Platelets for Neonatal Transfusion Study 2 (PlaNeT-2): Training Update

1. NHSBT CTU Platelets for Neonatal Transfusion Study 2 (PlaNeT-2): Training Update A randomised controlled trial of platelet transfusion thresholds

2. NHSBT Clinical Trials Unit NHSBT CTU Neonatal Thrombocytopenia • Prevalence: 1 - 5% of all newborns • 25% NICU admissions • 5-10% severe thrombocytopenia

3. RCT; n= 152 <1500g; GA < 33weeks; Platelet count Arm 1: Plt Tx to keep platelet count >150x109/L Arm 2: Plt Tx at threshold count 50-150x109/L No evidence ‘aggressive’ prophylaxis influenced incidence or extension of IVH Andrew et al (1993) NHSBT Clinical Trials Unit NHSBT CTU Neonatal Thrombocytopenia: Current Evidence (I)

4. No increased haemorrhage irrespective of whether platelets were administered Murray et al (2002) NHSBT Clinical Trials Unit NHSBT CTU Neonatal Thrombocytopenia: Current Evidence (II)

5. NHSBT Clinical Trials Unit NHSBT CTU Neonatal Thrombocytopenia: Current Evidence (III) • Retrospective Cohort Analysis of neonates with NEC and platelets <100x109/L • Results suggested platelet transfusions in infants with NEC associated with greater morbidity • Kenton et al (2005)

6. NHSBT Clinical Trials Unit NHSBT CTU Neonatal Thrombocytopenia: Current Evidence (IV) Baer et al (2007)

7. NHSBT CTU Neonatal Thrombocytopenia: Current Practice • Current national transfusion guidance based on consensus rather than evidence • British Committee for Standards in Haematology (2004) • United Kingdom Blood Services (2007) • Survey in the UK showed wide variation in platelet transfusion practice • Chaudhary and Clarke (2008)

8. NHSBT Clinical Trials Unit NHSBT Clinical Trials Unit NHSBT Clinical Trials Unit NHSBT CTU PlaNeT-1:A Study of Outcomes • Prospective observational study of NICU admissions with platelet counts <60x109/L • 7 NICUs • 169 neonates studied for 7 days, or until platelets >60x109/L • Platelet count • Haemorrhage • Platelet transfusions • Outcome • Stanworth et al (2009)

9. NHSBT Clinical Trials Unit NHSBT CTU PlaNeT-1:Haemorrhage

10. PlaNeT-1:Lowest Platelet Counts NHSBT CTU (++) indicates group median and (- -) IQR (++) indicates group median and (- -) IQR

11. NHSBT CTU PlaNeT-1:Transfusions • 2/3 received platelet transfusion • Most transfusions given as prophylaxis often well after “risk period” for haemorrhage has passed

12. NHSBT Clinical Trials Unit NHSBT CTU Moving forward!

13. NHSBT Clinical Trials Unit NHSBT CTU PlaNeT-2 Platelets for Neonatal Transfusion - Study 2

14. NHSBT CTU PlaNeT-2: Study design (I) • Two-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.

15. NHSBT CTU PlaNeT-2: Study design (II) • 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

16. NHSBT CTU PlaNeT-2:Platelet thresholds • Arm A Standard: transfuse platelets at <25x109/L • (330 neonates) • Arm B Intervention: transfuse platelets at <50x109/L • (330 neonates) • Dose: 15 ml/kg

17. NHSBT CTU PlaNeT-2:Additional platelet transfusions • May be considered under the following circumstances: • Therapeutically to treat major bleeding, following objective and documented signs of clinically relevant bleeding graded as moderate, major or severe, but not for minor bleeding. • Prior to planned invasive procedures as below only • Suprapubic aspiration • Lumbar puncture • Major surgery where haemostasis may be critical to outcome.

