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

2. NHSBT/MRC Clinical Studies Unit NHSBT Clinical Studies Unit 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) Neonatal Thrombocytopenia: Current Practice

3. NHSBT/MRC Clinical Studies Unit NHSBT Clinical Studies Unit Platelets for Neonatal Transfusion - Study 2 PlaNeT-2

4. NHSBT/MRC Clinical Studies Unit NHSBT Clinical Studies Unit 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.

5. NHSBT/MRC Clinical Studies Unit NHSBT Clinical Studies Unit 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

6. NHSBT/MRC Clinical Studies Unit NHSBT Clinical Studies Unit PlaNeT-2: Choosing platelet thresholds Last RCT done by Andrew et al (1993) assessed 50-150x10 9 /L vs. >150x10 9 /L PlaNeT-1 (2009): Most transfusions given at platelets 10–50x10 9 /L. 50 th and 90 th centile pre-transfusion platelet counts 27 and 48x10 9 /L. 42% transfusions <25x10 9 /L and 92% <50x10 9 /L

7. NHSBT/MRC Clinical Studies Unit NHSBT Clinical Studies Unit PlaNeT-2: Platelet thresholds Arm A Standard: transfuse platelets at <25x10 9 /L (330 neonates) Arm B Intervention: transfuse platelets at <50x10 9 /L (330 neonates) Dose: 15 ml/kg

8. NHSBT/MRC Clinical Studies Unit NHSBT Clinical Studies Unit PlaNeT-2: Additional platelet transfusions May be considered under the following circumstances: Therapeutically to treat moderate, major or severe bleeding 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.

9. NHSBT/MRC Clinical Studies Unit NHSBT 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

10. NHSBT/MRC Clinical Studies Unit NHSBT Clinical Studies Unit 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 exclude recent major IVH PlaNeT-2: Inclusion criteria

11. NHSBT/MRC Clinical Studies Unit NHSBT Clinical Studies Unit 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 PlaNeT-2: Exclusion criteria

12. NHSBT/MRC Clinical Studies Unit NHSBT Clinical Studies Unit When platelets <100x10 9 /L Parents will be counselled Written, informed consent will be obtained Documented in the clinical notes – Date and time Three copies signed: For parents For the clinical notes with Parent Information Sheet For the study file When platelets <50x10 9 /L Parents will be approached for consideration of immediate study participation. PlaNeT-2: Consent Document on PlaNeT-2 log book

13. NHSBT/MRC Clinical Studies Unit NHSBT Clinical Studies Unit PlaNeT-2: Randomisation When the consent is signed and platelets <50x10 9 /L: Pre- randomisation Platelet transfusion information (FA) Pre- randomisation form (F1) Eligibility for randomisation (F2) Current medical conditions & previous major bleeds (F3) Randomisation (F4)

14. NHSBT/MRC Clinical Studies Unit NHSBT Clinical Studies Unit FA – Platelet transfusion information

15. NHSBT/MRC Clinical Studies Unit NHSBT Clinical Studies Unit F1 – Pre-randomisation

16. NHSBT/MRC Clinical Studies Unit NHSBT Clinical Studies Unit F2 – Eligibility for randomisation

17. NHSBT/MRC Clinical Studies Unit NHSBT Clinical Studies Unit F3 – Current medical conditions And previous major bleeds

18. NHSBT/MRC Clinical Studies Unit NHSBT Clinical Studies Unit F4 – Randomisation

19. NHSBT/MRC Clinical Studies Unit NHSBT Clinical Studies Unit SD1BATSD2BATSD3BATSD4BATSD5BATSD6BATSD7BATUSSSD8BATSD9BATSD10BATSD11BATSD12BATSD13BATSD14BATUSSSD15SD16SD17SD18SD19SD20SD21WeeklyUSSSD22SD23SD24SD25SD26SD27SD28WeeklyUSSSD29SD30SD31SD32SD33SD34SD35WeeklySD36SD37…SD42Weekly……ENDUSS PlaNeT-2: Data collection (I)

