Phase II Study to Compare MDCO-2010 vs Placebo and Tranexamic Acid in Patients Undergoing Cardiac Surgery

• Sponsor: The Medicines Company (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT01530399
• Collaborator: (none)
• Enrollment: 44
• Locations: 5
• Arms: 6
• Duration (Months): 8
• Patients Per Site: 8.8
• Patients Per Site Per Month: 1.1

Study Details

Study Description

Brief Summary

The objective of this study is to determine the dose response relationship regarding blood loss, PK, PD and clinical outcomes of MDCO-2010 in comparison to placebo and tranexamic acid in patients undergoing primary cardiac surgery with cardiopulmonary bypass. The aim of the study is to define minimally effective dose of MDCO-2010.

Condition or Disease	Intervention/Treatment	Phase
Bleeding	Drug: MDCO 1; Drug: MDCO 2; Drug: MDCO 3; Drug: MDCO 4; Drug: Tranexamic Acid; Drug: Saline	Phase 2

Detailed Description

This was a two-stage, double-blind, randomized, parallel-group, multicenter Phase II dose-selection study to compare antifibrinolytic MDCO-2010 vs tranexamic acid and placebo in reducing blood loss.

This study was designed to examine a broad range of doses to fully characterize the dose-response relationship between MDCO-2010 dose, plasma PK, PD, and clinical effects.

In Stage 1, 90 patients were to be enrolled into one of six treatment groups with 15 patients per group: four groups were to receive MDCO-2010, one group was to receive tranexamic acid, and one group was to receive placebo. Stage 2 was to be an expansion of Stage 1.

The study was terminated after 49 patients were enrolled into Stage 1.

Study Design

• Study Type: Interventional
• Actual Enrollment: 44 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase II, Double-blind, Parallel Group, Dose-selection Study to Compare Antifibrinolytic MDCO-2010 vs. Placebo and Tranexamic Acid in Reducing Blood Loss in Patients Undergoing Primary Cardiac Surgery
• Study Start Date: Mar 1, 2012
• Actual Primary Completion Date: Nov 1, 2012
• Actual Study Completion Date: Nov 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: MDCO 1 MDCO-2010: load 15 μg/kg; infusion 30 μg/kg/h; CPB prime 0.11 μg/mL priming volume	Drug: MDCO 1; MDCO-2010 will be administered as a loading dose followed by a continuous infusion until sternal closure. In addition, the CPB reservoir will be primed with MDCO-2010. MDCO 1: load 15 μg/kg; infusion 30 μg/kg/h; CPB prime 0.11 μg/mL priming volume; Other Names: MDCO-2010
Experimental: MDCO 2 MDCO-2010: load 30 μg/kg; infusion 60 μg/kg/h; CPB prime 0.22 μg/mL priming volume	Drug: MDCO 2; MDCO-2010 will be administered as a loading dose followed by a continuous infusion until sternal closure. In addition, the CPB reservoir will be primed with MDCO-2010. MDCO 2: load 30 μg/kg; infusion 60 μg/kg/h; CPB prime 0.22 μg/mL priming volume; Other Names: MDCO-2010
Experimental: MDCO 3 MDCO-2010: load 60 μg/kg ; infusion 120 μg/kg/h; CPB prime 0.44 μg/mL priming volume	Drug: MDCO 3; MDCO-2010 will be administered as a loading dose followed by a continuous infusion until sternal closure. In addition, the CPB reservoir will be primed with MDCO-2010. MDCO 3: load 60 μg/kg ; infusion 120 μg/kg/h; CPB prime 0.44 μg/mL priming volume; Other Names: MDCO-2010
Experimental: MDCO 4 MDCO-2010: load 90 μg/kg; infusion 180 μg/kg/h; CPB prime 0.65 μg/mL priming volume	Drug: MDCO 4; MDCO-2010 will be administered as a loading dose followed by a continuous infusion until sternal closure. In addition, the CPB reservoir will be primed with MDCO-2010. MDCO 4: load 90 μg/kg; infusion 180 μg/kg/h; CPB prime 0.65 μg/mL priming volume; Other Names: MDCO-2010
Placebo Comparator: Saline Commercially available saline (0.9% NaCl solution)	Drug: Tranexamic Acid; Tranexamic acid will be administered as a loading dose followed by a continuous infusion until sternal closure. In addition, the CPB reservoir will be primed with tranexamic acid. The flow rates will be the same as for MDCO-2010.; Other Names: TXA
Active Comparator: Tranexamic acid Tranexamic acid: 12 mg/kg loading dose; 5 mg/kg/h infusion; 0.556 mg/mL CPB priming	Drug: Saline; A loading dose of saline will be followed by a continuous infusion of saline until sternal closure. In addition, the CPB reservoir will be primed with saline. The flow rates will be the same as for MDCO-2010.; Other Names: NaCl 0.9%

