PRedicting OutcomeS in Preterm nEonates With thromboCyTopenia (PROSPECT)

Sponsor

Leiden University Medical Center (Other)

Overall Status

Recruiting

CT.gov ID

NCT06043050

Collaborator

Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA) (Other), Sanquin Research & Blood Bank Divisions (Other)

1,200

Enrollment

Locations

15.1

Anticipated Duration (Months)

109.1

Patients Per Site

7.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Rationale: Preterm neonates with low platelet counts receive prophylactic platelet transfusions with the aim to prevent bleeding. However, it is not clear in which cases platelet transfusions reduce the risk of bleeding or whether they do more harm than good. A large, randomized trial showed that the higher platelet count threshold for transfusion was associated with a higher rate of death and major bleeding, which suggests that platelet transfusions caused harm in neonates. To gain insight into the risk/benefits of platelet transfusions, the investigators will validate a recently developed dynamic prediction model for major bleeding in multiple NICUs in Europe and investigate the effects of prophylactic platelet transfusions on the risks of bleeding and potential transfusion-associated adverse events. This model could then be used in future studies to define enhanced indications for transfusion, with the ultimate goal to prevent transfusion-associated harm in this vulnerable population.

Objectives:

Validation of the existing dynamic prediction model in an international cohort of preterm neonates with severe thrombocytopenia (platelet count <50x10^9/L) admitted to a NICU.
Model amendment to enable prediction of bleeding risks under various hypothetical platelet transfusion strategies in preterm neonates with severe thrombocytopenia.
To examine whether prophylactic platelet transfusions are causally associated with the occurrence of bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC), proven sepsis, retinopathy of prematurity (ROP), major bleeding, and mortality.

Study design: Multicenter international retrospective cohort study.

Study population: Neonates with a gestational age <34 weeks and a platelet count <50x10^9/L, admitted to a NICU between January 1st 2017 and January 1st 2022.

Main study endpoints: Major bleeding, BPD, NEC, proven sepsis, ROP and mortality.

Nature and extent of the burden and risks associated with participation, benefit, and group relatedness: Not applicable, as this is a retrospective study.

Condition or Disease	Intervention/Treatment	Phase
Neonatal Thrombocytopenia Intraventricular Hemorrhage Platelet Transfusion

Detailed Description

INTRODUCTION AND RATIONALE

Which severely thrombocytopenic neonates do and which do not benefit from prophylactic platelet transfusions?

Most platelet transfusions are given prophylactically to non-bleeding neonates with severe thrombocytopenia (i.e., platelet count <50x10^{9/L) with the aim to prevent
bleeding. The underlying assumption is that correction of thrombocytopenia reduces the
risk of bleeding, as platelets play a crucial role in clot formation during hemostasis.
However, it is unclear below which platelet count threshold impaired primary hemostasis
results in a higher bleeding risk, and if this threshold is similar for all preterm
neonates. Furthermore, it is not clear in which cases platelet transfusions reduce the
risk of bleeding, or whether platelet transfusions do more harm than good. An
international randomized controlled trial (PlaNeT-2/MATISSE), which compared high
(50x10}9/L) versus low (25x10^9/L) prophylactic platelet transfusion thresholds in preterm neonates, revealed an unexpected increase in major bleeding or death in the high threshold group (26% versus 19%, OR 1.57; 95% CI, 1.06 to 2.32). These findings suggest that platelet transfusions in preterm neonates may cause harm. This highlights the need for research examining which neonates benefit from platelet transfusions. In the current study, the investigators aim to i) validate and update a dynamic prediction model for major bleeding, and ii) examine whether prophylactic platelet transfusions may be causally associated with potential transfusion-associated adverse events, such as bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC), proven sepsis, retinopathy of prematurity (ROP), major bleeding and mortality

Dynamic prediction model for major bleeding in thrombocytopenic neonates

The current platelet transfusion guidelines for prophylactic transfusion decisions are based on platelet count thresholds. However, serious questions are raised regarding the value of platelet counts as a trigger for prophylactic platelet transfusion decisions. Several studies found little correlation between the degree of thrombocytopenia and the incidence of bleeding in preterm neonates, suggesting that factors other than platelet count might be important determinants of bleeding risk in thrombocytopenic neonates. Two neonates with similar platelet counts but different clinical conditions may have distinct risks of bleeding, and may benefit differently from platelet transfusions. Their risks of bleeding can be predicted with a recently developed dynamic model that includes multiple clinical variables in addition to platelet count. As opposed to other prediction models for neonatal bleeding, the advantage of this dynamic model is that clinical variables that change over time (e.g. platelet count and mechanical ventilation) are also taken into account. In this way, the clinical course of neonates can be incorporated into the model and bleeding risk can be estimated at any time point during the first week after the onset of severe thrombocytopenia.

Model validation on new patients is necessary before use in clinical practice

Prediction models that perform well in the development cohort often perform worse in other cohorts, because they were developed to fit the original dataset. Before considering their use in clinical practice, they need to be validated in another cohort that includes patients representative of those in whom clinicians would want to use the prediction model. Therefore, the investigators will validate the dynamic model in a new cohort of preterm infants who are admitted to a neonatal intensive care unit (NICU) in Europe.

Prediction of bleeding risks under hypothetical platelet transfusion strategies

Although prediction and etiology are typically two distinct research domains that differ in their aim, use, and statistical approach, methods from both prediction research and causal inference research are required when the goal of the model is to inform decision-making. The investigators will amend the existing dynamic model to enable prediction of bleeding risks under different hypothetical platelet transfusion strategies, so the model can be used to predict bleeding risks if no prophylactic platelet transfusion would be provided ('untreated risk') and if a prophylactic platelet transfusion would be provided ('treated risk'). When the model shows a good predictive performance, it could be used to define indications for transfusion, and a randomized controlled impact study could be designed to compare the effect of model-based transfusion decisions with that of platelet count-based transfusion decisions. Ultimately, estimates of individualized treatment effects could be used for the development of individualized platelet transfusion guidelines to optimize transfusion strategies for preterm neonates.

SAMPLE SIZE CALCULATION

In 2019, 3089 neonates with a gestational age <34 weeks were born in the Netherlands, of which 2176 (70%) neonates were admitted to one of the NICUs in the Netherlands. Data on the incidence of bleeding outcomes in severely thrombocytopenic preterm neonates admitted to a Dutch NICU were available from the development cohort of the dynamic prediction model [6]. During an inclusion period of 5 years (2010-2014) in 7 participating NICUs, 640 (6.9%) severely thrombocytopenic neonates were included out of 9333 neonates with a gestational <34 weeks. In this population, 63 out of 640 (10%) neonates developed major bleeding, 73 out of 640 neonates died (11%), and 132 out of 640 neonates either developed major bleeding or died (21%) during the 10-day follow-up period. To determine the minimum sample size needed for external validation, the investigators used a formula proposed by Riley and colleagues to target precise estimation of the observed/expected (O/E) ratio, calibration slope and c-statistic. The researcher's calculations suggest that at least 1200 participants (120 events of major bleeding) are required to precisely estimate the calibration and discrimination measures, with this number driven by the calibration slope. Over a 5-year period, the investigators expect to include approximately 900 neonates (circa 90 major bleeding events) from all NICUs of the Netherlands and 300 neonates (circa 30 major bleeding events) from NICUs of other European countries.

STATISTICAL ANALYSIS

The investigators will write a full statistical analysis plan prior to the start of data analyses. Missing data will be handled using simple imputation or multiple imputations where appropriate.

ETHICAL CONSIDERATIONS

This study will be conducted according to the principles of the Declaration of Helsinki (64th WMA General Assembly, October 2013) and the General Data Protection Regulation (GDPR). In addition, the study will be reported according to the Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis or Diagnosis (TRIPOD) guidelines. The Medical Research Involving Human Subjects Act (WMO) does not apply. The investigators will submit the study protocol to the institutional review boards of the coordinating and participating centers for ethical (non-WMO) approval.

HANDLING AND STORAGE OF DATA

A data sharing agreement (DSA) will be signed between the initiating and participating centers about the intended use, confidentiality, security, data sharing, and potential financial costs. All required data for this study will be collected on electronic standardized Case Report Forms (eCRFs) in a Castor database by study personnel, which may include research nurses, data managers, medical students and PhD students, under supervision of the local and coordinating investigator. Only approved members of the research team (e.g. the coordinating investigator, principal investigators, dedicated data managers and statisticians) will have access to the database, requiring user ID and password access. The dataset is encoded and the patient identification log will be stored separately from the data. The subject identification logs will be kept locally per site. The investigators will make the database as little identifiable as possible, requiring substantial effort to trace data back to individuals.

MONITORING AND QUALITY ASSURANCE

Given the neglectable risk associated with this observational study, an official monitoring plan is not required.

PUBLIC DISCLOSURE AND PUBLICATION POLICY

Planned publication in open-access peer-reviewed international scientific journals. Furthermore, results will be published in a PhD thesis.

Study Design

Study Type:

Observational

Anticipated Enrollment :

1200 participants

Observational Model:

Cohort

Time Perspective:

Retrospective

Official Title:

Dynamic Prediction of Bleeding in Thrombocytopenic Preterm Neonates

Actual Study Start Date :

Sep 26, 2022

Anticipated Primary Completion Date :

Dec 31, 2023

Anticipated Study Completion Date :

Dec 31, 2023

Arms and Interventions

Arm	Intervention/Treatment
Neonates with severe thrombocytopenia Neonates with a gestational age <34 weeks and a platelet count <50x10^9/L admitted to a NICU between January 1st, 2017 and January 1st, 2022.

Outcome Measures

Primary Outcome Measures

Major or severe bleeding is the primary outcome. The investigators defined this as either one of the following: [The study start point (T0) is the 1st time the platelet count drops below 50x10^9/L. The primary outcome is major bleeding within 3 days during the first 2 weeks after the onset of severe thrombocytopenia.]
Major intracranial bleeding: IVH grade 3 (>50% of ventricular area or distended ventricle) or grade 4 (IVH of any grade in combination with parenchymal involvement) based on the Papile grading system Solitary (non-cerebellar) parenchymal hemorrhage (without IVH) visible on ultrasound (contrary to small bleeds visible only on MRI) Cerebellar hemorrhage visible on ultrasound (contrary to small bleeds visible only on MRI) Other types of intracranial hemorrhage (e.g. subdural hemorrhage) Pulmonary bleeding defined as an acute fresh bleed through the endotracheal tube, associated with increased ventilatory requirements. Life-threatening bleeding associated with shock, or bleeding (including gastrointestinal hemorrhage) requiring at least one of the following: Fluid boluses Red blood cell transfusion (in the same 24 hours) Inotropic agents (either start of inotrope therapy, or increased dose of current therapy)

Secondary Outcome Measures

Bronchopulmonary dysplasia (BPD) [36 weeks of postmenstrual age (PMA)]
The number of study participants with BPD defined as dependency on oxygen for at least 28 days and/or the need for respiratory support at 36 weeks of postmenstrual age (PMA).
Necrotizing enterocolitis (NEC) [Up to 4 weeks after the onset of severe thrombocytopenia]
The number of study participants with a new episode of NEC defined as ≥grade IIA as per Bell's criteria
Proven sepsis [Up to 4 weeks after the onset of severe thrombocytopenia]
The number of study participants with a new episode of proven sepsis, including both early-onset (<72 hours after birth) and late-onset (≥72 hours after birth) sepsis, and defined as a positive blood culture treated with antibiotics for 5 or more days or shorter if death occurred while receiving antibiotics. Blood cultures positive for organisms generally considered to be contaminants were only considered sepsis episodes if C-Reactive Protein (CRP) levels were >10 mg/L within 2 days of the blood culture or if there were at least two cultures positive for the organism.
Retinopathy of prematurity (ROP) [Up to 38 weeks of PMA]
The number of study participants with unilateral or bilateral ROP stage ≥2 for which treatment is indicated (e.g., laser or bevacizumab therapy) up to 38 weeks of PMA
Mortality [Mortality within 3 days during the first 2 weeks after the onset of severe thrombocytopenia.]
Mortality, including if deaths were related to major bleeding (either as a direct result or following withdrawal of life-supporting treatment because of major bleeding). In a sensitivity analysis, the investigators will also assess the composite outcome of major bleeding or mortality.

Eligibility Criteria

Criteria

Ages Eligible for Study:

23 Weeks to 34 Weeks

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Admission to a level III NICU;
Gestational age at birth <34 weeks;
Severe thrombocytopenia (platelet count <50x10^9/L).

Exclusion Criteria:

All neonates whose parents did not give consent for their child's data to be used;
Neonates who had only platelet counts <50x10^9/L) with a high suspicion of being spurious (e.g. clots in sample, spontaneous platelet 'recovery' within 6 hours, or platelet count labelled as spurious in medical files);
Major or life-threatening congenital malformations (e.g. requiring surgical intervention, and/or associated with a bleeding diathesis);
Confirmed immune hematologic disorders: immune hemolytic anemia (AIHA), neonatal autoimmune thrombocytopenia, fetal/neonatal alloimmune thrombocytopenia (FNAIT), autoimmune neutropenia (AIN);
Thrombocytopenia occurring exclusively in the context of exchange transfusion;
Major bleeding prior to severe thrombocytopenia.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Máxima Medical Center	Veldhoven	Brabant	Netherlands	5504 DB
2	Radboud University Medical Center, Amalia Children's hospital	Nijmegen	Gelderland	Netherlands	6525 GA
3	Maastricht University Medical Center, MosaKids	Maastricht	Limburg	Netherlands	6229 HX
4	Amsterdam University Medical Center, Emma Children's hospital, location VUmc	Amsterdam	North Holland	Netherlands	1081 HV
5	Amsterdam University Medical Center, Emma Children's hospital, location AMC	Amsterdam	North Holland	Netherlands	1105 AZ
6	Isala clinics	Zwolle	Overijssel	Netherlands	8025 AB
7	Leiden University Medical Center, Willem Alexander Children's hospital	Leiden	South Holland	Netherlands	2333 ZA
8	Erasmus University Medical Center, Sophia pediatric hospital	Rotterdam	South Holland	Netherlands	3015 CN
9	University Medical Center Groningen, Beatrix Children's hospital	Groningen		Netherlands	9713 GZ
10	University Medical Center Utrecht, Wilhelmina Children's hospital	Utrecht		Netherlands	3584 EA
11	Karolinska University Hospital	Stockholm	Södermanland And Uppland	Sweden	171 76

Sponsors and Collaborators

Leiden University Medical Center
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Sanquin Research & Blood Bank Divisions

Investigators

Study Director: Hilde van der Staaij, MD, Leiden University Medical Center and Sanquin Blood Supply Foundation
Principal Investigator: Suzanne F Fustolo-Gunnink, MD/PhD, Sanquin Blood Supply Foundation
Principal Investigator: Enrico Lopriore, MD/PhD/Prof, Leiden University Medical Center
Principal Investigator: Johanna G van der Bom, MD/PhD/Prof, Leiden University Medical Center
Principal Investigator: Karin Fijnvandraat, MD/PhD/Prof, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Principal Investigator: Wes Onland, MD/PhD, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Principal Investigator: Camila Caram-Deelder, MD/PhD, Leiden University Medical Center