FONDACAST: 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

• Sponsor: GlaxoSmithKline (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00843492
• Collaborator: (none)
• Enrollment: 1,351
• Locations: 122
• Arms: 2
• Duration (Months): 18
• Patients Per Site: 11.1
• Patients Per Site Per Month: 0.6

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Thrombosis, Venous	Drug: Fondaparinux sodium; Drug: Nadroparin	Phase 3

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 1351 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Prevention
• 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 Start Date: Dec 1, 2008
• Actual Primary Completion Date: Jan 1, 2010
• Actual Study Completion Date: Jun 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: 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. Patients will then be followed up to five weeks (± one week) after the cast or brace removal.	Drug: 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.
Experimental: Fondaparinux After randomization (Day 1), subjects will receive subcutaneously, once daily, fondaparinux 2.5 mg (1.5 mg 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. Patients will then be followed up to five weeks (± one week) after the cast or brace removal.	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.

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Venous Thromboembolism (VTE) or Death up to the Time of Complete Mobilization [Day 1 to complete mobilization plus 2 days (average of 35.9 study days)]

   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).

Secondary Outcome Measures

1. Number of Participants With Any Adjudicated Components of VTE, Asymptomatic DVT, Symptomatic DVT, Symptomatic PE, and Death [Day 1 to complete mobilization plus 2 days (average of 35.7 study days)]

   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.

2. Number of Participants With Confirmed VTE and Death up to the Final Visit or Contact [Day 1 to 5 weeks (plus or minus 1 week) after complete mobilization (average of 67.8 study days)]

   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.

3. Number of Participants With Major Bleeding From Day 1 to Complete Mobilization and From Day 1 up to the Final Visit or Contact [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)]

   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.

4. 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 [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)]

   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.

5. Number of Participants With Minor Bleeding From Day 1 to Complete Mobilization and From Day 1 up to the Final Visit or Contact [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)]

   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.

