Study on Safety and Effectiveness of Three Doses of Argatroban as Anticoagulant in Percutaneous Coronary Intervention (PCI)

• Sponsor: Mitsubishi Tanabe Pharma Corporation (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00508924
• Collaborator: (none)
• Enrollment: 140
• Locations: 8
• Arms: 4
• Duration (Months): 14
• Patients Per Site: 17.5
• Patients Per Site Per Month: 1.3

Study Details

Study Description

Brief Summary

This is a phase II multi-centre study in 140 patients undergoing elective PCI to obtain the information on dose-response of argatroban in pharmacodynamic markers and to assess the anticoagulation, safety and efficacy of argatroban in reference to unfractionated heparin, in combination with dual antiplatelet therapy.

Condition or Disease	Intervention/Treatment	Phase
Coronary Artery Disease; Angina, Unstable	Drug: Argatroban; Drug: Argatroban; Drug: Argatroban; Drug: Heparin	Phase 2

Detailed Description

This is a phase II multi-centre study in Europe in patients with stable coronary artery disease or troponin negative unstable angina undergoing elective PCI, to obtain the information on the safety and effects on various pharmacodynamic markers, of three doses of argatroban in combination with clopidogrel and aspirin, and to assess the results of argatroban and unfractionated heparin, both used in combination with clopidogrel and aspirin, on clinical outcomes, adequacy of anticoagulation, various pharmacodynamic markers (approximately 35 patients per group).

Study Design

• Study Type: Interventional
• Actual Enrollment: 140 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomised, Open, Parallel-group, Multicentre Study to Examine the Safety and Effectiveness of Three Doses of Argatroban as Anticoagulant in Combination With Clopidogrel and Aspirin in Patients Undergoing Elective Percutaneous Coronary Intervention in Comparison With Unfractionated Heparin, Clopidogrel and Aspirin
• Study Start Date: Aug 1, 2005
• Actual Study Completion Date: Oct 1, 2006

Arms and Interventions

Arm	Intervention/Treatment
Experimental: ARG250	Drug: Argatroban
Experimental: ARG300	Drug: Argatroban
Experimental: ARG350	Drug: Argatroban
Placebo Comparator: Heparin	Drug: Heparin

Outcome Measures

Primary Outcome Measures

1. Activated Clotting Time (ACT) Value After the First Dosing of Study Treatment. [5 - 10 min after initial bolus]

2. Composite and Each of Death, Myocardial Infarction, and Urgent Revascularisation at Day 30, and Major Bleeding Events During Hospital Stay. [30 Days]

   Composite end point (a): all cause death, myocardial infarction and urgent revascularization at Day30 Composite end point (b): all cause death, myocardial infarction and urgent revascularization at Day30 as well as major bleeding events during hospital stay

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 (women of child bearing potential must have a negative pregnancy test prior to entry into the study)

• Aged over 18 years

• Diagnosis of stable coronary artery disease (CAD) or unstable angina (troponin negative, i.e. within the normal range for the study site) with low to moderate anatomic risk and a requirement for elective percutaneous coronary angioplasty or stent insertion with an approved device in one or more de novo-treated or re-stenotic lesions in native vessels

• Signed written informed consent

Exclusion Criteria:

• Any condition which, in the investigator's opinion, contraindicates the use of argatroban, heparin or clopidogrel or endangers the patient if he/she participated in this study.

• Known cirrhosis, hepatitis, clinically significant hepatic disorder, or history of hepatic disorder. Hepatic disorder is defined as having levels of liver function tests (bilirubin, Aspartate Aminotransferase (Serum Glutamate Oxaloacetate Transaminase)(AST (SGOT)), Alanine Aminotransferase (Serum Glutamate Pyruvate Transaminase)(ALT (SGPT)) greater than 3.0 times above the upper limit of the normal range of local laboratory.

