NHSBT/MRC Clinical Studies Unit Platelets for Neonatal Transfusion Study 2 (PlaNeT-2) A randomised controlled trial of platelet transfusion thresholds

NHSBT/MRC Clinical Studies Unit Neonatal Thrombocytopenia Prevalence: 1 - 5% of all infants 25% NICU admissions 5-10% severe thrombocytopenia

NHSBT/MRC Clinical Studies Unit

Current Evidence One RCT: Andrews et al, 1993 n= 152 <1500g; GA < 33weeks; Platelet count Arm 1. Plt Tx to keep plt count >150 x10 9 /L Arm 2. Plt Tx at threshold count x10 9 /L No evidence ‘aggressive’ prophylaxis influenced incidence or extension of IVH

NHSBT/MRC Clinical Studies Unit Murray et al No increased haemorrhage irrespective of whether platelets were administered Murray NA et al, Transfus Med Feb;12(1):35-41.

NHSBT/MRC Clinical Studies Unit Kenton et al, J Perinatol. 2005;25:173-7 Retrospective Cohort Analysis of neonates with NEC and Plts <100 Results suggested platelet transfusions in infants with NEC associated with greater morbidity

NHSBT/MRC Clinical Studies Unit Baer V et al, J Perinatol 2007;27:790-6.

NHSBT/MRC Clinical Studies Unit Current Practice Current national transfusion guidance Based on consensus rather than evidence (BCSH 2004 Handbook of Transfusion Medicine, 2007) Recent survey in the UK showed wide variation in platelet transfusion practice 2008 Chaudhary R et al, Acta Paediatrica; 97:135

NHSBT/MRC Clinical Studies Unit PLaNeT 1: A Study of Outcomes Prospective observational study of NICU admissions with platelet counts <60x10 9 /L 7 NICUs 169 neonates studied for 7 days, or until plts >60x10 9 /L Platelet count Haemorrhage Platelet transfusions Outcome Stanworth et al, Pediatrics, 2009; 124:826-34

NHSBT/MRC Clinical Studies Unit PlaNet 1

NHSBT/MRC Clinical Studies Unit Lowest Platelet Counts (++) indicates group median and (- -) IQR

NHSBT/MRC Clinical Studies Unit PlaNet 1Transfusion 2/3 received platelet transfusion Most transfusions given as prophylaxis often well after “risk period” for haemorrhage has passed

NHSBT/MRC Clinical Studies Unit Moving forward!

NHSBT/MRC Clinical Studies Unit Choosing Platelet Thresholds Only RCT assessed x 10 9 /L vs >150 x 10 9 /L PlaNet-1: Most transfusions given at platelets x 10 9 /L. 50 th and 90 th centile pre-transfusion platelet counts 27 and 48 x 10 9 /L. 42% transfusions <25 x 10 9 /L and 92% <50 x 10 9 /L

NHSBT/MRC Clinical Studies Unit Assessing Bleeding in Study Cohort Developing a bleeding assessment tool (BAT) Modifying the WHO bleeding score for use in neonates

NHSBT/MRC Clinical Studies Unit

Grade 1 Minor Haemorrhage Any bleed from the  skin, umbilical cord, skin around stoma, surgical scar, mucosa.  Any pink frothy or old bleed from the ET tube.  H1 haemorrhage on cranial US (Germinal Layer Haemorrhage, GLH) Grade 2 Moderate Haemorrhage Any frank bleed from the stoma macroscopic haematuria, IVH (H2 or H3) without dilatation (V0), Acute fresh bleed through ETT without ventilatory changes Grade 3 Major Haemorrhage Any Frank Rectal Acute fresh bleed through ETT with ventilatory change. Intracranial bleed An intracranial bleed is defined as a major bleed if any of the following apply: Neurosurgical intervention is required; Scans show a midline shift; Clinical signs and symptoms of neurolgical deficit with significant derangement of laboratory investigations Major IVH is defined as H2 or H3 with ventricular dilatation (V1); H1, H2, H3 with parenchymal involvement (P3) ; Any evolution of intracranial haemorrhage to H2V1, H3V1, or (H1, H2, H3) with parenchymal involvement (P3) Grade 4 Severe Haemorrhage Shock defined as life threatening major bleed associated with hypotension, hyopovolaemia or any other haemodynamic instability and/or bleeding requiring volume boluses, red cell transfusion in the same 24 hours, fatal major bleeding Modified WHO Bleeding Assessment Score

NHSBT/MRC Clinical Studies Unit Gaining Approval Ethics approval obtained from the regional ethics committee NIHR adopted MRC Protocol Review Committee

NHSBT/MRC Clinical Studies Unit PlaNet-2 2-stage, randomised, parallel group, superiority trial Aim: to compare two different platelet count thresholds for prophylactic platelet transfusion to preterm neonates. Primary Outcome Proportion of patients who either die or experience a major bleed up to and including study day 28.

