Cancer Venous Thromboembolism (VTE)

• Sponsor: Daiichi Sankyo, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02073682
• Collaborator: (none)
• Enrollment: 1,046
• Locations: 9
• Arms: 2
• Actual Duration (Months): 26
• Patients Per Site: 116.2
• Patients Per Site Per Month: 4.5

Study Details

Study Description

Brief Summary

The primary objective is to demonstrate the non-inferiority of edoxaban (preceded by a short course of LMWH) compared with dalteparin for the prevention of the combined outcome of recurrent venous thromboembolism (VTE) or major bleeding in subjects with VTE associated with cancer during a 12-month study period. If non-inferiority is established, LMWH/edoxaban will be compared with dalteparin for superiority.

Condition or Disease	Intervention/Treatment	Phase
Venous Thromboembolism (VTE); Deep Vein Thrombosis (DVT); Pulmonary Embolism (PE); Cancer	Drug: Edoxaban; Drug: Dalteparin; Drug: Low molecular weight heparin	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 1046 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 3b, Prospective, Randomized, Open-label, Blind Evaluator (PROBE) Study Evaluating the Efficacy and Safety of (LMW) Heparin/Edoxaban Versus Dalteparin in Venous Thromboembolism Associated With Cancer
• Actual Study Start Date: Jul 16, 2015
• Actual Primary Completion Date: Sep 15, 2017
• Actual Study Completion Date: Sep 15, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Edoxaban group After 5 days of low molecular weight heparin (LMWH), patients receive edoxaban treatment daily - tablet for oral use	Drug: Edoxaban; After the 5 day treatment with LMWH, patients receive edoxaban 60 mg once daily (QD) as 2 × 30 mg tablets (or 1 x 30 mg tablet QD for patients requiring dose adjustment) for the remainder of the treatment period.; Other Names: DU-176b ; Drug: Low molecular weight heparin; Therapeutic doses of subcutaneous LMWH were administered for at least 5 days (to patients in the edoxaban group); this 5-day period may have included the pre-randomization LMWH (if applicable). The choice of parenteral LMWH was up to the treating physician.; Other Names: LMWH
Active Comparator: Dalteparin group Participants receive Dalteparin treatment daily -solution for subcutaneous injection	Drug: Dalteparin; Dalteparin was administered via subcutaneous injection at a dose of 200 IU/kg (maximum daily dose 18,000 IU) for 30 days, and at a dose of 150 IU/kg from Day 31 to the end of treatment.; Other Names: Active comparator

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Adjudicated Recurrent Venous Thromboembolism (VTE) or Major Bleeding Event [12 months]

Secondary Outcome Measures

1. Number of Participants With Adjudicated Major Bleeding Events While on Treatment [12 months]

   The primary safety endpoint was major bleeding events during the On-Treatment Study Period (defined as on-study drug or up to 3 days after the last dose of study drug).

2. Number of Participants With Recurrent Venous Thromboembolism (VTE) During the Overall Study Period [12 months]

3. Number of Participants With Recurrent Deep Vein Thrombosis (DVT) During the Overall Study Period [12 months]

4. Number of Participants With Recurrent Non-Fatal Pulmonary Embolism (PE) During the Overall Study Period [12 months]

5. Number of Participants With VTE-Related Death [12 months]

6. Number of Participants With Recurrent VTE, Major Bleed or All-Cause Death [12 months]

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Male or female subjects with age ≥ 18 years or the otherwise legal lower age according to the country of residence;

• Confirmed acute lower extremity proximal DVT or PE for which long term treatment with low molecular weight heparin (LMWH) is indicated;

• Cancer, other than basal-cell or squamous-cell carcinoma of the skin;

• Able to provide written informed consent.

Exclusion Criteria:

• Thrombectomy, insertion of a caval filter, or use of a fibrinolytic agent to treat the current (index) episode of DVT and/or PE;

• Treatment with therapeutic doses of an anticoagulant other than that used for pretreatment of the current (index) VTE episode prior to randomization;

• Active bleeding or high risk for bleeding contraindicating treatment with LMWH or edoxaban;

• Any other contraindication listed in the local labeling of dalteparin, enoxaparin, or edoxaban;

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Brandon	Florida	United States
2		Jonesboro	Georgia	United States
3		Detroit	Michigan	United States
4		Norfolk	Virginia	United States
5		Leuven	Vlaams-Brabant	Belgium
6		Saint-Etienne cedex 2		France
7		Debrecen	Hajdu-Bihar Megye	Hungary
8		Varese		Italy
9		Amsterdam		Netherlands

Sponsors and Collaborators

• Daiichi Sankyo, Inc.

Investigators

• Study Director: Global Clinical Leader, Daiichi Sankyo, Inc.

