Amendment 1 was generated to adapt the study design to changed operational aspects of the Study, including: 1. Deletion of the clinical research organization (CRO) Pharmacovigilance signature and replacement with the Serious or Unexpected Adverse Drug Reaction report form in attachment B 2. Clarification of the randomization process, adding essentially that the study was single-blinded 3. Modification of laboratory tests to be performed, adding international normalized ratio (INR) to the pre-operative assessments, lowest ACT during surgery, as well as heparin sensitivity index at baseline and after infusion before the heparin dose and heparin resistance, and INR to the post-operative assessments 4. Deletion of central laboratory participation 5. Modification of heparin resistance criteria, one of the secondary efficacy endpoints, and assessment as noted in number 3. Heparin resistance definition was modified to: failure to reach an ACT > 450 seconds after a dose of up to 400 IU/kg of heparin, or failure to maintain this ACT value despite heparin supplementations of 100 IU/kg per each dose with an interval of at least 30 minutes between doses. As noted above in number 3, heparin resistance was measured once, immediately after anesthesia induction.

Amendment 2 was generated to adapt the study design to be compatible with both the standard cardiac surgery schedule and to changed operational aspects of the study. This amendment reflects mainly the following changes: 1. Deletion of inclusion criteria number 5 2. Modification of laboratory tests to be performed 3. Adaptation of study visits to the center’s standard operating schedule. Specifically, the modification of inclusion criteria number 5, “human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis A virus (HAV), and PARVO B19 status known prior to entry”, was cancelled or removed, because the Ethics Committee determined adherence to this criterion may have required some patients to wait several days until the tests results were available which may have been incompatible with the cardiac surgery schedule. Rather, it was determined to be sufficient that the subject have a blood sample drawn and stored before the first administration of the study product in case further viral serological investigations were needed. Inclusion criteria number 6, ‘signed the consent sheet’ in “subject has read the patient information and consent form and has agreed to participate in the trial and signed the consent sheet”, was modified for clarity, to “signed informed consent form.” Subject participation (since enrollment) was also extended from at least 1 month to 1.65 months (40 ± 10 days).

Amendment 3 was generated to adapt the study design to be compatible with both the standard cardiac surgery schedule and to changed operational aspects of the study. This amendment reflects: 1. Extension of enrollment period from 8 to 18 months, follow-up period, and total study duration with the total subject participation since enrollment of at least 1 month to 1.65 month (40 ± 10 days) extended to at least 1 month to 2.3 months (50 ± 20 days) and total study duration extended from 9 to 12 months to 18 to 20 months 2. Use of prescreening laboratory values routinely taken 24 hours prior to the informed consent signature which would lessen the burden on participating subjects; more exactly, avoiding unnecessary blood draws though the use of pre-screening laboratory values taken routinely 24 or 48 hours prior to the recruitment visit and preoperative visit, respectively 3. Modification of laboratory tests to be performed, including deletion of hepatitis B surface antigen (HBsAg) from the viral panel 4. Adaptation of study visits to center’s standard operating schedule. 5. Establishment of phone call follow-up visit for patients unable to return to the site during the scheduled follow-up period. Improvement of patient follow-up though the establishment of a phone call follow-up visit. 6. Modification of concomitant medication reporting in order to facilitate its documentation. 7. Adjustment of the definition of pre- and post-operative significant clinical chemistry (including hematology) laboratory values and vital signs to the particularities of the cardiac surgery setting.