NHSBT/MRC Clinical Studies Unit PlaNet 2 Arm A: transfuse platelets at < 25 (330 neonates) Arm B: transfuse platelets < 50 (330 neonates) Dose: 15ml/kg for both arms

NHSBT/MRC Clinical Studies Unit Secondary Outcomes Proportion of neonates surviving to home following a major bleed Mortality prior to day 28 Major bleeds by day 28 Platelets transfused to study day 28 Length of hospital stay Transfusion-related adverse events Neuro-developmental outcome

NHSBT/MRC Clinical Studies Unit PlaNet 2 Inclusion Criteria Admission to a participating NICU (includes postnatal transfers) <34 weeks GA at birth Platelet count of <50 x10 9 /L Cranial ultrasound scan undertaken <6 hours before randomisation to rule out recent major IVH

NHSBT/MRC Clinical Studies Unit PlaNet 2 Exclusion Criteria M ajor/life-threatening congenital malformations R ecent major haemorrhage within the last 72 hours A ll fetal intracranial haemorrhages K nown immune thrombocytopenia N eonates unlikely to survive N eonates not given parenteral vitamin K

NHSBT/MRC Clinical Studies Unit Consent Parents/ guardians will be counselled when platelets < 100 x10 9 /L. Written, informed consent will be obtained. Randomisation only when platelet count < 50 x10 9 /L. For neonates with an initial platelet count of <50 x10 9 /L, parents will be approached for consideration of immediate study participation.

NHSBT/MRC Clinical Studies Unit Randomisation When the neonate’s platelet count falls to <50  10 9 /L the randomiser will: ensure a cranial ultrasound has been undertaken within the last 6 hours complete the trial registration/randomisation form access the web based randomisation service at to obtain a unique trial number and assignment of treatment policy RANDOMISATIONS ( Via 24hr Internet-based service) :

NHSBT/MRC Clinical Studies Unit Data Collection Schedule

NHSBT/MRC Clinical Studies Unit Thrombocytopenia > Study Day 14 Treatment allocation will apply until end of study Weekly rather than daily assessment tool

NHSBT/MRC Clinical Studies Unit Additional Platelet Transfusions May be considered under the following circumstances: Therapeutically to treat major or severe bleeding but not for minor or moderate bleeding. Prior to planned invasive procedures as below only Suprapubic aspiration Lumbar puncture major surgery where haemostasis may be critical to outcome.

NHSBT/MRC Clinical Studies Unit Platelet transfusions The following are not considered as indications for transfusion outside of allocated threshold: Before/during insertion of percutaneous central lines or arterial lines Planned or current indomethacin (or ibuprofen) treatment of patent ductus arteriosus Extreme prematurity without additional risk factors, irrespective of the postnatal age of the infant Pre-emptive transfusions not allowed

NHSBT/MRC Clinical Studies Unit Transfer out of Recruiting Unit Inform study coordinator if neonate transferred out of recruiting unit and complete log Receiving hospital should: complete weekly assessment forms and perform cranial USS on study day 28 (+/- 3days) and as required by the protocol thereafter until 38 weeks CGA or discharge. Continue to give any required platelet transfusions according to the randomised platelet threshold.

NHSBT/MRC Clinical Studies Unit End of Study Data collection will cease and an End of Study Form will be completed at 38 weeks gestational age or time of discharge home.

