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

Thrombosis, Venous Clinical Trial

— FONDACAST  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00843492
• Other study ID #: 109350
• Status: Completed
• Phase: Phase 3
• First received: December 11, 2008
• Last updated: February 18, 2016
• Start date: December 2008
• Est. completion date: June 2010

Study information

• Verified date: February 2014
• Source: GlaxoSmithKline
• Contact: n/a
• Is FDA regulated: No
• Health authority: Spain: Agencia Española del Medicamento y Productos SanitariosItaly: Comitato Etico della ASL Città di MilanoGermany: Bundesinstitut für Arzneimittel und MedizinprodukteFrance: Agence Française de Sécurité Sanitaire des Produits de SantéNetherlands: De Centrale Commissie Mensgebonden Onderzoek
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1351
• Est. completion date: June 2010
• Est. primary completion date: January 2010
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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.

Study Design

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

Related Conditions & MeSH terms

• Knee Injuries
• Thrombosis
• Thrombosis, Venous
• Venous Thrombosis

Intervention

Drug:
• Fondaparinux sodium
After randomization (Day 1), subjects will receive subcutaneously once daily fondaparinux 2.5 mg [0.5mL] (1.5 mg [0.3mL] in patients with creatinine clearance between 30 and 50 mL/min) for at least 21 Days, up to complete mobilization, corresponding to cast or brace removal. The maximal duration of treatment is 45 days.
• Nadroparin
After randomization (Day 1), subjects will receive subcutaneously once daily nadroparin 2850 anti-Xa IU (0.3 mL) for at least 21 Days, up to complete mobilization, corresponding to cast or brace removal. The maximal duration of treatment is 45 days.

Locations

Country	Name	City	State
France	GSK Investigational Site	Agen Cedex 9
France	GSK Investigational Site	Angers
France	GSK Investigational Site	Antony Cedex
France	GSK Investigational Site	Argenteuil Cedex
France	GSK Investigational Site	Beauvais Cedex
France	GSK Investigational Site	Bobigny
France	GSK Investigational Site	Brest Cedex
France	GSK Investigational Site	Cergy Pontoise
France	GSK Investigational Site	Clermont Ferrand
France	GSK Investigational Site	Colmar Cedex
France	GSK Investigational Site	Créteil Cedex
France	GSK Investigational Site	Grenoble Cedex 9
France	GSK Investigational Site	Lille Cedex
France	GSK Investigational Site	Lyon
France	GSK Investigational Site	Lyon Cedex 03
France	GSK Investigational Site	Lyon Cedex 07
France	GSK Investigational Site	Mougins
France	GSK Investigational Site	Nantes
France	GSK Investigational Site	Orthez Cedex
France	GSK Investigational Site	Paris
France	GSK Investigational Site	Paris Cedex 12
France	GSK Investigational Site	Paris Cedex 13
France	GSK Investigational Site	Paris Cedex 14
France	GSK Investigational Site	Paris Cedex 4
France	GSK Investigational Site	Pringy Cedex
France	GSK Investigational Site	Rennes cedex 9
France	GSK Investigational Site	Roanne
France	GSK Investigational Site	Rouen Cedex
France	GSK Investigational Site	Saint Pierre cedex
France	GSK Investigational Site	Sainte Colombe Les Vienne
France	GSK Investigational Site	Saintes
France	GSK Investigational Site	Toulouse
France	GSK Investigational Site	Valenciennes
Germany	GSK Investigational Site	Altenburg	Thueringen
Germany	GSK Investigational Site	Berlin
Germany	GSK Investigational Site	Berlin
Germany	GSK Investigational Site	Berlin
Germany	GSK Investigational Site	Dresden	Sachsen
Germany	GSK Investigational Site	Dresden	Sachsen
Germany	GSK Investigational Site	Erlangen	Bayern
Germany	GSK Investigational Site	Gevelsberg	Nordrhein-Westfalen
Germany	GSK Investigational Site	Hamburg
Germany	GSK Investigational Site	Hamburg
Germany	GSK Investigational Site	Hannover	Niedersachsen
Germany	GSK Investigational Site	Heidelberg	Baden-Wuerttemberg
Germany	GSK Investigational Site	Luebeck	Schleswig-Holstein
Germany	GSK Investigational Site	Moers	Nordrhein-Westfalen
Germany	GSK Investigational Site	Muenchen	Bayern
Germany	GSK Investigational Site	Muenchen	Bayern
Germany	GSK Investigational Site	Schmiedeberg	Sachsen
Germany	GSK Investigational Site	Wiesbaden	Hessen
Germany	GSK Investigational Site	Zerbst	Sachsen-Anhalt
Germany	GSK Investigational Site	Zwickau	Sachsen
Italy	GSK Investigational Site	Bergamo	Lombardia
Italy	GSK Investigational Site	Bologna	Emilia-Romagna
Italy	GSK Investigational Site	Catania	Sicilia
Italy	GSK Investigational Site	Conegliano (TV)	Veneto
Italy	GSK Investigational Site	Genova	Liguria
Italy	GSK Investigational Site	Latina	Lazio
Italy	GSK Investigational Site	Milano	Lombardia
Italy	GSK Investigational Site	Orbassano (TO)	Piemonte
Italy	GSK Investigational Site	Padova	Veneto
Italy	GSK Investigational Site	Roma	Lazio
Italy	GSK Investigational Site	Siena	Toscana
Italy	GSK Investigational Site	Udine	Friuli-Venezia-Giulia
Netherlands	GSK Investigational Site	Amersfoort
Netherlands	GSK Investigational Site	Eindhoven
Netherlands	GSK Investigational Site	Maastricht
Netherlands	GSK Investigational Site	Sittard-geleen
Netherlands	GSK Investigational Site	Utrecht
Netherlands	GSK Investigational Site	Venlo
Russian Federation	GSK Investigational Site	Barnaul
Russian Federation	GSK Investigational Site	Ekaterinburg
Russian Federation	GSK Investigational Site	Ekaterinburg
Russian Federation	GSK Investigational Site	Irkutsk
Russian Federation	GSK Investigational Site	Kemerovo
Russian Federation	GSK Investigational Site	Kursk
Russian Federation	GSK Investigational Site	Moscow
Russian Federation	GSK Investigational Site	Novosibirsk
Russian Federation	GSK Investigational Site	Perm
Russian Federation	GSK Investigational Site	Ryazan
Russian Federation	GSK Investigational Site	Saint-Petersburg
Russian Federation	GSK Investigational Site	Samara
Russian Federation	GSK Investigational Site	Samara
Russian Federation	GSK Investigational Site	St. Petersburgh
Russian Federation	GSK Investigational Site	Stavropol
Russian Federation	GSK Investigational Site	Tomsk
Russian Federation	GSK Investigational Site	Tumen
Russian Federation	GSK Investigational Site	Tver
Russian Federation	GSK Investigational Site	Ufa
Russian Federation	GSK Investigational Site	Yaroslavl
Russian Federation	GSK Investigational Site	Yaroslavl
Spain	GSK Investigational Site	Aravaca
Spain	GSK Investigational Site	Avilés/Asturias
Spain	GSK Investigational Site	Barcelona
Spain	GSK Investigational Site	Barcelona
Spain	GSK Investigational Site	Castellón
Spain	GSK Investigational Site	Cordoba
Spain	GSK Investigational Site	Don Benito/Badajoz
Spain	GSK Investigational Site	Ferrol. La Coruña
Spain	GSK Investigational Site	Getafe/Madrid
Spain	GSK Investigational Site	Jaén
Spain	GSK Investigational Site	La Coruña
Spain	GSK Investigational Site	Linares
Spain	GSK Investigational Site	Lugo
Spain	GSK Investigational Site	Madrid
Spain	GSK Investigational Site	Madrid
Spain	GSK Investigational Site	Madrid
Spain	GSK Investigational Site	Madrid
Spain	GSK Investigational Site	Majadahonda/Madrid
Spain	GSK Investigational Site	Mondragón - Guipúzcoa
Spain	GSK Investigational Site	Ourense
Spain	GSK Investigational Site	Palencia
Spain	GSK Investigational Site	Palma de Mallorca
Spain	GSK Investigational Site	Pozoblanco/Córdoba
Spain	GSK Investigational Site	San Sebastián de los Reyes/Madrid
Spain	GSK Investigational Site	Santiago de Compostela
Spain	GSK Investigational Site	Sevilla
Spain	GSK Investigational Site	Torrelodones/Madrid
Spain	GSK Investigational Site	Torrevieja
Spain	GSK Investigational Site	Valdemoro/Madrid
Spain	GSK Investigational Site	Vigo/Pontevedra

