A Study of DU-176b in Preventing Blood Clots After Hip Replacement Surgery

• Sponsor: Daiichi Sankyo, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00398216
• Collaborator: (none)
• Enrollment: 903
• Locations: 30
• Duration (Months): 13
• Patients Per Site: 30.1
• Patients Per Site Per Month: 2.3

Study Details

Study Description

Brief Summary

This study is to assess if DU176b is effective in prevention of blood clots following hip replacement surgery. The duration is 7-10 days of treatment and 30 and 60 day follow-up visits.

Condition or Disease	Intervention/Treatment	Phase
Thrombosis; Hip Replacement	Drug: DU176b - action is the prevention of venous thromboembolism by the use of a Factor Xa inhibitor	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 903 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double
• Primary Purpose: Prevention
• Official Title: A Phase IIb, Randomized, Parallel Group, Double-Blind, Double-Dummy, Multi-Center, Multi-National, Multi-Dose, Study of DU-176b Compared to Dalteparin in Patients Undergoing Elective Unilateral Total Hip Replacement
• Study Start Date: May 1, 2006
• Actual Primary Completion Date: Jun 1, 2007
• Actual Study Completion Date: Jun 1, 2007

Outcome Measures

Primary Outcome Measures

1. Adjudicated Incidence of VTE [end of treatment]

   Assess the efficacy of DU-176b in the prevention of venous thromboembolism (VTE) from 6 to 8 hours after hip replacement surgery to 7 to 10 days after the surgery. A subject was judged to have a VTE if one or more of the following criteria were met: Observed lower extremity deep vein thrombosis (DVT) (either proximal, distal, or both ) as assessed by bilateral or unilateral ascending contrast venography prior to or at the end-of-treatment (EOT) visit Symptomatic and objectively proven pulmonary embolism prior to or at the EOT visit Symptomatic and objectively proven DVT prior to or at EOT visit end of treatment defined as 6 to 8 hours after after hip replacement surgery to 7 to 10 days after the surgery.

Secondary Outcome Measures

1. Change in Prothrombin Time (PT) From Baseline [end of treatment]

   change in prothrombin time (PT) from baseline to end of treatment end of treatment defined as 6-8 hours after hip replacement surgery to 7 to 10 days after the surgery

2. Change in Activated Partial Thromboplastin Time (aPTT) From Baseline [end of treatment]

   change in Activated Partial Thromboplastin Time (aPTT) from baseline to end of treatment end of treatment defined as 6-8 hours after hip replacement surgery to 7 to 10 days after the surgery

3. Adjudicated Incidence of Major or Clinically Relevant Non-major Bleeding Events [10 days after first dose]

   adjudicated incidence of major or clinically relevant non-major bleeding events through 10 days after first dose

Eligibility Criteria

Criteria

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

1. 18 years of age or older; male or female.

2. Able to provide written informed consent.

3. Must be scheduled for elective unilateral total hip replacement surgery. Only primary surgeries accepted.

4. If female, must be either one year post-menopausal, surgically sterile, or using medically accepted contraceptive measures as judged by the Investigator and in accordance with local regulatory requirements.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Hartford	Connecticut	United States
2		Sarasota	Florida	United States
3		Austin	Texas	United States
4		Ajax	Ontario	Canada
5		Cambridge	Ontario	Canada
6		Guelph	Ontario	Canada
7		Kitchner	Ontario	Canada
8		Toronto	Ontario	Canada
9		Hellerup		Denmark
10		Herlev		Denmark
11		Horsholm		Denmark
12		Gyula		Hungary
13		Kecskemet		Hungary
14		Szeged		Hungary
15		Riga		Latvia
16		Krasnoyarsk		Russian Federation
17		Moscow		Russian Federation
18		Saratov		Russian Federation
19		St. Petersburg		Russian Federation
20		Velikij Novgorod		Russian Federation
21		Volgograd		Russian Federation
22		Chernivtsy		Ukraine
23		Dnepropetrovsk		Ukraine
24		Donetsk		Ukraine
25		Kharkiv		Ukraine
26		Kharkov		Ukraine
27		Kiev		Ukraine
28		Lutsk		Ukraine
29		Lviv		Ukraine
30		Odessa		Ukraine

Sponsors and Collaborators

• Daiichi Sankyo, Inc.

