Acquired Bleeding Disorder, Cardiac Surgery Requiring Cardiopulmonary Bypass
Conditions
Brief summary
This trial is conducted in Canada, Asia, Europe and USA. The aim of this clinical trial is to investigate the effect and safety of rFXIII on transfusion needs in patients undergoing heart surgery.
Interventions
DRUGcatridecacog
Single dose via slow intravenous (i.v.) push at a rate not exceeding two mL per minute
DRUGplacebo
Single dose via slow intravenous (i.v.) push at a rate not exceeding two mL per minute
Sponsors
Novo Nordisk A/S
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* \- Planned coronary artery bypass grafting (CABG) or CABG plus single heart valve replacement/repair or planned replacement/repair of a single heart valve
Exclusion criteria
* Known intolerance to protamine * Known or suspected allergy to the used antifibrinolytic agent * Refusal to receive blood or blood product * Planned surgery including the aortic arch and/or descending aorta * Planned surgery including any implantable ventricular assist device * Adult congenital heart diseases * Two or more previous cardiac surgery procedures * Any known autoimmune diseases: Collagen vascular disease (Systemic lupus erythematosus, Rheumatoid arthritis, Sjögrens syndrome) - Endocrine: hyperthyroidism (Graves disease), adrenal insufficiency, Hashimoto's thyroiditis - Neurologic: Multiple sclerosis, myasthenia gravis - Skin: pemphigous vulgaris Hematologic: Pernicious anaemia, Autoimmune haemolytic anaemia - Vasculitis - Primary or secondary antiphospholipid syndrome * Weight above 140 kg
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Subjects Avoiding Any Allogeneic Transfusions for Seven Days Post-operative or Until Discharge, Whichever Came First | measured ongoing from dosing until day 7 or discharge, whichever came first | Proportion of patients avoiding blood products given via allogeneic transfusion. Blood products were defined as any of the following: RBC, platelets, FFP, fibrinogen concentrate and clotting factor(s) concentrate, including cryoprecipitate. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Subjects With Thromboembolic Events | measured from screening until 5-7 weeks post Trial Drug Administration | Percentage of subjects with thromboembolic events (AMI, cerebrovascular thromboembolic event, peripheral artery occlusion, DVT, pulmonary embolism) until end of trial |
| Percentage of Subjects With rFXIII Antibody Reaction | measured from screening until 5-7 weeks post Trial Drug Administration | Immunogenicity as number of subjects who manifested FXIII antibody reaction until end of trial. The percentage may be derived from the number of subjects treated with rFXIII with available antibody measurement at visit 8. |
| Percentage of Subjects With Critical Adverse Events | measured from screening until 5-7 weeks post Trial Drug Administration | Percentage of subjects with critical adverse events (thromboembolic events (AMI, cerebrovascular thromboembolic event, peripheral artery occlusion, DVT, pulmonary embolism), renal dysfunction, re-operation and death) until end of trial |
| Percentage of Subjects With Serious Adverse Events | measured from screening until 5-7 weeks post Trial Drug Administration | Percentage of subjects with serious adverse events until end of trial. |
Countries
Canada, Denmark, Germany, Israel, Italy, Japan, Spain, Sweden, United Kingdom, United States
Participant flow
Recruitment details
Of a total of 32 initiated trial sites, 30 sites randomised and dosed at least one patient. The country distribution for these 30 sites was as follows (number of sites per country in parenthesis): Canada (5), Denmark (1), Germany (4), Great Britain (3), Israel (2), Italy (2), Japan (4), Spain (3) and the United States (6).
Pre-assignment details
Seventy (70) of 479 subjects randomised in the trial were withdrawn before trial product administration.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Recombinant factor XIII placebo was administered as a single dose via slow i.v. push at a rate not exceeding two mL per minute. | 128 |
| FXIII17.5IU/Kg Recombinant factor XIII at a single dose of 17.5 IU/kg lean body mass (LBM) was administered via slow i.v. push at a rate not exceeding two mL per minute. | 143 |
| FXIII35IU/Kg Recombinant factor XIII at a single dose of 35 IU/kg lean body mass (LBM) was administered via slow i.v. push at a rate not exceeding two mL per minute. | 138 |
| Total | 409 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 1 |
| Overall Study | Death | 0 | 1 | 1 |
| Overall Study | Protocol Violation | 8 | 6 | 3 |
| Overall Study | unclassified | 16 | 9 | 7 |
Baseline characteristics
| Characteristic | Placebo | FXIII17.5IU/Kg | FXIII35IU/Kg | Total |
|---|---|---|---|---|
| Age, Continuous | 68.8 years STANDARD_DEVIATION 8.4 | 68.7 years STANDARD_DEVIATION 9 | 69.0 years STANDARD_DEVIATION 7.9 | 68.8 years STANDARD_DEVIATION 8.4 |
| Sex: Female, Male Female | 28 Participants | 24 Participants | 21 Participants | 73 Participants |
| Sex: Female, Male Male | 100 Participants | 119 Participants | 117 Participants | 336 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 120 / 128 | 129 / 143 | 128 / 138 |
| serious Total, serious adverse events | 35 / 128 | 43 / 143 | 32 / 138 |
Outcome results
Primary
Percentage of Subjects Avoiding Any Allogeneic Transfusions for Seven Days Post-operative or Until Discharge, Whichever Came First
Proportion of patients avoiding blood products given via allogeneic transfusion. Blood products were defined as any of the following: RBC, platelets, FFP, fibrinogen concentrate and clotting factor(s) concentrate, including cryoprecipitate.
Time frame: measured ongoing from dosing until day 7 or discharge, whichever came first
Population: Full analysis set consisted of all subjects who were randomised and exposed to randomised treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Percentage of Subjects Avoiding Any Allogeneic Transfusions for Seven Days Post-operative or Until Discharge, Whichever Came First | Transfused | 35.2 percentage (%) of subjects |
| Placebo | Percentage of Subjects Avoiding Any Allogeneic Transfusions for Seven Days Post-operative or Until Discharge, Whichever Came First | Not transfused | 64.8 percentage (%) of subjects |
| FXIII17.5IU/Kg | Percentage of Subjects Avoiding Any Allogeneic Transfusions for Seven Days Post-operative or Until Discharge, Whichever Came First | Transfused | 35.7 percentage (%) of subjects |
| FXIII17.5IU/Kg | Percentage of Subjects Avoiding Any Allogeneic Transfusions for Seven Days Post-operative or Until Discharge, Whichever Came First | Not transfused | 64.3 percentage (%) of subjects |
| FXIII35IU/Kg | Percentage of Subjects Avoiding Any Allogeneic Transfusions for Seven Days Post-operative or Until Discharge, Whichever Came First | Transfused | 34.1 percentage (%) of subjects |
| FXIII35IU/Kg | Percentage of Subjects Avoiding Any Allogeneic Transfusions for Seven Days Post-operative or Until Discharge, Whichever Came First | Not transfused | 65.9 percentage (%) of subjects |
p-value: 0.864895% CI: [0.6095, 1.8029]Regression, Logistic
p-value: 0.963495% CI: [0.5673, 1.7176]Regression, Logistic
Secondary
Percentage of Subjects With Critical Adverse Events
Percentage of subjects with critical adverse events (thromboembolic events (AMI, cerebrovascular thromboembolic event, peripheral artery occlusion, DVT, pulmonary embolism), renal dysfunction, re-operation and death) until end of trial
Time frame: measured from screening until 5-7 weeks post Trial Drug Administration
Population: The safety analysis set included all subjects who were exposed to at least one dose of trial product.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Percentage of Subjects With Critical Adverse Events | All events | 14.84 percentage (%) of subjects |
| Placebo | Percentage of Subjects With Critical Adverse Events | Peri-operative Acute Myocardial Infarcti | 6.25 percentage (%) of subjects |
| Placebo | Percentage of Subjects With Critical Adverse Events | Renal dysfunction | 7.03 percentage (%) of subjects |
| Placebo | Percentage of Subjects With Critical Adverse Events | Re-operation | 1.56 percentage (%) of subjects |
| Placebo | Percentage of Subjects With Critical Adverse Events | Cerebrovascular Thromboembolic Event | 2.34 percentage (%) of subjects |
| Placebo | Percentage of Subjects With Critical Adverse Events | Death | 0.00 percentage (%) of subjects |
| Placebo | Percentage of Subjects With Critical Adverse Events | Deep vein thrombosis | 0.78 percentage (%) of subjects |
| Placebo | Percentage of Subjects With Critical Adverse Events | Peripheral artery Occlusion | 0.00 percentage (%) of subjects |
| FXIII17.5IU/Kg | Percentage of Subjects With Critical Adverse Events | Renal dysfunction | 6.99 percentage (%) of subjects |
| FXIII17.5IU/Kg | Percentage of Subjects With Critical Adverse Events | Deep vein thrombosis | 0.00 percentage (%) of subjects |
| FXIII17.5IU/Kg | Percentage of Subjects With Critical Adverse Events | Re-operation | 5.59 percentage (%) of subjects |
| FXIII17.5IU/Kg | Percentage of Subjects With Critical Adverse Events | Cerebrovascular Thromboembolic Event | 1.40 percentage (%) of subjects |
| FXIII17.5IU/Kg | Percentage of Subjects With Critical Adverse Events | Death | 0.70 percentage (%) of subjects |
| FXIII17.5IU/Kg | Percentage of Subjects With Critical Adverse Events | All events | 16.78 percentage (%) of subjects |
| FXIII17.5IU/Kg | Percentage of Subjects With Critical Adverse Events | Peri-operative Acute Myocardial Infarcti | 6.99 percentage (%) of subjects |
| FXIII17.5IU/Kg | Percentage of Subjects With Critical Adverse Events | Peripheral artery Occlusion | 0.00 percentage (%) of subjects |
| FXIII35IU/Kg | Percentage of Subjects With Critical Adverse Events | Renal dysfunction | 3.62 percentage (%) of subjects |
| FXIII35IU/Kg | Percentage of Subjects With Critical Adverse Events | Peri-operative Acute Myocardial Infarcti | 5.07 percentage (%) of subjects |
| FXIII35IU/Kg | Percentage of Subjects With Critical Adverse Events | All events | 11.59 percentage (%) of subjects |
| FXIII35IU/Kg | Percentage of Subjects With Critical Adverse Events | Re-operation | 2.90 percentage (%) of subjects |
| FXIII35IU/Kg | Percentage of Subjects With Critical Adverse Events | Deep vein thrombosis | 0.72 percentage (%) of subjects |
| FXIII35IU/Kg | Percentage of Subjects With Critical Adverse Events | Death | 0.72 percentage (%) of subjects |
| FXIII35IU/Kg | Percentage of Subjects With Critical Adverse Events | Cerebrovascular Thromboembolic Event | 0.00 percentage (%) of subjects |
| FXIII35IU/Kg | Percentage of Subjects With Critical Adverse Events | Peripheral artery Occlusion | 0.72 percentage (%) of subjects |
Secondary
Percentage of Subjects With rFXIII Antibody Reaction
Immunogenicity as number of subjects who manifested FXIII antibody reaction until end of trial. The percentage may be derived from the number of subjects treated with rFXIII with available antibody measurement at visit 8.
Time frame: measured from screening until 5-7 weeks post Trial Drug Administration
Population: Safety analysis set includes all subj. exposed to at least one dose of trial product. 1 subj with a low titre antibody at baseline was also reported with low titre FXIII antibody at visit 8. 27, 19 and 17 subjects in placebo, FXIII 17.5 and 35 IU/KG, respectively, did not have antibody measurement.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Subjects With rFXIII Antibody Reaction | 0 participants |
| FXIII17.5IU/Kg | Percentage of Subjects With rFXIII Antibody Reaction | 1 participants |
| FXIII35IU/Kg | Percentage of Subjects With rFXIII Antibody Reaction | 0 participants |
Secondary
Percentage of Subjects With Serious Adverse Events
Percentage of subjects with serious adverse events until end of trial.