20. NHSBT/MRC Clinical Studies Unit NHSBT Clinical Studies Unit F5 – Bleeding Assessment Tool (BAT)

21. NHSBT/MRC Clinical Studies Unit NHSBT Clinical Studies Unit F6 – Daily Platelet Count

22. NHSBT/MRC Clinical Studies Unit NHSBT Clinical Studies Unit F7 – Weekly Data Collection

23. NHSBT/MRC Clinical Studies Unit NHSBT Clinical Studies Unit Platelet Transfusion Data (F8) Necrotising enterocolitis (NEC) / Sepsis Form (F9) Discontinuation of Treatment Allocation (F10) Major/Severe Bleed (F13) Serious Adverse Event (F14) Serious Platelet Transfusion Related Adverse Event (F15) PlaNeT-2: Data collection (II) F9 F13 F10 F14 F15 F8

24. NHSBT/MRC Clinical Studies Unit NHSBT Clinical Studies Unit F8 – Platelet Transfusion Data

25. NHSBT/MRC Clinical Studies Unit NHSBT Clinical Studies Unit 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. PlaNeT-2: NEC/Sepsis form

26. NHSBT/MRC Clinical Studies Unit NHSBT Clinical Studies Unit F9 – NEC/Sepsis form

27. NHSBT/MRC Clinical Studies Unit NHSBT Clinical Studies Unit F10 – Discontinuation of Treatment Allocation

28. NHSBT/MRC Clinical Studies Unit NHSBT Clinical Studies Unit 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. 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: 01223 588136 PlaNeT-2: Major/Severe bleed form

29. NHSBT/MRC Clinical Studies Unit NHSBT Clinical Studies Unit F13 – Major/Severe Bleed

30. NHSBT/MRC Clinical Studies Unit NHSBT Clinical Studies Unit SAE NOTIFICATION Within one working day of becoming aware of an SAE, please fax a completed SAE form to the NHSBT/MRC CSU Fax: 01223 588136 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 A SAE is an adverse event that results: PlaNeT-2: Serious Adverse Event (SAE)

31. NHSBT/MRC Clinical Studies Unit NHSBT Clinical Studies Unit F14 – Serious Adverse Event

32. NHSBT/MRC Clinical Studies Unit NHSBT Clinical Studies Unit 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) PlaNeT-2: Serious platelet transfusion related adverse event

33. NHSBT/MRC Clinical Studies Unit NHSBT Clinical Studies Unit F15 – Serious platelet transfusion related adverse event

34. NHSBT/MRC Clinical Studies Unit NHSBT Clinical Studies Unit 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)

35. NHSBT/MRC Clinical Studies Unit NHSBT Clinical Studies Unit F11 – Cranial USS at the end of study

36. NHSBT/MRC Clinical Studies Unit NHSBT Clinical Studies Unit F12 – End of study

37. NHSBT/MRC Clinical Studies Unit NHSBT Clinical Studies 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 If a cranial USS has no been done in the last 7 days, please perform one before the baby leaves. PlaNeT-2: Transfer out of recruiting unit

38. NHSBT/MRC Clinical Studies Unit NHSBT Clinical Studies Unit PlaNeT-2: Two years follow up Thames Regional Perinatal Outcome Group/ Standard Electronic Neonatal Database/ National Neonatal Audit Programme (TRPG/SEND/NNAP) 2- year corrected age outcome form

39. NHSBT/MRC Clinical Studies Unit NHSBT Clinical Studies Unit 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 PlaNeT-2: Data Quality

40. NHSBT/MRC Clinical Studies Unit NHSBT Clinical Studies Unit Check what you need to score from the CRFs Follow the Unit’s guidelines Good quality shot of the right view Ask for a second opinion to a senior staff if you need PlaNeT-2 is a trial based on these USS so that all scans are reviewed at local level and overseen nationally. PlaNeT-2: Data Quality – Cranial USS

41. NHSBT/MRC Clinical Studies Unit NHSBT Clinical Studies Unit Local queries: For general trial queries: contact Karen Willoughby; copy Ana Mora. For medical queries regarding transfusions, SAEs, grading major/severe bleeds or transfusion reactions contact Simon Stanworth, Anna Curley or Vidheya Venkatesh. PlaNeT-2: Communications www.planet-2.com

42. NHSBT/MRC Clinical Studies Unit NHSBT Clinical Studies Unit Two criteria to put a baby’s sticker in the PlaNeT-2 book Baby born at less than 34 weeks GA Platelets <100

43. NHSBT/MRC Clinical Studies Unit NHSBT Clinical Studies Unit What is the right documentation of consent? Three copies of the consent forms signed. Original in site file Complete documentation of parental discussion in the notes

44. NHSBT/MRC Clinical Studies Unit NHSBT Clinical Studies Unit (Please add here examples of your current documentation practice) Our practice documenting…

45. NHSBT/MRC Clinical Studies Unit NHSBT Clinical Studies Unit If the baby is consented and his platelets go up to 52 then 51 and then 50 in next three days, what should you do? I should wait. As long as the platelet count is 50 or above, the baby can not be randomised.

46. NHSBT/MRC Clinical Studies Unit NHSBT Clinical Studies Unit Two places where you can find forms In the PlaNeT-2 box behind the desk Online at www.planet-2.com

47. NHSBT/MRC Clinical Studies Unit NHSBT Clinical Studies Unit Where are the details to access to www.sealedenvelope.com? In the PlaNeT-2 book

48. NHSBT/MRC Clinical Studies Unit NHSBT Clinical Studies Unit What is wrong with this data collection plan?

49. NHSBT/MRC Clinical Studies Unit NHSBT Clinical Studies Unit So, is this plan right now?

50. NHSBT/MRC Clinical Studies Unit NHSBT Clinical Studies Unit Is this a better plan then? Completed: 48%

51. NHSBT/MRC Clinical Studies Unit NHSBT Clinical Studies Unit How can you know at glance what form is due to be completed? Looking at the front of the pack; each PlaNeT-2 baby has a form with the due dates.

52. NHSBT/MRC Clinical Studies Unit NHSBT Clinical Studies Unit CRF Game You will be given 4 CRF Forms : 5 – Find 3 sets of mistakes 6 - Which two corrections are right? 7 - Can you find the two missing fields? 9 – What is missing?

53. NHSBT/MRC Clinical Studies Unit NHSBT Clinical Studies Unit Find the three sets of mistakes

54. NHSBT/MRC Clinical Studies Unit NHSBT Clinical Studies Unit Which two corrections are right?

55. NHSBT/MRC Clinical Studies Unit NHSBT Clinical Studies Unit Can you find the two missing fields?

56. NHSBT/MRC Clinical Studies Unit NHSBT Clinical Studies Unit

57. NHSBT/MRC Clinical Studies Unit NHSBT Clinical Studies Unit The baby is transferred out of the Unit, three things you should do: Inform the PlaNeT-2 team Keep all the PlaNeT-2 forms A cranial USS if none has been done in the last 7 days

58. NHSBT/MRC Clinical Studies Unit NHSBT Clinical Studies Unit Where is the PlaNeT-2 box kept?

59. NHSBT/MRC Clinical Studies Unit NHSBT Clinical Studies Unit What should you do if an enrolled baby develops a rectal bleeding? Inform the PlaNeT-2 team. (A rectal bleeding is a major bleed that should be reported as soon as possible)

60. NHSBT/MRC Clinical Studies Unit NHSBT Clinical Studies Unit What should you do if a SAE happens? Proceed as Trust protocol indicates for that situation Inform the research team as soon as possible

61. NHSBT/MRC Clinical Studies Unit NHSBT Clinical Studies Unit If you are not sure, what two things you should do? Ask us!! We are here to support you. Check on-line: www.planet-2.com

62. NHSBT/MRC Clinical Studies Unit NHSBT Clinical Studies Unit Thank you!