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• ClinicalTrials.gov Identifier: NCT00398216
• Other Study ID Numbers: DU176b-PRT011; 2006-000758-29
• First Posted: Nov 10, 2006
• Last Update Posted: Feb 26, 2019
• Last Verified: Feb 1, 2015

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by , ,: Anti-coagulant; hip replacement; hip replacement surgery; unilateral hip replacement surgery; DeepVein Thrombosis; Venous Thromboembolism; pulmonary embolism; Prevention of Blood Clots
• Additional relevant MeSH terms: Thrombosis; Edoxaban; Factor Xa Inhibitors

Study Results

Participant Flow

Arm/Group Title	Edoxaban 15mg QD	Edoxaban 30mg QD	Edoxaban 60mg QD	Edoxaban 90mg QD	Dalteparin
Arm/Group Description	edoxaban 15mg QD (once daily) orally (PO)	edoxaban 30mg QD PO	edoxaban 60mg QD PO	edoxaban 90mg QD PO	dalteparin 2500 IU/mL initial dose followed by 5000 IU once daily subcutaneously
Period Title: Overall Study
STARTED	192	170	185	177	172
COMPLETED	181	151	164	155	157
NOT COMPLETED	11	19	21	22	15

Baseline Characteristics

Arm/Group Title	Edoxaban 15mg QD	Edoxaban 30mg QD	Edoxaban 60mg QD	Edoxaban 90mg QD	Dalteparin	Total
Arm/Group Description	edoxaban 15mg QD (once daily) orally (PO)	edoxaban 30mg QD PO	edoxaban 60mg QD PO	edoxaban 90mg QD PO	dalteparin 2500 IU/mL initial dose followed by 5000 IU once daily subcutaneously	Total of all reporting groups
Overall Participants	192	170	185	177	172	896
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	126 65.6%	111 65.3%	126 68.1%	114 64.4%	110 64%	587 65.5%
>=65 years	66 34.4%	59 34.7%	59 31.9%	63 35.6%	62 36%	309 34.5%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	57.3 (12.49)	57.2 (12.28)	58.3 (11.52)	58.5 (12.27)	57.5 (12.43)	57.8 (12.13)
Sex: Female, Male (Count of Participants)
Female	113 58.9%	111 65.3%	118 63.8%	93 52.5%	105 61%	540 60.3%
Male	79 41.1%	59 34.7%	67 36.2%	84 47.5%	67 39%	356 39.7%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	1 0.5%	1 0.6%	1 0.5%	0 0%	0 0%	3 0.3%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	1 0.5%	1 0.6%	3 1.6%	1 0.6%	4 2.3%	10 1.1%
White	188 97.9%	167 98.2%	178 96.2%	176 99.4%	165 95.9%	874 97.5%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	2 1%	1 0.6%	3 1.6%	0 0%	3 1.7%	9 1%
Region of Enrollment (participants) [Number]
North America	33 17.2%	20 11.8%	33 17.8%	33 18.6%	29 16.9%	148 16.5%
Europe	159 82.8%	150 88.2%	152 82.2%	144 81.4%	143 83.1%	748 83.5%

Outcome Measures

1. Primary Outcome

Title	Adjudicated Incidence of VTE
Description	Assess the efficacy of DU-176b in the prevention of venous thromboembolism (VTE) from 6 to 8 hours after hip replacement surgery to 7 to 10 days after the surgery. A subject was judged to have a VTE if one or more of the following criteria were met: Observed lower extremity deep vein thrombosis (DVT) (either proximal, distal, or both ) as assessed by bilateral or unilateral ascending contrast venography prior to or at the end-of-treatment (EOT) visit Symptomatic and objectively proven pulmonary embolism prior to or at the EOT visit Symptomatic and objectively proven DVT prior to or at EOT visit end of treatment defined as 6 to 8 hours after after hip replacement surgery to 7 to 10 days after the surgery.
Time Frame	end of treatment

