- Planet 2

Report
Platelets for Neonatal
Transfusion Study 2 (PlaNeT-2):
Training Update
A randomised controlled trial of platelet
transfusion thresholds
NHSBT/MRC
Clinical Studies Unit
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Neonatal Thrombocytopenia
• Prevalence: 1 - 5% of all newborns
• 25% NICU admissions
• 5-10% severe thrombocytopenia
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Neonatal Thrombocytopenia:
Current Evidence (I)
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)
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Neonatal Thrombocytopenia:
Current Evidence (II)
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 et al (2002)
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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)
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Clinical Studies
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Neonatal Thrombocytopenia:
Current Evidence (IV)
Baer et al (2007)
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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)
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Clinical Studies Unit
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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
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PlaNeT-1: Lowest Platelet Counts
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Studies
Unitgroup median and (- -) IQR
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CTU
(++)
indicates
(++) 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!
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PlaNeT-2
Platelets for Neonatal Transfusion - Study 2
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Clinical
Trials Unit
Unit
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Clinical Studies
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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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Clinical Studies Unit
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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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Clinical Studies Unit
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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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Clinical Studies Unit
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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.
NHSBT/MRC
Clinical Studies Unit
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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 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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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
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Clinical Studies Unit
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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
NHSBT/MRC
Clinical Studies Unit
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PlaNeT-2: Consent
When platelets <100x109/L
When platelets <50x109/L
Parents will
be
counselled
Documented
in the clinical
notes
Written,
informed
consent will
be obtained
Three copies
signed:
•For parents
•For the clinical
notes with Parent
Information Sheet
•For the study file
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Clinical Studies Unit
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Parents will be approached
for consideration of immediate
study participation.
Document on PlaNeT-2 log book
PlaNeT-2: Randomisation
When the consent is signed and platelets <50x109/L:
Prerandomisation
Platelet
transfusion
information
(FA)
Prerandomisation
form (F1)
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Clinical Studies Unit
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CTU
Eligibility for
randomisation
(F2)
Current
medical
conditions &
previous major
bleeds (F3)
Randomisation
(F4)
FA – Platelet transfusion information
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Clinical Studies Unit
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CTU
F1 – Pre-randomisation
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Clinical Studies Unit
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F2 – Eligibility for randomisation
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Clinical Studies Unit
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F3 – Current medical conditions
And previous major bleeds
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Clinical Studies Unit
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F4 – Randomisation
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Clinical Studies Unit
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CTU
PlaNeT-2: Data collection (I)
SD1
SD2
SD3
SD4
SD5
SD6
SD7
SD8
SD9
SD10
SD11
SD12
SD13
SD14
BAT
BAT
BAT
BAT
BAT
BAT
BAT
BAT
BAT
BAT
BAT
BAT
BAT
BAT
USS
USS
SD15
SD16
SD17
SD18
SD19
SD20
SD21
SD22
SD23
SD24
SD25
SD26
SD27
SD28
BAT
BAT
BAT
BAT
BAT
BAT
BAT
BAT
BAT
BAT
BAT
BAT
BAT
BAT
USS
SD29
SD30
SD31
SD32
SD33
SD34
SD35
Weekly
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Clinical Studies Unit
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CTU
USS
SD36
SD37
…
…
…
…
END
USS
F5 – Bleeding Assessment Tool (BAT)
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Clinical Studies Unit
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CTU
F7 – Weekly Data Collection
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Clinical Studies Unit
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CTU
PlaNeT-2: Data collection (II)
F8
Platelet Transfusion Data (F8)
F9
F10
Discontinuation of Treatment Allocation (F10)
F13
Major/Severe Bleed (F13)
F14
F15
Necrotising enterocolitis (NEC) /Sepsis Form (F9)
Serious Adverse Event (F14)
Serious Platelet Transfusion Related Adverse Event (F15)
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Clinical Studies Unit
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CTU
F8 – Platelet Transfusion Data
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Clinical Studies Unit
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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.
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Clinical Studies Unit
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CTU
F9 – NEC/Sepsis form
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Clinical Studies Unit
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CTU
F10 – Discontinuation of Treatment Allocation
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Clinical Studies Unit
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CTU
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.
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
F13 – Major/Severe Bleed
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Clinical Studies Unit
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CTU
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
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
F14 – Serious Adverse Event
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Clinical Studies Unit
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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)
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Clinical Studies Unit
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CTU
F15 – Serious platelet
transfusion related adverse event
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Clinical Studies Unit
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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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Clinical Studies Unit
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CTU
F11 – Cranial USS at the end of study
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Clinical Studies Unit
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F12 – End of study
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Clinical Studies Unit
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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.
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Clinical Studies Unit
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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
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Clinical Studies Unit
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PlaNeT-2:
Research & Development and Ethics approval
• Ethics approval obtained from the regional ethics
committee
• NIHR adopted
• CLRN adopted
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Clinical Studies Unit
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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
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Clinical Studies Unit
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CTU
PlaNeT-2: TMG Group
•
•
•
•
•
•
Louise Choo
Paul Clarke
Anna Curley
Alison Deary
Rizwan Khan
Renate Hodge
NHSBT/MRC
Clinical Studies Unit
NHSBT
CTU
•
•
•
•
•
•
Priya Muthukumar
Helen New
Simon Stanworth
Vidheya Venkatesh
Tim Watts
Karen Willoughby
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.
NHSBT/MRC
Clinical Studies Unit
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CTU
PlaNeT-2: Communications
• 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]
www.planet-2.com
NHSBT/MRC
Clinical Studies Unit
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CTU
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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Clinical Studies Unit
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CTU
Thank you!
NHSBT/MRC
Clinical Studies Unit
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CTU

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