18. NHSBT CTU Modified WHO Bleeding Assessment Score • 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 bleedAn 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

19. NHSBT CTU PlaNeT-2: Inclusion criteria • Admission to a participating NICU (includes postnatal transfers) • <34 weeks GA at birth • Platelet count of <50 x109/L • Cranial ultrasound scan: undertaken <6 hours before randomisation to exclude recent major IVH

20. NHSBT CTU PlaNeT-2: Exclusion criteria • Major/life-threatening congenital malformations • Recent major haemorrhage within the last 72 hours • All fetal intracranial haemorrhages • Known immune thrombocytopenia • Neonates unlikely to survive • Neonates not given parenteral vitamin K

21. NHSBT CTU Parents will be approached for consideration of immediate study participation. PlaNeT-2: Consent When platelets <100x109/L When platelets <50x109/L Document on PlaNeT-2 log book

22. NHSBT CTU PlaNeT-2: Randomisation Pre-randomisation Platelet transfusion information (FA) Pre-randomisation form (F1) Eligibility for randomisation (F2) Current medical conditions & previous major bleeds (F3) Randomisation (F4) When the consent is signed and platelets <50x109/L:

23. NHSBT CTU FA – Platelet transfusion information

24. NHSBT CTU F1 – Pre-randomisation

25. NHSBT CTU F2 – Eligibility for randomisation

26. NHSBT CTU F3 – Current medical conditions And previous major bleeds

27. NHSBT CTU F4 – Randomisation

28. NHSBT CTU PlaNeT-2: Data collection (I)

29. NHSBT CTU F5 – Bleeding Assessment Tool (BAT)

30. NHSBT CTU F7 – Weekly Data Collection

31. NHSBT CTU PlaNeT-2: Data collection (II) F8 F9 F10 F13 F14 F15

32. NHSBT CTU F8 – Platelet Transfusion Data

33. NHSBT CTU PlaNeT-2: 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.

34. NHSBT CTU F9 – NEC/Sepsis form

35. NHSBT CTU F10 – Discontinuation of Treatment Allocation

36. PlaNeT-2: Major/Severe bleed form • All new major bleeding events will be reported to the CSU without disclosing allocation arm. • Each report will be forwarded to the Independent Data Monitoring Committee 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.

37. NHSBT CTU F13 – Major/Severe Bleed

38. PlaNeT-2: Serious Adverse Event (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

39. NHSBT CTU F14 – Serious Adverse Event

40. NHSBT CTU PlaNeT-2: Serious platelet transfusion related adverse event 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)

41. NHSBT CTU F15 – Serious platelet transfusion related adverse event

42. NHSBT CTU PlaNeT-2:End of study Data collection will cease when the baby is 38 weeks corrected gestational age or time of discharge home • Cranial Ultrasound at End of Study (F11) • End of Study (F12)

43. NHSBT CTU F11 – Cranial USS at the end of study

44. NHSBT CTU F12 – End of study

45. NHSBT CTU PlaNeT-2:Transfer out of recruiting unit • Inform the local PlaNeT-2 team if neonate transferred out of recruiting unit • Keep all the forms, do not send them with the patient • Receiving hospital should: • Collect information 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.

46. NHSBT CTU PlaNeT-2:Data Quality • Black ink • For platelet count use the date and time the sample is received in the lab • Do not leave blank fields, enter leading zeros • Any data incorrectly recorded must be crossed through with a single line and the correct value documented by the side. All corrections must be initialled and dated by the individual making the changes

47. NHSBT CTU PlaNeT-2:Research & Development and Ethics approval • Ethics approval obtained from the regional ethics committee • NIHR adopted • CLRN adopted

48. NHSBT CTU PlaNeT-2: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

49. NHSBT CTU PlaNeT-2:TMG Group • Louise Choo • Paul Clarke • Anna Curley • Alison Deary • Rizwan Khan • Renate Hodge • Priya Muthukumar • Helen New • Simon Stanworth • Vidheya Venkatesh • Tim Watts • Karen Willoughby

50. NHSBT CTU PlaNeT-2: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.