6. 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 [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)]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	GSK Investigational Site	Agen Cedex 9		France	47923
2	GSK Investigational Site	Angers		France	49100
3	GSK Investigational Site	Antony Cedex		France	92166
4	GSK Investigational Site	Argenteuil Cedex		France	95107
5	GSK Investigational Site	Beauvais Cedex		France	60021
6	GSK Investigational Site	Bobigny		France	93009
7	GSK Investigational Site	Brest Cedex		France	29609
8	GSK Investigational Site	Cergy Pontoise		France	95303
9	GSK Investigational Site	Clermont Ferrand		France	63000
10	GSK Investigational Site	Colmar Cedex		France	68024
11	GSK Investigational Site	Créteil Cedex		France	94010
12	GSK Investigational Site	Grenoble Cedex 9		France	38043
13	GSK Investigational Site	Lille Cedex		France	59037
14	GSK Investigational Site	Lyon Cedex 03		France	69437
15	GSK Investigational Site	Lyon Cedex 07		France	69365
16	GSK Investigational Site	Lyon		France	69275
17	GSK Investigational Site	Mougins		France	06250
18	GSK Investigational Site	Nantes		France	44093
19	GSK Investigational Site	Orthez Cedex		France	64301
20	GSK Investigational Site	Paris Cedex 12		France	75571
21	GSK Investigational Site	Paris Cedex 13		France	75651
22	GSK Investigational Site	Paris Cedex 14		France	75679
23	GSK Investigational Site	Paris Cedex 4		France	75181
24	GSK Investigational Site	Paris		France	75015
25	GSK Investigational Site	Pringy Cedex		France	74374
26	GSK Investigational Site	Rennes cedex 9		France	35033
27	GSK Investigational Site	Roanne		France	42300
28	GSK Investigational Site	Rouen Cedex		France	76031
29	GSK Investigational Site	Saint Pierre cedex		France	97448
30	GSK Investigational Site	Sainte Colombe Les Vienne		France	69560
31	GSK Investigational Site	Saintes		France	17108
32	GSK Investigational Site	Toulouse		France	31059
33	GSK Investigational Site	Valenciennes		France	59300
34	GSK Investigational Site	Heidelberg	Baden-Wuerttemberg	Germany	69120
35	GSK Investigational Site	Erlangen	Bayern	Germany	91054
36	GSK Investigational Site	Muenchen	Bayern	Germany	80335
37	GSK Investigational Site	Muenchen	Bayern	Germany	80339
38	GSK Investigational Site	Wiesbaden	Hessen	Germany	65191
39	GSK Investigational Site	Hannover	Niedersachsen	Germany	30625
40	GSK Investigational Site	Gevelsberg	Nordrhein-Westfalen	Germany	58285
41	GSK Investigational Site	Moers	Nordrhein-Westfalen	Germany	47441
42	GSK Investigational Site	Zerbst	Sachsen-Anhalt	Germany	39261
43	GSK Investigational Site	Dresden	Sachsen	Germany	01187
44	GSK Investigational Site	Dresden	Sachsen	Germany	01307
45	GSK Investigational Site	Schmiedeberg	Sachsen	Germany	01762
46	GSK Investigational Site	Zwickau	Sachsen	Germany	08060
47	GSK Investigational Site	Luebeck	Schleswig-Holstein	Germany	23538
48	GSK Investigational Site	Altenburg	Thueringen	Germany	04600
49	GSK Investigational Site	Berlin		Germany	10559
50	GSK Investigational Site	Berlin		Germany	12627
51	GSK Investigational Site	Berlin		Germany	13353
52	GSK Investigational Site	Hamburg		Germany	20246
53	GSK Investigational Site	Hamburg		Germany	22415
54	GSK Investigational Site	Bologna	Emilia-Romagna	Italy	40136
55	GSK Investigational Site	Udine	Friuli-Venezia-Giulia	Italy	33100
56	GSK Investigational Site	Latina	Lazio	Italy	04100
57	GSK Investigational Site	Roma	Lazio	Italy	00141
58	GSK Investigational Site	Genova	Liguria	Italy	16132
59	GSK Investigational Site	Bergamo	Lombardia	Italy	24128
60	GSK Investigational Site	Milano	Lombardia	Italy	20161
61	GSK Investigational Site	Orbassano (TO)	Piemonte	Italy	10043
62	GSK Investigational Site	Catania	Sicilia	Italy	95126
63	GSK Investigational Site	Siena	Toscana	Italy	53100
64	GSK Investigational Site	Conegliano (TV)	Veneto	Italy	31015
65	GSK Investigational Site	Padova	Veneto	Italy	35128
66	GSK Investigational Site	Amersfoort		Netherlands	3818 ES
67	GSK Investigational Site	Eindhoven		Netherlands	5623 EJ
68	GSK Investigational Site	Maastricht		Netherlands	6229 HX
69	GSK Investigational Site	Sittard-geleen		Netherlands	6162 BG
70	GSK Investigational Site	Utrecht		Netherlands	3582 KE
71	GSK Investigational Site	Venlo		Netherlands	5912 BL
72	GSK Investigational Site	Barnaul		Russian Federation	656024
73	GSK Investigational Site	Ekaterinburg		Russian Federation	620039
74	GSK Investigational Site	Ekaterinburg		Russian Federation	620102
75	GSK Investigational Site	Irkutsk		Russian Federation	664003
76	GSK Investigational Site	Kemerovo		Russian Federation	650002
77	GSK Investigational Site	Kursk		Russian Federation	305035
78	GSK Investigational Site	Moscow		Russian Federation	125299
79	GSK Investigational Site	Novosibirsk		Russian Federation	630117
80	GSK Investigational Site	Perm		Russian Federation	614036
81	GSK Investigational Site	Ryazan		Russian Federation	390026
82	GSK Investigational Site	Saint-Petersburg		Russian Federation	198260
83	GSK Investigational Site	Samara		Russian Federation	443010
84	GSK Investigational Site	Samara		Russian Federation	443095
85	GSK Investigational Site	St. Petersburgh		Russian Federation	192242
86	GSK Investigational Site	Stavropol		Russian Federation	355030
87	GSK Investigational Site	Tomsk		Russian Federation	634063
88	GSK Investigational Site	Tumen		Russian Federation	625023
89	GSK Investigational Site	Tver		Russian Federation	170036
90	GSK Investigational Site	Ufa		Russian Federation	450000
91	GSK Investigational Site	Yaroslavl		Russian Federation	150003
92	GSK Investigational Site	Yaroslavl		Russian Federation	150023
93	GSK Investigational Site	Aravaca		Spain	28023
94	GSK Investigational Site	Avilés/Asturias		Spain	33400
95	GSK Investigational Site	Barcelona		Spain	08006
96	GSK Investigational Site	Barcelona		Spain	08036
97	GSK Investigational Site	Castellón		Spain	12004
98	GSK Investigational Site	Cordoba		Spain	14004
99	GSK Investigational Site	Don Benito/Badajoz		Spain	06400
100	GSK Investigational Site	Ferrol. La Coruña		Spain	15405
101	GSK Investigational Site	Getafe/Madrid		Spain	28905
102	GSK Investigational Site	Jaén		Spain	23007
103	GSK Investigational Site	La Coruña		Spain	15006
104	GSK Investigational Site	Linares		Spain	23700
105	GSK Investigational Site	Lugo		Spain	27004
106	GSK Investigational Site	Madrid		Spain	28006
107	GSK Investigational Site	Madrid		Spain	28034
108	GSK Investigational Site	Madrid		Spain	28040
109	GSK Investigational Site	Madrid		Spain	28041
110	GSK Investigational Site	Majadahonda/Madrid		Spain	28220
111	GSK Investigational Site	Mondragón - Guipúzcoa		Spain	20500
112	GSK Investigational Site	Ourense		Spain	32005
113	GSK Investigational Site	Palencia		Spain	340014
114	GSK Investigational Site	Palma de Mallorca		Spain	07010
115	GSK Investigational Site	Pozoblanco/Córdoba		Spain	14400
116	GSK Investigational Site	San Sebastián de los Reyes/Madrid		Spain
117	GSK Investigational Site	Santiago de Compostela		Spain	15706
118	GSK Investigational Site	Sevilla		Spain	41071
119	GSK Investigational Site	Torrelodones/Madrid		Spain	28250
120	GSK Investigational Site	Torrevieja		Spain	03184
121	GSK Investigational Site	Valdemoro/Madrid		Spain	28340
122	GSK Investigational Site	Vigo/Pontevedra		Spain	36200