Outcome Measure Data

Analysis Population Description

per protocol analysis set

Arm/Group Title	Edoxaban 15mg QD	Edoxaban 30mg QD	Edoxaban 60mg QD	Edoxaban 90mg QD	Dalteparin
Arm/Group Description	edoxaban 15mg QD (once daily) orally (PO)	edoxaban 30mg QD PO	edoxaban 60mg QD PO	edoxaban 90mg QD PO	dalteparin 2500 IU/mL initial dose followed by 5000 IU once daily subcutaneously
Measure Participants	162	143	153	139	137
Number (95% Confidence Interval) [percentage of participants with VTE]	29.0 15.1%	20.3 11.9%	15.7 8.5%	11.5 6.5%	46.0 26.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Edoxaban 15mg QD, Dalteparin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.003
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Edoxaban 30mg QD, Dalteparin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Edoxaban 60mg QD, Dalteparin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Edoxaban 90mg QD, Dalteparin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Fisher Exact
	Comments

2. Secondary Outcome

Title	Change in Prothrombin Time (PT) From Baseline
Description	change in prothrombin time (PT) from baseline to end of treatment end of treatment defined as 6-8 hours after hip replacement surgery to 7 to 10 days after the surgery
Time Frame	end of treatment

Outcome Measure Data

Analysis Population Description

perp protocol analysis set

Arm/Group Title	Edoxaban 15mg QD	Edoxaban 30mg QD	Edoxaban 60mg QD	Edoxaban 90mg QD	Dalteparin
Arm/Group Description	edoxaban 15mg QD (once daily) orally (PO)	edoxaban 30mg QD PO	edoxaban 60mg QD PO	edoxaban 90mg QD PO	dalteparin 2500 IU/mL initial dose followed by 5000 IU once daily subcutaneously
Measure Participants	153	137	146	134	132
Mean (Standard Deviation) [seconds]	.90 (3.205)	1.07 (1.875)	2.87 (6.279)	2.74 (5.821)	.67 (1.88)

3. Secondary Outcome

Title	Change in Activated Partial Thromboplastin Time (aPTT) From Baseline
Description	change in Activated Partial Thromboplastin Time (aPTT) from baseline to end of treatment end of treatment defined as 6-8 hours after hip replacement surgery to 7 to 10 days after the surgery
Time Frame	end of treatment

Outcome Measure Data

Analysis Population Description

perp protocol analysis set

Arm/Group Title	Edoxaban 15mg QD	Edoxaban 30mg QD	Edoxaban 60mg QD	Edoxaban 90mg QD	Dalteparin
Arm/Group Description	edoxaban 15mg QD (once daily) orally (PO)	edoxaban 30mg QD PO	edoxaban 60mg QD PO	edoxaban 90mg QD PO	dalteparin 2500 IU/mL initial dose followed by 5000 IU once daily subcutaneously
Measure Participants	149	137	145	134	131
Mean (Standard Deviation) [seconds]	-0.33 (6.562)	1.67 (13.092)	4.39 (16.930)	3.26 (13.169)	2.34 (12.396)

4. Secondary Outcome

Title	Adjudicated Incidence of Major or Clinically Relevant Non-major Bleeding Events
Description	adjudicated incidence of major or clinically relevant non-major bleeding events through 10 days after first dose
Time Frame	10 days after first dose

