Induced Systemic Hypothermia in Asphyxiated New-Born Infants: a Randomized, Controlled

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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 >

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Enlarging the study population from severe and moderate asphyxia to mild asphyxia as well

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Reasoning

1. RECRUITMENT RATE

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

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

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 (Lit) supports this speculation. Consequently, the investigation of the neuroprotective effect in a larger group of more moderately asphyxiated newborns appear reasonable.

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.

The new set of inclusion criteria uses the same variables, however with other cut-offs.

On the basis of these experiences the study protocol will be amended as follows:

Page 4: Synopsis

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.

Page 9: Hypotheses

Secondary(a):Hypothermia reduces neurodevelopmental retardation (measured by Griffith GQ) at 18 - 21months to a significant larger extent in the group with mild or moderate abnormal EEG compared to the group with severely abnormal EEG.

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.

Inclusion Criteria for mildly asphyxiated newborns

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:

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:

·  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)

AND

B. Neurological signs of encephalopathy within 5.5 hours of age with as least one of the following signs:

·  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

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).

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.

Page 15: Outcome measure for Subgroup Analysis

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.

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

¬ Title of study : Induced systemic hypothermia...

¬ Name of the hospital

¬ mild / moderate / severe asphyxia

¬ A patient number.

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.

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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

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 Signature Date

Medical University Innsbruck

Biometrician:

Prof. Dr. W. Gaus ______

Department Biometry and Signature Date

Medical Documentation

University of Ulm