Sponsors and Collaborators

• GlaxoSmithKline

Investigators

• Study Director: GSK Clinical Trials, GlaxoSmithKline

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: GlaxoSmithKline
• ClinicalTrials.gov Identifier: NCT00843492
• Other Study ID Numbers: 109350
• First Posted: Feb 13, 2009
• Last Update Posted: Mar 16, 2016
• Last Verified: Feb 1, 2014

• Keywords provided by GlaxoSmithKline: deep vein thrombosis; immobilization; nadroparin; isolated lower-extremity injuries distal to the knee; plaster cast; non-surgical leg injury; venous thromboembolism; bleeding events; fondaparinux
• Additional relevant MeSH terms: Thrombosis; Venous Thrombosis; Knee Injuries; PENTA; Nadroparin; Fondaparinux

Study Results

Participant Flow

Arm/Group Title	Nadroparin	Fondaparinux
Arm/Group Description	2850 anti-Xa International Units (IU) nadroparin calcium (in 0.3 milliliters [ml] in disposable prefilled syringes) was injected once daily subcutaneously after randomization (Day 1) until the end of immobilization and treatment period Day 45 (Visit 3)	2.5 milligrams (mg) fondaparinux sodium (in 0.5 ml) or 1.5 mg fondaparinux (in 0.3 ml) (in participants with creatinine clearance between 30 and 50 ml per minute) was injected once daily subcutaneously from Day 1 until Day 45 (Visit 3)
Period Title: Overall Study
STARTED	622	621
COMPLETED	614	607
NOT COMPLETED	8	14

