E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Bleeding in patients undergoing complex cardiac surgery (involving CPB) |
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E.1.1.1 | Medical condition in easily understood language |
Bleeding in patients undergoing complex cardiac surgery involving Cardiopulmonary bypass |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10017501 |
E.1.2 | Term | Functional disturbances following cardiac surgery |
E.1.2 | System Organ Class | 10022117 - Injury, poisoning and procedural complications |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective of the study is to evaluate the efficacy of FGTW in combination with Standard of care in reducing the need for allogeneic transfusions within the first 24 hours after randomization in complex cardiac surgery patients.
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E.2.2 | Secondary objectives of the trial |
- To evaluate the efficacy associated with the use of FGTW versus Placebo in reducing the number and volume of RBC, FFP, and platelet concentrate transfusions in the 24 hours after randomization until hospital discharge - To evaluate the efficacy associated with the use of FGTW versus Placebo in reducing the blood drainage volume within 12 hours after randomization - To evaluate the number of patients with total avoidance of allogeneic transfusions after randomization - To evaluate the safety of FGTW - To evaluate the impact of FGTW on mortality and surgical morbidity - To evaluate the duration of hospitalization in both treatment arms - To evaluate the length of stay in ICU in both treatment arms |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
A patient must meet all the following criteria to be eligible to participate in this study: 1. Male or female adult patients ≥18 years 2. Patients undergoing a planned complex cardiac surgery procedure involving CPB, including reoperation and/or complex surgical procedures. Complex surgical procedures are defined as any procedure other than first time isolated coronary artery bypass grafting (CABG), single valve repair/replacement and repair of atrial septal defect (ASD). This criterion represents the main eligibility criterion and so used in the definition of the full analysis set. 3. With a FIBTEM MCF ≤10 mm during the last 20 minutes of CPB. 4. Patients requiring an IMP dose ≤8 g calculated with the formula based on patient’s weight and the value of FIBTEM MCF 5. Signed and dated informed consent form (ICF) 6. Willingness to comply with all study procedures and availability for the duration of the study 7. Covered by healthcare insurance in accordance with local requirements 8. FIBTEM MCF ≤14 mm during the screening period prior to the surgery. FIBTEM MCF is the recommended test, for consistency with end of CPB FIBTEM MCF. Fibrinogen concentration (Clauss method) may be substituted, with fibrinogen level ≤3 g/L |
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E.4 | Principal exclusion criteria |
A patient who meets any of the following criteria will be excluded from participation in this study: 1. Heart transplantation 2. Repair of complex congenital abnormalities 3. Any known pulmonary, hepatic, or renal disease or any other major concomitant significant medical condition that might interfere with treatment evaluation according to the Investigator’s judgment 4. Known hypersensitivity or other severe reaction to any component of the IMP 5. Patients at high risk of thrombotic events unable to stop prophylactic low-molecular-weight heparin (LMWH) 12 hours and fondaparinux 24 hours before surgery (longer interval in case of impaired renal function) 6. Patients unable to stop treatment by vitamin K antagonists 3-5 days before surgery to obtain an international normalized ratio (INR) <1.5 7. Patients unable to stop treatment by direct oral anticoagulant at least 48 hours before surgery (except aspirin) 8. Patients unable to stop treatment by P2Y12 inhibitors before surgery (discontinuation duration before surgery: ticagrelor 3 days, clopidogrel 5 days, and prasugrel 7 days) [30] 9. Severe anemia with hemoglobin (Hb) ≤10 g/dL 10. Excessive hemodilution with hematocrit (Ht) <22% in men and women at the time of taking sample for FIBTEM MCF during the last 20 minutes of CPB 11. Congenital coagulation deficiencies (von Willebrand disease, factor V Leiden, Protein C deficiency, cryoglobulinemia, antiphospholipid syndrome…) 12. Any known thromboembolic disorder 13. Female of reproductive potential not using effective contraception (condoms; occlusive caps with spermicide; injectable, patch, or combined oral estro-progestative or progestative contraceptives; depot intramuscular medroxyprogesterone; or subcutaneous implants of progestative contraceptive implants) for at least one month prior to screening 14. Known pregnancy or positive blood pregnancy test for women of childbearing potential and/or breast-feeding women 15. Participation in another clinical study involving an investigational medicinal product within 30 days prior to screening or 5 half-lives of this investigational medicinal product, whichever is longer, or concomitantly with the study 16. Treatment with any fibrinogen concentrate and/or fibrinogen containing product within 32 days prior to infusion of FGTW 17. Previous cardiac surgical procedure within three months before randomization 18. Evidence or suspicion of infection (fever >38.5°C and white blood cell count >11/mm3) 19. Active endocarditis 20. Emergency surgery, patients in cardiogenic shock, or expected mortality within 24 hours of surgery 21. Pre-existing thrombocytopenia with platelet count < 150 000/ mm3 |
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary efficacy endpoint The primary efficacy endpoint is the number of units of allogeneic blood products (RBC plus FFP plus platelet concentrate) given to patients between randomization and 24 hours thereafter.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary endpoint will be evaluated 24 hours after randomization. |
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E.5.2 | Secondary end point(s) |
The secondary efficacy endpoints are defined as follows: 1. Blood drainage volume within 12 hours after randomization 2. Percentage of patients with total avoidance of allogeneic transfusions within 24 hours after randomization 3. Number of transfusion units infused between 24 hours after randomization and the hospital discharge for each class of allogeneic blood product (RBC, FFP, and platelet concentrate) 4. Volume of transfusion units infused between 24 hours after randomization and the hospital discharge for each class of allogeneic blood product (RBC, FFP, and platelet concentrate) 5. Number of pre-donated autologous RBC concentrate units, RBC concentrate prepared by cell-saver, colloids, and crystalloids after randomization 6. Mortality at 24 hours, 7 days, and 30 days after randomization 7. Percentage of patients with each surgical morbidity at 24 hours, 7 days, and 30 days after randomization (see Section 9.2.8) 8. Percentage of patients with post-surgery stage 1 AKI (with increase in creatinine by >50% from baseline until hospital discharge) 9. Percentage of patients with surgical re-exploration for bleeding within 24 hours after randomization 10. Percentage of patients with fibrinogen concentration below the LLN from visit 2 to visit 5 11. Percentage of patients receiving aPCCs, rFVIIa, cryoprecipitate or additional FC as rescue therapy within 24 hours after randomization 12. Duration of hospitalization 13. Length of stay in ICU |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
The timepoints for the secondary end points listed under E.5.2 are as follows: 1. Within 12h after randomization 2. Within 24h after randomization 3. Between 24h after randomization and the hospital discharge for each class of allogeneic blood product (RBC, FFP, and platelet concentrate) 4. Between 24h after randomization and the hospital discharge for each class of allogeneic blood product (RBC, FFP, and platelet concentrate) 5. After randomization 6 & 7. At 24h, 7 days, and 30 days after randomization 8. From baseline until hospital discharge 9. Within 24h after randomization 10. From the point fibrinogen concentration is below the LLN from visit 2 to visit 5 11. Within 24h after randomization 12. Duration of hospitalization 13. Length of stay in ICU |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 11 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
United Kingdom |
Germany |
Italy |
Spain |
Sweden |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | 8 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 5 |
E.8.9.2 | In all countries concerned by the trial days | 7 |