PRedicting OutcomeS in Preterm nEonates With thromboCyTopenia (PROSPECT)

Intraventricular Hemorrhage Clinical Trial

— PROSPECT  

Official title:

Dynamic Prediction of Bleeding in Thrombocytopenic Preterm Neonates

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06043050
• Other study ID #: 22-3028
• Status: Recruiting
• Start date: September 26, 2022
• Est. completion date: December 31, 2023

Study information

• Verified date: September 2023
• Source: Leiden University Medical Center
• Contact: Hilde van der Staaij, MD
• Phone: +31 (0)71 5262965
• Email: h.van_der_staaij[@]lumc.nl
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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:

1. 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.

2. Model amendment to enable prediction of bleeding risks under various hypothetical platelet transfusion strategies in preterm neonates with severe thrombocytopenia.

3. 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.

Description:

1. 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.

2. 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.

3. 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.

4. 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.

5. 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.

6. MONITORING AND QUALITY ASSURANCE

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

7. PUBLIC DISCLOSURE AND PUBLICATION POLICY

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

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 1200
• Est. completion date: December 31, 2023
• Est. primary completion date: December 31, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 23 Weeks to 34 Weeks

Eligibility

Inclusion Criteria:

1. Admission to a level III NICU;

2. Gestational age at birth <34 weeks;

3. Severe thrombocytopenia (platelet count <50x10^9/L).

Exclusion Criteria:

1. All neonates whose parents did not give consent for their child's data to be used;

2. 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);

3. Major or life-threatening congenital malformations (e.g. requiring surgical intervention, and/or associated with a bleeding diathesis);

4. Confirmed immune hematologic disorders: immune hemolytic anemia (AIHA), neonatal autoimmune thrombocytopenia, fetal/neonatal alloimmune thrombocytopenia (FNAIT), autoimmune neutropenia (AIN);

5. Thrombocytopenia occurring exclusively in the context of exchange transfusion;

6. Major bleeding prior to severe thrombocytopenia.

Related Conditions & MeSH terms

• Hemorrhage
• Intraventricular Hemorrhage
• Neonatal Thrombocytopenia
• Platelet Transfusion
• Thrombocytopenia

Locations

Country	Name	City	State
Netherlands	Amsterdam University Medical Center, Emma Children's hospital, location AMC	Amsterdam	North Holland
Netherlands	Amsterdam University Medical Center, Emma Children's hospital, location VUmc	Amsterdam	North Holland
Netherlands	University Medical Center Groningen, Beatrix Children's hospital	Groningen
Netherlands	Leiden University Medical Center, Willem Alexander Children's hospital	Leiden	South Holland
Netherlands	Maastricht University Medical Center, MosaKids	Maastricht	Limburg
Netherlands	Radboud University Medical Center, Amalia Children's hospital	Nijmegen	Gelderland
Netherlands	Erasmus University Medical Center, Sophia pediatric hospital	Rotterdam	South Holland
Netherlands	University Medical Center Utrecht, Wilhelmina Children's hospital	Utrecht
Netherlands	Máxima Medical Center	Veldhoven	Brabant
Netherlands	Isala clinics	Zwolle	Overijssel
Sweden	Karolinska University Hospital	Stockholm	Södermanland And Uppland

Sponsors (3)

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

Countries where clinical trial is conducted

Netherlands,  Sweden, 

References & Publications (20)

Altman DG, Vergouwe Y, Royston P, Moons KG. Prognosis and prognostic research: validating a prognostic model. BMJ. 2009 May 28;338:b605. doi: 10.1136/bmj.b605. No abstract available. — View Citation

Baer VL, Lambert DK, Henry E, Christensen RD. Severe Thrombocytopenia in the NICU. Pediatrics. 2009 Dec;124(6):e1095-100. doi: 10.1542/peds.2009-0582. Epub 2009 Nov 16. — View Citation

Curley A, Stanworth SJ, Willoughby K, Fustolo-Gunnink SF, Venkatesh V, Hudson C, Deary A, Hodge R, Hopkins V, Lopez Santamaria B, Mora A, Llewelyn C, D'Amore A, Khan R, Onland W, Lopriore E, Fijnvandraat K, New H, Clarke P, Watts T; PlaNeT2 MATISSE Collaborators. Randomized Trial of Platelet-Transfusion Thresholds in Neonates. N Engl J Med. 2019 Jan 17;380(3):242-251. doi: 10.1056/NEJMoa1807320. Epub 2018 Nov 2. — View Citation

Davenport P, Sola-Visner M. Hemostatic Challenges in Neonates. Front Pediatr. 2021 Mar 2;9:627715. doi: 10.3389/fped.2021.627715. eCollection 2021. — View Citation

Foglia EE, Roberts RS, Stoller JZ, Davis PG, Haslam R, Schmidt B; Trial of Indomethacin Prophylaxis in Preterms Investigators. Effect of Prophylactic Indomethacin in Extremely Low Birth Weight Infants Based on the Predicted Risk of Severe Intraventricular Hemorrhage. Neonatology. 2018;113(2):183-186. doi: 10.1159/000485172. Epub 2017 Dec 20. — View Citation

Fustolo-Gunnink SF, Fijnvandraat K, Putter H, Ree IM, Caram-Deelder C, Andriessen P, d'Haens EJ, Hulzebos CV, Onland W, Kroon AA, Vijlbrief DC, Lopriore E, van der Bom JG. Dynamic prediction of bleeding risk in thrombocytopenic preterm neonates. Haematologica. 2019 Nov;104(11):2300-2306. doi: 10.3324/haematol.2018.208595. Epub 2019 Feb 28. — View Citation

Lee J, Hong M, Yum SK, Lee JH. Perinatal prediction model for severe intraventricular hemorrhage and the effect of early postnatal acidosis. Childs Nerv Syst. 2018 Nov;34(11):2215-2222. doi: 10.1007/s00381-018-3868-9. Epub 2018 Jun 18. — View Citation

Luque MJ, Tapia JL, Villarroel L, Marshall G, Musante G, Carlo W, Kattan J; Neocosur Neonatal Network. A risk prediction model for severe intraventricular hemorrhage in very low birth weight infants and the effect of prophylactic indomethacin. J Perinatol. 2014 Jan;34(1):43-8. doi: 10.1038/jp.2013.127. Epub 2013 Oct 10. — View Citation

Moons KG, Kengne AP, Grobbee DE, Royston P, Vergouwe Y, Altman DG, Woodward M. Risk prediction models: II. External validation, model updating, and impact assessment. Heart. 2012 May;98(9):691-8. doi: 10.1136/heartjnl-2011-301247. Epub 2012 Mar 7. — View Citation

Ramspek CL, Jager KJ, Dekker FW, Zoccali C, van Diepen M. External validation of prognostic models: what, why, how, when and where? Clin Kidney J. 2020 Nov 24;14(1):49-58. doi: 10.1093/ckj/sfaa188. eCollection 2021 Jan. — View Citation

Riley RD, Debray TPA, Collins GS, Archer L, Ensor J, van Smeden M, Snell KIE. Minimum sample size for external validation of a clinical prediction model with a binary outcome. Stat Med. 2021 Aug 30;40(19):4230-4251. doi: 10.1002/sim.9025. Epub 2021 May 24. — View Citation

Singh R, Visintainer PF. Predictive models for severe intraventricular hemorrhage in preterm infants. J Perinatol. 2014 Oct;34(10):802. doi: 10.1038/jp.2014.152. No abstract available. — View Citation

Sokou R, Piovani D, Konstantinidi A, Tsantes AG, Parastatidou S, Lampridou M, Ioakeimidis G, Iacovidou N, Bonovas S, Tsantes AE. Prospective Temporal Validation of the Neonatal Bleeding Risk (NeoBRis) Index. Thromb Haemost. 2021 Sep;121(9):1263-1266. doi: 10.1055/a-1343-3342. Epub 2021 Jan 16. No abstract available. — View Citation

Sparger KA, Assmann SF, Granger S, Winston A, Christensen RD, Widness JA, Josephson C, Stowell SR, Saxonhouse M, Sola-Visner M. Platelet Transfusion Practices Among Very-Low-Birth-Weight Infants. JAMA Pediatr. 2016 Jul 1;170(7):687-94. doi: 10.1001/jamapediatrics.2016.0507. — View Citation

Steyerberg EW, Moons KG, van der Windt DA, Hayden JA, Perel P, Schroter S, Riley RD, Hemingway H, Altman DG; PROGRESS Group. Prognosis Research Strategy (PROGRESS) 3: prognostic model research. PLoS Med. 2013;10(2):e1001381. doi: 10.1371/journal.pmed.1001381. Epub 2013 Feb 5. — View Citation

van de Bor M, Verloove-Vanhorick SP, Brand R, Keirse MJ, Ruys JH. Incidence and prediction of periventricular-intraventricular hemorrhage in very preterm infants. J Perinat Med. 1987;15(4):333-9. doi: 10.1515/jpme.1987.15.4.333. — View Citation

van Diepen M, Ramspek CL, Jager KJ, Zoccali C, Dekker FW. Prediction versus aetiology: common pitfalls and how to avoid them. Nephrol Dial Transplant. 2017 Apr 1;32(suppl_2):ii1-ii5. doi: 10.1093/ndt/gfw459. — View Citation

van Geloven N, Swanson SA, Ramspek CL, Luijken K, van Diepen M, Morris TP, Groenwold RHH, van Houwelingen HC, Putter H, le Cessie S. Prediction meets causal inference: the role of treatment in clinical prediction models. Eur J Epidemiol. 2020 Jul;35(7):619-630. doi: 10.1007/s10654-020-00636-1. Epub 2020 May 22. — View Citation

Vogtmann C, Koch R, Gmyrek D, Kaiser A, Friedrich A. Risk-adjusted intraventricular hemorrhage rates in very premature infants: towards quality assurance between neonatal units. Dtsch Arztebl Int. 2012 Aug;109(31-32):527-33. doi: 10.3238/arztebl.2012.0527. Epub 2012 Aug 6. — View Citation

von Lindern JS, van den Bruele T, Lopriore E, Walther FJ. Thrombocytopenia in neonates and the risk of intraventricular hemorrhage: a retrospective cohort study. BMC Pediatr. 2011 Feb 11;11:16. doi: 10.1186/1471-2431-11-16. — View Citation

* Note: There are 20 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Major or severe bleeding is the primary outcome. The investigators defined this as either one of the following:	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)	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.
Secondary	Bronchopulmonary dysplasia (BPD)	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).	36 weeks of postmenstrual age (PMA)
Secondary	Necrotizing enterocolitis (NEC)	The number of study participants with a new episode of NEC defined as =grade IIA as per Bell's criteria	Up to 4 weeks after the onset of severe thrombocytopenia
Secondary	Proven sepsis	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.	Up to 4 weeks after the onset of severe thrombocytopenia
Secondary	Retinopathy of prematurity (ROP)	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	Up to 38 weeks of PMA
Secondary	Mortality	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.	Mortality within 3 days during the first 2 weeks after the onset of severe thrombocytopenia.