E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Neonates and infants who are at risk of mediastinal bleeding following cardiopulmonary bypass surgery for congenital heart disease |
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E.1.1.1 | Medical condition in easily understood language |
Babies and young infants (<12kg) with congenital heart disease who require major heart surgery using cardiopulmonary bypass, and are thus at risk of postoperative bleeding from within the chest |
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E.1.1.2 | Therapeutic area | Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 16.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10055817 |
E.1.2 | Term | Haemorrhage intrapericardial |
E.1.2 | System Organ Class | 100000004849 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 16.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10010495 |
E.1.2 | Term | Congenital heart disease NOS |
E.1.2 | System Organ Class | 100000004850 |
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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 |
To determine the dose of intraoperative human fibrinogen concentrate required to achieve physiological levels of fibrin polymerization of 8 to 13 mm as measured by the ROTEM measure of fibrin-based clotting: FibTEM MCF (equating to plasma fibrinogen concentrations of 1.5 to 2.5 g/L), immediately prior to separation from cardiopulmonary bypass in
neonates and children < 12kg |
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E.2.2 | Secondary objectives of the trial |
(a) To provide preliminary efficacy and safety data following human fibrinogen concentrate administration
(b) To document ROTEM profiles intra- and post-operatively |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
i) Congenital heart disease requiring non-emergency* surgery on cardiopulmonary bypass
ii) Age range: > 36 weeks corrected gestation
iii) Weight 2.5 – 12 kg
iv) Informed consent to participate
*Non-emergency is defined as surgery that can be delayed >24 hours following diagnosis of congenital heart disease |
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E.4 | Principal exclusion criteria |
i) Known pre-existing inherited coagulopathy
ii) Known pre-existing inherited thrombophilia
iii) Recent, acute (within previous 2 weeks) thrombosis in a major vessel or thrombotic-related major complications (as defined in sections 2.43 and 7.3)
iv) Administration of antiplatelet agents (e.g. aspirin) <48 hrs prior to surgery
v) Known hypersensitivity / allergy to study drug or similar products
vi) History of anaphylaxis
vii) Enrolment in another clinical trial in the previous 3 months
viii) Parent/guardian unable to provide informed consent (this can include insufficient understanding of the trial, as judged by the clinician taking consent)
ix) major co-morbidity likely to increase risk of mortality from surgical procedure
x) significant renal/liver impairment within 2 days of planned surgery (creatinine > 2x ULN, ALT > 2x ULN) |
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E.5 End points |
E.5.1 | Primary end point(s) |
Fibrinogen concentration and Fib-TEM MCF measured within 5 minutes of completion of IMP administration
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Within 5 minutes of completion of IMP administration |
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E.5.2 | Secondary end point(s) |
(ACTIVE and MONITORING arms)
Efficacy
•Mediastinal drain losses in first 24 hours after PICU admission
• Requirement for delayed sternal closure due to clinical bleeding / tamponade
•Requirement for ancillary blood transfusions in first 24 hours after PICU admission
•Use of intra- and post-operative ancillary clotting products (as per transfusion algorithm)
•Fibrinogen levels and ROTEM variables T4 – T6
Safety
#Incidence of major thrombotic event / thromboembolic-associated complications
•surgical shunt occlusion
•imaging evidence of intracardiac/major vessel thrombosis up to discharge or day 30 post operative
•Stroke from sinovenous thrombosis or arterial ischaemia of cardioembolic origin
•Pulmonary embolism
•Superior vena cava syndrome
•Thrombotic vessel obstruction requiring active treatment with:
thrombolysis/mechanical intervention (open thrombectomy, cardiac catheter)
•Cardiopulmonary arrest associated with thrombosis
#allergic / hypersensitivity reaction to study drug
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
All safety analyses will be up to hospital discharge or day 30 post operative (whichever comes first).
The remaining endpoints will be evaluated up to 24 hours after (Paediatric Intensive Care Unit (PICU) admission with Fibrinogen levels and ROTEM variables evaluated at timepoints T4 - T6.
T4: at Paediatric intensive care Unit (PICU) admission
T5: 4hrs after PICU admission
T6: 24hrs after PICU admission |
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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 | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
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) | 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) | 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
| 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 | 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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LVLS (90th patient in the ACTIVE arm) |
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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 | 2 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |