Late Phase 2 Study of DU-176b in Patients With Non-Valvular Atrial Fibrillation

• Sponsor: Daiichi Sankyo Co., Ltd. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00829933
• Collaborator: (none)
• Enrollment: 536
• Location: 1
• Arms: 4
• Duration (Months): 18.1
• Patients Per Site Per Month: 29.7

Study Details

Study Description

Brief Summary

The primary objective of this study is to compare the incidence of hemorrhagic events in patients treated for non-valvular atrial fibrillation with DU-176b at each dose level versus warfarin potassium (warfarin). The secondary objective includes between-group comparisons with regard to incidence of thromboembolic events, pharmacodynamic parameters, and biomarkers for the efficacy evaluation, as well as incidence of adverse events and adverse reaction for the safety evaluation.

Condition or Disease	Intervention/Treatment	Phase
Atrial Fibrillation	Drug: DU-176b tablets; Drug: Warfarin potassium tablets	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 536 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: A Randomized Dose-ranging Controlled Trial of DU-176b Versus Warfarin Potassium in Patients With Non-valvular Atrial Fibrillation
• Study Start Date: Mar 1, 2007
• Actual Primary Completion Date: Jul 1, 2008
• Actual Study Completion Date: Sep 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1 DU-176b low dose	Drug: DU-176b tablets; DU-176b tablets taken once daily for up to 12 weeks
Experimental: 2 DU-176b intermediate dose	Drug: DU-176b tablets; DU-176b tablets taken once daily for up to 12 weeks
Experimental: 3 DU-176b high dose	Drug: DU-176b tablets; DU-176b tablets taken once daily for up to 12 weeks
Active Comparator: 4 Warfarin	Drug: Warfarin potassium tablets; Warfarin potassium tablets taken once daily for up to 12 weeks

Outcome Measures

Primary Outcome Measures

1. Incidence of Bleeding Events (Major Bleeding, Clinically Relevant Non-major Bleeding and Minor Bleeding ) Identified During the Period From the Entry Into the Treatment Period Until Completion or Termination of the Treatment. [12 weeks]

   The primary endpoint was the incidence of bleeding events (major bleeding, clinically relevant non-major bleeding, or minor bleeding) that occurred during the treatment period.

Secondary Outcome Measures

1. Incidence of Thromboembolic Events (Cerebral Infarction and Systemic Embolism) Identified During the Period From the Entry to the Treatment Period Until Completion or Termination of the Treatment. [12 weeks]

2. Incidence of Adverse Events and Adverse Reactions Identified During the Period From the Entry to the Treatment Period Until Completion or Termination of the Treatment [12 weeks]

3. Pharmacodynamic Parameters (PT, PT-INR, and APTT) [12 weeks]

   PT - prothrombin time INR - International Normalized Ratio APTT - Activated Partial Thromboplastin time

4. Plasma DU-176 Concentration [12 weeks]

5. Pharmacodynamic Biomarkers (F1+2, TAT, and D-dimer ) [12 weeks]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 20 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients with non-valvular atrial fibrillation who meet all of the following requirements will be considered for admission to the study:

• Age≧20years

• Atrial fibrillation confirmed by at least 2 electrocardiographic(ECG) tracings taken at an interval of ≧1week during the year before enrollment

• Presence of any (at least )one of the following risk factors for embolism:

• Hypertension

• Diabetes mellitus

• Congestive heart failure

• Previous transient ischemic attack (TIA) or cerebral infarction (more than 30 days before giving informed consent )

• Age≧75 years

• At time of giving informed consent.

• To be confirmed on ECG charts, etc.

Exclusion Criteria:

• Presence of any of the following conditions with increased risk of hemorrhage:

• History of intracranial, intraocular (excluding bleeding beneath the bulbar conjunctiva ), intrathecal, retroperitoneal, or non-traumatic intraarticular hemorrhage

• History of gastrointestinal hemorrhage during the year before giving informed consent

• History of peptic ulcers during the 90 days before giving informed consent

• Surgical treatment or trauma requiring hospitalization during the 30 days before giving informed consent

• Hemoglobin level <10 g/dL platelet count <10 ×10000 /μL at screening examinations

• Active hemorrhage* present at giving informed consent or at enrollment

• Any invasive therapeutic or diagnostic procedure (e.g., surgery, tissue, biopsy, and tooth extraction) scheduled during the period from the time of informed consent until completion of the trial treatment.

• Any congenital hemorrhagic disease

• History of cerebral infarction or TIA within 30 days before giving informed consent

• Current treatment with any anticoagulant(other than warfarin)

• Concurrent rheumatic valvular disease

• History of valvular surgery

• Concurrent infectious endocarditis

• Concurrent cardiac myxoma

• Confirmed left ventricular or left atrial thrombosis

• Any congenital condition with a tendency toward thrombosis

• Electrical or pharmacological defibrillation scheduled during the trial treatment

• Uncontrolled hypertension (persistently high systolic ［>160mmHg］or diastolic [>100mmHg] pressure)

• Uncontrolled diabetes mellitus

• Renal or hepatic dysfunction (as defined below ), confirmed at screening examinations

• Serum creatinine>1.5mg/dL

• AST(GOT)or ALT(GPT)≧twice the upper limit of the reference range

• Total bilirubin ≧twice the upper limit of the reference range

• Current antiplatelet therapy for any concomitant illness that may be aggravated after discontinuation of the therapy.

• Any concurrent severe cardiac disease

• Known allergy to warfarin or any condition contraindicating its use

• Inability to discontinue current treatment with vitamin K

• Confirmed or potential pregnancy, wish to become pregnant during the study period, or current breast feeding

• Previous treatment with DU-176b

• Participation in a trial of any other drug during the 6 month before giving informed consent

• Any other condition that disqualifies the patient for the study in the opinion of the investigator/subinvestigator *This includes ecchymosis identified as at least one hematoma sized ≧5 cm in longer diameter, macroscopic hematuria, and microscopic hematuria defined as a ≧2+test or a 1+ test for occult blood with a urine sediment containing ≧10 red cells per high-power field (except for a 2+ occult blood test persisting for 1 year before giving informed consent).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Tokyo		Japan

Sponsors and Collaborators

• Daiichi Sankyo Co., Ltd.

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Daiichi Sankyo Co., Ltd.
• ClinicalTrials.gov Identifier: NCT00829933
• Other Study ID Numbers: DU176b-C-J225
• First Posted: Jan 27, 2009
• Last Update Posted: Feb 25, 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.: Atrial fibrillation; Factor Xa inhibition
• Additional relevant MeSH terms: Atrial Fibrillation; Warfarin; Edoxaban

Study Results

Participant Flow

Arm/Group Title	DU-176b Low Dose 30mg	DU-176b Intermediate Dose 45mg	DU-176b High Dose 60mg	Warfarin
Arm/Group Description	DU-176b tablets: DU-176b tablets taken once daily for 12 weeks	DU-176b tablets: DU-176b tablets taken once daily for 12 weeks	DU-176b tablets: DU-176b tablets taken once daily for 12 weeks	Warfarin potassium tablets: Warfarin potassium tablets taken once daily for 12 weeks while adjusting dose
Period Title: Overall Study
STARTED	135	135	132	134
Baseline Analysis Population	131	134	131	129
COMPLETED	121	122	119	120
NOT COMPLETED	14	13	13	14

Baseline Characteristics

Arm/Group Title	DU-176b Low Dose 30mg	DU-176b Intermediate Dose 45mg	DU-176b High Dose 60mg	Warfarin	Total
Arm/Group Description	DU-176b tablets taken once daily for 12 weeks	DU-176b tablets taken once daily for 12 weeks	DU-176b tablets taken once daily for 12 weeks	Warfarin potassium tablets taken once daily for 12 weeks while adjusting dose	Total of all reporting groups
Overall Participants	131	134	131	129	525
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	69.4 (7.5)	69.5 (8.8)	68.4 (8.2)	68.8 (8.2)	69.0 (8.2)
Sex: Female, Male (Count of Participants)
Female	21 16%	25 18.7%	24 18.3%	22 17.1%	92 17.5%
Male	110 84%	109 81.3%	107 81.7%	107 82.9%	433 82.5%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	131 100%	134 100%	131 100%	129 100%	525 100%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%	0 0%	0 0%
White	0 0%	0 0%	0 0%	0 0%	0 0%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
Japan	131 100%	134 100%	131 100%	129 100%	525 100%

Outcome Measures

1. Primary Outcome

Title	Incidence of Bleeding Events (Major Bleeding, Clinically Relevant Non-major Bleeding and Minor Bleeding ) Identified During the Period From the Entry Into the Treatment Period Until Completion or Termination of the Treatment.
Description	The primary endpoint was the incidence of bleeding events (major bleeding, clinically relevant non-major bleeding, or minor bleeding) that occurred during the treatment period.
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

Primary endpoint analyzed for subjects who proceeded to treatment period in FAS.

