COOLING PLUS STUDIES SUMMARY – Updated April, 2014
STUDY DESIGN/
PHASE/NAME
Phase 3 RCT
N=330
INTERVENTION/
CONTROL
Cooling + EPO
Cooling + placebo
INCLUSION
Mod-severe enceph
≥36 wks
Neuroepo
Phase 3 (4 group RCT)
N= 726
Longer, Deeper
3 Exp Cooling longer or
deeper
Control: standard
protocol
Acute perinatal event
Encephalopathy or
seizures
≥36 wks
EXCLUSION
PRIMARY OUTCOME
Hypothermia not
controlled by 6 hrs
Chromosomal/Congenita
l abn
Trauma
Survival without neurol
dis (2 yrs)
Inability to randomise by
6 hrs
Chromosomal/
congenital abn
IUGR (<1800g)
Death/mod severe dis at
18-22mths)
SECONDARY OUTCOMES
Mortality rate (2yrs)
Rate of Mod-severe
neuroodis
Mod/Severe
MRI
Disability rates (mild,
mod and severe)
MEASURES
GMFCS
Brunet-Lezine (<85; <70)
Hearing
Vision
CP diagnosis: clinical exam
GMFCS
BSID-III
CP diagnosis: Clinical exam eg tone
Hearing
Vision
Seizure disorder
MRI
NICHD MRI scoring system
Phase 3
N= 300
Cooling plus MgSO4
Cooling
Mod severe
encephalopathy
≥35 wks
>6hrs old
Congenital abn
Death/ severe disability
at 18-24mths)
Disability rates
MagCool
Phase 2 and 3
N= 168
Cooling initiated later
Cooling 96 hrs
Control: no cooling
Acute perinatal event
≥36 wks
6-24 hrs after birth
Mod severe enceph
Known chromosomal abn
<1800 g
Death or Mod/severe
disability
MRI (0-14 days)
Multiple medical
outcomes eg pulm
haemorrhage
Disability rates (mild,
mod,severe)
GMFCS
BSID=III
Hearing impairment
CVI
Seizure disorder
microcephaly
CP diagnosis:
COOLING PLUS STUDIES SUMMARY – Updated April, 2014
STUDY DESIGN/
PHASE/NAME
Phase 2
N=20
Cooling + Topiromate
INTERVENTION/
CONTROL
Cooling + Topiromate
Control: cooling
INCLUSION
Mod-severe enceph
≥36 wks
>1800 g
Abnormal aEEG
EXCLUSION
Chromosomal
abnormality
infection
PRIMARY OUTCOME
SECONDARY OUTCOMES
Neurodevelopmental
outcome
MEASURES
GMFCS
HINE
BSID-III
CP diagnosis: HINE
NeoNATI
Phase 1 and 2
N=42
Cooling + topiramate (5
doses, 5mg/kg daily)
Control: cooling
>=34 weeks
<6h old
Mod-severe
encephalopathy
Signs early perinatal
depression
Known congenital
myopathy or congenital
neuropathy
Seizures (clinical or
electrical)
Cooling + Xenon (50% 18
hrs)
Control: cooling
Mod-severe enceph
≥36 wks
30 mins Abnormal aEEG
Congenital abnormalities
aEEG
MRI (<2weeks)
Cooling + erythropoietin
Control: cooling
>=36 weeks
<23 h age
Perinatal depression
Mod-severe NE
Hypothermia by 6h age
Markers of organ
function
Phase 1 and 2
N= 130
Cooling + xenon (30% 24
hrs)
Mod-severe enceph
≥36 wks <43 wks
30 mins Abnormal aEEG
Major congenital
malformation
Suspected genetic,
metabolic or TORCH
infection
IUGR (<1800g)
Considering withdrawal
of support
Head circumference
<2SD for gestation
Delayed hypothermia >
6hrs
TOBYXe
Control: cooling
Cooling and Topiramate
Phase 1 and 2
N=24
MRI
Okereafor (1-5)
HIE score
Time for normalization of
aEEG
S100-beta levels
MRI score
Developmental outcome
BSID-III
N/A
Cooling and Xenon Pilot
Phase 1 and 2
N=50
NEAT O
Reduction in Lac/NAA
ratio on magnetic
resonance spectroscopy
or preserved fractional
anisotropy measured on
diffusion weighted
magnetic resonance
imaging
Alberta Infant Motor
Score (AIMS) (12
months)
AIMS
N/A
COOLING PLUS STUDIES SUMMARY – Updated April, 2014
STUDY DESIGN/
PHASE/NAME
Phase 1 and 2 (3 group
RCT)
N= 45
Cooling and Darbe
Prospective
observational case
control
N=62
INTERVENTION/
CONTROL
INCLUSION
Cooling + low dose darbe
(2 doses)
Cooling + high dose
darbe (2 doses)
Control: Cooling +
placebo
Mod severe acute
perinatal HIE
>36 wks
<12 hrs
Cooling
Survivors of original
CoolCap study now 6-8
years of age
Control: standard care
EXCLUSION
Congenital abnormalities
<1800 g
PRIMARY OUTCOME