• Patients not currently taking aspirin

• Renal insufficiency, defined as serum creatinine greater than 2.0 mg/dL (greater than 177mmol/L)

• Platelets less than 125,000/ml

• If already taking any form of heparin prior to study enrolment, Activated Partial Thromboplastin Time(aPTT) equal or greater than 35 sec or ACT greater than 160 sec

• Use of low molecular heparin (LMWH) during 12 h prior to PCI

• If taking oral anticoagulant medication prior to study enrolment, International Normalised Ratio(INR) greater than 1.2

• Q wave MI with cardiogenic shock or thrombolytic therapy within 72 h of study dosing

• Use of Glycoprotein IIb / IIIa(GPIIb/IIIa) inhibitors within prior 3 weeks

• Documented coagulation disorder or bleeding diathesis

• Lumbar puncture within the past 2 weeks

• History of previous cerebral aneurysm, haemorrhagic stroke, or thrombotic stroke within the past 6 months

• Active, uncontrolled peptic ulcer disease or any gastrointestinal bleeding or genitourinary bleeding within 3 months prior to study enrolment

• Major surgery, serious trauma, puncture of non-compressible vessel, or biopsy of parenchymal organ within prior 2 months

• Planned staged procedure, planned rotational atherectomy, directional coronary atherectomy, brachytherapy, or thrombectomy catheters

• Planned surgical intervention other than study procedure within next 7 days

• Presence of greater than 50% stenosis of unprotected left main coronary artery

• Severe peripheral vascular disease, precluding femoral access

• History of vasculitis

• Uncontrolled hypertension defined as greater than 180/120 mmHg

• Pregnancy (exclusion by routine urine test)

• Lactating woman

• Woman of children bearing age who are or were not using accepted contraceptive methods

• Participation in other clinical trials of investigational products within 3 months prior to study enrolment

• Terminally ill patients with a life expectancy of < 3 months

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Aalst		Belgium
2		Bad Nauheim		Germany
3		Cologne		Germany
4		Dachau		Germany
5		Dueren		Germany
6		Frankfurt		Germany
7		Halle		Germany
8		Mainz		Germany

Sponsors and Collaborators

• Mitsubishi Tanabe Pharma Corporation

Investigators

• Principal Investigator: Professor, Information at Mitsubishi Pharma Europe

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• ClinicalTrials.gov Identifier: NCT00508924
• Other Study ID Numbers: ARG-E04
• First Posted: Jul 30, 2007
• Last Update Posted: Dec 5, 2012
• Last Verified: Nov 1, 2012

• Keywords provided by , ,: Argatroban; Direct thrombin inhibitor; Percutaneous coronary intervention; Activated clotting time; PCI; ACT
• Additional relevant MeSH terms: Coronary Artery Disease; Angina, Unstable; Heparin; Argatroban

Study Results

Participant Flow

Arm/Group Title	ARG250	ARG300	ARG350	Heparin
Arm/Group Description	250μg/kg i.v. bolus of argatroban followed by infusion of 15μg/kg/min additional 150μg/kg i.v. boluses (maximum 2 additional) could be given in order to reach the target ACT level of 250 sec	300μg/kg i.v. bolus followed by infusion of 20μg/kg/min additional 150μg/kg i.v. boluses (maximum 2 additional) could be given in order to reach the target ACT level of 250 sec	350μg/kg i.v. bolus followed by infusion of 25μg/kg/min additional 150μg/kg i.v. boluses (maximum 2 additional) could be given in order to reach the target ACT level of 250 sec	70-100 IU/kg i.v. bolus additional 2,000-5,000 IU boluses could be given in order to reach the target ACT level of 250 sec
Period Title: Overall Study
STARTED	36	38	32	34
COMPLETED	36	38	31	33
NOT COMPLETED	0	0	1	1

