Clinical Trial Results:
Albumin vs. Plasma for PEdiAtric pRiming (APPEAR) trial
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Summary
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EudraCT number |
2014-000177-39 |
Trial protocol |
IT |
Global end of trial date |
31 Jan 2018
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Results information
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Results version number |
v1(current) |
This version publication date |
19 Nov 2021
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First version publication date |
19 Nov 2021
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Other versions |
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Summary report(s) |
Published paper including results of the study |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
Linea7-2013/06-APPEAR
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02738190 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
IRCCS Policlinico San Donato
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Sponsor organisation address |
Piazza Edmondo Malan 2, San Donato Milanese, Italy, 20097
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Public contact |
Study Coordinator, IRCCS Policlinico San Donato, 39 0252774754, ekaterina.baryshnikova@gmail.com
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Scientific contact |
Study Coordinator, IRCCS Policlinico San Donato, 39 0252774754, ekaterina.baryshnikova@gmail.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
31 Jan 2018
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
31 Jan 2018
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
Compare the effects of extracorporeal circulation circuit priming containing Albumin 5% versus fresh frozen plasma of hemostasis and coagulation
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Protection of trial subjects |
This study was approved by the Local Ethics Committee (San Raffaele Hospital, protocol number 116/int/2017, approved on 12 October 2017), and parents of all patients provided a written informed consent.
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Background therapy |
Every subject received our standard surgical care and CPB technique. A total intraoperative dose of 30 mg/kg of tranexamic acid was administered in all patients. CPB was established after a loading dose of 300 IU/kg of unfractioned heparin plus additional doses (80 IU/kg) to reach and maintain a target activated clotting time >= 450 s. The CPB circuit included a hollow-fibre oxygenator, a roller head pump, or a centrifugal pump. The target patient temperature was chosen based on the type of surgical procedure and cardioplegia protocol. Every volume addition needed during CPB was made giving albumin 5% or RBCs according to our target hematocrit. Ultrafiltration was a standard of care; conventional or modified ultrafiltration was applied during and after CPB, respectively, according to surgeon's preference. The ultrafiltrated volume was fixed at 30 ml/kg. During ultrafiltration, patients on the late FFP arm had half of the volume replaced with FFP (15 ml/kg). With the same timing, patients in the early FFP group received the same replacement with albumin 5%. Patients in the late FFP arm received an additional dose of 15 ml/kg of FFP during hemostasis and before transfer to the ICU. | ||
Evidence for comparator |
In newborns and small infants undergoing cardiac surgery, red blood cells (RBCs) are usually added to the CPB priming volume to prevent excessive haemodilution. At the same time, maintenance of physiologic colloid oncotic pressure during CPB must be preserved to prevent interstitial fluid accumulation; this is achieved by adding either 5% albumin, fresh frozen plasma (FFP), or colloids to priming. At present, few studies have investigated the superiority of FFP or albumin-based priming solutions in newborns and small infants, and the results are conflicting. Potential advantages of the use of albumin in the priming solution are avoidance or limitation of exposure to allogeneic blood-derived FFP and prevention of fibrinogen adsorbtion and platelet adhesion to the foreign surfaces of the CPB circuit and oxygenator. Conversely, FFP-based priming may retain a slightly higher colloid oncotic pressure and prevent haemodilution of soluble coagulation factors and fibrinogen. | ||
Actual start date of recruitment |
01 Mar 2014
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Italy: 80
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Worldwide total number of subjects |
80
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EEA total number of subjects |
80
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
17
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Infants and toddlers (28 days-23 months) |
63
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
0
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
The first patient was randomized on January 22, 2015, and the last on March 16, 2016. | |||||||||
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Pre-assignment
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Screening details |
213 patients were considered eligible for the study (considering the elective cardiac surgery requiring CPB, weight < 10 kg, blood priming required). 133 patients were excluded (declined to participate, not meeting inclusion criteria, no staff available). 80 patients were enrolled and randomized. | |||||||||
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Pre-assignment period milestones
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Number of subjects started |
80 | |||||||||
Number of subjects completed |
80 | |||||||||
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Period 1
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Period 1 title |
Overall data (overall period)
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Is this the baseline period? |
Yes | |||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Single blind | |||||||||
Roles blinded |
Subject | |||||||||
Blinding implementation details |
The attending anesthesiologist and the surgical staff were not blinded; conversely, ICU and ward doctors were blinded, as well as the person in charge of database data entry.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Late FFP (albumin priming) | |||||||||
Arm description |
Patients in this group receive priming required to start the cardiopulmonary bypass made of albumin 5% and red blood cells. The solution is titrated to reach an on-pump hematocrit of 30%. The volume of RBCs used in the priming solution varied according to the patient's baseline HCT and weight and priming volume. | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
Albumin
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Intravenous use, Extracorporeal use
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Dosage and administration details |
5% albumin solution was used instead of fresh frozen plasma for priming solution preparation, titrated to reach an on-pump hematocrit (HCT) of 30%. In this arm, CPB priming was formulated with albumin 5% and RBCs. The volume of RBCs used varied according to the patient's baseline hematocrit (HCT), weight and priming volume.
