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A Phase 3 Study of DU-176b, Prevention of Venous Thromboembolism in Patients After Total Knee Arthroplasty

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ClinicalTrials.gov Identifier: NCT01181102
Recruitment Status : Completed
First Posted : August 13, 2010
Results First Posted : February 19, 2015
Last Update Posted : February 19, 2015
Sponsor:
Information provided by (Responsible Party):
Daiichi Sankyo, Inc. ( Daiichi Sankyo Co., Ltd. )

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Prevention
Condition Venous Thromboembolism
Interventions Drug: edoxaban
Drug: enoxaparin sodium
Enrollment 716
Recruitment Details  
Pre-assignment Details  
Arm/Group Title DU-176b Enoxaparin Sodium
Hide Arm/Group Description

DU-176b oral tablets, 30 mg., taken once daily for 2 weeks

edoxaban

enoxaparin sodium 20mg(=2000IU)/0.2ml twice daily, subcutaneous injection for 2 weeks

enoxaparin sodium

Period Title: Overall Study
Started 360 356
Safety Analysis Set 354 349
Efficacy Analysis Population 299 295
Completed 309 310
Not Completed 51 46
Reason Not Completed
Adverse Event             28             26
Lack of Efficacy             3             1
Lost to Follow-up             2             0
Physician Decision             3             1
Protocol Violation             5             6
Withdrawal by Subject             10             12
Arm/Group Title DU-176b Enoxaparin Sodium Total
Hide Arm/Group Description

DU-176b oral tablets, 30 mg., taken once daily for 2 weeks

edoxaban

enoxaparin sodium 20mg(=2000IU)/0.2ml twice daily, subcutaneous injection for 2 weeks

enoxaparin sodium

Total of all reporting groups
Overall Number of Baseline Participants 299 295 594
Hide Baseline Analysis Population Description
Number of baseline participants reflects the efficacy analysis population
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 299 participants 295 participants 594 participants
72.6  (7.5) 72.1  (7.8) 72.4  (7.6)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 299 participants 295 participants 594 participants
Female
245
  81.9%
229
  77.6%
474
  79.8%
Male
54
  18.1%
66
  22.4%
120
  20.2%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 299 participants 295 participants 594 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
0
   0.0%
Asian
299
 100.0%
295
 100.0%
594
 100.0%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
0
   0.0%
0
   0.0%
0
   0.0%
White
0
   0.0%
0
   0.0%
0
   0.0%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 299 participants 295 participants 594 participants
Taiwan 26 25 51
Japan 273 270 543
1.Primary Outcome
Title Incidence of Subjects With Venous Thromboembolism Events.
Hide Description

The primary efficacy endpoint was the proportion of subjects who experienced at least one of the thromboembolic events listed below during the period from the start of study treatment to the venography at the end of study treatment.

  • Lower extremity Deep Vein Thrombosis (DVT) confirmed by unilateral venography at the end of study treatment
  • Definite diagnosis of symptomatic Pulmonary Embolism (PE)
  • Symptomatic DVT confirmed before the venography at the end of study treatment The objectives were to verify the non-inferiority of edoxaban to enoxaparin with regard to prevention of venous Thromboembolism (VTE)
Time Frame 2 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Efficacy Analysis population. 22 (7.4%) - DU-176b 41 (13.9%) - enoxaparin
Arm/Group Title DU-176b Enoxaparin Sodium
Hide Arm/Group Description:

DU-176b oral tablets, 30 mg., taken once daily for 2 weeks

edoxaban

enoxaparin sodium 20mg(=2000IU)/0.2ml twice daily, subcutaneous injection for 2 weeks

enoxaparin sodium

Overall Number of Participants Analyzed 299 295
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percent of participants with VTE events
7.4
(4.4 to 10.3)
13.9
(10.0 to 17.8)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection DU-176b, Enoxaparin Sodium
Comments The incidence proportion of thromboembolic events in the DU-176b group (P˅DU) = The incidence proportion of thromboembolic events in the enoxaparin group (P˅E) + Δ (5%). Alternative hypothesis H˅11: P˅DU < P˅E + Δ (level of significance, 0.025; one-sided). If the null hypothesis H˅01 was rejected, the following analysis had to be sequentially performed using the χ2 test statistic. Null hypothesis H˅02: P˅DU = P˅E Alternative hypothesis H˅12: P˅DU ≠ P˅E (level of significance, 0.05; two-sided).
Type of Statistical Test Non-Inferiority or Equivalence
Comments

(non-inferiority) When analyzed using the Z test at a one-sided 0.025 significance level, with the addition of a non-inferiority margin of 5% to the incidence in the enoxaparin group.

(superiority) The incidence of thromboembolic events for the FAS was compared using the χ2 test (two-sided significance level: 0.05)

Statistical Test of Hypothesis P-Value <0.001
Comments non-inferiority:P < 0.001 superiority:P = 0.010
Method non-inferiority:Z test. superiority:χ2 t
Comments [Not Specified]
Method of Estimation Estimation Parameter Cox Proportional Hazard
Estimated Value -6.5
Confidence Interval (2-Sided) 95%
-11.5 to -1.6
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Incidence of Major Bleeding or Clinically Relevant Non-major Bleeding.
Hide Description [Not Specified]
Time Frame 2 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The Safety Analysis Set was defined as all subjects who were enrolled in the study, but excluded those who had significant GCP violations, who did not receive any doses of the study drug, or who had no safety data after the start of study treatment
Arm/Group Title DU-176b Enoxaparin Sodium
Hide Arm/Group Description:

DU-176b oral tablets, 30 mg., taken once daily for 2 weeks

edoxaban

enoxaparin sodium 20mg(=2000IU)/0.2ml twice daily, subcutaneous injection for 2 weeks

enoxaparin sodium

Overall Number of Participants Analyzed 354 349
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of subjects with bleeds
6.2
(4.1 to 9.2)
3.7
(2.2 to 6.3)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection DU-176b, Enoxaparin Sodium
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter χ2 test
Estimated Value 2.5
Confidence Interval (2-Sided) 95%
-0.8 to 5.9
Estimation Comments [Not Specified]
Time Frame [Not Specified]
Adverse Event Reporting Description The Safety Analysis Set was defined as all subjects who were enrolled in the study, but excluded those who had significant GCP violations, who did not receive any doses of the study drug, or who had no safety data after the start of study treatment.
 
Arm/Group Title DU-176b Enoxaparin Sodium
Hide Arm/Group Description

DU-176b oral tablets, 30 mg., taken once daily for 2 weeks

edoxaban

enoxaparin sodium 20mg(=2000IU)/0.2ml twice daily, subcutaneous injection for 2 weeks

