairment of activities of daily life).	From Randomization to Day 90	Yes
Secondary	Heparin Induced Thrombocytopenia	All subjects who develop thrombocytopenia (platelets less than 80 x 109/L and/or with >50% decrease from baseline) will be investigated for Heparin Induced Thrombocytopenia (HIT) by having ELISA and serotonin release assays to confirm or refute a diagnosis of HIT. HIT will be diagnosed with a positive PF4 (platelet factor 4) HIT ELISA assay.	From Randomization to Day 90	Yes