Baseline Characteristics

Arm/Group Title	Nadroparin	Fondaparinux	Total
Arm/Group Description	2850 anti-Xa International Units (IU) nadroparin calcium (in 0.3 milliliters [ml] in disposable prefilled syringes) was injected once daily subcutaneously after randomization (Day 1) until the end of immobilization and treatment period Day 45 (Visit 3)	2.5 milligrams (mg) fondaparinux sodium (in 0.5 ml) or 1.5 mg fondaparinux (in 0.3 ml) (in participants with creatinine clearance between 30 and 50 ml per minute) was injected once daily subcutaneously from Day 1 until Day 45 (Visit 3)	Total of all reporting groups
Overall Participants	622	621	1243
Age (Years) [Mean (Standard Deviation) ]
Years	46.5 (15.7)	46.1 (16.0)	46.3 (15.8)
Sex: Female, Male (Count of Participants)
Female	336 54%	328 52.8%	664 53.4%
Male	286 46%	293 47.2%	579 46.6%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Venous Thromboembolism (VTE) or Death up to the Time of Complete Mobilization
Description	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).
Time Frame	Day 1 to complete mobilization plus 2 days (average of 35.9 study days)

Outcome Measure Data

Analysis Population Description

Intent-to-Treat (ITT) Population: all randomized participants with a VTE status or experiencing death. Participants without evaluation of the primary endpoint in the timeframe requested by the protocol were considered as missing data and therefore not included in the primary efficacy analysis.

Arm/Group Title	Nadroparin	Fondaparinux
Arm/Group Description	2850 anti-Xa International Units (IU) nadroparin calcium (in 0.3 milliliters [ml] in disposable prefilled syringes) was injected once daily subcutaneously after randomization (Day 1) until the end of immobilization and treatment period Day 45 (Visit 3)	2.5 milligrams (mg) fondaparinux sodium (in 0.5 ml) or 1.5 mg fondaparinux (in 0.3 ml) (in participants with creatinine clearance between 30 and 50 ml per minute) was injected once daily subcutaneously from Day 1 until Day 45 (Visit 3)
Measure Participants	586	584
Number [participants]	48 7.7%	15 2.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nadroparin, Fondaparinux
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.30
	Confidence Interval	(2-Sided) 95%; 0.15 to 0.54
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Number of Participants With Any Adjudicated Components of VTE, Asymptomatic DVT, Symptomatic DVT, Symptomatic PE, and Death
Description	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.
Time Frame	Day 1 to complete mobilization plus 2 days (average of 35.7 study days)

Outcome Measure Data

Analysis Population Description

ITT Population. Only those participants contributing data at the indicated time points were analyzed.

Arm/Group Title	Nadroparin	Fondaparinux
Arm/Group Description	2850 anti-Xa International Units (IU) nadroparin calcium (in 0.3 milliliters [ml] in disposable prefilled syringes) was injected once daily subcutaneously after randomization (Day 1) until the end of immobilization and treatment period Day 45 (Visit 3)	2.5 milligrams (mg) fondaparinux sodium (in 0.5 ml) or 1.5 mg fondaparinux (in 0.3 ml) (in participants with creatinine clearance between 30 and 50 ml per minute) was injected once daily subcutaneously from Day 1 until Day 45 (Visit 3)
Measure Participants	622	621
Any VTE, n=586, 583	48 7.7%	14 2.3%
Any asymptomatic DVT, n=585, 582	42 6.8%	11 1.8%
Any symptomatic DVT, n=622, 621	7 1.1%	2 0.3%
Any symptomatic PE, n=622, 621	0 0%	2 0.3%
Death, n=622, 621	0 0%	1 0.2%

3. Secondary Outcome

Title	Number of Participants With Confirmed VTE and Death up to the Final Visit or Contact
Description	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.
Time Frame	Day 1 to 5 weeks (plus or minus 1 week) after complete mobilization (average of 67.8 study days)