Number of adverse
events (first 30 days)
SECONDARY OUTCOMES
MEASURES
Pharmokinetic profile of
Darbe
Function on set of skills
basic to daily life
WeeFIM
CoolCap followup study
Prospective
observational
N=115 NE
Cooling
Mod-severe enceph
36 - 43 weeks
Life threatening
congenital
malformations
Syndromes
Metabolic disorders
Meningitis/encephalitis
Thalamic 1H MRS NAA
concentration and
Lac/NAA
Cooling
Participant of Toby study
No consent for further
contact
Survival with IQ > 84
Standard care
Age 6 years – 7 years 3
months
Phase 1 and 2
Whole body cooling
using phase changing
material
N=35
Cooling (phase changing
material)
Apgar < 5 at 5 mins or
continued resusc at 5
mins
NE
< 36 weeks
Major congenital
malformations
<1.8kg
Imminent death
Stability of cooling (temp
33-34C)
Brain tissue injury (MR)
Adverse
neurodevelopment
Mortality
EEG abnormality
Sepsis
RCT
N=100
Cooling blanket
Up to 6 hours
>= 35 weeks
(Mod-severe HIE)
Being cooled during
transport
Congenital/lethal
chromosomal
abnormality
Not providing full
intensive care
No consent
Temperatures in target
range 33-34C
Time to target temp
Temp in target range at
1hr
Temp ranges during
transport
Safety outcomes
Controls (healthy
newborn infants)
MARBLE
Healthy adults
Cross-sectional
observational
N=239
Neurodevelopmental
outcome
TOBY Children
Standard care
Standard cooling practice
California Transport
Cooling Trial (CTCT)
BSID-III
WPPSI-III or WISC
NEPSY 2nd ed
Working memory test battery for
children
Neurological examination by
paediatrician
Questionnaire by parents/teachers
DASII
GMFCS
Head circumference
Vision/hearing impairment
COOLING PLUS STUDIES SUMMARY – Updated April, 2014
STUDY DESIGN/
PHASE/NAME
Prospective
observational
N=25
INTERVENTION/
CONTROL
HIE receiving whole body
cooling
No control
NeoAdapt 3
Phase 1 and 2
N=30
Safety of Clonidine in
infants with HIE during
therapeutic hypothermia
HIE; cooling; receiving
clonidine at dosing
intervals every 4, 6, 8,
12, 18 or 24 hours.
INCLUSION
EXCLUSION
PRIMARY OUTCOME
SECONDARY OUTCOMES
Up to 3 days old
>36 weeks
HIE in NICU receiving
whole body cooling
Informed consent
Congenital
hydrops/malformations
likely to affect
cardiovascular
adaptation
Chromosomal anomalies
Non-viability
Surgery within 72h of
birth
Superior vena cava flow
(SVCF)
Pleth Variability Index
(PVI)
Pharmacokinetic data (if
dobutamine received)
>35 weeks
HIE, treated with
hypothermia
Informed consent
Indwelling arterial lines
Suspected major
chromosomal anomalies
(except trisomy 21)
Major cardiovascular
anomalies
Moribund
Require >20ug/kg/min
dopamine or addition
epinephrine/dobutamine
to maintain MAP
>=45mmHg, or milrinone
for cardiovascular
supportfor
cardiovascular support
Baseline HR <80bpm
during hypothermia
Severe persistent
pulmonary hypertension
of newborn, need ECMO
Major chromosomal or
congenital defects
Maximum tolerated dose
of clonidine
SVCF and PVI correlation
to circulatory status (e.g
mean blood pressure and
capillary refill time),
clinical outcomes (e.g.
MRI)
Comparison SVCF/PVI
between dobutamine
and no-dobumatine
infants
Clonidine plasma levels
Time to onset of
shivering after clonidine
Shiverine
No control
Phase 1
N=60
Melatonin – 6 doses over
48h
Melatonin Treatment for
Newborn Infants With
Moderate to Severe
Hypoxic Ischemic
Encephalopathy
Control: placebo
(Believe all receive
cooling per “purpose”
section of trial record –
though isn’t specified in
inclusion/exclusion etc)
Up to 8 hrs
>=36 weeks
Mod-severe HIE
First drug dose within 8h
life
Neurodevelopment at
18m
Seizure burden
Reduction in burst
suppression
Improved cerebral
oxygenation
MEASURES
BSID-III