Outcome Measures

Primary Outcome Measures

1. Chest Tube Drainage at 12 Hours After Surgery [12 hours post CABG]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 85 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• For Stage 1: Planned primary isolated CABG surgery

• For Stage 2: Planned primary isolated CABG surgery, OR Planned primary combined CABG and aortic valve replacement surgery

• Men, aged 18 to 85 years, or Women, aged 18 to 85 years, either of postmenopausal status, defined as ≥1 year since last menstrual period AND if less than 65 years old with a negative pre-operative pregnancy test within 24 hours of surgery OR with medical history of hysterectomy or bilateral oophorectomy

• Written informed consent

Exclusion Criteria:

• Off-pump surgery or hybrid procedures

• Patients undergoing repeat sternotomy

• Planned deep hypothermic circulatory arrest (<28°C)

• Known allergy, sensitivity, or contraindications to tranexamic acid

• Epileptiform disorders, history of seizure activity, or anticonvulsive medication

• Administration of clopidogrel, ticagrelor or ticlopidine within 5 days prior to surgery or prasugrel within 7 days prior to surgery.

• Administration of low molecular weight heparin, glycoprotein IIb/IIIa inhibitors, or fondaparinux within 12 hours prior to surgery

• Known history of coronary stent thrombosis within the last three months

• History of stroke or transient ischemic attack within 3 months prior to surgery

• History of deep venous thrombosis or pulmonary embolism

• LVEF ≤35% or Grade III or IV

• Body mass index <20 or >35

• Known active gastrointestinal (GI) or other non-catheterization bleeding within 7 days prior to surgery

• Preoperative coagulation abnormalities defined as:

• Platelet count <100,000/L or >350,000/L, or

• International normalized ration (INR) >1.5, or

• Hematocrit <36%, or

• aPTT >1.5 x ULN

• Major surgical procedures within 30 days prior to surgery

• Patient inability or refusal to receive donor blood products if necessary

• Creatinine >2 mg/dL or estimated glomerular filtration rate (eGFR) (calculated using Modification of Diet in Renal Disease [MDRD] equation <30 mL/min)

• Known heparin-induced thrombocytopenia type II

• Known history of thrombophilia, such as AT-III, Protein C or Protein S deficiency, Factor V Leiden, anti-phospholipid syndrome

• Active liver disease defined as any known current infectious, neoplastic or metabolic pathology of the liver OR ALT or AST elevation >2x ULN or total bilirubin elevation

1.5x ULN at Screening

• Any condition requiring ongoing chronic immunosuppressive medication

• Malignancy within 5 years prior to surgery

• Receipt of an investigational drug or device within 60 days prior to surgery Any other condition which, in the opinion of the Principal Investigator, would put the subject at increased risk from participating in the study or otherwise prevent a patient"s participation in the study

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Charité Berlin	Berlin		Germany
2	Universitätsklinikum Bonn	Bonn		Germany
3	Universität Heidelberg	Heidelberg		Germany
4	Universität Leipzig - Herzzentrum	Leipzig		Germany
5	University Hospital/Inselspital Bern	Bern		Switzerland

Sponsors and Collaborators

• The Medicines Company

Investigators

• Principal Investigator: Lars Englberger, PD DR. med, University Hospital Inselspital, Bern

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: The Medicines Company
• ClinicalTrials.gov Identifier: NCT01530399
• Other Study ID Numbers: TMC-MDC-11-01
• First Posted: Feb 9, 2012
• Last Update Posted: Dec 10, 2015
• Last Verified: Nov 1, 2015

