| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Major bleeding during cardiac surgery not related to vitamin K antagonists |
|
| E.1.1.1 | Medical condition in easily understood language |
| Bleeding during cardiac surgery |
|
| E.1.1.2 | Therapeutic area | Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Surgical Procedures, Operative [E04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10051536 |
| E.1.2 | Term | Intraoperative bleeding |
| E.1.2 | System Organ Class | 100000004863 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10036277 |
| E.1.2 | Term | Postoperative bleeding |
| E.1.2 | System Organ Class | 100000004863 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10042609 |
| E.1.2 | Term | Surgery |
| E.1.2 | System Organ Class | 10042613 - Surgical and medical procedures |
|
| 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 |
| To determine the recruitment rate – defined as proportion of participants who consent to the study and receive intervention. |
|
| E.2.2 | Secondary objectives of the trial |
1. Assess the delivery of different components of the trial
2. Compare the impact of FFP and PCC on the haemostatic capacity of bleeding patients, through the use of standard clotting tests and other global clotting tests.
3. Perform qualitative research to obtain input from patients, public and healthcare professionals on the design/running of the large trial, as well as identify the most important primary/secondary outcomes for the trial.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Title: Obtaining Patient and public input and reaching a consensus on outcome measures for the PROPHESY trial
Version 01
Objectives: To identify and reach consensus on the main outcome measures to be used in the large multicentre PROPHESY trial
|
|
| E.3 | Principal inclusion criteria |
- Age ≥18 years
- Able to give consent
- Any cardiovascular surgeries excluding procedures under exclusion criteria
|
|
| E.4 | Principal exclusion criteria |
A participant is not eligible if any of the following criteria are met:
- Unable to consent
- Patients refusing blood transfusion for any reason
- First time isolated coronary artery bypass grafts (CABG)
- First time isolated aortic valve replacement (excluding active endocarditis)
- Thoraco-abdominal surgeries
- Minor surgeries that do not involve cardiopulmonary bypass
- Use of warfarin within three days
- Use of direct oral anticoagulants (i.e. dabigaran, rivaroxban, apixaban or edoxaban) within 48 hrs (or 72 hours if patient has renal impairment – i.e. estimated glomerular filtration rate of <30ml/min)
- Inherited bleeding disorder (i.e. any inherited clotting factor deficiencies, or platelet disorders)
- Pregnancy
- Known or suspected allergy to FFP, or LG-octaplas, or PCC
- Known or suspected allergy to heparin, Sodium citrate dihydrate, sodium
dihydrogenphosphate dihydrate and Glycine
- History of Heparin-induced thrombocytopenia
- Individuals who have IgA deficiency with known antibodies against IgA
- Documented venous thromboembolism in the last three months
- Documented antiphospholipid syndrome
- Severe Protein S deficiency
- Patients who are likely to go on Extracorporeal Membrane Oxygenation (ECMO) after cardiac surgery
- Any other reasons the investigator may consider the patient to be ineligible for the study
- Participation in another clinical trial, where the patient has received IMP in the last 3 months |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The proportion of eligible participants who consent, and the proportion of participants who are randomised and receive intervention within 24 hours of surgery, out of all consenting participants. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Time to study drug administration
Proportion of patients for whom clinical outcome data were collected up to 90 days, or death, whichever occur first
Proportion of patients who are randomised within 24 hours of surgery
Proportion of participants who consent, bleed and receive a protocol intervention within 24 hours of surgery (whether or not they are randomised)
Proportion of patients for whom timing of administration, and completion of intervention(s) were documented
Proportion of patients where there was protocol adherence, and protocol violation
Reasons for non-participation
Proportion of patients who do not consent to intervention, but agree to collection of de-identified data for up to 24 hours after surgery
Obtain data on event rates in control group to help estimate the sample size for the large trial
Clinical data that will be collected for eligible participants who have consented but not received intervention, and those who have agreed to provide pseudo-anonymised data for up to 24 hours after surgery
- Baseline data: age, gender, hospital, type of surgery,
- Previous medical history
- Type of surgery
- Date of admission
- clinical data for up to 24 hours after surgery
Clinical data that will be collected for participants who have consented and who receive intervention
- Baseline data: age, gender, hospital, type of surgery,
- Previous medical history
- Type of surgery
- Date of discharge
- Mortality (all cause) up to 90 days
- Date and time of administration and cessation of study drug
- time from intervention to chest closure
- amount and type of fluid and other haemostatic agents administered in the first 24 hours after randomisation.
- number of patients who require resternotomy within 24 hours of first surgery;
- total blood loss collected in chest drains in first 24 hours or until drain removal (whichever comes first)
- thrombotic events (arterial and venous) as confirmed by radiological imaging
- overall transfusion at 24 hours and until hospital discharge or 28 days, or death, whichever is first
- length of stay in Intensive Care/High Dependency units
- single or multiple organ failure
- Duration of organ support (i.e. ventilatory, cardiovascular, and renal replacement support)
- severe sepsis
- transfusion related side effects
- any other known and unknown Serious Adverse Event
For patients who are consented, as a pragmatic feasibility trial, there is awareness that there may be situations outside of the research team’s control where;
1. The subject bleeds and receives intervention, but was not randomised
2. The subject is randomised but does not receive intervention e.g. bleeding stops post intervention request
Analysis of this data will be according to the statistical analysis plan, and these cases will be identified in the analysis and publication. These patients will still be followed up for 3 months, to capture data for these subjects for safety analysis.
2) Haemostatic capacity of patients
For assessment of haemostatic capacity, an additional 15 mL blood samples will be taken at three-time points: prior to intervention, within one hour of intervention being completed, and 24 hours after intervention administration. Haemostatic capacity will be determined through assessment of individual clotting factors, thrombin generation markers, endothelial markers and anticoagulant activity.
3) Qualitative research
A Delphi survey will be sent to 15 experts (cardiothoracic surgeons, anaesthetists, transfusion laboratory scientists, pre-assessment nurses and haematologists – three on each group) and 3 members of a Barts patient and public (PPI) group to reach a consensus on components of the primary and secondary outcome that they consider to be
most important.
We will also conduct research interviews with 6 patients (and their families) participating in the study to explore understanding of, and experience, with the intervention delivered; and get their input on the most important clinical outcome data that we need to collect for the large trial. Clinical staff who are involved with the pilot study (cardiothoracic
surgeons, anaesthetists, and pre-assessment nurses, laboratory scientists n= 8, two from each group) will also be interviewed to understand: how best to optimise the identification of participants; how to optimise the recruitment and consent of participants; and how to improve adherence of the trial protocols. Interviews will be recorded, transcribed
and analysed using thematic analysis.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| At time of consent, at time of intervention administration, 24 hours post surgery, 90 days post surgery. |
|
| 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 | Yes |
| E.6.4 | Safety | No |
| E.6.5 | Efficacy | No |
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
| Feasibility of a larger trial |
|
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| LG-Octaplas, Fresh Frozen Plasma (FFP) |
|
| 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| 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
|
| The end of trial definition for this study will be the last subject finishes the last visit and data collection point, or when the the last alive subject recruited into the trial has completed the follow up visit - whichever is later. |
|
| 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 | 9 |
| E.8.9.1 | In the Member State concerned days | 2 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
Print