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jan 20, 2016

More Information

Publications

None provided.

• Responsible Party: Daiichi Sankyo, Inc.
• ClinicalTrials.gov Identifier: NCT02073682
• Other Study ID Numbers: DU176b-D-U311; 2014-004708-30
• First Posted: Feb 27, 2014
• Last Update Posted: Mar 6, 2019
• Last Verified: Sep 1, 2018

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by Daiichi Sankyo, Inc.: Active Cancer with Metastasis
• Additional relevant MeSH terms: Pulmonary Embolism; Thrombosis; Embolism; Thromboembolism; Venous Thromboembolism; Venous Thrombosis; Heparin; Heparin, Low-Molecular-Weight; Tinzaparin; Dalteparin; Edoxaban

Study Results

Participant Flow

Recruitment Details	1050 participants were randomized from 114 sites in Western Europe (31), Central Europe (11), South Europe (36), Australia/New Zealand (13) and North America (23)
Pre-assignment Detail	Of 1050 participants randomized, 1046 took study drug and were included in the modified Intent to Treat (mITT) and Safety Analysis Sets

Arm/Group Title	Edoxaban Group	Dalteparin Group
Arm/Group Description	After 5 days of low molecular weight heparin (LMWH), participants received edoxaban treatment daily	Participants received dalteparin daily
Period Title: Overall Study
STARTED	522	524
COMPLETED	200	154
NOT COMPLETED	322	370

Baseline Characteristics

Arm/Group Title	Edoxaban Group	Dalteparin Group	Total
Arm/Group Description	After 5 days of low molecular weight heparin (LMWH), participants received edoxaban treatment daily	Participants received dalteparin daily	Total of all reporting groups
Overall Participants	522	524	1046
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	66	65	65
Age, Customized (Count of Participants)
18-64 Years	246 47.1%	261 49.8%	507 48.5%
65-84 Years	267 51.1%	254 48.5%	521 49.8%
85 years and over	9 1.7%	9 1.7%	18 1.7%
Sex: Female, Male (Count of Participants)
Female	245 46.9%	261 49.8%	506 48.4%
Male	277 53.1%	263 50.2%	540 51.6%
Race/Ethnicity, Customized (Count of Participants)
White	453 86.8%	427 81.5%	880 84.1%
Black or African American	17 3.3%	21 4%	38 3.6%
Asian	6 1.1%	13 2.5%	19 1.8%
Native Hawaiian/Pacific Islander	0 0%	1 0.2%	1 0.1%
Other	33 6.3%	44 8.4%	77 7.4%
Region of Enrollment (participants) [Number]
Netherlands	61 11.7%	57 10.9%	118 11.3%
Belgium	22 4.2%	19 3.6%	41 3.9%
Hungary	17 3.3%	16 3.1%	33 3.2%
United States	104 19.9%	103 19.7%	207 19.8%
Italy	45 8.6%	45 8.6%	90 8.6%
France	58 11.1%	64 12.2%	122 11.7%
Austria	13 2.5%	15 2.9%	28 2.7%
Germany	30 5.7%	29 5.5%	59 5.6%
Czechia	11 2.1%	10 1.9%	21 2%
Spain	35 6.7%	35 6.7%	70 6.7%
Australia	16 3.1%	16 3.1%	32 3.1%
New Zealand	12 2.3%	13 2.5%	25 2.4%
Canada	98 18.8%	102 19.5%	200 19.1%
Type of Cancer (Count of Participants)
Solid Tumor	465 89.1%	467 89.1%	932 89.1%
Haematological Malignancy	56 10.7%	55 10.5%	111 10.6%
Solid Tumor and Haematological Malignancy	1 0.2%	2 0.4%	3 0.3%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Adjudicated Recurrent Venous Thromboembolism (VTE) or Major Bleeding Event
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

modified Intent to Treat (mITT), equating to the Safety Analysis Set

Arm/Group Title	Edoxaban Group	Dalteparin Group
Arm/Group Description	After 5 days of low molecular weight heparin (LMWH), participants received edoxaban treatment daily	Participants received dalteparin daily
Measure Participants	522	524
Count of Participants [Participants]	67 12.8%	71 13.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Edoxaban Group, Dalteparin Group
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	Edoxaban Group was considered non-inferior to the Dalteparin Group if the upper limit of the 2-sided 95% confidence interval (CI) for the Hazard Ratio ([LMW] Edoxaban Group to Dalteparin Group) was less than 1.5.
Statistical Test of Hypothesis	p-Value	0.0056
	Comments
	Method	Cox proportional hazard
	Comments
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	0.97
	Confidence Interval	(2-Sided) 95%; 0.696 to 1.359
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Edoxaban Group, Dalteparin Group
	Comments
	Type of Statistical Test	Superiority
	Comments	The hazard ratio (HR), two-sided confidence interval (CI) and p-value are based on the Cox proportional hazard model including treatment and the two stratification factors as covariates: the dichotomized bleeding risk and the dichotomized dose-adjustment factor.
Statistical Test of Hypothesis	p-Value	0.8712
	Comments
	Method	Cox proportional hazard
	Comments

2. Secondary Outcome

Title	Number of Participants With Adjudicated Major Bleeding Events While on Treatment
Description	The primary safety endpoint was major bleeding events during the On-Treatment Study Period (defined as on-study drug or up to 3 days after the last dose of study drug).
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

Safety analysis set

Arm/Group Title	Edoxaban Group	Dalteparin Group
Arm/Group Description	After 5 days of low molecular weight heparin (LMWH), participants received edoxaban treatment daily	Participants received dalteparin daily
Measure Participants	522	524
Count of Participants [Participants]	32 6.1%	16 3.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Edoxaban Group, Dalteparin Group
	Comments	The HR, 2-sided CI and p-value are based on the Cox regression model with counting process approach for on-treatment including treatment and the 2 stratification factors as covariates: the dichotomized bleeding risk and the dichotomized dose-adjustment factor.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0254
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	2.0
	Confidence Interval	(2-Sided) 95%; 1.089 to 3.657
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Number of Participants With Recurrent Venous Thromboembolism (VTE) During the Overall Study Period
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

mITT (Safety Analysis Set)

Arm/Group Title	Edoxaban Group	Dalteparin Group
Arm/Group Description	After 5 days of low molecular weight heparin (LMWH), participants received edoxaban treatment daily	Participants received dalteparin daily
Measure Participants	522	524
Count of Participants [Participants]	41 7.9%	59 11.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Edoxaban Group, Dalteparin Group
	Comments	The HR, 2-sided CI, and p-value are based on the Cox proportional hazard model including treatment and the 2 stratification factors as covariates: the dichotomized bleeding risk and the dichotomized dose-adjustment factor.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0931
	Comments
	Method	Cox proportional hazard
	Comments
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	0.71
	Confidence Interval	(2-Sided) 95%; 0.476 to 1.059
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Number of Participants With Recurrent Deep Vein Thrombosis (DVT) During the Overall Study Period
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

mITT (Safety Analysis Set)

Arm/Group Title	Edoxaban Group	Dalteparin Group
Arm/Group Description	After 5 days of low molecular weight heparin (LMWH), participants received edoxaban treatment daily	Participants received dalteparin daily
Measure Participants	522	524
Count of Participants [Participants]	19 3.6%	35 6.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Edoxaban Group, Dalteparin Group
	Comments	The HR, 2-sided CI, and p-value are based on the Cox proportional hazard model including treatment and the 2 stratification factors as covariates: the dichotomized bleeding risk and the dichotomized dose-adjustment factor.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0394
	Comments
	Method	Cox proportional hazard
	Comments
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	0.56
	Confidence Interval	(2-Sided) 95%; 0.318 to 0.972
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Number of Participants With Recurrent Non-Fatal Pulmonary Embolism (PE) During the Overall Study Period
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

mITT (Safety Analysis Set)

Arm/Group Title	Edoxaban Group	Dalteparin Group
Arm/Group Description	After 5 days of low molecular weight heparin (LMWH), participants received edoxaban treatment daily	Participants received dalteparin daily
Measure Participants	522	524
Count of Participants [Participants]	21 4%	24 4.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Edoxaban Group, Dalteparin Group
	Comments	The HR, 2-sided CI, and p-value are based on the Cox proportional hazard model including treatment and the 2 stratification factors as covariates: the dichotomized bleeding risk and the dichotomized dose-adjustment factor.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7324
	Comments
	Method	Cox proportional hazard
	Comments
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	0.90
	Confidence Interval	(2-Sided) 95%; 0.502 to 1.624
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Number of Participants With VTE-Related Death
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

mITT (Safety Analysis Set)

Arm/Group Title	Edoxaban Group	Dalteparin Group
Arm/Group Description	After 5 days of low molecular weight heparin (LMWH), participants received edoxaban treatment daily	Participants received dalteparin daily
Measure Participants	522	524
Count of Participants [Participants]	6 1.1%	4 0.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Edoxaban Group, Dalteparin Group
	Comments	The HR, 2-sided CI, and p-value are based on the Cox proportional hazard model including treatment and the 2 stratification factors as covariates: the dichotomized bleeding risk and the dichotomized dose-adjustment factor.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4873
	Comments
	Method	Cox proportional hazard
	Comments
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	1.56
	Confidence Interval	(2-Sided) 95%; 0.444 to 5.505
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Number of Participants With Recurrent VTE, Major Bleed or All-Cause Death
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

mITT (Safety Analysis Set)

Arm/Group Title	Edoxaban Group	Dalteparin Group
Arm/Group Description	After 5 days of low molecular weight heparin (LMWH), participants received edoxaban treatment daily	Participants received dalteparin daily
Measure Participants	522	524
Count of Participants [Participants]	235 45%	228 43.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Edoxaban Group, Dalteparin Group
	Comments	The HR, 2-sided CI, and p-value are based on the Cox proportional hazard model including treatment and the 2 stratification factors as covariates: the dichotomized bleeding risk and the dichotomized dose-adjustment factor.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4199
	Comments
	Method	Cox proportional hazard
	Comments
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	1.08
	Confidence Interval	(2-Sided) 95%; 0.898 to 1.293
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	12 months
Arm/Group Title	Edoxaban Group		Dalteparin Group
Arm/Group Description	After 5 days of low molecular weight heparin (LMWH), participants received edoxaban treatment daily		Participants received dalteparin daily
All Cause Mortality
	Edoxaban Group		Dalteparin Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	206/522 (39.5%)		192/524 (36.6%)
Serious Adverse Events
	Edoxaban Group		Dalteparin Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	276/522 (52.9%)		251/524 (47.9%)
Blood and lymphatic system disorders
Anaemia	4/522 (0.8%)	4	2/524 (0.4%)	2
Disseminated intravascular coagulation	0/522 (0%)	0	1/524 (0.2%)	1
Heparin-induced thrombocytopenia	0/522 (0%)	0	4/524 (0.8%)	4
Immune thrombocytopenic purpura	1/522 (0.2%)	1	0/524 (0%)	0
Cardiac disorders
Acute coronary syndrome	1/522 (0.2%)	1	0/524 (0%)	0
Acute myocardial infarction	1/522 (0.2%)	1	1/524 (0.2%)	1
Angina pectoris	1/522 (0.2%)	1	0/524 (0%)	0
Atrial fibrillation	3/522 (0.6%)	3	0/524 (0%)	0
Atrial flutter	0/522 (0%)	0	1/524 (0.2%)	1
Cardiac arrest	1/522 (0.2%)	1	3/524 (0.6%)	3
Cardiac failure	2/522 (0.4%)	2	0/524 (0%)	0
Cardiac failure congestive	2/522 (0.4%)	2	0/524 (0%)	0
Cardiac tamponade	0/522 (0%)	0	1/524 (0.2%)	1
Cardiopulmonary failure	1/522 (0.2%)	1	1/524 (0.2%)	1
Cardiovascular disorder	1/522 (0.2%)	1	0/524 (0%)	0
Intracardiac mass	1/522 (0.2%)	1	0/524 (0%)	0
Ischaemic cardiomyopathy	1/522 (0.2%)	1	0/524 (0%)	0
Myocardial infarction	1/522 (0.2%)	1	3/524 (0.6%)	3
Pulseless electrical activity	0/522 (0%)	0	1/524 (0.2%)	1
Tachycardia	0/522 (0%)	0	1/524 (0.2%)	1
Congenital, familial and genetic disorders
Atrial septal defect	1/522 (0.2%)	1	0/524 (0%)	0
Gastrointestinal disorders
Abdominal incarcerated hernia	1/522 (0.2%)	1	0/524 (0%)	0
Abdominal wall haematoma	1/522 (0.2%)	1	0/524 (0%)	0
Colonic fistula	0/522 (0%)	0	1/524 (0.2%)	1
Diarrhoea	1/522 (0.2%)	1	0/524 (0%)	0
Dysphagia	1/522 (0.2%)	1	0/524 (0%)	0
Faecaloma	0/522 (0%)	0	1/524 (0.2%)	1
Gastric ulcer	1/522 (0.2%)	1	0/524 (0%)	0
Gastrointestinal haemorrhage	11/522 (2.1%)	12	3/524 (0.6%)	3
Haematemesis	0/522 (0%)	0	1/524 (0.2%)	1
Haematochezia	0/522 (0%)	0	2/524 (0.4%)	2
Haemorrhoidal haemorrhage	1/522 (0.2%)	1	0/524 (0%)	0
Ileal stenosis	1/522 (0.2%)	1	0/524 (0%)	0
Ileus	1/522 (0.2%)	1	0/524 (0%)	0
Intestinal obstruction	1/522 (0.2%)	1	1/524 (0.2%)	1
Intra-abdominal haemorrhage	1/522 (0.2%)	1	0/524 (0%)	0
Lower gastrointestinal haemorrhage	2/522 (0.4%)	2	1/524 (0.2%)	1
Melaena	4/522 (0.8%)	4	0/524 (0%)	0
Peptic ulcer	0/522 (0%)	0	1/524 (0.2%)	1
Peritoneal haemorrhage	0/522 (0%)	0	1/524 (0.2%)	1
Rectal haemorrhage	5/522 (1%)	5	0/524 (0%)	0
Retroperitoneal haematoma	0/522 (0%)	0	1/524 (0.2%)	1
Retroperitoneal haemorrhage	1/522 (0.2%)	1	1/524 (0.2%)	1
Small intestinal obstruction	1/522 (0.2%)	1	0/524 (0%)	0
Upper gastrointestinal haemorrhage	4/522 (0.8%)	6	0/524 (0%)	0
Vomiting	0/522 (0%)	0	1/524 (0.2%)	1
General disorders
Adverse drug reaction	0/522 (0%)	0	1/524 (0.2%)	1
Asthenia	1/522 (0.2%)	1	1/524 (0.2%)	1
Catheter site haemorrhage	0/522 (0%)	0	1/524 (0.2%)	1
Chest pain	1/522 (0.2%)	1	1/524 (0.2%)	2
Death	4/522 (0.8%)	4	4/524 (0.8%)	4
Disease progression	4/522 (0.8%)	4	2/524 (0.4%)	2
Euthanasia	1/522 (0.2%)	1	0/524 (0%)	0
Fatigue	0/522 (0%)	0	1/524 (0.2%)	1
General physical health deterioration	0/522 (0%)	0	1/524 (0.2%)	1
Malaise	0/522 (0%)	0	1/524 (0.2%)	1
Multi-organ failure	2/522 (0.4%)	2	3/524 (0.6%)	3
Oedema peripheral	1/522 (0.2%)	1	0/524 (0%)	0
Peripheral swelling	0/522 (0%)	0	1/524 (0.2%)	1
Pyrexia	3/522 (0.6%)	3	0/524 (0%)	0
Sudden death	1/522 (0.2%)	1	0/524 (0%)	0
Systemic inflammatory response syndrome	0/522 (0%)	0	1/524 (0.2%)	1
Hepatobiliary disorders
Acute hepatic failure	1/522 (0.2%)	1	0/524 (0%)	0
Bile duct stenosis	1/522 (0.2%)	1	0/524 (0%)	0
Cholangitis	0/522 (0%)	0	1/524 (0.2%)	1
Cholecystitis	1/522 (0.2%)	1	0/524 (0%)	0
Hepatic function abnormal	1/522 (0.2%)	1	0/524 (0%)	0
Portal vein thrombosis	1/522 (0.2%)	1	0/524 (0%)	0
Infections and infestations
Abscess limb	1/522 (0.2%)	1	0/524 (0%)	0
Appendicitis	1/522 (0.2%)	1	0/524 (0%)	0
Bronchitis	0/522 (0%)	0	1/524 (0.2%)	1
Campylobacter gastroenteritis	1/522 (0.2%)	1	0/524 (0%)	0
Cellulitis	2/522 (0.4%)	4	2/524 (0.4%)	2
Erysipelas	0/522 (0%)	0	1/524 (0.2%)	1
Gastroenteritis	1/522 (0.2%)	1	0/524 (0%)	0
Infection	0/522 (0%)	0	1/524 (0.2%)	1
Infectious pleural effusion	0/522 (0%)	0	1/524 (0.2%)	1
Influenza	1/522 (0.2%)	1	0/524 (0%)	0
Lower respiratory tract infection	1/522 (0.2%)	1	1/524 (0.2%)	1
Lower respiratory tract infection bacterial	0/522 (0%)	0	1/524 (0.2%)	1
Lung infection	0/522 (0%)	0	1/524 (0.2%)	1
Meningococcal sepsis	1/522 (0.2%)	1	0/524 (0%)	0
Pneumonia	16/522 (3.1%)	17	13/524 (2.5%)	13
Pneumonia bacterial	1/522 (0.2%)	1	0/524 (0%)	0
Pneumonia viral	1/522 (0.2%)	1	0/524 (0%)	0
Post procedural sepsis	0/522 (0%)	0	1/524 (0.2%)	1
Postoperative abscess	0/522 (0%)	0	1/524 (0.2%)	1
Pyelonephritis	0/522 (0%)	0	3/524 (0.6%)	3
Respiratory syncytial virus infection	0/522 (0%)	0	1/524 (0.2%)	1
Sepsis	4/522 (0.8%)	4	7/524 (1.3%)	7
Septic shock	3/522 (0.6%)	3	1/524 (0.2%)	1
Staphylococcal sepsis	1/522 (0.2%)	1	0/524 (0%)	0
Subcutaneous abscess	1/522 (0.2%)	1	0/524 (0%)	0
Subdiaphragmatic abscess	0/522 (0%)	0	1/524 (0.2%)	1
Urinary tract infection	1/522 (0.2%)	1	4/524 (0.8%)	4
Urosepsis	1/522 (0.2%)	1	0/524 (0%)	0
Injury, poisoning and procedural complications
Ankle fracture	1/522 (0.2%)	1	0/524 (0%)	0
Fall	0/522 (0%)	0	3/524 (0.6%)	3
Femur fracture	2/522 (0.4%)	2	1/524 (0.2%)	1
Foot fracture	1/522 (0.2%)	1	0/524 (0%)	0
Head injury	1/522 (0.2%)	1	0/524 (0%)	0
Post procedural haematoma	0/522 (0%)	0	1/524 (0.2%)	1
Post procedural haematuria	0/522 (0%)	0	1/524 (0.2%)	1
Stoma site haemorrhage	1/522 (0.2%)	1	0/524 (0%)	0
Urinary tract stoma complication	0/522 (0%)	0	1/524 (0.2%)	1
Vascular procedure complication	0/522 (0%)	0	1/524 (0.2%)	1
Wound haemorrhage	1/522 (0.2%)	1	0/524 (0%)	0
Investigations
Creatinine renal clearance decreased	1/522 (0.2%)	1	0/524 (0%)	0
Hepatic enzyme increased	0/522 (0%)	0	3/524 (0.6%)	3
Transaminases increased	1/522 (0.2%)	1	0/524 (0%)	0
Metabolism and nutrition disorders
Cachexia	4/522 (0.8%)	4	2/524 (0.4%)	2
Dehydration	0/522 (0%)	0	1/524 (0.2%)	1
Diabetic ketoacidosis	0/522 (0%)	0	1/524 (0.2%)	1
Hyponatraemia	0/522 (0%)	0	1/524 (0.2%)	1
Musculoskeletal and connective tissue disorders
Muscle haemorrhage	0/522 (0%)	0	1/524 (0.2%)	1
Pain in extremity	1/522 (0.2%)	1	1/524 (0.2%)	1
Pathological fracture	0/522 (0%)	0	1/524 (0.2%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma	2/522 (0.4%)	2	3/524 (0.6%)	3
Adenocarcinoma gastric	2/522 (0.4%)	2	1/524 (0.2%)	1
Adenocarcinoma of colon	0/522 (0%)	0	1/524 (0.2%)	1
Adenocarcinoma pancreas	1/522 (0.2%)	1	0/524 (0%)	0
B-cell lymphoma	0/522 (0%)	0	1/524 (0.2%)	1
Bladder cancer	1/522 (0.2%)	1	0/524 (0%)	0
Brain cancer metastatic	0/522 (0%)	0	1/524 (0.2%)	1
Breast cancer	1/522 (0.2%)	1	0/524 (0%)	0
Breast cancer metastatic	0/522 (0%)	0	4/524 (0.8%)	4
Cervix cancer metastatic	1/522 (0.2%)	1	0/524 (0%)	0
Cholangiocarcinoma	2/522 (0.4%)	2	0/524 (0%)	0
Colon cancer	0/522 (0%)	0	1/524 (0.2%)	1
Colon cancer metastatic	2/522 (0.4%)	2	1/524 (0.2%)	1
Colorectal cancer	1/522 (0.2%)	1	1/524 (0.2%)	1
Colorectal cancer metastatic	2/522 (0.4%)	2	1/524 (0.2%)	1
Endometrial adenocarcinoma	1/522 (0.2%)	1	1/524 (0.2%)	1
Endometrial cancer	2/522 (0.4%)	2	2/524 (0.4%)	2
Endometrial cancer metastatic	1/522 (0.2%)	1	3/524 (0.6%)	3
Gallbladder cancer	1/522 (0.2%)	1	0/524 (0%)	0
Gastric cancer	2/522 (0.4%)	2	0/524 (0%)	0
Glioblastoma	1/522 (0.2%)	1	1/524 (0.2%)	1
Huerthle cell carcinoma	1/522 (0.2%)	1	0/524 (0%)	0
Liposarcoma	0/522 (0%)	0	1/524 (0.2%)	1
Lung adenocarcinoma	1/522 (0.2%)	1	1/524 (0.2%)	1
Lung adenocarcinoma metastatic	3/522 (0.6%)	3	2/524 (0.4%)	2
Lung cancer metastatic	3/522 (0.6%)	3	4/524 (0.8%)	4
Lung neoplasm malignant	8/522 (1.5%)	8	6/524 (1.1%)	6
Malignant neoplasm of unknown primary site	1/522 (0.2%)	1	1/524 (0.2%)	1
Malignant anorectal neoplasm	1/522 (0.2%)	1	0/524 (0%)	0
Malignant neoplasm progression	69/522 (13.2%)	69	67/524 (12.8%)	67
Metastases to central nervous system	3/522 (0.6%)	3	2/524 (0.4%)	2
Metastases to liver	0/522 (0%)	0	1/524 (0.2%)	1
Metastases to lung	0/522 (0%)	0	1/524 (0.2%)	1
Metastases to lymph nodes	0/522 (0%)	0	1/524 (0.2%)	1
Metastases to rectum	0/522 (0%)	0	1/524 (0.2%)	1
Metastatic carcinoma of the bladder	2/522 (0.4%)	2	0/524 (0%)	0
Metastatic neoplasm	1/522 (0.2%)	1	2/524 (0.4%)	2
Myelodysplastic syndrome	0/522 (0%)	0	1/524 (0.2%)	1
Neoplasm malignant	1/522 (0.2%)	1	2/524 (0.4%)	2
Neoplasm progression	24/522 (4.6%)	24	21/524 (4%)	21
Non-small cell lung cancer	2/522 (0.4%)	2	2/524 (0.4%)	2
Non-small cell lung cancer metastatic	0/522 (0%)	0	1/524 (0.2%)	1
Ovarian cancer	0/522 (0%)	0	3/524 (0.6%)	3
Ovarian cancer metastatic	1/522 (0.2%)	1	0/524 (0%)	0
Pancreatic carcinoma	4/522 (0.8%)	4	0/524 (0%)	0
Pancreatic carcinoma metastatic	2/522 (0.4%)	2	3/524 (0.6%)	3
Plasma cell myeloma	0/522 (0%)	0	1/524 (0.2%)	1
Prostate cancer	0/522 (0%)	0	3/524 (0.6%)	3
Prostate cancer metastatic	3/522 (0.6%)	3	0/524 (0%)	0
Rectal adenocarcinoma	0/522 (0%)	0	1/524 (0.2%)	1
Rectal cancer metastatic	1/522 (0.2%)	1	0/524 (0%)	0
Renal cancer	1/522 (0.2%)	1	0/524 (0%)	0
Renal cancer metastatic	1/522 (0.2%)	1	0/524 (0%)	0
Renal cell carcinoma	0/522 (0%)	0	1/524 (0.2%)	1
Sarcoma	1/522 (0.2%)	1	0/524 (0%)	0
Small cell carcinoma	1/522 (0.2%)	1	0/524 (0%)	0
Squamous cell carcinoma	1/522 (0.2%)	1	0/524 (0%)	0
Transitional cell carcinoma	0/522 (0%)	0	1/524 (0.2%)	1
Tumour haemorrhage	0/522 (0%)	0	1/524 (0.2%)	1
Uterine cancer	1/522 (0.2%)	1	0/524 (0%)	0
Vulvar cancer	1/522 (0.2%)	1	0/524 (0%)	0
Nervous system disorders
Altered state of consciousness	0/522 (0%)	0	1/524 (0.2%)	1
Basal ganglia haemorrhage	1/522 (0.2%)	1	0/524 (0%)	0
Central nervous system haemorrhage	1/522 (0.2%)	1	0/524 (0%)	0
Cerebral haematoma	0/522 (0%)	0	1/524 (0.2%)	1
Cerebral haemorrhage	2/522 (0.4%)	2	1/524 (0.2%)	1
Cerebral infarction	2/522 (0.4%)	2	0/524 (0%)	0
Cerebrovascular accident	3/522 (0.6%)	3	4/524 (0.8%)	4
Encephalopathy	1/522 (0.2%)	1	0/524 (0%)	0
Haemorrhage intracranial	2/522 (0.4%)	2	3/524 (0.6%)	3
Haemorrhagic stroke	1/522 (0.2%)	1	0/524 (0%)	0
Intracranial haematoma	1/522 (0.2%)	1	0/524 (0%)	0
Ischaemic stroke	6/522 (1.1%)	6	4/524 (0.8%)	4
Leukoencephalopathy	1/522 (0.2%)	1	0/524 (0%)	0
Loss of consciousness	0/522 (0%)	0	1/524 (0.2%)	1
Seizure	1/522 (0.2%)	1	0/524 (0%)	0
Spinal cord haemorrhage	0/522 (0%)	0	1/524 (0.2%)	1
Subarachnoid haemorrhage	0/522 (0%)	0	1/524 (0.2%)	2
Syncope	1/522 (0.2%)	1	0/524 (0%)	0
Thrombotic stroke	1/522 (0.2%)	1	0/524 (0%)	0
Transient ischaemic attack	2/522 (0.4%)	3	1/524 (0.2%)	1
VIIth nerve paralysis	0/522 (0%)	0	1/524 (0.2%)	1
Pregnancy, puerperium and perinatal conditions
Abortion spontaneous	1/522 (0.2%)	1	0/524 (0%)	0
Unintended pregnancy	1/522 (0.2%)	1	0/524 (0%)	0
Psychiatric disorders
Confusional state	1/522 (0.2%)	1	0/524 (0%)	0
Depression	0/522 (0%)	0	1/524 (0.2%)	1
Renal and urinary disorders
Acute kidney injury	0/522 (0%)	0	2/524 (0.4%)	2
Calculus bladder	1/522 (0.2%)	1	0/524 (0%)	0
Calculus ureteric	1/522 (0.2%)	1	0/524 (0%)	0
Haematuria	5/522 (1%)	6	4/524 (0.8%)	4
Hydronephrosis	0/522 (0%)	0	1/524 (0.2%)	1
Renal failure	2/522 (0.4%)	2	0/524 (0%)	0
Renal infarct	1/522 (0.2%)	1	0/524 (0%)	0
Reproductive system and breast disorders
Benign prostatic hyperplasia	0/522 (0%)	0	1/524 (0.2%)	1
Genital haemorrhage	1/522 (0.2%)	1	0/524 (0%)	0
Vaginal haemorrhage	2/522 (0.4%)	2	0/524 (0%)	0
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome	0/522 (0%)	0	1/524 (0.2%)	1
Acute respiratory failure	1/522 (0.2%)	1	2/524 (0.4%)	2
Asthma	0/522 (0%)	0	1/524 (0.2%)	1
Chronic obstructive pulmonary disease	1/522 (0.2%)	1	1/524 (0.2%)	3
Dyspnoea	3/522 (0.6%)	3	2/524 (0.4%)	2
Epistaxis	5/522 (1%)	6	1/524 (0.2%)	1
Haemoptysis	1/522 (0.2%)	1	3/524 (0.6%)	4
Haemothorax	1/522 (0.2%)	1	0/524 (0%)	0
Hyperventilation	0/522 (0%)	0	1/524 (0.2%)	1
Hypoxia	1/522 (0.2%)	1	0/524 (0%)	0
Interstitial lung disease	1/522 (0.2%)	1	0/524 (0%)	0
Laryngeal haemorrhage	1/522 (0.2%)	1	0/524 (0%)	0
Lung disorder	1/522 (0.2%)	1	0/524 (0%)	0
Lung infiltration	0/522 (0%)	0	1/524 (0.2%)	1
Pleural effusion	2/522 (0.4%)	2	1/524 (0.2%)	1
Pneumonitis	1/522 (0.2%)	1	0/524 (0%)	0
Pneumothorax	1/522 (0.2%)	1	0/524 (0%)	0
Pulmonary embolism	8/522 (1.5%)	9	16/524 (3.1%)	17
Pulmonary oedema	0/522 (0%)	0	1/524 (0.2%)	1
Respiratory arrest	0/522 (0%)	0	1/524 (0.2%)	1
Respiratory failure	7/522 (1.3%)	7	6/524 (1.1%)	6
Skin and subcutaneous tissue disorders
Drug eruption	1/522 (0.2%)	1	0/524 (0%)	0
Rash	0/522 (0%)	0	1/524 (0.2%)	1
Stevens-Johnson syndrome	0/522 (0%)	0	1/524 (0.2%)	1
Vascular disorders
Aortic aneurysm	1/522 (0.2%)	1	0/524 (0%)	0
Arterial haemorrhage	0/522 (0%)	0	1/524 (0.2%)	1
Deep vein thrombosis	13/522 (2.5%)	13	8/524 (1.5%)	8
Embolism arterial	1/522 (0.2%)	1	0/524 (0%)	0
Femoral artery embolism	1/522 (0.2%)	1	0/524 (0%)	0
Haematoma	1/522 (0.2%)	1	2/524 (0.4%)	2
Hypertension	1/522 (0.2%)	1	0/524 (0%)	0
Peripheral ischaemia	1/522 (0.2%)	2	0/524 (0%)	0
Thrombophlebitis superficial	1/522 (0.2%)	1	0/524 (0%)	0
Venous thrombosis	1/522 (0.2%)	1	1/524 (0.2%)	1
Other (Not Including Serious) Adverse Events
	Edoxaban Group		Dalteparin Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	75/522 (14.4%)		67/524 (12.8%)
Respiratory, thoracic and mediastinal disorders
Epistaxis	41/522 (7.9%)	44	30/524 (5.7%)	42
Vascular disorders
Deep vein thrombosis	34/522 (6.5%)	40	37/524 (7.1%)	45

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.