Sponsors (1)

Lead Sponsor	Collaborator
GlaxoSmithKline

Countries where clinical trial is conducted

France,  Germany,  Italy,  Netherlands,  Russian Federation,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants With Venous Thromboembolism (VTE) or Death up to the Time of Complete Mobilization	VTE is defined as asymptomatic deep vein thrombosis (DVT: the formation of a blood clot in a deep vein) detected by systematic compression ultrasonography, symptomatic DVT, or symptomatic fatal or non-fatal pulmonary embolism (PE). An embolism is a clot in the blood that forms and blocks a blood vessel. A pulmonary embolism is a blood clot that has travelled from elsewhere in the body through the blood stream to block the main artery of the lung or one of its branches. All venous thromboembolic events and deaths were adjudicated by the independent Central Adjudication Committee (CAC).	Day 1 to complete mobilization plus 2 days (average of 35.9 study days)	No
Secondary	Number of Participants With Any Adjudicated Components of VTE, Asymptomatic DVT, Symptomatic DVT, Symptomatic PE, and Death	All components of the primary endpoint were considered separately: any VTE; symptomatic (providing no evidence of disease existence) DVT (the formation of a blood clot in a deep vein) detected by systematic compression ultrasonography; symptomatic(providing evidence of disease existence) DVT; symptomatic PE (blood clot that has travelled from elsewhere in the body through the blood stream to block the main artery of the lung of one of its branches); and death.	Day 1 to complete mobilization plus 2 days (average of 35.7 study days)	No
Secondary	Number of Participants With Confirmed VTE and Death up to the Final Visit or Contact	The number of participants with VTE (defined as asymptomatic deep vein thrombosis [DVT: the formation of a blood clot in a deep vein] detected by systematic compression ultrasonography, symptomatic DVT, or symptomatic fatal or non-fatal pulmonary embolism [PE]) and death was assessed. An embolism is a clot in the blood that forms and blocks a blood vessel. A PE is a blood clot that has travelled from elsewhere in the body through the blood stream to block the main artery of the lung or one of its branches.	Day 1 to 5 weeks (plus or minus 1 week) after complete mobilization (average of 67.8 study days)	No
Secondary	Number of Participants With Major Bleeding From Day 1 to Complete Mobilization and From Day 1 up to the Final Visit or Contact	Major bleeding is defined as bleeding that results in a fatality, symptomatic bleeding in a critical area or organ, bleeding causing a fall in hemoglobin level of 20 grams/liter (1.24 millimoles/liter) or more compared with the pre-randomization hemoglobin level, or bleeding that leads to a transfusion of two or more units of whole blood or red blood cells. All episodes of bleeding were adjudicated by an independent CAC. The committee members were unaware of the participants' treatment assignment.	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)	No
Secondary	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	Clinically relevant non-major bleeding that does not qualify as major is defined as bleeding leading to treatment discontinuation, and/or epistaxis (bleeding through the nose) that lasts for more than 5 minutes or necessitates intervention (e.g., packing), spontaneous macroscopic haematuria (blood in urine), gastrointestinal haemorrhage, haemoptysis (coughing up blood), or subcutaneous haematoma (localized collection of blood) > 100 centimeters squared. All episodes of bleeding were adjudicated by an independent CAC. The committee members were unaware of the participants' treatment assignment.	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)	No
Secondary	Number of Participants With Minor Bleeding From Day 1 to Complete Mobilization and From Day 1 up to the Final Visit or Contact	Minor bleeding is defined as clinically overt bleeding events that do not meet the criteria for major or clinically relevant non-major bleeding. All episodes of bleeding were adjudicated by an independent CAC. The committee members were unaware of the participants' treatment assignment.	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)	No
Secondary	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	All episodes of bleeding, except minor bruising, skin hematomas not greater than 5 centimeters in diameter, self-limited epistaxis (bleeding through the nose), and self-limited gingival (gum) bleeding, were adjudicated by an independent CAC. The committee members were unaware of the participants' treatment assignment.	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)	No