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

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

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.

Study Overview

• Status: Terminated
• Conditions: Bleeding
• Intervention / Treatment: Drug: MDCO 1; Drug: MDCO 2; Drug: MDCO 3; Drug: MDCO 4; Drug: Tranexamic Acid; Drug: Saline

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 Type: Interventional
• Enrollment (Actual): 44
• Phase: Phase 2

Contacts and Locations

Study Locations

• Germany
  • Berlin, Germany
    • Charite Berlin
  • Bonn, Germany
    • Universitatsklinikum Bonn
  • Heidelberg, Germany
    • Universitat Heidelberg
  • Leipzig, Germany
    • Universität Leipzig - Herzzentrum
• Switzerland
  • Bern, Switzerland
    • University Hospital/Inselspital Bern

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

6

Arms and Interventions

Participant Group / 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%

What is the study measuring?

Primary Outcome Measures

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

Collaborators and Investigators

• Sponsor: The Medicines Company
• Investigators: Principal Investigator: Lars Englberger, PD DR. med, University Hospital Inselspital, Bern

Study record dates

Study Major Dates

• Study Start: March 1, 2012
• Primary Completion (Actual): November 1, 2012
• Study Completion (Actual): November 1, 2012

Study Registration Dates

• First Submitted: February 7, 2012
• First Submitted That Met QC Criteria: February 7, 2012
• First Posted (Estimate): February 9, 2012

Study Record Updates

• Last Update Posted (Estimate): December 10, 2015
• Last Update Submitted That Met QC Criteria: November 4, 2015
• Last Verified: November 1, 2015

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Fibrin Modulating Agents; Antifibrinolytic Agents; Hemostatics; Coagulants; Tranexamic Acid
• Other Study ID Numbers: TMC-MDC-11-01