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Nadroparin	Fondaparinux
Arm/Group Description	2850 anti-Xa International Units (IU) nadroparin calcium (in 0.3 milliliters [ml] in disposable prefilled syringes) was injected once daily subcutaneously after randomization (Day 1) until the end of immobilization and treatment period Day 45 (Visit 3)	2.5 milligrams (mg) fondaparinux sodium (in 0.5 ml) or 1.5 mg fondaparinux (in 0.3 ml) (in participants with creatinine clearance between 30 and 50 ml per minute) was injected once daily subcutaneously from Day 1 until Day 45 (Visit 3)
Measure Participants	622	621
Number [participants]	49 7.9%	15 2.4%

4. Secondary Outcome

Title	Number of Participants With Major Bleeding From Day 1 to Complete Mobilization and From Day 1 up to the Final Visit or Contact
Description	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.
Time Frame	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)

Outcome Measure Data

Analysis Population Description

As-Treated Population: all participants who received at least one dose of study treatment

Arm/Group Title	Nadroparin	Fondaparinux
Arm/Group Description	2850 anti-Xa International Units (IU) nadroparin calcium (in 0.3 milliliters [ml] in disposable prefilled syringes) was injected once daily subcutaneously after randomization (Day 1) until the end of immobilization and treatment period Day 45 (Visit 3)	2.5 milligrams (mg) fondaparinux sodium (in 0.5 ml) or 1.5 mg fondaparinux (in 0.3 ml) (in participants with creatinine clearance between 30 and 50 ml per minute) was injected once daily subcutaneously from Day 1 until Day 45 (Visit 3)
Measure Participants	670	674
Up to complete mobilization plus 4 days	0 0%	1 0.2%
Up to the final visit or contact	0 0%	1 0.2%

5. Secondary Outcome

Title	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
Description	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.
Time Frame	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)

Outcome Measure Data

Analysis Population Description

As-Treated Population

Arm/Group Title	Nadroparin	Fondaparinux
Arm/Group Description	2850 anti-Xa International Units (IU) nadroparin calcium (in 0.3 milliliters [ml] in disposable prefilled syringes) was injected once daily subcutaneously after randomization (Day 1) until the end of immobilization and treatment period Day 45 (Visit 3)	2.5 milligrams (mg) fondaparinux sodium (in 0.5 ml) or 1.5 mg fondaparinux (in 0.3 ml) (in participants with creatinine clearance between 30 and 50 ml per minute) was injected once daily subcutaneously from Day 1 until Day 45 (Visit 3)
Measure Participants	670	674
Up to complete mobilization plus 4 days	3 0.5%	1 0.2%
Up to the final visit or contact	4 0.6%	1 0.2%

6. Secondary Outcome

Title	Number of Participants With Minor Bleeding From Day 1 to Complete Mobilization and From Day 1 up to the Final Visit or Contact
Description	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.
Time Frame	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)

Outcome Measure Data

Analysis Population Description

As-Treated Population

Arm/Group Title	Nadroparin	Fondaparinux
Arm/Group Description	2850 anti-Xa International Units (IU) nadroparin calcium (in 0.3 milliliters [ml] in disposable prefilled syringes) was injected once daily subcutaneously after randomization (Day 1) until the end of immobilization and treatment period Day 45 (Visit 3)	2.5 milligrams (mg) fondaparinux sodium (in 0.5 ml) or 1.5 mg fondaparinux (in 0.3 ml) (in participants with creatinine clearance between 30 and 50 ml per minute) was injected once daily subcutaneously from Day 1 until Day 45 (Visit 3)
Measure Participants	670	674
Up to complete mobilization plus 4 days	3 0.5%	9 1.4%
Up to the final visit or contact	3 0.5%	9 1.4%

7. Secondary Outcome

Title	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
Description	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.
Time Frame	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)