NHSBT/MRC Clinical Studies Unit Two Year Follow Up Thames Regional Perinatal Outcome Group/ Standard Electronic Neonatal Database/ National Neonatal Audit Programme (TRPG/SEND/NNAP) 2- year corrected age outcome form filled in locally

NHSBT/MRC Clinical Studies Unit Serious adverse events (SAE) A SAE is an adverse event that results in death is life-threatening requires hospitalisation or prolongation of existing hospitalisation (including readmission within 28 study days if discharged home earlier) There is a likelihood of persistent or significant disability or incapacity SAE NOTIFICATION Within one working day of becoming aware of an SAE, please fax a completed SAE form to the NHSBT/MRC CSU Fax:

NHSBT/MRC Clinical Studies Unit SAE SAE forms should be completed by PI and faxed to CSU within one working day of investigator becoming aware of event. SAEs will include serious platelet transfusion related adverse reactions/events The CI (Simon Stanworth or delegate) will review all SAEs received and must submit related and unexpected SAEs to main REC within 15 days of CI being aware. Other SAEs including related and expected events (platelet transfusion reactions/events) will be submitted annually to the research ethics committee by the Sponsor (NHSBT) SAE NOTIFICATION Within one working day of becoming aware of an SAE, please fax a completed SAE form to the NHSBT/MRC CSU Fax:

NHSBT/MRC Clinical Studies Unit Platelet related adverse events Data collected on serious transfusion related adverse reactions/events will be based on current definitions used by hospitals reporting to UK national haemovigilance reporting schemes (SHOT and MHRA). These definitions cover the following: Incorrect blood component transfused Acute transfusion reactions Transfusion-related acute lung injury (TRALI) Transfusion transmitted infections, including bacterial transmission Transfusion associated Circulatory Overload (TACO)

NHSBT/MRC Clinical Studies Unit NEC/Sepsis Form Necrotising enterocolitis ≥ Stage 2 defined as per Bells Criteria (Bell et al, 1978) Sepsis: culture positive sepsis or culture negative sepsis where a course of at least 5 days of antibiotics is to be administered for proven or clinically-suspected sepsis. All episodes of NEC and sepsis must be recorded on the adverse event form A listing of adverse events will be reported six monthly to the Independent Data Monitoring Committee.

NHSBT/MRC Clinical Studies Unit Major Bleeding Major/ severe bleeding events will not be reported on an SAE form. All new major bleeding events will be reported using the major bleed form as soon as possible, and preferably within 24 hours, to the CSU without disclosing allocation arm. Each report will be forwarded to the IDMC for review as soon as it is received at the CSU. In cases of uncertainty the local team may contact one of the CIs or neonatal medical experts. MAJOR BLEED FORM Within one working day of becoming aware of an Major Bleed, please fax a completed Major Bleed form to the NHSBT/MRC CSU Fax:

NHSBT/MRC Clinical Studies Unit Trial Governance The Trial Management Group (TMG) will be responsible for the daily management of the trial. The TMG is responsible to the Trial Steering Committee which has oversight of the trial and provides advice as needed

NHSBT/MRC Clinical Studies Unit TMG Members Brennan Kahan Paul Clarke Anna Curley Alison Deary Rizwan Khan Renate Hodge Priya Muthukumar Helen New Simon Stanworth Vidheya Venkatesh Tim Watts Karen Willoughby

NHSBT/MRC Clinical Studies Unit Trial Steering Committee This trial will be overseen by a Trial Steering Committee (TSC) Prof Colin Morley Independent Chair and Retired Professor of Neonatology Dr Sandy CalvertIndependent Consultant Neonatologist Dr Anthony EmmersonIndependent Consultant Neonatologist Dr Anna CurleyConsultant Neonatologist and joint CI Dr Simon StanworthConsultant Haematologist and joint CI Dr Brennan KahanCSU Statistician TBAParent Representative(s) Dr Charlotte Llewelyn CSU Manager

NHSBT/MRC Clinical Studies Unit IDMC An Independent Data Monitoring Committee will review safety data and trial progress on a six monthly basis In addition, all SAEs and major bleeds will be reviewed as they are reported to the CSU

NHSBT/MRC Clinical Studies Unit Finance The trial is funded by a Project Grant from the NHSBT which is administered by the National Research & Development Committee. Any payments will be made to participating centres to cover costs associated with the undertaking of this trial, as specified in Individual Investigator Site Agreements.

NHSBT/MRC Clinical Studies Unit Communications For general trial queries contact Karen Willoughby; copy Alison Deary For medical queries regarding transfusions, SAEs, grading major/severe bleeds or transfusion reactions contact Simon Stanworth, Anna Curley, Tim Watts or Paul Clarke For data management queries, contact Renate Hodge

NHSBT/MRC Clinical Studies Unit Thank you!