Time frame: measured from screening until 5-7 weeks post Trial Drug Administration
Population: The safety analysis set included all subjects who were exposed to at least one dose of trial product.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Percentage of Subjects With Serious Adverse Events | General disorders and administration sit | 1.56 percentage (%) of subjects |
| Placebo | Percentage of Subjects With Serious Adverse Events | Cardiac disorders | 8.59 percentage (%) of subjects |
| Placebo | Percentage of Subjects With Serious Adverse Events | Eye disorders | 0.00 percentage (%) of subjects |
| Placebo | Percentage of Subjects With Serious Adverse Events | Gastrointestinal disorders | 1.56 percentage (%) of subjects |
| Placebo | Percentage of Subjects With Serious Adverse Events | Blood and lymphatic system disorders | 0.00 percentage (%) of subjects |
| Placebo | Percentage of Subjects With Serious Adverse Events | Infections and infestations | 5.47 percentage (%) of subjects |
| Placebo | Percentage of Subjects With Serious Adverse Events | Injury, poisoning and procedural compli | 2.34 percentage (%) of subjects |
| Placebo | Percentage of Subjects With Serious Adverse Events | Investigations | 0.00 percentage (%) of subjects |
| Placebo | Percentage of Subjects With Serious Adverse Events | Musculoskeletal and connective tissue d | 0.00 percentage (%) of subjects |
| Placebo | Percentage of Subjects With Serious Adverse Events | Neoplasms benign, malignant and unspecif | 0.78 percentage (%) of subjects |
| Placebo | Percentage of Subjects With Serious Adverse Events | Nervous system disorders | 3.91 percentage (%) of subjects |
| Placebo | Percentage of Subjects With Serious Adverse Events | Psychiatric disorders | 0.00 percentage (%) of subjects |
| Placebo | Percentage of Subjects With Serious Adverse Events | Renal and urinary disorders | 1.56 percentage (%) of subjects |
| Placebo | Percentage of Subjects With Serious Adverse Events | Respiratory, thoracic and mediastinal d | 7.03 percentage (%) of subjects |
| Placebo | Percentage of Subjects With Serious Adverse Events | Skin and subcutaneous tissue disorders | 0.78 percentage (%) of subjects |
| Placebo | Percentage of Subjects With Serious Adverse Events | Vascular disorders | 1.56 percentage (%) of subjects |
| FXIII17.5IU/Kg | Percentage of Subjects With Serious Adverse Events | Infections and infestations | 5.59 percentage (%) of subjects |
| FXIII17.5IU/Kg | Percentage of Subjects With Serious Adverse Events | Injury, poisoning and procedural compli | 4.90 percentage (%) of subjects |
| FXIII17.5IU/Kg | Percentage of Subjects With Serious Adverse Events | Investigations | 0.00 percentage (%) of subjects |
| FXIII17.5IU/Kg | Percentage of Subjects With Serious Adverse Events | Respiratory, thoracic and mediastinal d | 6.29 percentage (%) of subjects |
| FXIII17.5IU/Kg | Percentage of Subjects With Serious Adverse Events | Musculoskeletal and connective tissue d | 0.70 percentage (%) of subjects |
| FXIII17.5IU/Kg | Percentage of Subjects With Serious Adverse Events | Neoplasms benign, malignant and unspecif | 0.00 percentage (%) of subjects |
| FXIII17.5IU/Kg | Percentage of Subjects With Serious Adverse Events | Vascular disorders | 1.40 percentage (%) of subjects |
| FXIII17.5IU/Kg | Percentage of Subjects With Serious Adverse Events | Nervous system disorders | 2.80 percentage (%) of subjects |
| FXIII17.5IU/Kg | Percentage of Subjects With Serious Adverse Events | Blood and lymphatic system disorders | 0.70 percentage (%) of subjects |
| FXIII17.5IU/Kg | Percentage of Subjects With Serious Adverse Events | Skin and subcutaneous tissue disorders | 0.00 percentage (%) of subjects |
| FXIII17.5IU/Kg | Percentage of Subjects With Serious Adverse Events | Cardiac disorders | 12.59 percentage (%) of subjects |
| FXIII17.5IU/Kg | Percentage of Subjects With Serious Adverse Events | Psychiatric disorders | 0.70 percentage (%) of subjects |
| FXIII17.5IU/Kg | Percentage of Subjects With Serious Adverse Events | Eye disorders | 0.70 percentage (%) of subjects |
| FXIII17.5IU/Kg | Percentage of Subjects With Serious Adverse Events | Gastrointestinal disorders | 0.70 percentage (%) of subjects |
| FXIII17.5IU/Kg | Percentage of Subjects With Serious Adverse Events | General disorders and administration sit | 0.00 percentage (%) of subjects |
| FXIII17.5IU/Kg | Percentage of Subjects With Serious Adverse Events | Renal and urinary disorders | 2.10 percentage (%) of subjects |
