A Phase 3 Study of DU-176b, Prevention of Venous Thromboembolism in Patients After Total Knee Arthroplasty
Sponsor
Daiichi Sankyo Co., Ltd. (Industry)
Overall Status
Completed
CT.gov ID
NCT01181102
Collaborator
(none)
716
3
2
11.1
238.7
21.6
Study Details
Study Description
Brief Summary
The objective of this study is to assess the efficacy and safety of DU-176b compared with enoxaparin sodium for the prevention of venous thromboembolism in patients after elective total knee arthroplasty.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 3 |
Study Design
Study Type:
Interventional
Actual Enrollment
:
716 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:
Prevention
Official Title:
A Phase 3, Randomized, Double-Blind, Double-Dummy Efficacy and Safety Study of the Oral Factor Xa Inhibitor DU-176b Compared With Enoxaparin Sodium for Prevention of Venous Thromboembolism in Patients After Total Knee Arthroplasty (STARS E-3 Trial)
Study Start Date
:
Mar 1, 2009
Actual Primary Completion Date
:
Sep 1, 2009
Actual Study Completion Date
:
Feb 1, 2010
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: DU-176b DU-176b oral tablets, 30 mg., taken once daily for 2 weeks, initiated within 6 to 24 hours after surgery. |
Drug: edoxaban
|
| Active Comparator: enoxaparin sodium enoxaparin sodium 20mg (=2000IU) 0.2ml twice daily, subcutaneous injection for 2 weeks, initiated within 24 to 36 hours after surgery. |
Drug: enoxaparin sodium
|
Outcome Measures
Primary Outcome Measures
- Incidence of Subjects With Venous Thromboembolism Events. [2 weeks]
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)
Secondary Outcome Measures
- Incidence of Major Bleeding or Clinically Relevant Non-major Bleeding. [2 weeks]
Eligibility Criteria
Criteria
Ages Eligible for Study:
20 Years
to 84 Years
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Inclusion Criteria:
- Patients undergoing unilateral total knee arthroplasty
Exclusion Criteria:
-
Subjects with risks of hemorrhage
-
Subjects with thromboembolic risks
-
Subjects who weigh less than 40 kg
-
Subjects who are pregnant or suspect pregnancy, or subjects who want to become pregnant.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Osaka | Japan | |||
| 2 | Tokyo | Japan | |||
| 3 | Kaohsiung | Taiwan |
Sponsors and Collaborators
- Daiichi Sankyo Co., Ltd.
Investigators
- Principal Investigator: Takeshi Fuji, Osaka Koseinenkin Hospital
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.Responsible Party:
Daiichi Sankyo Co., Ltd.
ClinicalTrials.gov Identifier:
NCT01181102
Other Study ID Numbers:
- DU176b-B-J302
First Posted:
Aug 13, 2010
Last Update Posted:
Mar 5, 2019
Last Verified:
Feb 1, 2015
Individual Participant Data (IPD) Sharing Statement:
Yes
Plan to Share IPD:
Yes
Keywords provided by Daiichi Sankyo Co., Ltd.