Outcome Measure Data

Analysis Population Description

safety analysis dataset

Arm/Group Title	Edoxaban 15mg QD	Edoxaban 30mg QD	Edoxaban 60mg QD	Edoxaban 90mg QD	Dalteparin
Arm/Group Description	edoxaban 15mg QD (once daily) orally (PO)	edoxaban 30mg QD PO	edoxaban 60mg QD PO	edoxaban 90mg QD PO	dalteparin 2500 IU/mL initial dose followed by 5000 IU once daily subcutaneously
Measure Participants	192	170	185	177	172
Number (95% Confidence Interval) [percentage of subjects with bleed events]	1.6	1.8	2.2	2.3	0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Edoxaban 15mg QD, Dalteparin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.250
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Edoxaban 30mg QD, Dalteparin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.122
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Edoxaban 60mg QD, Dalteparin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.124
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Edoxaban 90mg QD, Dalteparin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.123
	Comments
	Method	Fisher Exact
	Comments

Adverse Events

Arm/Group Title	Edoxaban 15mg QD		Edoxaban 30mg QD		Edoxaban 60mg QD		Edoxaban 90mg QD		Dalteparin
Arm/Group Description	edoxaban 15mg QD (once daily) orally (PO)		edoxaban 30mg QD PO		edoxaban 60mg QD PO		edoxaban 90mg QD PO		dalteparin 2500 IU/mL initial dose followed by 5000 IU once daily subcutaneously
All Cause Mortality
	Edoxaban 15mg QD		Edoxaban 30mg QD		Edoxaban 60mg QD		Edoxaban 90mg QD		Dalteparin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Edoxaban 15mg QD		Edoxaban 30mg QD		Edoxaban 60mg QD		Edoxaban 90mg QD		Dalteparin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/192 (4.2%)		6/170 (3.5%)		8/185 (4.3%)		10/177 (5.6%)		3/172 (1.7%)
Cardiac disorders
acute myocardial infarction	0/192 (0%)	0	0/170 (0%)	0	0/185 (0%)	0	1/177 (0.6%)	1	0/172 (0%)	0
angina pectoris	1/192 (0.5%)	1	0/170 (0%)	0	0/185 (0%)	0	0/177 (0%)	0	0/172 (0%)	0
cardiopulmonary failure	1/192 (0.5%)	1	0/170 (0%)	0	0/185 (0%)	0	0/177 (0%)	0	0/172 (0%)	0
myocardial infarction	1/192 (0.5%)	1	1/170 (0.6%)	1	0/185 (0%)	0	0/177 (0%)	0	0/172 (0%)	0
myocardial ischemia	0/192 (0%)	0	1/170 (0.6%)	1	0/185 (0%)	0	0/177 (0%)	0	0/172 (0%)	0
supraventricular tachycardia	0/192 (0%)	0	0/170 (0%)	0	0/185 (0%)	0	1/177 (0.6%)	1	0/172 (0%)	0
Gastrointestinal disorders
upper gastrointestinal haemorrhage	1/192 (0.5%)	1	0/170 (0%)	0	0/185 (0%)	0	0/177 (0%)	0	0/172 (0%)	0
General disorders
death	0/192 (0%)	0	1/170 (0.6%)	1	0/185 (0%)	0	0/177 (0%)	0	0/172 (0%)	0
secretion of discharge	0/192 (0%)	0	0/170 (0%)	0	0/185 (0%)	0	1/177 (0.6%)	1	0/172 (0%)	0
Immune system disorders
anaphylactic reaction	0/192 (0%)	0	0/170 (0%)	0	0/185 (0%)	0	1/177 (0.6%)	1	0/172 (0%)	0
drug hypersensitivity	0/192 (0%)	0	0/170 (0%)	0	0/185 (0%)	0	0/177 (0%)	0	1/172 (0.6%)	1
Infections and infestations