| FXIII35IU/Kg | Percentage of Subjects With Serious Adverse Events | Nervous system disorders | 2.17 percentage (%) of subjects |
| FXIII35IU/Kg | Percentage of Subjects With Serious Adverse Events | Infections and infestations | 3.62 percentage (%) of subjects |
| FXIII35IU/Kg | Percentage of Subjects With Serious Adverse Events | Renal and urinary disorders | 2.17 percentage (%) of subjects |
| FXIII35IU/Kg | Percentage of Subjects With Serious Adverse Events | Eye disorders | 0.00 percentage (%) of subjects |
| FXIII35IU/Kg | Percentage of Subjects With Serious Adverse Events | Injury, poisoning and procedural compli | 2.90 percentage (%) of subjects |
| FXIII35IU/Kg | Percentage of Subjects With Serious Adverse Events | Vascular disorders | 1.45 percentage (%) of subjects |
| FXIII35IU/Kg | Percentage of Subjects With Serious Adverse Events | Blood and lymphatic system disorders | 0.00 percentage (%) of subjects |
| FXIII35IU/Kg | Percentage of Subjects With Serious Adverse Events | Investigations | 0.72 percentage (%) of subjects |
| FXIII35IU/Kg | Percentage of Subjects With Serious Adverse Events | Psychiatric disorders | 0.72 percentage (%) of subjects |
| FXIII35IU/Kg | Percentage of Subjects With Serious Adverse Events | General disorders and administration sit | 2.17 percentage (%) of subjects |
| FXIII35IU/Kg | Percentage of Subjects With Serious Adverse Events | Musculoskeletal and connective tissue d | 0.00 percentage (%) of subjects |
| FXIII35IU/Kg | Percentage of Subjects With Serious Adverse Events | Respiratory, thoracic and mediastinal d | 7.25 percentage (%) of subjects |
| FXIII35IU/Kg | Percentage of Subjects With Serious Adverse Events | Cardiac disorders | 7.25 percentage (%) of subjects |
| FXIII35IU/Kg | Percentage of Subjects With Serious Adverse Events | Neoplasms benign, malignant and unspecif | 0.00 percentage (%) of subjects |
| FXIII35IU/Kg | Percentage of Subjects With Serious Adverse Events | Gastrointestinal disorders | 0.00 percentage (%) of subjects |
| FXIII35IU/Kg | Percentage of Subjects With Serious Adverse Events | Skin and subcutaneous tissue disorders | 0.00 percentage (%) of subjects |
Secondary
Percentage of Subjects With Thromboembolic Events
Percentage of subjects with thromboembolic events (AMI, cerebrovascular thromboembolic event, peripheral artery occlusion, DVT, pulmonary embolism) until end of trial
Time frame: measured from screening until 5-7 weeks post Trial Drug Administration
Population: The safety analysis set included all subjects who were exposed to at least one dose of trial product.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Percentage of Subjects With Thromboembolic Events | Deep vein thrombosis | 0.78 percentage of subjects |
| Placebo | Percentage of Subjects With Thromboembolic Events | Cerebrovascular Thromboembolic Event | 2.34 percentage of subjects |
| Placebo | Percentage of Subjects With Thromboembolic Events | All events | 9.38 percentage of subjects |
| Placebo | Percentage of Subjects With Thromboembolic Events | Peri-operative Acute Myocardial infarcti | 6.25 percentage of subjects |
| Placebo | Percentage of Subjects With Thromboembolic Events | Peripheral Artery Occlusion | 0.00 percentage of subjects |
| FXIII17.5IU/Kg | Percentage of Subjects With Thromboembolic Events | Cerebrovascular Thromboembolic Event | 1.40 percentage of subjects |
| FXIII17.5IU/Kg | Percentage of Subjects With Thromboembolic Events | All events | 8.39 percentage of subjects |
| FXIII17.5IU/Kg | Percentage of Subjects With Thromboembolic Events | Peri-operative Acute Myocardial infarcti | 6.99 percentage of subjects |
| FXIII17.5IU/Kg | Percentage of Subjects With Thromboembolic Events | Deep vein thrombosis | 0.00 percentage of subjects |
| FXIII17.5IU/Kg | Percentage of Subjects With Thromboembolic Events | Peripheral Artery Occlusion | 0.00 percentage of subjects |
| FXIII35IU/Kg | Percentage of Subjects With Thromboembolic Events | Peripheral Artery Occlusion | 0.72 percentage of subjects |
| FXIII35IU/Kg | Percentage of Subjects With Thromboembolic Events | Deep vein thrombosis | 0.72 percentage of subjects |
| FXIII35IU/Kg | Percentage of Subjects With Thromboembolic Events | All events | 6.52 percentage of subjects |
| FXIII35IU/Kg | Percentage of Subjects With Thromboembolic Events | Cerebrovascular Thromboembolic Event | 0.00 percentage of subjects |
| FXIII35IU/Kg | Percentage of Subjects With Thromboembolic Events | Peri-operative Acute Myocardial infarcti | 5.07 percentage of subjects |