Arm/Group Title	DU-176b Low Dose 30mg	DU-176b Intermediate Dose 45mg	DU-176b High Dose 60mg	Warfarin
Arm/Group Description	DU-176b tablets taken once daily for 12 weeks	DU-176b tablets taken once daily for 12 weeks	DU-176b tablets taken once daily for 12 weeks	Warfarin potassium tablets taken once daily for 12 weeks while adjusting dose
Measure Participants	130	134	130	125
Number (95% Confidence Interval) [percent of subjects with bleeding event]	18.5	22.4	27.7	20.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	DU-176b Low Dose 30mg, DU-176b Intermediate Dose 45mg
	Comments	For the incidence of bleeding events, paired comparison between the DU-176b groups was performed using the χ2 test.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.429
	Comments
	Method	Chi-squared
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	DU-176b Low Dose 30mg, DU-176b High Dose 60mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.077
	Comments
	Method	Chi-squared
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	DU-176b Low Dose 30mg, Warfarin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	-1.5
	Confidence Interval	(2-Sided) 95%; -11.2 to 8.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	DU-176b Intermediate Dose 45mg, DU-176b High Dose 60mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.320
	Comments
	Method	Chi-squared
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	DU-176b Intermediate Dose 45mg, Warfarin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	2.4
	Confidence Interval	(2-Sided) 95%; -7.6 to 12.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	DU-176b High Dose 60mg, Warfarin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	7.7
	Confidence Interval	(2-Sided) 95%; -2.7 to 18.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Incidence of Thromboembolic Events (Cerebral Infarction and Systemic Embolism) Identified During the Period From the Entry to the Treatment Period Until Completion or Termination of the Treatment.
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

3. Secondary Outcome

Title	Incidence of Adverse Events and Adverse Reactions Identified During the Period From the Entry to the Treatment Period Until Completion or Termination of the Treatment
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

4. Secondary Outcome

Title	Pharmacodynamic Parameters (PT, PT-INR, and APTT)
Description	PT - prothrombin time INR - International Normalized Ratio APTT - Activated Partial Thromboplastin time
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

5. Secondary Outcome

Title	Plasma DU-176 Concentration
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

6. Secondary Outcome

Title	Pharmacodynamic Biomarkers (F1+2, TAT, and D-dimer )
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Arm/Group Title	DU-176b Low Dose 30mg		DU-176b Intermediate Dose 45mg		DU-176b High Dose 60mg		Warfarin
Arm/Group Description	DU-176b tablets taken once daily for 12 weeks		DU-176b tablets taken once daily for 12 weeks		DU-176b tablets taken once daily for 12 weeks		Warfarin potassium tablets taken once daily for 12 weeks while adjusting dose
All Cause Mortality
	DU-176b Low Dose 30mg		DU-176b Intermediate Dose 45mg		DU-176b High Dose 60mg		Warfarin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	DU-176b Low Dose 30mg		DU-176b Intermediate Dose 45mg		DU-176b High Dose 60mg		Warfarin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/130 (3.1%)		2/134 (1.5%)		2/130 (1.5%)		7/125 (5.6%)
Cardiac disorders
atrial fibrillation	1/130 (0.8%)	1	0/134 (0%)	0	0/130 (0%)	0	0/125 (0%)	0
cardiac failure	0/130 (0%)	0	0/134 (0%)	0	0/130 (0%)	0	1/125 (0.8%)	1
cardiac failure congestive	0/130 (0%)	0	0/134 (0%)	0	0/130 (0%)	0	1/125 (0.8%)	1
General disorders
sudden death	0/130 (0%)	0	0/134 (0%)	0	0/130 (0%)	0	1/125 (0.8%)	1
Infections and infestations
upper respiratory tract infection	0/130 (0%)	0	0/134 (0%)	0	0/130 (0%)	0	1/125 (0.8%)	1
Injury, poisoning and procedural complications
tooth fracture	1/130 (0.8%)	1	0/134 (0%)	0	0/130 (0%)	0	0/125 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
colon cancer	0/130 (0%)	0	1/134 (0.7%)	1	0/130 (0%)	0	0/125 (0%)	0
metastases to spine	0/130 (0%)	0	0/134 (0%)	0	0/130 (0%)	0	1/125 (0.8%)	1
Nervous system disorders
cerebral haemorrhage	0/130 (0%)	0	0/134 (0%)	0	1/130 (0.8%)	1	0/125 (0%)	0
cerebral infarction	0/130 (0%)	0	1/134 (0.7%)	1	0/130 (0%)	0	0/125 (0%)	0
transient ischemic attack	1/130 (0.8%)	1	0/134 (0%)	0	0/130 (0%)	0	0/125 (0%)	0
Renal and urinary disorders
haematuria	0/130 (0%)	0	0/134 (0%)	0	1/130 (0.8%)	1	0/125 (0%)	0
nephrotic syndrome	0/130 (0%)	0	0/134 (0%)	0	0/130 (0%)	0	1/125 (0.8%)	1
Reproductive system and breast disorders
benign prostatic hyperplasia	0/130 (0%)	0	0/134 (0%)	0	0/130 (0%)	0	1/125 (0.8%)	1
Respiratory, thoracic and mediastinal disorders
interstitial lung disease	1/130 (0.8%)	1	0/134 (0%)	0	0/130 (0%)	0	0/125 (0%)	0
Other (Not Including Serious) Adverse Events
	DU-176b Low Dose 30mg		DU-176b Intermediate Dose 45mg		DU-176b High Dose 60mg		Warfarin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	85/130 (65.4%)		103/134 (76.9%)		103/130 (79.2%)		88/125 (70.4%)
Eye disorders
Conjunctival haemorrhage	0/130 (0%)	0	1/134 (0.7%)	1	4/130 (3.1%)	5	0/125 (0%)	0
Gastrointestinal disorders
Gingival bleeding	4/130 (3.1%)	6	3/134 (2.2%)	3	5/130 (3.8%)	5	5/125 (4%)	5
Haemorrhoidal haemorrhage	4/130 (3.1%)	6	3/134 (2.2%)	3	5/130 (3.8%)	5	5/125 (4%)	5
Infections and infestations
nasopharyngitis	19/130 (14.6%)	19	25/134 (18.7%)	27	14/130 (10.8%)	15	18/125 (14.4%)	19
Investigations
Aspartate aminotransferase increased	6/130 (4.6%)	6	8/134 (6%)	8	4/130 (3.1%)	4	2/125 (1.6%)	2
Blood triglycerides increased	1/130 (0.8%)	1	5/134 (3.7%)	5	5/130 (3.8%)	5	9/125 (7.2%)	10
Gamma-glutamyltransferase increased	7/130 (5.4%)	7	8/134 (6%)	8	7/130 (5.4%)	7	4/125 (3.2%)	4
glucose urine present	5/130 (3.8%)	6	9/134 (6.7%)	10	6/130 (4.6%)	6	7/125 (5.6%)	8
glood urine present	17/130 (13.1%)	19	24/134 (17.9%)	26	30/130 (23.1%)	33	18/125 (14.4%)	20
protein urine present	3/130 (2.3%)	3	6/134 (4.5%)	6	3/130 (2.3%)	3	8/125 (6.4%)	8
Alanine aminotransferase increased	5/130 (3.8%)	5	5/134 (3.7%)	5	4/130 (3.1%)	4	1/125 (0.8%)	1
Blood bilirubin increased	1/130 (0.8%)	1	2/134 (1.5%)	2	4/130 (3.1%)	4	2/125 (1.6%)	2
Eosinophil count increased	1/130 (0.8%)	1	3/134 (2.2%)	3	4/130 (3.1%)	4	3/125 (2.4%)	3
Platelet count decreased	2/130 (1.5%)	2	5/134 (3.7%)	5	0/130 (0%)	0	0/125 (0%)	0
Blood alkaline phosphatase increased	1/130 (0.8%)	1	4/134 (3%)	4	0/130 (0%)	0	2/125 (1.6%)	2
Respiratory, thoracic and mediastinal disorders
epistaxis	7/130 (5.4%)	7	13/134 (9.7%)	14	16/130 (12.3%)	17	6/125 (4.8%)	7
Skin and subcutaneous tissue disorders
Haemorrhage subcutaneous	7/130 (5.4%)	8	6/134 (4.5%)	7	8/130 (6.2%)	12	6/125 (4.8%)	16

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.