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Arm title
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Early FFP (FFP priming) | |||||||||
Arm description |
Patients in the early FFP group received priming solution made of fresh frozen plasma (FFP) and red blood cells (RBC). The priming was titrated to achieve an on-pump hematocrit (HCT) of 30%. The volume of RBCs used varied according to the patient's baseline HCT, weight, and priming volume. | |||||||||
Arm type |
Placebo | |||||||||
Investigational medicinal product name |
Fresh Frozen Plasma
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Extracorporeal use, Intravenous use
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Dosage and administration details |
Patients in the early FFP arm received a priming solution with FFP plus RBCs. The solution was titrated to reach an "on pump" hematocrit of 30%. The amount of RBCs used for priming varied depending on the patient's baseline hematocrit, weight, and priming volume. The "clear prime volume" (FFP) was obtained as the difference between the circuit priming volume and the calculated amount of RBCs.
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Baseline characteristics reporting groups
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Reporting group title |
Late FFP (albumin priming)
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Reporting group description |
Patients in this group receive priming required to start the cardiopulmonary bypass made of albumin 5% and red blood cells. The solution is titrated to reach an on-pump hematocrit of 30%. The volume of RBCs used in the priming solution varied according to the patient's baseline HCT and weight and priming volume. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Early FFP (FFP priming)
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Reporting group description |
Patients in the early FFP group received priming solution made of fresh frozen plasma (FFP) and red blood cells (RBC). The priming was titrated to achieve an on-pump hematocrit (HCT) of 30%. The volume of RBCs used varied according to the patient's baseline HCT, weight, and priming volume. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Late FFP (albumin priming)
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Reporting group description |
Patients in this group receive priming required to start the cardiopulmonary bypass made of albumin 5% and red blood cells. The solution is titrated to reach an on-pump hematocrit of 30%. The volume of RBCs used in the priming solution varied according to the patient's baseline HCT and weight and priming volume. | ||
Reporting group title |
Early FFP (FFP priming)
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Reporting group description |
Patients in the early FFP group received priming solution made of fresh frozen plasma (FFP) and red blood cells (RBC). The priming was titrated to achieve an on-pump hematocrit (HCT) of 30%. The volume of RBCs used varied according to the patient's baseline HCT, weight, and priming volume. | ||
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End point title |
Postoperative bleeding | ||||||||||||
End point description |
Postoperative blood loss from chest drains
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End point type |
Primary
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End point timeframe |
First 24 postoperative hours
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| Notes [1] - Three patients in the group were withdrawn due to the need for extracorporeal membrane oxygenation. [2] - Four patients in the group were withdrawn due to the need for extracorporeal membrane oxygenation. |
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Statistical analysis title |
Comparison of postoperative bleeding between arms | ||||||||||||
Statistical analysis description |
Postoperative bleeding from chest drains during the first 24 postoperative hours was significantly (p=0.028) higher in the late FFP arm than in the early FFP arm.
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Comparison groups |
Late FFP (albumin priming) v Early FFP (FFP priming)
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Number of subjects included in analysis |
73
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Analysis specification |
Pre-specified
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Analysis type |
equivalence | ||||||||||||
P-value |
= 0.028 | ||||||||||||
Method |
t-test, 2-sided | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Confidence interval |
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End point title |
Postoperative bleeding | ||||||||||||
End point description |
Postoperative blood loss standardized for weight
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End point type |
Primary
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End point timeframe |
First 24 postoperative hours
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| Notes [3] - Three patients in the group were withdrawn due to the need for extracorporeal membrane oxygenation. [4] - Four patients in the group were withdrawn due to the need for extracorporeal membrane oxygenation. |
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Statistical analysis title |
Difference between arms | ||||||||||||
Statistical analysis description |
Chest drain blood loss in the first 24 postoperative hours was significantly higher in the late FFP group than in the early FFP group.
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Comparison groups |
Early FFP (FFP priming) v Late FFP (albumin priming)
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Number of subjects included in analysis |
73
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Analysis specification |
Pre-specified
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Analysis type |
equivalence | ||||||||||||
P-value |
= 0.028 | ||||||||||||
Method |
t-test, 2-sided | ||||||||||||
Confidence interval |
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End point title |
Incidence of severe bleeding | |||||||||
End point description |
Severe bleeding was arbitrarily defined as a chest drain blood loss > 30 ml/kg (roughly corresponding to the upper tertile of chest blood loss in our historical database).
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End point type |
Primary
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End point timeframe |
First 24 postoperative hours
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| Notes [5] - Three patients in the group were withdrawn due to the need for extracorporeal membrane oxygenation. [6] - Four patients in the group were withdrawn due to the need for extracorporeal membrane oxygenation. |
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Statistical analysis title |
Difference in incidence of severe bleeding | |||||||||
Statistical analysis description |
Seventeen patients (46%) in the late FFP group experienced a serious bleed vs. 7 (19.4%) in the early FFP arm.
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Comparison groups |
Late FFP (albumin priming) v Early FFP (FFP priming)
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Number of subjects included in analysis |
73
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Analysis specification |
Pre-specified
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Analysis type |
equivalence | |||||||||
P-value |
= 0.016 | |||||||||
Method |
Fisher exact | |||||||||
Parameter type |
Risk ratio (RR) | |||||||||
Point estimate |
3.5
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Confidence interval |
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level |
95% | |||||||||
sides |
2-sided
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lower limit |
1.2 | |||||||||
upper limit |
10 | |||||||||
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End point title |
Transfusion of Platelet Concentrates | |||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
First 48 postoperative hours
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| Notes [7] - Three patients in the group were withdrawn due to the need for extracorporeal membrane oxygenation. [8] - Four patients in the group were withdrawn due to the need for extracorporeal membrane oxygenation. |
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| No statistical analyses for this end point | ||||||||||
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End point title |
Fibrinogen concentrate administration | |||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
First 48 postoperative hours
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| Notes [9] - Three patients in the group were withdrawn due to the need for extracorporeal membrane oxygenation. [10] - Four patients in the group were withdrawn due to the need for extracorporeal membrane oxygenation. |
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| No statistical analyses for this end point | ||||||||||
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End point title |
Dose of fibrinogen concentrate administration | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
First 48 postoperative hours
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| Notes [11] - Three patients in the group were withdrawn due to the need for extracorporeal membrane oxygenation. [12] - Four patients in the group were withdrawn due to the need for extracorporeal membrane oxygenation. |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Mechanical ventilation duration | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Duration of mechanical ventilation during the ICU stay
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| Notes [13] - Three patients in the group were withdrawn due to the need for extracorporeal membrane oxygenation. [14] - Four patients in the group were withdrawn due to the need for extracorporeal membrane oxygenation. |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
ICU stay | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Overall stay in the intensive care unit
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| Notes [15] - Three patients in the group were withdrawn due to the need for extracorporeal membrane oxygenation. [16] - Four patients in the group were withdrawn due to the need for extracorporeal membrane oxygenation. |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Postoperative hospital stay | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Postoperative hospital stay, from the day of surgery to the day of discharge.
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| Notes [17] - Three patients in the group were withdrawn due to the need for extracorporeal membrane oxygenation. [18] - Four patients in the group were withdrawn due to the need for extracorporeal membrane oxygenation. |
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| No statistical analyses for this end point | |||||||||||||
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Adverse events information [1]
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Timeframe for reporting adverse events |
Overall hospital stay
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Adverse event reporting additional description |
No serious adverse drug reactions (SADRs) nor serious adverse events (SAEs) specifically related to the study procedures have been observed.
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Assessment type |
Non-systematic | ||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||
Dictionary version |
24.0
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| Frequency threshold for reporting non-serious adverse events: 0% | |||
| Notes [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported. Justification: No non-serious adverse events have been recorded for this trial. |
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? No | |||
Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| We have no specific limitations and caveats for this summary of the results to notify. | |||
Online references |
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| http://www.ncbi.nlm.nih.gov/pubmed/28510741 |
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