Additional relevant MeSH terms:
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | DU-176b | Enoxaparin Sodium |
|---|---|---|
| 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 |
Baseline Characteristics
| Arm/Group Title | DU-176b | Enoxaparin Sodium | Total |
|---|---|---|---|
| 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 Participants | 299 | 295 | 594 |
| Age (years) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [years] |
72.6
(7.5)
|
72.1
(7.8)
|
72.4
(7.6)
|
| Sex: Female, Male (Count of Participants) | |||
| Female |
245
81.9%
|
229
77.6%
|
474
79.8%
|
| Male |
54
18.1%
|
66
22.4%
|
120
20.2%
|
| Race (NIH/OMB) (Count of Participants) | |||
| American Indian or Alaska Native |
0
0%
|
0
0%
|
0
0%
|
| Asian |
299
100%
|
295
100%
|
594
100%
|
| Native Hawaiian or Other Pacific Islander |
0
0%
|
0
0%
|
0
0%
|
| Black or African American |
0
0%
|
0
0%
|
0
0%
|
| White |
0
0%
|
0
0%
|
0
0%
|
| More than one race |
0
0%
|
0
0%
|
0
0%
|
| Unknown or Not Reported |
0
0%
|
0
0%
|
0
0%
|
| Region of Enrollment (participants) [Number] | |||
| Taiwan |
26
8.7%
|
25
8.5%
|
51
8.6%
|
| Japan |
273
91.3%
|
270
91.5%
|
543
91.4%
|
Outcome Measures
| Title | Incidence of Subjects With Venous Thromboembolism Events. |
|---|---|
| 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Efficacy Analysis population. 22 (7.4%) - DU-176b 41 (13.9%) - enoxaparin |
| Arm/Group Title | DU-176b | Enoxaparin Sodium |
|---|---|---|
| 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 |
| Measure Participants | 299 | 295 |
| Number (95% Confidence Interval) [percent of participants with VTE events] |
7.4
2.5%
|
13.9
4.7%
|
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 | ||
| Method of Estimation | Estimation Parameter | Cox Proportional Hazard |
| Estimated Value | -6.5 | |
| Confidence Interval |
(2-Sided) 95% -11.5 to -1.6 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Incidence of Major Bleeding or Clinically Relevant Non-major Bleeding. |
|---|---|
| Description | |
| Time Frame | 2 weeks |
Outcome Measure Data
| 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 |
|---|---|---|
| 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 |
| Measure Participants | 354 | 349 |
| Number (95% Confidence Interval) [percentage of subjects with bleeds] |
6.2
|
3.7
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | DU-176b, Enoxaparin Sodium |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | χ2 test |
| Estimated Value | 2.5 | |
| Confidence Interval |
(2-Sided) 95% -0.8 to 5.9 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Adverse Events
| Time Frame | ||||
|---|---|---|---|---|
| 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 | ||
| 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 (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | / (NaN) | / (NaN) | ||
Serious Adverse Events |
||||
| DU-176b | Enoxaparin Sodium | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 10/354 (2.8%) | 11/349 (3.2%) | ||
| Cardiac disorders | ||||
| cyanosis | 0/354 (0%) | 0 | 1/349 (0.3%) | 1 |
| myocardial infarction | 1/354 (0.3%) | 1 | 0/349 (0%) | 0 |
| Eye disorders | ||||
| retinal artery occlusion | 0/354 (0%) | 0 | 1/349 (0.3%) | 1 |
| Gastrointestinal disorders | ||||
| gastrointestinal haemorrhage | 0/354 (0%) | 0 | 1/349 (0.3%) | 1 |
| melaena | 1/354 (0.3%) | 1 | 0/349 (0%) | 0 |
| General disorders | ||||
