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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
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 x109/L
• Arm 2. Plt Tx at threshold count 50-150 x109/L
• No evidence ‘aggressive’ prophylaxis influenced
incidence or extension of IVH
NHSBT/MRC Clinical Studies Unit
Murray et al 2002.
Preterm neonates
4444
Platelet count nadir < 30
17/44 (39%)
Given
platelet transfusions
15/17 (88%)
Not given
platelet transfusions
2/17 (12%)
Platelet count nadir 30-50
27/44 (61%)
Given
platelet transfusions
10/27 (37%)
Not given
platelet transfusions
17/27 (63%)
• No increased haemorrhage irrespective of whether
platelets were administered
Murray NA et al, Transfus Med. 2002 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 <60x109/L
• 7 NICUs
• 169 neonates studied for 7 days, or until plts
>60x109/L
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•
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•
Platelet count
Haemorrhage
Platelet transfusions
Outcome
Stanworth et al, Pediatrics, 2009; 124:826-34
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PlaNet 1
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Lowest Platelet Counts
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(++) indicates group median and (- -) IQR
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 50-150 x 109/L vs >150 x 109/L
PlaNet-1:
• Most transfusions given at platelets 10 - 50x 109/L.
• 50th and 90th centile pre-transfusion platelet counts
27 and 48 x 109/L.
• 42% transfusions <25 x 109/L and 92% <50 x 109/L
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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
NHSBT/MRC Clinical Studies Unit
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 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
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Gaining Approval
• Ethics approval obtained from the regional
ethics committee
• NIHR adopted
• MRC Protocol Review Committee
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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.
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PlaNet 2
• Arm A: transfuse platelets at < 25
(330 neonates)
• Arm B: transfuse platelets < 50
(330 neonates)
• Dose: 15ml/kg for both arms
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Secondary Outcomes
• Proportion of neonates surviving
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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to
home
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 rule
out recent major IVH
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PlaNet 2 Exclusion Criteria
•
ajor/life-threatening congenital malformations
•
ecent major haemorrhage within the last 72 hours
•
ll fetal intracranial haemorrhages
•
nown immune thrombocytopenia
•
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eonates unlikely to survive
Consent
• Parents/ guardians will be counselled when platelets <
100 x109/L.
• Written, informed consent will be obtained.
• Randomisation only when platelet count < 50 x109/L.
• For neonates with an initial platelet count of <50 x109/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 109/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
http://www.sealedenvelope.com to obtain a unique trial
number and assignment of treatment policy
RANDOMISATIONS (Via 24hr Internet-based service):
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Unit
http://www.sealedenvelope.com
Data Collection Schedule
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Thrombocytopenia > Study Day 14
• Treatment allocation will apply until end of
study
• Weekly rather than daily assessment tool
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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
irrespective of the postnatal age of the infant
• Pre-emptive transfusions not allowed
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risk
factors,
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.
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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.
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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 Clinical
Studies Unit
NHSBT/MRC CSU
Fax: 01223 588136
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 Clinical
Studies Unit
NHSBT/MRC CSU
Fax: 01223 588136
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:
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Incorrect blood component transfused
Acute transfusion reactions
Transfusion-related acute lung injury (TRALI)
Transfusion transmitted infections, including bacterial transmission
Transfusion associated Circulatory Overload (TACO)
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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
NHSBT/MRC Clinical Studies
Unit
fax a completed
Major Bleed form to the NHSBT/MRC CSU
Fax: 01223 588136
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
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Brennan Kahan
Paul Clarke
Anna Curley
Alison Deary
Rizwan Khan
Renate Hodge
NHSBT/MRC Clinical Studies Unit
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Priya Muthukumar
Helen New
Simon Stanworth
Vidheya Venkatesh
Tim Watts
Karen Willoughby
Trial Steering Committee
• This trial will be overseen by a Trial Steering Committee
(TSC)
• Prof Colin Morley
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Neonatology
Dr Sandy Calvert
Dr Anthony Emmerson
Dr Anna Curley
Dr Simon Stanworth
Dr Brennan Kahan
TBA
Dr Charlotte Llewelyn
NHSBT/MRC Clinical Studies Unit
Independent Chair and Retired
Professor of
Independent Consultant Neonatologist
Independent Consultant Neonatologist
Consultant Neonatologist and joint CI
Consultant Haematologist and joint CI
CSU Statistician
Parent Representative(s)
CSU Manager
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!
NHSBT/MRC Clinical Studies Unit