gastroenteritis	1/192 (0.5%)	1	0/170 (0%)	0	0/185 (0%)	0	0/177 (0%)	0	0/172 (0%)	0
paronychia	1/192 (0.5%)	1	0/170 (0%)	0	0/185 (0%)	0	0/177 (0%)	0	0/172 (0%)	0
Injury, poisoning and procedural complications
dislocation of joint prosthesis	0/192 (0%)	0	1/170 (0.6%)	1	1/185 (0.5%)	1	0/177 (0%)	0	1/172 (0.6%)	1
fat embolism	1/192 (0.5%)	1	0/170 (0%)	0	0/185 (0%)	0	0/177 (0%)	0	0/172 (0%)	0
hip fracture	0/192 (0%)	0	0/170 (0%)	0	1/185 (0.5%)	1	0/177 (0%)	0	0/172 (0%)	0
incision site hematoma	0/192 (0%)	0	0/170 (0%)	0	1/185 (0.5%)	1	1/177 (0.6%)	1	0/172 (0%)	0
post-procedural complication	0/192 (0%)	0	0/170 (0%)	0	0/185 (0%)	0	1/177 (0.6%)	1	0/172 (0%)	0
Investigations
hepatic enzyme increased	0/192 (0%)	0	0/170 (0%)	0	0/185 (0%)	0	1/177 (0.6%)	1	0/172 (0%)	0
Nervous system disorders
syncope	0/192 (0%)	0	0/170 (0%)	0	1/185 (0.5%)	1	0/177 (0%)	0	0/172 (0%)	0
transient ischemic attack	1/192 (0.5%)	1	0/170 (0%)	0	0/185 (0%)	0	0/177 (0%)	0	0/172 (0%)	0
Respiratory, thoracic and mediastinal disorders
acute respiratory distress syndrome	1/192 (0.5%)	1	0/170 (0%)	0	0/185 (0%)	0	0/177 (0%)	0	0/172 (0%)	0
pulmonary congestion	0/192 (0%)	0	0/170 (0%)	0	0/185 (0%)	0	1/177 (0.6%)	1	0/172 (0%)	0
pulmonary embolism	0/192 (0%)	0	0/170 (0%)	0	2/185 (1.1%)	2	0/177 (0%)	0	1/172 (0.6%)	1
Vascular disorders
cardiovascular insufficiency	0/192 (0%)	0	1/170 (0.6%)	1	0/185 (0%)	0	0/177 (0%)	0	0/172 (0%)	0
deep vein thrombosis	2/192 (1%)	2	1/170 (0.6%)	1	2/185 (1.1%)	2	1/177 (0.6%)	1	0/172 (0%)	0
hematoma	1/192 (0.5%)	1	0/170 (0%)	0	1/185 (0.5%)	1	0/177 (0%)	0	0/172 (0%)	0
wound hemorrhage	0/192 (0%)	0	0/170 (0%)	0	0/185 (0%)	0	1/177 (0.6%)	1	0/172 (0%)	0
Other (Not Including Serious) Adverse Events
	Edoxaban 15mg QD		Edoxaban 30mg QD		Edoxaban 60mg QD		Edoxaban 90mg QD		Dalteparin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	30/192 (15.6%)		16/170 (9.4%)		22/185 (11.9%)		25/177 (14.1%)		22/172 (12.8%)
Gastrointestinal disorders
constipation	5/192 (2.6%)		3/170 (1.8%)		8/185 (4.3%)		14/177 (7.9%)		6/172 (3.5%)
nausea	13/192 (6.8%)		4/170 (2.4%)		8/185 (4.3%)		8/177 (4.5%)		6/172 (3.5%)
General disorders
edema peripheral	11/192 (5.7%)		5/170 (2.9%)		7/185 (3.8%)		6/177 (3.4%)		8/172 (4.7%)
pyrexia	15/192 (7.8%)		3/170 (1.8%)		8/185 (4.3%)		6/177 (3.4%)		6/172 (3.5%)
Injury, poisoning and procedural complications
procedural pain	10/192 (5.2%)		5/170 (2.9%)		8/185 (4.3%)		9/177 (5.1%)		8/172 (4.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

A study site may not publish results of a study until after a coordinated multicenter publication has been submitted for publication or until one year after the study has ended, whichever occurs first. The study site will have the opportunity to publish results of the study, provided Daiichi Sankyo has had the opportunity to review and comment on the study site's proposed publication prior to being submitted for publication with the advice of patent council and need for subject protection.