Outcome Measure Data

Analysis Population Description

As-Treated Population

Arm/Group Title	Nadroparin	Fondaparinux
Arm/Group Description	2850 anti-Xa International Units (IU) nadroparin calcium (in 0.3 milliliters [ml] in disposable prefilled syringes) was injected once daily subcutaneously after randomization (Day 1) until the end of immobilization and treatment period Day 45 (Visit 3)	2.5 milligrams (mg) fondaparinux sodium (in 0.5 ml) or 1.5 mg fondaparinux (in 0.3 ml) (in participants with creatinine clearance between 30 and 50 ml per minute) was injected once daily subcutaneously from Day 1 until Day 45 (Visit 3)
Measure Participants	670	674
Up to complete mobilization plus 4 days	6 1%	11 1.8%
Up to the final visit or contact	7 1.1%	11 1.8%

Adverse Events

Adverse Event Reporting Description	Serious adverse events (SAEs) and non-serious AEs were collected in members of the As-Treated Population, comprised of all participants having received at least one dose of study treatment.
Arm/Group Title	Nadroparin		Fondaparinux
Arm/Group Description	2850 anti-Xa International Units (IU) nadroparin calcium (in 0.3 milliliters [ml] in disposable prefilled syringes) was injected once daily subcutaneously after randomization (Day 1) until the end of immobilization and treatment period Day 45 (Visit 3)		2.5 milligrams (mg) fondaparinux sodium (in 0.5 ml) or 1.5 mg fondaparinux (in 0.3 ml) (in participants with creatinine clearance between 30 and 50 ml per minute) was injected once daily subcutaneously from Day 1 until Day 45 (Visit 3)
All Cause Mortality
	Nadroparin		Fondaparinux
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Nadroparin		Fondaparinux
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/670 (1.3%)		6/674 (0.9%)
Cardiac disorders
Cardiac failure	0/670 (0%)		1/674 (0.1%)
Gastrointestinal disorders
Abdominal wall haematoma	0/670 (0%)		1/674 (0.1%)
Faecaloma	1/670 (0.1%)		0/674 (0%)
General disorders
Pyrexia	1/670 (0.1%)		0/674 (0%)
Infections and infestations
Appendicitis	0/670 (0%)		1/674 (0.1%)
Haematoma infection	1/670 (0.1%)		0/674 (0%)
Subcutaneous abscess	1/670 (0.1%)		0/674 (0%)
Injury, poisoning and procedural complications
Joint dislocation	1/670 (0.1%)		1/674 (0.1%)
Ankle fracture	1/670 (0.1%)		0/674 (0%)
Musculoskeletal and connective tissue disorders
Fracture malunion	1/670 (0.1%)		0/674 (0%)
Haemarthrosis	1/670 (0.1%)		0/674 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Prostate cancer	1/670 (0.1%)		0/674 (0%)
Nervous system disorders
Presyncope	0/670 (0%)		1/674 (0.1%)
Transient ischaemic attack	1/670 (0.1%)		0/674 (0%)
Skin and subcutaneous tissue disorders
Angioedema	0/670 (0%)		1/674 (0.1%)
Blister	1/670 (0.1%)		0/674 (0%)
Other (Not Including Serious) Adverse Events
	Nadroparin		Fondaparinux
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	95/670 (14.2%)		93/674 (13.8%)
Blood and lymphatic system disorders
Lymphadenopathy	13/670 (1.9%)		8/674 (1.2%)
Gastrointestinal disorders
Nausea	10/670 (1.5%)		12/674 (1.8%)
General disorders
Injection site haematoma	31/670 (4.6%)		10/674 (1.5%)
Oedema peripheral	7/670 (1%)		11/674 (1.6%)
Musculoskeletal and connective tissue disorders
Pain in extremity	18/670 (2.7%)		21/674 (3.1%)
Arthralgia	8/670 (1.2%)		14/674 (2.1%)
Nervous system disorders
Headache	33/670 (4.9%)		24/674 (3.6%)
Dizziness	6/670 (0.9%)		7/674 (1%)
Skin and subcutaneous tissue disorders
Pruritus	8/670 (1.2%)		6/674 (0.9%)
Vascular disorders
Hypertension	8/670 (1.2%)		7/674 (1%)
Haematoma	1/670 (0.1%)		9/674 (1.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

GSK agreements may vary with individual investigators, but will not prohibit any investigator from publishing. GSK supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.