Baseline Characteristics

Arm/Group Title	ARG250	ARG300	ARG350	Heparin	Total
Arm/Group Description	250μg/kg i.v. bolus of argatroban followed by infusion of 15μg/kg/min additional 150μg/kg i.v. boluses (maximum 2 additional) could be given in order to reach the target ACT level of 250 sec	300μg/kg i.v. bolus followed by infusion of 20μg/kg/min additional 150μg/kg i.v. boluses (maximum 2 additional) could be given in order to reach the target ACT level of 250 sec	350μg/kg i.v. bolus followed by infusion of 25μg/kg/min additional 150μg/kg i.v. boluses (maximum 2 additional) could be given in order to reach the target ACT level of 250 sec	70-100 IU/kg i.v. bolus additional 2,000-5,000 IU boluses could be given in order to reach the target ACT level of 250 sec	Total of all reporting groups
Overall Participants	36	38	32	34	140
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	63.4 (8.9)	65.5 (9.5)	68.3 (7.9)	65.9 (9.8)	65.7 (9.2)
Sex: Female, Male (Count of Participants)
Female	11 30.6%	8 21.1%	9 28.1%	5 14.7%	33 23.6%
Male	25 69.4%	30 78.9%	23 71.9%	29 85.3%	107 76.4%

Outcome Measures

1. Primary Outcome

Title	Activated Clotting Time (ACT) Value After the First Dosing of Study Treatment.
Time Frame	5 - 10 min after initial bolus

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	ARG250	ARG300	ARG350	Heparin
Arm/Group Description	250μg/kg i.v. bolus of argatroban followed by infusion of 15μg/kg/min additional 150μg/kg i.v. boluses (maximum 2 additional) could be given in order to reach the target ACT level of 250 sec	300μg/kg i.v. bolus followed by infusion of 20μg/kg/min additional 150μg/kg i.v. boluses (maximum 2 additional) could be given in order to reach the target ACT level of 250 sec	350μg/kg i.v. bolus followed by infusion of 25μg/kg/min additional 150μg/kg i.v. boluses (maximum 2 additional) could be given in order to reach the target ACT level of 250 sec	70-100 IU/kg i.v. bolus additional 2,000-5,000 IU boluses could be given in order to reach the target ACT level of 250 sec
Measure Participants	36	38	31	33
Median (Inter-Quartile Range) [second]	301.0	330.0	354.0	237.5

2. Primary Outcome

Title	Composite and Each of Death, Myocardial Infarction, and Urgent Revascularisation at Day 30, and Major Bleeding Events During Hospital Stay.
Description	Composite end point (a): all cause death, myocardial infarction and urgent revascularization at Day30 Composite end point (b): all cause death, myocardial infarction and urgent revascularization at Day30 as well as major bleeding events during hospital stay
Time Frame	30 Days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	ARG250	ARG300	ARG350	Heparin
Arm/Group Description	250μg/kg i.v. bolus of argatroban followed by infusion of 15μg/kg/min additional 150μg/kg i.v. boluses (maximum 2 additional) could be given in order to reach the target ACT level of 250 sec	300μg/kg i.v. bolus followed by infusion of 20μg/kg/min additional 150μg/kg i.v. boluses (maximum 2 additional) could be given in order to reach the target ACT level of 250 sec	350μg/kg i.v. bolus followed by infusion of 25μg/kg/min additional 150μg/kg i.v. boluses (maximum 2 additional) could be given in order to reach the target ACT level of 250 sec	70-100 IU/kg i.v. bolus additional 2,000-5,000 IU boluses could be given in order to reach the target ACT level of 250 sec
Measure Participants	36	38	31	33
Composite end point (a)	1 2.8%	0 0%	1 3.1%	1 2.9%
Composite end point (b)	1 2.8%	0 0%	1 3.1%	2 5.9%
All cause death	0 0%	0 0%	0 0%	0 0%
Myocardial infarction	0 0%	0 0%	1 3.1%	1 2.9%
Urgent revascularization	1 2.8%	0 0%	1 3.1%	0 0%
Major bleeding	0 0%	0 0%	0 0%	1 2.9%

Adverse Events

Arm/Group Title	ARG250		ARG300		ARG350		Heparin
Arm/Group Description	250μg/kg i.v. bolus of argatroban followed by infusion of 15μg/kg/min additional 150μg/kg i.v. boluses (maximum 2 additional) could be given in order to reach the target ACT level of 250 sec		300μg/kg i.v. bolus followed by infusion of 20μg/kg/min additional 150μg/kg i.v. boluses (maximum 2 additional) could be given in order to reach the target ACT level of 250 sec		350μg/kg i.v. bolus followed by infusion of 25μg/kg/min additional 150μg/kg i.v. boluses (maximum 2 additional) could be given in order to reach the target ACT level of 250 sec		70-100 IU/kg i.v. bolus additional 2,000-5,000 IU boluses could be given in order to reach the target ACT level of 250 sec
All Cause Mortality
	ARG250		ARG300		ARG350		Heparin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	ARG250		ARG300		ARG350		Heparin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/36 (11.1%)		5/38 (13.2%)		7/32 (21.9%)		4/34 (11.8%)
Blood and lymphatic system disorders
Anaemia	0/36 (0%)		0/38 (0%)		0/32 (0%)		1/34 (2.9%)
Cardiac disorders
Acute myocardial infarction	0/36 (0%)		0/38 (0%)		0/32 (0%)		1/34 (2.9%)
Angina pectoris	0/36 (0%)		1/38 (2.6%)		0/32 (0%)		0/34 (0%)
Angina unstable	1/36 (2.8%)		0/38 (0%)		0/32 (0%)		0/34 (0%)
Artrial fibrillation	1/36 (2.8%)		0/38 (0%)		0/32 (0%)		0/34 (0%)
Coronary artery dissection	0/36 (0%)		0/38 (0%)		1/32 (3.1%)		0/34 (0%)
Coronary artery occlusion	1/36 (2.8%)		0/38 (0%)		0/32 (0%)		0/34 (0%)
Myocardial infarction	0/36 (0%)		0/38 (0%)		1/32 (3.1%)		0/34 (0%)
Gastrointestinal disorders
Abdominal pain upper	0/36 (0%)		0/38 (0%)		1/32 (3.1%)		0/34 (0%)
Retroperitoneal haematoma	0/36 (0%)		0/38 (0%)		0/32 (0%)		1/34 (2.9%)
General disorders
Catheter site haemorrhage	0/36 (0%)		0/38 (0%)		1/32 (3.1%)		0/34 (0%)
Chest pain	0/36 (0%)		1/38 (2.6%)		1/32 (3.1%)		0/34 (0%)
Immune system disorders
Hypersensitivity	0/36 (0%)		1/38 (2.6%)		0/32 (0%)		0/34 (0%)
Infections and infestations
Groin infection	0/36 (0%)		0/38 (0%)		0/32 (0%)		1/34 (2.9%)
Pneumonia	0/36 (0%)		0/38 (0%)		0/32 (0%)		1/34 (2.9%)
Injury, poisoning and procedural complications
Lower limb fracture	1/36 (2.8%)		0/38 (0%)		0/32 (0%)		0/34 (0%)
Musculoskeletal and connective tissue disorders
Rhabdomyolysis	0/36 (0%)		1/38 (2.6%)		0/32 (0%)		0/34 (0%)
Nervous system disorders
Basilar migraine	0/36 (0%)		0/38 (0%)		1/32 (3.1%)		0/34 (0%)
Cerebrovascular accident	0/36 (0%)		1/38 (2.6%)		0/32 (0%)		0/34 (0%)
Syncope	0/36 (0%)		0/38 (0%)		1/32 (3.1%)		0/34 (0%)
Psychiatric disorders
Panic attack	0/36 (0%)		1/38 (2.6%)		0/32 (0%)		0/34 (0%)
Vascular disorders
Peripheral ischaemia	1/36 (2.8%)		0/38 (0%)		0/32 (0%)		0/34 (0%)
Other (Not Including Serious) Adverse Events
	ARG250		ARG300		ARG350		Heparin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	22/36 (61.1%)		25/38 (65.8%)		23/32 (71.9%)		27/34 (79.4%)
Cardiac disorders
Angina pectoris	2/36 (5.6%)		3/38 (7.9%)		4/32 (12.5%)		4/34 (11.8%)
Bradycardia	0/36 (0%)		0/38 (0%)		0/32 (0%)		3/34 (8.8%)
Sinus bradycardia	0/36 (0%)		0/38 (0%)		2/32 (6.3%)		0/34 (0%)
Ear and labyrinth disorders
Vertigo	0/36 (0%)		3/38 (7.9%)		2/32 (6.3%)		1/34 (2.9%)
Gastrointestinal disorders
Abdominal pain	0/36 (0%)		2/38 (5.3%)		1/32 (3.1%)		0/34 (0%)
Nausea	1/36 (2.8%)		3/38 (7.9%)		3/32 (9.4%)		4/34 (11.8%)
General disorders
Catheter site haematoma	12/36 (33.3%)		9/38 (23.7%)		9/32 (28.1%)		10/34 (29.4%)
Catheter site haemorrhage	3/36 (8.3%)		0/38 (0%)		3/32 (9.4%)		2/34 (5.9%)
Catheter site pain	0/36 (0%)		0/38 (0%)		0/32 (0%)		2/34 (5.9%)
Chest pain	0/36 (0%)		2/38 (5.3%)		1/32 (3.1%)		3/34 (8.8%)
Pyrexia	0/36 (0%)		0/38 (0%)		0/32 (0%)		2/34 (5.9%)
Investigations
Cardiac enzymes increased	3/36 (8.3%)		1/38 (2.6%)		1/32 (3.1%)		0/34 (0%)
Haematocrit decreased	0/36 (0%)		1/38 (2.6%)		1/32 (3.1%)		3/34 (8.8%)
Haemoglobin decreased	1/36 (2.8%)		1/38 (2.6%)		2/32 (6.3%)		3/34 (8.8%)
Red blood cell count decreased	0/36 (0%)		0/38 (0%)		1/32 (3.1%)		3/34 (8.8%)
Troponin T increased	2/36 (5.6%)		2/38 (5.3%)		0/32 (0%)		0/34 (0%)
Metabolism and nutrition disorders
Hyperglycaemia	0/36 (0%)		0/38 (0%)		0/32 (0%)		2/34 (5.9%)
Hyponatraemia	0/36 (0%)		0/38 (0%)		2/32 (6.3%)		0/34 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/36 (2.8%)		0/38 (0%)		0/32 (0%)		3/34 (8.8%)
Back pain	2/36 (5.6%)		1/38 (2.6%)		3/32 (9.4%)		4/34 (11.8%)
Pain in extremity	1/36 (2.8%)		2/38 (5.3%)		0/32 (0%)		0/34 (0%)
Nervous system disorders
Headache	1/36 (2.8%)		1/38 (2.6%)		2/32 (6.3%)		0/34 (0%)
Syncope vasovagal	3/36 (8.3%)		1/38 (2.6%)		0/32 (0%)		1/34 (2.9%)
Psychiatric disorders
Agitation	1/36 (2.8%)		0/38 (0%)		0/32 (0%)		2/34 (5.9%)
Respiratory, thoracic and mediastinal disorders
Cough	1/36 (2.8%)		0/38 (0%)		2/32 (6.3%)		0/34 (0%)
Vascular disorders
Hypertension	0/36 (0%)		4/38 (10.5%)		2/32 (6.3%)		5/34 (14.7%)
Hypotension	3/36 (8.3%)		2/38 (5.3%)		4/32 (12.5%)		5/34 (14.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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