• Additional relevant MeSH terms: Tranexamic Acid

Study Results

Participant Flow

Arm/Group Title	MDCO 1	MDCO 2	MDCO 3	MDCO 4	Saline	Tranexamic Acid
Arm/Group Description	MDCO-2010 Dose 1: MDCO-2010 will be administered as a loading dose followed by a continuous infusion until sternal closure. In addition, the CPB reservoir will be primed with MDCO-2010. MDCO 1: load 15 μg/kg; infusion 30 μg/kg/h; CPB prime 0.11 μg/mL priming volume	MDCO-2010 Dose 2: MDCO-2010 will be administered as a loading dose followed by a continuous infusion until sternal closure. In addition, the CPB reservoir will be primed with MDCO-2010. MDCO 2: load 30 μg/kg; infusion 60 μg/kg/h; CPB prime 0.22 μg/mL priming volume	MDCO-2010 Dose 3: MDCO-2010 will be administered as a loading dose followed by a continuous infusion until sternal closure. In addition, the CPB reservoir will be primed with MDCO-2010. MDCO 3: load 60 μg/kg ; infusion 120 μg/kg/h; CPB prime 0.44 μg/mL priming volume	MDCO-2010 Dose 4: MDCO-2010 will be administered as a loading dose followed by a continuous infusion until sternal closure. In addition, the CPB reservoir will be primed with MDCO-2010. MDCO 4: load 90 μg/kg; infusion 180 μg/kg/h; CPB prime 0.65 μg/mL priming volume	Tranexamic Acid: Tranexamic acid will be administered as a loading dose followed by a continuous infusion until sternal closure. In addition, the CPB reservoir will be primed with tranexamic acid. The flow rates will be the same as for MDCO-2010.	saline: A loading dose of saline will be followed by a continuous infusion of saline until sternal closure. In addition, the CPB reservoir will be primed with saline. The flow rates will be the same as for MDCO-2010.
Period Title: Overall Study
STARTED	8	10	8	10	6	7
COMPLETED	7	8	7	10	6	6
NOT COMPLETED	1	2	1	0	0	1

Baseline Characteristics

Arm/Group Title	MDCO 1	MDCO 2	MDCO 3	MDCO 4	Saline	Tranexamic Acid	Total
Arm/Group Description	MDCO-2010 Dose 1: MDCO-2010 will be administered as a loading dose followed by a continuous infusion until sternal closure. In addition, the CPB reservoir will be primed with MDCO-2010. MDCO 1: load 15 μg/kg; infusion 30 μg/kg/h; CPB prime 0.11 μg/mL priming volume	MDCO-2010 Dose 2: MDCO-2010 will be administered as a loading dose followed by a continuous infusion until sternal closure. In addition, the CPB reservoir will be primed with MDCO-2010. MDCO 2: load 30 μg/kg; infusion 60 μg/kg/h; CPB prime 0.22 μg/mL priming volume	MDCO-2010 Dose 3: MDCO-2010 will be administered as a loading dose followed by a continuous infusion until sternal closure. In addition, the CPB reservoir will be primed with MDCO-2010. MDCO 3: load 60 μg/kg ; infusion 120 μg/kg/h; CPB prime 0.44 μg/mL priming volume	MDCO-2010 Dose 4: MDCO-2010 will be administered as a loading dose followed by a continuous infusion until sternal closure. In addition, the CPB reservoir will be primed with MDCO-2010. MDCO 4: load 90 μg/kg; infusion 180 μg/kg/h; CPB prime 0.65 μg/mL priming volume	Tranexamic Acid: Tranexamic acid will be administered as a loading dose followed by a continuous infusion until sternal closure. In addition, the CPB reservoir will be primed with tranexamic acid. The flow rates will be the same as for MDCO-2010.	saline: A loading dose of saline will be followed by a continuous infusion of saline until sternal closure. In addition, the CPB reservoir will be primed with saline. The flow rates will be the same as for MDCO-2010.	Total of all reporting groups
Overall Participants	8	10	8	10	6	7	49
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	71	70	66	73	66	58	69
Sex: Female, Male (Count of Participants)
Female	1 12.5%	2 20%	1 12.5%	2 20%	2 33.3%	0 0%	8 16.3%
Male	7 87.5%	8 80%	7 87.5%	8 80%	4 66.7%	7 100%	41 83.7%
Region of Enrollment (participants) [Number]
Germany	6 75%	7 70%	5 62.5%	7 70%	4 66.7%	4 57.1%	33 67.3%
Switzerland	2 25%	3 30%	3 37.5%	3 30%	2 33.3%	3 42.9%	16 32.7%

