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

NHSBT/MRC Clinical Studies Unit

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

Training UpdateA randomised controlled trial of platelet

transfusion thresholds

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Neonatal Thrombocytopenia

• Prevalence: 1 - 5% of all newborns

• 25% NICU admissions

• 5-10% severe thrombocytopenia

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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)

Neonatal Thrombocytopenia: Current Evidence (I)



No increased haemorrhage irrespective of whether platelets were administered

Murray et al (2002)

G iv enp la te le t tra ns fu sio ns

1 5 /17 (88 % )

N o t g ivenp la te le t tra ns fu sio ns

2 /1 7 (1 2 % )

P la te le t c o un t na d ir < 301 7 /44 (39 % )

G iv enp la te le t tra ns fu sio ns

1 0 /27 (37 % )

N o t g iv enp la te le t tra ns fu sio ns

1 7 /27 (63 % )

P la te le t cou n t n a d ir 30 -502 7 /44 (61 % )

P re te rm ne o na tes4 44 4

Neonatal Thrombocytopenia: Current Evidence (II)



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)

Neonatal Thrombocytopenia: Current Evidence (III)



Baer et al (2007)

Neonatal Thrombocytopenia: Current Evidence (IV)



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

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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)

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PlaNeT-1: Haemorrhage


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

PlaNeT-1: Lowest Platelet Counts

NHSBT CTU (++) indicates group median and (- -) IQR


PlaNeT-1: Transfusions

• 2/3 received platelet transfusion

• Most transfusions given as prophylaxis often well after “risk period” for haemorrhage has passed

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Moving forward!



Platelets for Neonatal Transfusion - Study 2

PlaNeT-2



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.

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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

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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

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PlaNeT-2: Additional platelet transfusionsMay 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.

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Grade 1 – Minor HaemorrhageAny 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 HaemorrhageAny 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

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• 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

PlaNeT-2: Inclusion criteria

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• 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

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When platelets <100x109/L

Parents will be

counselled

Written, informed

consent will be obtained

Documented in the clinical

notes

Three copies signed:• For parents• For the clinical

notes with Parent Information Sheet

• For the study file

When platelets <50x109/L

Parents will be approached for consideration of immediate

study participation.

PlaNeT-2: Consent

Document on PlaNeT-2 log book

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PlaNeT-2: Randomisation

When the consent is signed and platelets <50x109/L:

Pre-randomisation

Platelet transfusion information

(FA)

Pre-randomisation

form (F1)

Eligibility for randomisation

(F2)

Current medical

conditions & previous major

bleeds (F3)

Randomisation (F4)

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FA – Platelet transfusion information

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F1 – Pre-randomisation

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F2 – Eligibility for randomisation

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F3 – Current medical conditionsAnd previous major bleeds

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F4 – Randomisation

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http://www.sealedenvelope.com/


SD1

BAT

SD2

BAT

SD3

BAT

SD4

BAT

SD5

BAT

SD6

BAT

SD7

BATUSS

SD8

BAT

SD9

BAT

SD10

BAT

SD11

BAT

SD12

BAT

SD13

BAT

SD14

BAT

USS

SD15

BAT

SD16

BAT

SD17

BAT

SD18

BAT

SD19

BAT

SD20

BAT

SD21

BATUSS

SD22

BAT

SD23

BAT

SD24

BAT

SD25

BAT

SD26

BAT

SD27

BAT

SD28

BAT

USS

SD29 SD30 SD31 SD32 SD33 SD34

SD35

Weekly

SD36 SD37 … … … …

END

USS

PlaNeT-2: Data collection (I)

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F5 – Bleeding Assessment Tool (BAT)

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F7 – Weekly Data Collection

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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

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F8 – Platelet Transfusion Data

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• 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

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F9 – NEC/Sepsis form

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F10 – Discontinuation of Treatment Allocation

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• 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 FORMWithin one working day of becoming aware of an Major Bleed, please fax a completed Major Bleed form to the NHSBT/MRC

CSUFax: 01223 588136

PlaNeT-2: Major/Severe bleed form


F13 – Major/Severe Bleed

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NHSBT/MRC Clinical Studies UnitSAE 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)


F14 – Serious Adverse Event

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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

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F15 – Serious platelet transfusion related adverse event

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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)

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F11 – Cranial USS at the end of study

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F12 – End of study

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• 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.

PlaNeT-2: Transfer out of recruiting unit

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• 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

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• Ethics approval obtained from the regional ethics committee

• NIHR adopted

• CLRN adopted

PlaNeT-2: Research & Development and Ethics approval

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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

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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

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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.

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• For general trial queries: contact • Karen Willoughby [email protected], copy to

[email protected]

• For medical queries regarding transfusions, SAEs, grading major/severe bleeds or transfusion reactions contact

• Simon Stanworth: [email protected], or • Anna Curley: [email protected]

PlaNeT-2: Communications

www.planet-2.com

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http://www.planet-2.com/home.html


References• Andrew M, Vegh P, Caco C, Kirpalani H, Jeffries A, Ohlsson A, Watts J, Sagial S, Milner R, Wang EA. (1993) Randomised

controlled trial of platelet transfusions in thrombocytopenic premature infants. Journal of Pediatrics 123 285–291. • Baer VL, Lambert DK, Henry E, Snow GL, Sola-Visner MC, Christensen RD (2007) Do platelet transfusions in the NICU

adversely affect survival? Analysis of 1600 thrombocytopenic neonates in a multihospital healthcare systemMultiple platelet transfusions and survival. Journal of Perinatology 27 790-796.

• British Committee for Standards in Haematology (2004) Transfusion Guidelines for neonates and older children. British Journal of Haematology 124 433-453.

• Chaudhary R, Clarke P. (2008) Current transfusion practices for platelets and fresh, frozen plasma in UK tertiary level neonatal units. Acta Pædiatrica 97(1) 135.

• Kenton AB, Hegemier S, Smith EO, O'Donovan DJ, Brandt ML, Cass DL, Helmrath MA, Washburn K, Weihe EK, Fernandes CJ (2005) Platelet transfusions in infants with necrotizing enterocolitis do not lower mortality but may increase morbidity. Journay of Perinatology 25(3) 173–177

• Murray NA, Howarth LJ, McCloy MP, Letsky EA, Roberts IAG (2002) Platelet transfusion in the management of severe thrombocytopenia in neonatal intensive care unit patients. Transfusion Medicine 12(1) 35-41.

• Stanworth S, Clarke P, Watts T, Ballard S, Choo L, Morris T, Murphy MF, Roberts I (2009) Prospective, observational study of outcomes in neonates with severe thrombocytopenia. Pediatrics 124 826-834.

• United Kingdom Blood Services (2007) Handbook of Transfusion Medicine. 4th ed. Norwich: The Stationary Office. [online]. Available from: http://www.transfusionguidelines.org.uk/index.aspx?Publication=HTM

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Thank you!

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

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