Clinical trial NCT00843492: A Study to Evaluate the Efficacy and Safety of Fondaparinux for the Prevention of Venous Blood Clots in Patients With a Plaster Cast or Other Type of Immobilization for a Below-knee Injury Not Needing Surgery
Official title: A Multicentre, Randomized, Open-label Study to Evaluate the Efficacy andSafety of Fondaparinux Versus Low Molecular Weight Heparin(Nadroparin) in Patients Requiring Rigid or Semi-rigid Immobilization for at Least 21 Days and up to 45 Days Because of Isolated Non-surgical Below-Knee Injury
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Thrombosis, Venous
Keywords: deep vein thrombosis
immobilization
nadroparin
isolated lower-extremity injuries distal to the knee
plaster cast
non-surgical leg injury
venous thromboembolism
bleeding events
fondaparinux
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2009-02-13
Enrollment: 1351
Sex: ALL
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 evaluate the efficacy and safety of fondaparinux in comparison with a heparin (nadroparin) in preventing deep vein thrombosis (blood clots in the leg veins), whether symptomatic or detected by ultrasound, and pulmonary embolism (blood clots that migrate to the lungs) in patients with leg injuries below the knee that require a cast or other type of immobilization but not surgery.

Detailed description: The study is designed to evaluate the efficacy and safety of fondaparinux sodium 2.5 mg (1.5 mg in patients with a creatinine clearance between 30 and 50 mL/min) once daily versus Low-Molecular Weight Heparin (nadroparin 2850 anti-Xa IU, 0.3 mL, once daily), with respect to the occurrence of venous thromboembolism, death and bleeding complications in patients requiring rigid or semi-rigid immobilization for at least 21 days and up to 45 days because of isolated nonsurgical below-knee injury. Treatment will be continued up to complete mobilization, e.g. plaster cast or brace removal, for a maximum of 45 days. The study will be a European, multicentre, randomized, open-label, controlled, two-parallel-group, phase III study in 1350 male and female patients 18 years of age or older, presenting with at least one additional major risk factor for VTE. After randomization (Day 1), subjects will receive subcutaneously, once daily, either fondaparinux or nadroparin up to complete mobilization. After cast or brace removal, a systematic, bilateral compression ultrasound will be done in all patients. Patients will be contacted five weeks (± one week) after complete mobilization. All suspected venous thromboembolic events, including asymptomatic deep vein thrombosis, all deaths, and all bleeding events (with the exception of certain types of minor bleeding events defined in the protocol) will be reviewed by an independent adjudication committee blind to treatment assignment.

Eligibility criteria: Inclusion Criteria:

* Requiring rigid or semi-rigid immobilization (e.g. with a plaster cast or brace) for at least 21 days and up to 45 days because of isolated non-surgical below-knee injury
* With a no weight-bearing recommendation at the time of inclusion (partial weight bearing is permitted e.g. crutches, walking cast, relief shoes),
* Presenting at least one of the following risk factors for venous thromboembolism: below-knee fracture or Achilles tendon rupture, age ≥40 years, body mass index \> 30 kg/m2, oestrogen-containing hormonal replacement therapy or oral contraception, active cancer (treatment ongoing or stopped for less than one year), history of VTE, congenital or acquired hypercoagulable state,
* Requiring thromboprophylaxis according to the Investigator's judgement up to complete mobilization (corresponding to cast or brace removal)
* Able and willing to provide written informed consent

Exclusion Criteria:

* Delay between injury and randomization greater than two days,
* Treatment with antithrombotic or anticoagulant therapy, including low-dose anticoagulation, for more than 2 days prior to randomization,
* Anticoagulant therapy required or likely to be required during the study period for another reason (e.g. planned surgery justifying pharmacological thromboprophylaxis, curative dose for treatment of VTE, etc.)
* Known hypersensitivity to fondaparinux or nadroparin or their excipient,
* Known history of heparin-induced thrombocytopenia,
* Women of childbearing potential not using a reliable contraceptive method throughout the study period,
* Women pregnant or breast-feeding during the study period.
* Active, clinically significant bleeding,
* Clinically significant bleeding within the past six months,
* Major surgery within the previous three months,
* Intraocular (other than cataract), spinal, and/or brain surgery within the previous twelve months,
* Haemorrhagic stroke within the previous twelve months,
* Severe head injury within the previous three months,
* Documented congenital or acquired bleeding tendency/disorder(s),
* Previous (within 12 months) or active or currently treated peptic ulcer disease,
* Uncontrolled arterial hypertension (systolic blood pressure over 180 mm Hg or diastolic blood pressure over 110 mm Hg),
* Treatment with more than one antiplatelet agents (e.g. clopidogrel and aspirin) at any dose,
* Need for chronic aspirin at doses≥ 325 mg or chronic NSAIDs,
* Bacterial endocarditis,
* Severe hepatic impairment,
* Calculated creatinine clearance \< 30 mL/min,
* Thrombocytopenia ( \<100x10_9/L)
* Body weight \< 50 kg.
* Any condition that could prevent the patient from providing written informed consent or from adhering to study treatment,
* Life expectancy under six months,
* Participation in any study using an investigational drug during the previous three months,
* Patient in whom V3 is unlikely to be feasible (e.g. patient moving house),
* In France, a subject will not be eligible for inclusion in this study if not either affiliated to or a beneficiary of a social security system. This is an additional exclusion criterion only applying to subjects enrolled in France.

Primary outcomes:
measure: Number of Participants With Venous Thromboembolism (VTE) or Death up to the Time of Complete Mobilization
timeFrame: Day 1 to complete mobilization plus 2 days (average of 35.9 study days)
Secondary outcomes:
measure: Number of Participants With Any Adjudicated Components of VTE, Asymptomatic DVT, Symptomatic DVT, Symptomatic PE, and Death
timeFrame: Day 1 to complete mobilization plus 2 days (average of 35.7 study days)
measure: Number of Participants With Confirmed VTE and Death up to the Final Visit or Contact
timeFrame: Day 1 to 5 weeks (plus or minus 1 week) after complete mobilization (average of 67.8 study days)
measure: Number of Participants With Major Bleeding From Day 1 to Complete Mobilization and From Day 1 up to the Final Visit or Contact
timeFrame: Day 1 to complete mobilization plus 4 days (average of 37.7 study days); Day 1 up to final visit or contact (average of 66.3 study days)
measure: Number of Participants With Clinically Relevant Non-major Bleeding From Day 1 to Complete Mobilization and From Day 1 up to the Final Visit or Contact
timeFrame: Day 1 to complete mobilization plus 4 days (average of 37.7 study days); Day 1 up to final visit or contact (average of 66.3 study days)
measure: Number of Participants With Minor Bleeding From Day 1 to Complete Mobilization and From Day 1 up to the Final Visit or Contact
timeFrame: Day 1 to complete mobilization plus 4 days (average of 37.7 study days); Day 1 up to final visit or contact (average of 66.3 study days)
measure: Participants With Any Incidence of Any Bleeding Event as Adjudicated by a CAC) From Day 1 to Complete Mobilization and From Day 1 up to the Final Visit or Contact
timeFrame: Day 1 to complete mobilization plus 4 days (average of 37.7 study days); Day 1 up to final visit or contact (average of 66.3 study days)
Other outcomes:
Locations:
city: Agen Cedex 9
country: France
facility: GSK Investigational Site
city: Angers
country: France
facility: GSK Investigational Site
city: Antony Cedex
country: France
facility: GSK Investigational Site
city: Argenteuil Cedex
country: France
facility: GSK Investigational Site
city: Beauvais Cedex
country: France
facility: GSK Investigational Site
city: Bobigny
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facility: GSK Investigational Site
city: Brest Cedex
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facility: GSK Investigational Site
city: Cergy Pontoise
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facility: GSK Investigational Site
city: Clermont Ferrand
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facility: GSK Investigational Site
city: Colmar Cedex
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facility: GSK Investigational Site
city: Créteil Cedex
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facility: GSK Investigational Site
city: Grenoble Cedex 9
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facility: GSK Investigational Site
city: Lille Cedex
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facility: GSK Investigational Site
city: Lyon Cedex 03
country: France
facility: GSK Investigational Site
city: Lyon Cedex 07
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facility: GSK Investigational Site
city: Lyon
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facility: GSK Investigational Site
city: Mougins
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facility: GSK Investigational Site
city: Nantes
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city: Orthez Cedex
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facility: GSK Investigational Site
city: Paris Cedex 12
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facility: GSK Investigational Site
city: Paris Cedex 13
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facility: GSK Investigational Site
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city: Paris Cedex 4
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city: Paris
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city: Pringy Cedex
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facility: GSK Investigational Site
city: Rennes cedex 9
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facility: GSK Investigational Site
city: Roanne
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facility: GSK Investigational Site
city: Rouen Cedex
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facility: GSK Investigational Site
city: Saint Pierre cedex
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facility: GSK Investigational Site
city: Sainte Colombe Les Vienne
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facility: GSK Investigational Site
city: Saintes
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facility: GSK Investigational Site
city: Toulouse
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facility: GSK Investigational Site
city: Valenciennes
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facility: GSK Investigational Site
city: Heidelberg
country: Germany
facility: GSK Investigational Site
state: Baden-Wuerttemberg
city: Erlangen
country: Germany