Outcome Measures

1. Primary Outcome

Title	Chest Tube Drainage at 12 Hours After Surgery
Time Frame	12 hours post CABG

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	MDCO 1	MDCO 2	MDCO 3	MDCO 4	Saline	Tranexamic Acid
Arm/Group Description	MDCO-2010 Dose 1: MDCO-2010 will be administered as a loading dose followed by a continuous infusion until sternal closure. In addition, the CPB reservoir will be primed with MDCO-2010. MDCO 1: load 15 μg/kg; infusion 30 μg/kg/h; CPB prime 0.11 μg/mL priming volume	MDCO-2010 Dose 2: MDCO-2010 will be administered as a loading dose followed by a continuous infusion until sternal closure. In addition, the CPB reservoir will be primed with MDCO-2010. MDCO 2: load 30 μg/kg; infusion 60 μg/kg/h; CPB prime 0.22 μg/mL priming volume	MDCO-2010 Dose 3: MDCO-2010 will be administered as a loading dose followed by a continuous infusion until sternal closure. In addition, the CPB reservoir will be primed with MDCO-2010. MDCO 3: load 60 μg/kg ; infusion 120 μg/kg/h; CPB prime 0.44 μg/mL priming volume	MDCO-2010 Dose 4: MDCO-2010 will be administered as a loading dose followed by a continuous infusion until sternal closure. In addition, the CPB reservoir will be primed with MDCO-2010. MDCO 4: load 90 μg/kg; infusion 180 μg/kg/h; CPB prime 0.65 μg/mL priming volume	Tranexamic Acid: Tranexamic acid will be administered as a loading dose followed by a continuous infusion until sternal closure. In addition, the CPB reservoir will be primed with tranexamic acid. The flow rates will be the same as for MDCO-2010.	saline: A loading dose of saline will be followed by a continuous infusion of saline until sternal closure. In addition, the CPB reservoir will be primed with saline. The flow rates will be the same as for MDCO-2010.
Measure Participants	7	7	6	10	6	6
Median (Inter-Quartile Range) [mL]	600	580	480	453	645	593

Adverse Events

Time Frame	30 (+5) days post treatment
Arm/Group Title	MDCO 1		MDCO 2		MDCO 3		MDCO 4		Saline		Tranexamic Acid
Arm/Group Description	MDCO-2010 Dose 1: MDCO-2010 will be administered as a loading dose followed by a continuous infusion until sternal closure. In addition, the CPB reservoir will be primed with MDCO-2010. MDCO 1: load 15 μg/kg; infusion 30 μg/kg/h; CPB prime 0.11 μg/mL priming volume		MDCO-2010 Dose 2: MDCO-2010 will be administered as a loading dose followed by a continuous infusion until sternal closure. In addition, the CPB reservoir will be primed with MDCO-2010. MDCO 2: load 30 μg/kg; infusion 60 μg/kg/h; CPB prime 0.22 μg/mL priming volume		MDCO-2010 Dose 3: MDCO-2010 will be administered as a loading dose followed by a continuous infusion until sternal closure. In addition, the CPB reservoir will be primed with MDCO-2010. MDCO 3: load 60 μg/kg ; infusion 120 μg/kg/h; CPB prime 0.44 μg/mL priming volume		MDCO-2010 Dose 4: MDCO-2010 will be administered as a loading dose followed by a continuous infusion until sternal closure. In addition, the CPB reservoir will be primed with MDCO-2010. MDCO 4: load 90 μg/kg; infusion 180 μg/kg/h; CPB prime 0.65 μg/mL priming volume		Tranexamic Acid: Tranexamic acid will be administered as a loading dose followed by a continuous infusion until sternal closure. In addition, the CPB reservoir will be primed with tranexamic acid. The flow rates will be the same as for MDCO-2010.		saline: A loading dose of saline will be followed by a continuous infusion of saline until sternal closure. In addition, the CPB reservoir will be primed with saline. The flow rates will be the same as for MDCO-2010.
All Cause Mortality
	MDCO 1		MDCO 2		MDCO 3		MDCO 4		Saline		Tranexamic Acid
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	MDCO 1		MDCO 2		MDCO 3		MDCO 4		Saline		Tranexamic Acid
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/7 (28.6%)		2/8 (25%)		1/7 (14.3%)		2/10 (20%)		0/6 (0%)		0/6 (0%)
Blood and lymphatic system disorders
Haemorrhagic anaemia	1/7 (14.3%)		0/8 (0%)		0/7 (0%)		0/10 (0%)		0/6 (0%)		0/6 (0%)
Cardiac disorders
Cardiac tamponade	0/7 (0%)		1/8 (12.5%)		0/7 (0%)		0/10 (0%)		0/6 (0%)		0/6 (0%)
Coronary artery occlusion	0/7 (0%)		1/8 (12.5%)		0/7 (0%)		0/10 (0%)		0/6 (0%)		0/6 (0%)
Low cardiac output syndrome	0/7 (0%)		1/8 (12.5%)		1/7 (14.3%)		0/10 (0%)		0/6 (0%)		0/6 (0%)
Injury, poisoning and procedural complications
Vascular graft thrombosis	0/7 (0%)		0/8 (0%)		0/7 (0%)		1/10 (10%)		0/6 (0%)		0/6 (0%)
Nervous system disorders
Ischaemic stroke	1/7 (14.3%)		0/8 (0%)		0/7 (0%)		0/10 (0%)		0/6 (0%)		0/6 (0%)
Renal and urinary disorders
Renal failure	1/7 (14.3%)		0/8 (0%)		0/7 (0%)		0/10 (0%)		0/6 (0%)		0/6 (0%)
Respiratory, thoracic and mediastinal disorders
Respiratory failure	1/7 (14.3%)		0/8 (0%)		0/7 (0%)		0/10 (0%)		0/6 (0%)		0/6 (0%)
Vascular disorders
Arterial thrombosis limb	0/7 (0%)		0/8 (0%)		0/7 (0%)		1/10 (10%)		0/6 (0%)		0/6 (0%)
Extremity necrosis	1/7 (14.3%)		0/8 (0%)		0/7 (0%)		0/10 (0%)		0/6 (0%)		0/6 (0%)
Jugular vein thrombosis	0/7 (0%)		0/8 (0%)		0/7 (0%)		1/10 (10%)		0/6 (0%)		0/6 (0%)
Other (Not Including Serious) Adverse Events
	MDCO 1		MDCO 2		MDCO 3		MDCO 4		Saline		Tranexamic Acid
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/7 (71.4%)		7/8 (87.5%)		4/7 (57.1%)		7/10 (70%)		5/6 (83.3%)		4/6 (66.7%)
Blood and lymphatic system disorders
Troponin T increased	1/7 (14.3%)		2/8 (25%)		1/7 (14.3%)		1/10 (10%)		0/6 (0%)		0/6 (0%)
Cardiac disorders
Atrial fibrillation	1/7 (14.3%)		2/8 (25%)		1/7 (14.3%)		2/10 (20%)		1/6 (16.7%)		2/6 (33.3%)
Gastrointestinal disorders
Nausea	2/7 (28.6%)		1/8 (12.5%)		0/7 (0%)		1/10 (10%)		2/6 (33.3%)		0/6 (0%)
AST increased	0/7 (0%)		0/8 (0%)		0/7 (0%)		0/10 (0%)		0/6 (0%)		2/6 (33.3%)
Hepatobiliary disorders
AST increased	0/7 (0%)		2/8 (25%)		0/7 (0%)		0/10 (0%)		0/6 (0%)		0/6 (0%)
Renal and urinary disorders
Urinary tract infection	0/7 (0%)		0/8 (0%)		1/7 (14.3%)		2/10 (20%)		2/6 (33.3%)		0/6 (0%)
Respiratory, thoracic and mediastinal disorders
Pleural effusion	3/7 (42.9%)		2/8 (25%)		1/7 (14.3%)		1/10 (10%)		1/6 (16.7%)		0/6 (0%)
Pneumothorax	0/7 (0%)		2/8 (25%)		1/7 (14.3%)		0/10 (0%)		0/6 (0%)		0/6 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

After initial multicenter results communications are published, or after 12 months from study closure (whichever occurs first), sponsor can review results communications prior to submission and can embargo submissions for a period of 45 days from the time submitted to the sponsor for review, agreeing to resolve differences of opinion or interpretation through scientific debate. Sponsor can request further delay for an additional 90 days to file any patent applications if deemed necessary