1
neo.nEuro.network
Study protocol:
Induced systemic hypothermia in asphyxiated new-born
infants: a randomized, controlled, multicenter study
Amendment 1
30.10.2003
Principal Investigator and Organizer:
Simbruner G, M.D., Professor of Pediatrics
Department of Neonatology
Medical University Innsbruck
Anichstraße 37, A - 6080 Innsbruck, Austria
Fax : + 49 512 504 5883 ;
e-mail > georg.simbruner@uibk.ac.at
2
Enlarging the study population from severe and moderate asphyxia to mild
asphyxia as well
____________________________________________________________________
5
Reasoning
1. RECRUITMENT RATE
10
15
20
25
The previous recruitment rate is only half as large as assumed on the basis of a
survey done before start of the study. After finishing the intended two year recruitment
phase only 75 instead of 150 infants were enrolled into the study up to July 2003. This
low recruitment rate resulted even though new french neonatology centres could be
acquired for the hypothermia trial who enrolled more than half of the patients.
Reasons for the essentially lower recruitment rate are:
 overestimation of the number of asphyxiated newborns in German centres (e.g.
Berlin supposed to enroll 5 to 10 infants per year, actually only 3 patients were
enclosed into the study)
 a decline in the incidence rate of birth asphyxia during the study period
 birth ashyxia is a rare event and therefore an asphyxiated newborn may have been
only recruited to the study if the responsible investigator was present at time of
birth
The american collegues participating in the „NIH-study“ also report a recruitment rate
half as large as anticipated in the study protocol.
2. PROPORTION OF MODERATELY AND SEVERELY ASPHYXIATED INFANTS
30
35
40
In our study protocol we estimated to recruit 40% of severely and 60% of moderately
asphyxiated newborns for the study. Actually, at the second interim analysis the study
acquired
 severely asphyxiated newborns
=
23%
 moderately asphyxiated newborns =
77%

total
= 100%
In personal communication with Professor P.D. Gluckmann and his coworkers from
the University of Auckland, New Zealand we received the information, that in the
“Olympic Medical Trial” about 20% to 25% of the recruited newborns were moderately
asphyxiated, but 75% to 80% were severely asphyxiated. This proportion is the same
as our own observation.
3. EXPECTED EFFICACY
45
50
Clinical experience of treating severely asphyxiated newborns with hypothermia
according to protocol or beyond protocols, has raised the suspicion amongst
colleagues, that applying hypothermia to severely asphyxiated newborns is not as
effective as it should be to cure the patients. In contrast, moderately asphyxiated
newborns seem to have real profit from hypothermia. The publication of Battin et al
3
(Lit) supports this speculation. Consequently, the investigation of the neuroprotective
effect in a larger group of more moderately asphyxiated newborns appear reasonable.
4
55
60
Therefore the Hypothermia trial will be continued
 in maintaining the previously used inclusion criteria (Study protocol
neo.nEuro.network , May 3, 2000), but
 expanding the study population by infants with mild asphyxia.
The advantage of such an extension of the inclusion criteria lies in the fact, that the
study commenced continues unaltered, but at the same time, the investigation of
hypothermia applied to a mild asphyxiated group will yield new information on whether
the neuroprotective effect of hypothermia is higher in less severely affected patients
compared to the severely affected one.
65
The new set of inclusion criteria uses the same variables, however with other cut-offs.
70
On the basis of these experiences the study protocol will be amended as follows:
75
Page 4: Synopsis
80
This randomized, controlled multicenter study aims to determine whether inducing
systemic hypothermia in birth-asphyxiated new-born infants born at term increases the
chance of survival without severe neurodevelopmental handicap. Secondary
objectives are to determine whether the treatment benefit is greater in mild or
moderate rather than severe asphyxia, and whether systemic hypothermia is
associated with significant side-effects.
85
Page 9: Hypotheses
90
Secondary (a): Hypothermia reduces neurodevelopmental retardation (measured by
Griffith GQ) at 18 - 21 months to a significant larger extent in the group with mild or
moderate abnormal EEG compared to the group with severely abnormal EEG.
95
Page 10: Inclusion Criteria
Inclusion Criteria for moderately und severely asphyxiated newborns
The inclusion criteria defined in the study protocol from 3 May 2003 are still valid. But
in future, newborns with mild asphyxia are included as well.
100
5
Inclusion Criteria for mildly asphyxiated newborns
105
If an asphyxiated newborn infant does not fulfill the inclusion criteria for the
moderately or severely asphyxiated group as defined in the study protocol from 3 May
2003, the following inclusion criteria must be fulfilled to assign a newborn to the mildly
asphyxiated group:
6
110
The infant will be assessed sequentially by criteria A, B , C as listed below:
A. Evidence of birth asphyxia characterized by at least one of the following signs:
115




Apgar score of 5 or less at five minutes
pH < 7.1
base deficit > 10 mEqu on cord blood (41) or a blood sample (venous or arterial)
obtained within 60 minutes of birth
respiratory assistance (positive pressure ventilation by mask or intubation) longer
than 5 min due to respiratory depression (early and immediate sign of central
nervous system depression)
120
AND
B. Neurological signs of encephalopathy within 5.5 hours of age with as least one of
the following signs:
125
130
135









abnormal muscle tone
abnormal level of consciousness
clinical seizures
posture
abnormal suck reflex
abnormal grasp reflex
abnormal Moro reflex
respiratory pattern: hyperventilation, apnoic spell or cessation of breathing
bulging fontanelle
These 9 neurological signs are also used for scoring the severity of the
encephalopathy from day 1 onwards according to Thompson (40).
AND
140
C. Moderately Abnormal aEEG or EEG
Moderately abnormal aEEG between NICU admission and 6 hours postpartum is
defined according to the published study of Al Naqueeb et al. (42) and to Lamblin et al
(45).
145
150
155
Evidence of moderate neurophysiological dysfunction: At least 30 minutes duration of
amplitude integrated EEG or standard EEG recording that shows abnormal
background EEG activity or seizures (see definitions : Appendix 1). The aEEG or EEG
may be performed from one hour of age onwards. aEEG or EEG should be read by
trained personnel. Classification of the aEEG is according to al Naqeeb et al. (42).
The classification of the EEG is according to Lamblin et al (45). The aEEG or EEG 30
min following IV anticonvulsant therapy, e.g. phenobarbitone should not be used for
classification.
7
Page 15: Outcome measure for Subgroup Analysis
160
Subgroup analysis of infants with mild, moderate or severe asphyxia in order to
determine which of these subgroups is more responsive to hypothermia treatment.
Griffith General Quotient will be used as outcome measure.
165
Page 17: Randomization
Randomization will be stratified for hospitals as well as for the severity of asphyxia
(mild/moderate/severe). .... The envelopes are identified by
170
Title of study : Induced systemic hypothermia...
Name of the hospital
mild / moderate / severe asphyxia
A patient number.
175
Each participating hospital will receive three piles of envelopes, one pile for mild
asphyxia, one pile for moderate asphyxia and one pile for severe asphyxia.
8
LITERATURE
40
Palisano R, Rosenbaum P, Walter S, Russell D, Wood E, Galuppi B.
Development and reliability of a system to classify gross motor function in children with cerebral palsy. Dev Med Child Neurology 1997; 39: 214-223
41
Thompson CM, Puterman AS, Linley LL, Hann FM, van der Elst CW, Molteno
CD, Malan AF. The value of a scoring system for hypoxic ischaemic encephalopathy in predicting neurodevelopmental outcome. Acta Paediatr 1997; 86:
757-61
42
al Naqeeb N, Edwards AD, Cowan FM, Azzopardi D. Assessment of Neonatal
Encephalopathy by Amplitude-intergrated Electroencephalography. Pediatrics
1999; 103; 1263-1271
43
Hellström-Westas L, Rosén I, Svenningsen NW (1995) Predictive value of
early continuous amplitude integrated EEG recordings on outcome after
severe birth asphyxia in full term infants. Arch Dis Child 72: F34-F38
44
Toet MC, Eken P, Groenendaal F, de Vries LS Comparison of amplitude
integrated EEG in birth asphyxiated term neonates between 3 and 6 hours
after birth (Abstr 1902, Neurology; Ped Res 1998; 43, Part 2 of 2)
45
Lamblin MD, Andre M, Challamel MJ, Curzi-Dascalova L, dÁllest AM, De Giovanni E , Moussalli-Salefranque F, Navelet Y, Plouin P, Radvanyi-Bouvet MF,
Samson-Dollfus D, Vecchierini-Blineau MF. Electroencephalographie du nouveau-ne premature at a term. Aspects maturativs et glossaire. Neurophysiol
Clin 1999; 29: 123 - 219
9
SIGNATURES
The signatures of the principal investigator and the responsible biometrician
document their consent with the Study Protocol in the version on hand.
Principal investigator:
Prof. Dr. med. G. Simbruner
_____________________
_________________
Department of Neonatology
Medical University Innsbruck
Signature
Date
Prof. Dr. W. Gaus
_____________________
_________________
Department Biometry and
Medical Documentation
University of Ulm
Signature
Date
Biometrician: