Clinical trial NCT06043050: PRedicting OutcomeS in Preterm nEonates With thromboCyTopenia (PROSPECT)
Official title: Sequential Causal Predictions for Repeated Interventions: Estimating the Risk of Major Bleeding or Death With and Without Prophylactic Platelet Transfusion in Thrombocytopenic Neonates.
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Neonatal Thrombocytopenia
Intraventricular Hemorrhage
Platelet Transfusion
Keywords: Sequential prediction under interventions
Causal prediction
Hemorrhage
Neonate
Thrombocytopenia
Lead sponsor: Leiden University Medical Center
Sponsor class: OTHER
Collaborators: name: Sanquin Research & Blood Bank Divisions
name: Amsterdam University Medical Center
First posted: 2023-09-21
Enrollment: 1042
Sex: ALL
Minimum age (years): 22
Maximum age (years): 34
Standard ages: CHILD
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: RETROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Neonates with a gestational age below 34 weeks and at least one platelet count below 50x10\^9/L, admitted to a NICU between January 1st, 2017 and January 1st, 2022.

Brief summary: Preterm neonates often receive platelet transfusions when their platelet count is low to prevent bleeding. However, it is currently unclear which infants benefit from such transfusions. A recent randomized controlled trial (PlaNeT-2/MATISSE trial) showed that the higher platelet count threshold for transfusion was associated with a higher risk of major bleeding or death. Current transfusion protocols are based only on platelet count thresholds. However, neonates with similar platelet counts may have different bleeding risks due to varying clinical conditions. There is an important unmet medical need to identify which neonates with low platelet counts (i.e., severe thrombocytopenia) will benefit from a transfusion. Ideally, clinicians would be able to repeatedly predict a neonate's risk of major bleeding or death with and without giving a platelet transfusion, taking into account the neonate's clinical condition at that particular time. Obtaining personalized risk estimates under specific treatment strategies, with updated predictions at each new treatment decision moment, is called 'sequential prediction under interventions'. The investigators set up an international multicenter retrospective cohort study to develop a model to predict major bleeding or death with and without platelet transfusion at any time point during the first week after the onset of severe thrombocytopenia. This model is designed to support platelet transfusion decisions in the NICU and may help clinicians balance the benefits and harms of platelet transfusion based on updated characteristics of the neonate at the time of prediction.

Detailed description: Main objective: To develop a sequential interventional prediction model to support transfusion decisions by predicting the risk of major bleeding or death with and without giving a platelet transfusion to neonates with severe thrombocytopenia (i.e., platelet count below 50x10\^9/L), conditional on their characteristics present at the moment of prediction.

Study design: Multicenter international retrospective cohort study.

Study population: Neonates with a gestational age below 34 weeks and at least one platelet count below 50x10\^9/L, admitted to a neonatal intensive care unit (NICU) between January 1st 2017 and January 1st 2022.

Main study endpoint: Major bleeding or mortality during NICU admission

Assessments: Only routine care data will be collected. This includes platelet counts and transfusions, cranial (head) ultrasounds and other information on bleeding, and multiple clinical variables.

Statistical analyses: Development of a sequential prediction model under interventions using the cloning-censoring-weighting approach with inverse probability weighting. Validation of the model in a separate cohort of preterm neonates with severe thrombocytopenia.

Eligibility criteria: Inclusion Criteria:

1. Gestational age at birth \<34 weeks;
2. At least one platelet count \<50x109/L;
3. Admission to a participating tertiary care NICU, including postnatal transfers, between January 1st, 2017 and January 1st, 2022.

Exclusion Criteria:

1. A severe congenital malformation;
2. Only spurious platelet counts \<50x109/L (e.g. clots in the sample, or a very rapid recovery to a normal platelet count without platelet transfusion);
3. Only platelet counts \<50x109/L in the context of exchange transfusion;
4. Major intracranial bleeding prior to the onset of severe thrombocytopenia. Neonates with major bleeding after the end of follow-up will not be excluded, but will be recorded as having had no major bleeding during the study.

Primary outcomes:
measure: A composite of major bleeding or death during NICU admission is the primary outcome. Neonates who first had a major bleeding and then died reach the endpoint at the time of the major bleeding.
timeFrame: From onset of severe thrombocytopenia until one week thereafter. The risk of major bleeding or death is predicted within 3 days and within 14 days from each moment of prediction during this time frame.
Secondary outcomes:
Other outcomes:
Locations:
city: Berlin
country: Germany
facility: Charité - Universitätsmedizin Berlin
state: Metropolregion Berlin-Brandenburg
city: Veldhoven
country: Netherlands
facility: Máxima Medical Center
state: Brabant
city: Nijmegen
country: Netherlands
facility: Radboud University Medical Center, Amalia Children's hospital
state: Gelderland
city: Maastricht
country: Netherlands
facility: Maastricht University Medical Center, MosaKids
state: Limburg
city: Amsterdam
country: Netherlands
facility: Amsterdam University Medical Center, Emma Children's hospital, location VUmc
state: North Holland
city: Amsterdam
country: Netherlands
facility: Amsterdam University Medical Center, Emma Children's hospital, location AMC
state: North Holland
city: Zwolle
country: Netherlands
facility: Isala clinics
state: Overijssel
city: Leiden
country: Netherlands
facility: Leiden University Medical Center, Willem Alexander Children's hospital
state: South Holland
city: Rotterdam
country: Netherlands
facility: Erasmus University Medical Center, Sophia pediatric hospital
state: South Holland
city: Groningen
country: Netherlands
facility: University Medical Center Groningen, Beatrix Children's hospital
city: Utrecht
country: Netherlands
facility: University Medical Center Utrecht, Wilhelmina Children's hospital
city: Stockholm
country: Sweden
facility: Karolinska University Hospital
state: Södermanland And Uppland
Study officials:
affiliation: Leiden University Medical Center and Sanquin Blood Supply Foundation
name: Hilde van der Staaij, MD
role: STUDY_DIRECTOR
affiliation: Leiden University Medical Center
name: Johanna G van der Bom, MD/PhD/Prof
role: PRINCIPAL_INVESTIGATOR
affiliation: Leiden University Medical Center
name: Camila Caram-Deelder, MSc/PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Leiden University Medical Center
name: Enrico Lopriore, MD/PhD/Prof
role: PRINCIPAL_INVESTIGATOR
affiliation: Amsterdam University Medical Center
name: Karin Fijnvandraat, MD/PhD/Prof
role: PRINCIPAL_INVESTIGATOR
affiliation: Sanquin Blood Supply Foundation
name: Suzanne F Fustolo-Gunnink, MD/PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Amsterdam University Medical Center
name: Wes Onland, MD/PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Leiden University Medical Center
name: Nan van Geloven, MSc/PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Leiden University Medical Center
name: Ilaria Prosepe, MSc
role: PRINCIPAL_INVESTIGATOR
References:
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.
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.
citation: Davenport PE, Wood TR, Heagerty PJ, Sola-Visner MC, Juul SE, Patel RM. Platelet Transfusion and Death or Neurodevelopmental Impairment in Children Born Extremely Preterm. JAMA Netw Open. 2024 Jan 2;7(1):e2352394. doi: 10.1001/jamanetworkopen.2023.52394.
citation: Fustolo-Gunnink SF, Fijnvandraat K, van Klaveren D, Stanworth SJ, Curley A, Onland W, Steyerberg EW, de Kort E, d'Haens EJ, Hulzebos CV, Huisman EJ, de Boode WP, Lopriore E, van der Bom JG; PlaNeT2 and MATISSE collaborators. Preterm neonates benefit from low prophylactic platelet transfusion threshold despite varying risk of bleeding or death. Blood. 2019 Dec 26;134(26):2354-2360. doi: 10.1182/blood.2019000899.
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.
citation: Hernan MA, Wang W, Leaf DE. Target Trial Emulation: A Framework for Causal Inference From Observational Data. JAMA. 2022 Dec 27;328(24):2446-2447. doi: 10.1001/jama.2022.21383.
citation: Keogh RH, Van Geloven N. Prediction Under Interventions: Evaluation of Counterfactual Performance Using Longitudinal Observational Data. Epidemiology. 2024 May 1;35(3):329-339. doi: 10.1097/EDE.0000000000001713. Epub 2024 Apr 18.
citation: van der Staaij H, Stanworth SJ, Fustolo-Gunnink SF. Prophylactic Platelet Transfusions: Why Less Is More. Clin Perinatol. 2023 Dec;50(4):775-792. doi: 10.1016/j.clp.2023.07.007. Epub 2023 Aug 31.
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.