enoxaparin sodium

All-Cause Mortality
DU-176b Enoxaparin Sodium
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
DU-176b Enoxaparin Sodium
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   10/354 (2.82%)      11/349 (3.15%)    
Cardiac disorders     
cyanosis  1  0/354 (0.00%)  0 1/349 (0.29%)  1
myocardial infarction  1  1/354 (0.28%)  1 0/349 (0.00%)  0
Eye disorders     
retinal artery occlusion  1  0/354 (0.00%)  0 1/349 (0.29%)  1
Gastrointestinal disorders     
gastrointestinal haemorrhage  1  0/354 (0.00%)  0 1/349 (0.29%)  1
melaena  1  1/354 (0.28%)  1 0/349 (0.00%)  0
General disorders     
pyrexia  1  0/354 (0.00%)  0 1/349 (0.29%)  1
Infections and infestations     
postoperative wound infection  1  1/354 (0.28%)  1 0/349 (0.00%)  0
stitch abcess  1  1/354 (0.28%)  1 0/349 (0.00%)  0
Injury, poisoning and procedural complications     
Femoral neck fracture  1  0/354 (0.00%)  0 1/349 (0.29%)  1
Lumbar vertebral fracture  1  1/354 (0.28%)  1 0/349 (0.00%)  0
Wound complication  1  1/354 (0.28%)  1 0/349 (0.00%)  0
Ligament rupture  1  1/354 (0.28%)  1 0/349 (0.00%)  0
Investigations     
Alanine aminotransferase increased  1  0/354 (0.00%)  0 1/349 (0.29%)  1
Aspartate aminotransferase increased  1  0/354 (0.00%)  0 1/349 (0.29%)  1
C-reactive protein increased  1  0/354 (0.00%)  0 1/349 (0.29%)  1
Musculoskeletal and connective tissue disorders     
haemarthrosis  1  1/354 (0.28%)  1 0/349 (0.00%)  0
joint contracture  1  0/354 (0.00%)  0 1/349 (0.29%)  1
Nervous system disorders     
carotid artery stenosis  1  0/354 (0.00%)  0 1/349 (0.29%)  1
cerebellar infarction  1  1/354 (0.28%)  1 0/349 (0.00%)  0
convulsion  1  0/354 (0.00%)  0 1/349 (0.29%)  1
syncope  1  0/354 (0.00%)  0 1/349 (0.29%)  1
Skin and subcutaneous tissue disorders     
pyoderma gangrenosum  1  0/354 (0.00%)  0 1/349 (0.29%)  1
urticaria  1  1/354 (0.28%)  1 0/349 (0.00%)  0
Vascular disorders     
hypotension  1  0/354 (0.00%)  0 1/349 (0.29%)  1
deep vein thrombosis  1  0/354 (0.00%)  0 1/349 (0.29%)  1
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA JV12.0
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 2%
DU-176b Enoxaparin Sodium
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   237/354 (66.95%)      256/349 (73.35%)    
Gastrointestinal disorders     
Diarrhoea  1  12/354 (3.39%)  12 10/349 (2.87%)  12
Vomiting  1  9/354 (2.54%)  9 7/349 (2.01%)  7
Infections and infestations     
Cystitis  1  8/354 (2.26%)  8 6/349 (1.72%)  6
Nasopharyngitis  1  16/354 (4.52%)  16 15/349 (4.30%)  15
Investigations     
Alanine aminotransferase increased  1  25/354 (7.06%)  25 94/349 (26.93%)  94
Aspartate aminotransferase increased  1  12/354 (3.39%)  12 87/349 (24.93%)  87
Gamma-glutamyltransferase increased  1  33/354 (9.32%)  33 64/349 (18.34%)  65
blood urine present  1  34/354 (9.60%)  35 31/349 (8.88%)  32
Blood bilirubin increased  1  14/354 (3.95%)  14 7/349 (2.01%)  8
Blood lactate dehydrogenase increased  1  6/354 (1.69%)  6 16/349 (4.58%)  16
Blood triglycerides increased  1  9/354 (2.54%)  9 6/349 (1.72%)  6
Haemoglobin decreased  1  34/354 (9.60%)  35 31/349 (8.88%)  32
Blood alkaline phosphatase increased  1  34/354 (9.60%)  35 31/349 (8.88%)  32
Musculoskeletal and connective tissue disorders     
Haemarthrosis  1  7/354 (1.98%)  7 7/349 (2.01%)  7
Skin and subcutaneous tissue disorders     
Haemorrhage subcutaneous  1  22/354 (6.21%)  25 28/349 (8.02%)  30
rash  1  9/354 (2.54%)  9 4/349 (1.15%)  4
Vascular disorders     
wound haemorrhage  1  18/354 (5.08%)  19 10/349 (2.87%)  10
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA JV12.0
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
PI shall not publish the results of the Study at any time without the prior written approval of Sponsor.
Results Point of Contact
Name/Title: Kei Ibusuki, Associate Director
Organization: Daiichi Sankyo.,LTD
Phone: 81-90-2732-9505
Responsible Party: Daiichi Sankyo, Inc. ( Daiichi Sankyo Co., Ltd. )
ClinicalTrials.gov Identifier: NCT01181102     History of Changes
Other Study ID Numbers: DU176b-B-J302
First Submitted: August 12, 2010
First Posted: August 13, 2010
Results First Submitted: January 15, 2015
Results First Posted: February 19, 2015
Last Update Posted: February 19, 2015