facility: GSK Investigational Site
state: Bayern
city: Muenchen
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facility: GSK Investigational Site
state: Bayern
city: Muenchen
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facility: GSK Investigational Site
state: Bayern
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facility: GSK Investigational Site
state: Hessen
city: Hannover
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facility: GSK Investigational Site
state: Niedersachsen
city: Gevelsberg
country: Germany
facility: GSK Investigational Site
state: Nordrhein-Westfalen
city: Moers
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facility: GSK Investigational Site
state: Nordrhein-Westfalen
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facility: GSK Investigational Site
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state: Sachsen
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facility: GSK Investigational Site
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facility: GSK Investigational Site
state: Schleswig-Holstein
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state: Toscana
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state: Veneto
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state: Veneto
city: Amersfoort
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facility: GSK Investigational Site
city: Maastricht
country: Netherlands
facility: GSK Investigational Site
city: Sittard-geleen
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facility: GSK Investigational Site
city: Utrecht
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city: Barnaul
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facility: GSK Investigational Site
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facility: GSK Investigational Site
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facility: GSK Investigational Site
city: Kursk
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city: Moscow
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facility: GSK Investigational Site
city: Novosibirsk
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facility: GSK Investigational Site
city: Perm
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facility: GSK Investigational Site
city: Ryazan
country: Russian Federation
facility: GSK Investigational Site
city: Saint-Petersburg
country: Russian Federation
facility: GSK Investigational Site
city: Samara
country: Russian Federation
facility: GSK Investigational Site
city: Samara
country: Russian Federation
facility: GSK Investigational Site
city: St. Petersburgh
country: Russian Federation
facility: GSK Investigational Site
city: Stavropol
country: Russian Federation
facility: GSK Investigational Site
city: Tomsk
country: Russian Federation
facility: GSK Investigational Site
city: Tumen
country: Russian Federation
facility: GSK Investigational Site
city: Tver
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facility: GSK Investigational Site
city: Ufa
country: Russian Federation
facility: GSK Investigational Site
city: Yaroslavl
country: Russian Federation
facility: GSK Investigational Site
city: Yaroslavl
country: Russian Federation
facility: GSK Investigational Site
city: Aravaca
country: Spain
facility: GSK Investigational Site
city: Avilés/Asturias
country: Spain
facility: GSK Investigational Site
city: Barcelona
country: Spain
facility: GSK Investigational Site
city: Barcelona
country: Spain
facility: GSK Investigational Site
city: Castellón
country: Spain
facility: GSK Investigational Site
city: Cordoba
country: Spain
facility: GSK Investigational Site
city: Don Benito/Badajoz
country: Spain
facility: GSK Investigational Site
city: Ferrol. La Coruña
country: Spain
facility: GSK Investigational Site
city: Getafe/Madrid
country: Spain
facility: GSK Investigational Site
city: Jaén
country: Spain
facility: GSK Investigational Site
city: La Coruña
country: Spain
facility: GSK Investigational Site
city: Linares
country: Spain
facility: GSK Investigational Site
city: Lugo
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Majadahonda/Madrid
country: Spain
facility: GSK Investigational Site
city: Mondragón - Guipúzcoa
country: Spain
facility: GSK Investigational Site
city: Ourense
country: Spain
facility: GSK Investigational Site
city: Palencia
country: Spain
facility: GSK Investigational Site
city: Palma de Mallorca
country: Spain
facility: GSK Investigational Site
city: Pozoblanco/Córdoba
country: Spain
facility: GSK Investigational Site
city: San Sebastián de los Reyes/Madrid
country: Spain
facility: GSK Investigational Site
city: Santiago de Compostela
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facility: GSK Investigational Site
city: Sevilla
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facility: GSK Investigational Site
city: Torrelodones/Madrid
country: Spain
facility: GSK Investigational Site
city: Torrevieja
country: Spain
facility: GSK Investigational Site
city: Valdemoro/Madrid
country: Spain
facility: GSK Investigational Site
city: Vigo/Pontevedra
country: Spain
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References: