Table 4. Flow chart of study procedures and information collected at each study visit*.
| Assessments | Visit 1POD 0Prerandomisation visit(blood bank) | Visit 2POD 0–1First visit after IMP initiation(0–24 hours after IMP initiation)† | Visit 3POD 2–7 after IMP initiation (or at discharge if earlier) | Visit 4POD 30 after IMP initiation (in person if in hospital or by phone) |
| Blood bank receives PCC or FP order‡ | x | |||
| Inclusion and exclusion criteria§ | x | |||
| Body weight | x | |||
| Randomisation | x | |||
| IMP (PCC or FP) administration¶ | x | |||
| Patient (or legally authorised representative) debriefing and consent** | x | (x) | (x) | |
| Baseline data | ||||
| Demographics | x | |||
| Medical history | x | |||
| Preoperative medications | x | |||
| Laboratory assessments | X | |||
| Surgical data | ||||
| Bleeding score | x | |||
| Intraoperative medications | x | |||
| CPB time | x | |||
| Cross-clamp time | x | |||
| Circulatory arrest | x | |||
| Fluid intake and output monitoring | x | |||
| Inotropes and vasopressors | x | |||
| Start and end time of IMP administration | X | |||
| OR length of stay | x | |||
| Laboratory assessments | ||||
| Clinical chemistry†† | x | x | ||
| Haematology (CBC)†† | x‡‡ | x§§ | ||
| Coagulation measures††¶¶ | x*** | x | ||
| Safety laboratory analyses†† | x | x | ||
| INR | x††† | |||
| Transfusions and haemostatic therapies and timings | ||||
| Second dose of PCC (IMP), if needed‡‡‡ | x | |||
| Second dose of FP (IMP), if needed‡‡‡ | x | |||
| FP (non-interventional) | x | x | ||
| RBCs | x | x | ||
| Pooled and apheresis platelets | x | x | ||
| Cryoprecipitate | x | x | ||
| Fibrinogen concentrate | X | X | ||
| Activated recombinant factor VII | x | x | ||
| Other haemostatic products | x | x | ||
| Blood loss determination | ||||
| Total chest tube drainage at 1, 6, 12 and 24 hours after chest closure | X | X | ||
| Bleeding-related clinical endpoints | ||||
| Occurrence of intracerebral haemorrhage§§§ | x | X | ||
| Occurrence of gastrointestinal haemorrhage§§§ | x | X | ||
| Occurrence of surgical re-exploration§§§ | x | X | ||
| Extubation time | x | (x) | (x) | |
| ICU length of stay | (x) | (x) | ||
| Hospital length of stay | (x) | (x) | ||
| Hospital readmissions | X | |||
| AEs and SAEs | x | x | x | |
| Concomitant medications | x | x | x | |
| Patient survival | X |
() If needed.
All data are collected by trained research personnel. All outcome data collectors are blinded research personnel. In-hospital data are obtained from patients or their medical records and recorded into electronic case report forms (eCRFs) with validity checks (see online supplemental appendixAppendix). Post--discharge data are collected from the patients by blinded research personnel. Independent monitors review collected data against patients’ records to ensure completeness and accuracy. Missing data or loss to follow-up should be minimal as the vast majority of data is are in-hospital. The investigator will ensure that the patient’s confidentiality is preserved. On CRFs or any other documents submitted to the sponsor, the patients are not identified by their names, but by a unique patient identifier. Documents not intended for submission to the sponsor, that is, the confidential patient identification code list, original consent forms, and source records, are maintained by the investigator in strict confidence.
For any specified activity that cannot be completed during the first visit after IMP initiation, additional visits are made on postoperative day 1 until all study data are obtained.
After the start of surgery.
In the USA, a screening visit is performed ≤28 days before surgery to apply the study inclusion criteria requiring that the patient is aged ≥18 years, is to undergo index cardiac surgery employing CPB and provides written informed consent, as well as to apply all exclusion criteria. If screening is performed before the day of surgery, the exclusion criterion of severe right heart failure (clinical diagnosis±echocardiography) is rechecked on the day of surgery.
IMP is administered during surgery based on objective clinical criteria of bleeding status and point-of-care INR, as assessed by the surgical staff.
At study centres in Canada, due to the emergency nature of the condition being studied, informed consent is obtained from the patient or legally authorised representative as soon as possible after surgery. If neither the patient nor the legally authorised representative is reachable for consent during the follow-up period, a family member who is not a legally authorised representative is provided with an opportunity to object to the patient’s participation in the study. In the USA, prospective, voluntarily given, written (signed and dated), informed consent must be obtained from the patient at a screening visit performed ≤28 days before surgery. Model informed consent forms are provided in Appendix.
As per standard practice.
Measure haemoglobin within 30 min before and at 60 min after IMP initiation.
Measure haemoglobin at 24 hours after IMP initiation and document results.
For example, PT, aPTT, INR, plasma fibrinogen level, ROTEM EXTEM CT and MCF, FIBTEM MCF, platelet count and function (PlateletWorks; Helena Laboratories, Texas, USA). Either ROTEM or TEG can be used.
Measure INR within 30 min before and at 60 min after IMP initiation and document results.
If the patient continues to have at least moderate bleeding and a suspected coagulation deficiency (eg, INR ≥1.5) after completion of the first dose.
If the patient continues to have at least moderate bleeding and a suspected coagulation deficiency (eg, INR ≥1.5) after completion of the first dose.
Data collected during visit 2 (0–24 hours after IMP initiation).
AE, adverse event; aPTT, activated partial thromboplastin time; CBC, complete blood count; CPB, cardiopulmonary bypass; CT, clotting time; DC, discharge; FP, frozen plasma; ICU, intensive care unit; IMP, investigational medicinal product; INR, international normalised ratio; MCF, maximum clot firmness; OR, operating room; PCC, prothrombin complex concentrate; POD, postoperative day; PT, prothrombin time; RBC, red blood cell; ROTEM, rotational thromboelastometry; SAE, serious adverse event; TEG, thrombelastography