| pyrexia | 0/354 (0%) | 0 | 1/349 (0.3%) | 1 |
| Infections and infestations | ||||
| postoperative wound infection | 1/354 (0.3%) | 1 | 0/349 (0%) | 0 |
| stitch abcess | 1/354 (0.3%) | 1 | 0/349 (0%) | 0 |
| Injury, poisoning and procedural complications | ||||
| Femoral neck fracture | 0/354 (0%) | 0 | 1/349 (0.3%) | 1 |
| Lumbar vertebral fracture | 1/354 (0.3%) | 1 | 0/349 (0%) | 0 |
| Wound complication | 1/354 (0.3%) | 1 | 0/349 (0%) | 0 |
| Ligament rupture | 1/354 (0.3%) | 1 | 0/349 (0%) | 0 |
| Investigations | ||||
| Alanine aminotransferase increased | 0/354 (0%) | 0 | 1/349 (0.3%) | 1 |
| Aspartate aminotransferase increased | 0/354 (0%) | 0 | 1/349 (0.3%) | 1 |
| C-reactive protein increased | 0/354 (0%) | 0 | 1/349 (0.3%) | 1 |
| Musculoskeletal and connective tissue disorders | ||||
| haemarthrosis | 1/354 (0.3%) | 1 | 0/349 (0%) | 0 |
| joint contracture | 0/354 (0%) | 0 | 1/349 (0.3%) | 1 |
| Nervous system disorders | ||||
| carotid artery stenosis | 0/354 (0%) | 0 | 1/349 (0.3%) | 1 |
| cerebellar infarction | 1/354 (0.3%) | 1 | 0/349 (0%) | 0 |
| convulsion | 0/354 (0%) | 0 | 1/349 (0.3%) | 1 |
| syncope | 0/354 (0%) | 0 | 1/349 (0.3%) | 1 |
| Skin and subcutaneous tissue disorders | ||||
| pyoderma gangrenosum | 0/354 (0%) | 0 | 1/349 (0.3%) | 1 |
| urticaria | 1/354 (0.3%) | 1 | 0/349 (0%) | 0 |
| Vascular disorders | ||||
| hypotension | 0/354 (0%) | 0 | 1/349 (0.3%) | 1 |
| deep vein thrombosis | 0/354 (0%) | 0 | 1/349 (0.3%) | 1 |
Other (Not Including Serious) Adverse Events |
||||
| DU-176b | Enoxaparin Sodium | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 237/354 (66.9%) | 256/349 (73.4%) | ||
| Gastrointestinal disorders | ||||
| Diarrhoea | 12/354 (3.4%) | 12 | 10/349 (2.9%) | 12 |
| Vomiting | 9/354 (2.5%) | 9 | 7/349 (2%) | 7 |
| Infections and infestations | ||||
| Cystitis | 8/354 (2.3%) | 8 | 6/349 (1.7%) | 6 |
| Nasopharyngitis | 16/354 (4.5%) | 16 | 15/349 (4.3%) | 15 |
| Investigations | ||||
| Alanine aminotransferase increased | 25/354 (7.1%) | 25 | 94/349 (26.9%) | 94 |
| Aspartate aminotransferase increased | 12/354 (3.4%) | 12 | 87/349 (24.9%) | 87 |
| Gamma-glutamyltransferase increased | 33/354 (9.3%) | 33 | 64/349 (18.3%) | 65 |
| blood urine present | 34/354 (9.6%) | 35 | 31/349 (8.9%) | 32 |
| Blood bilirubin increased | 14/354 (4%) | 14 | 7/349 (2%) | 8 |
| Blood lactate dehydrogenase increased | 6/354 (1.7%) | 6 | 16/349 (4.6%) | 16 |
| Blood triglycerides increased | 9/354 (2.5%) | 9 | 6/349 (1.7%) | 6 |
| Haemoglobin decreased | 34/354 (9.6%) | 35 | 31/349 (8.9%) | 32 |
| Blood alkaline phosphatase increased | 34/354 (9.6%) | 35 | 31/349 (8.9%) | 32 |
| Musculoskeletal and connective tissue disorders | ||||
| Haemarthrosis | 7/354 (2%) | 7 | 7/349 (2%) | 7 |
| Skin and subcutaneous tissue disorders | ||||
| Haemorrhage subcutaneous | 22/354 (6.2%) | 25 | 28/349 (8%) | 30 |
| rash | 9/354 (2.5%) | 9 | 4/349 (1.1%) | 4 |
| Vascular disorders | ||||
| wound haemorrhage | 18/354 (5.1%) | 19 | 10/349 (2.9%) | 10 |
Limitations/Caveats
[Not Specified]
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
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 |
| ibusuki.kei.tx@daiichisankyo.co.jp |
Responsible Party:
Daiichi Sankyo Co., Ltd.
ClinicalTrials.gov Identifier:
NCT01181102
Other Study ID Numbers:
- DU176b-B-J302
First Posted:
Aug 13, 2010
Last Update Posted:
Mar 5, 2019
Last Verified:
Feb 1, 2015