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Protocol anz version 2 july 2003.doc

PROTOCOL
Non-specific intravenous immunoglobulin (Intragam P) therapy for suspected or proven neonatal sepsis: an international, placebo controlled multi-centre randomised trial V2, July 2003 - Australian and New Zealand Version
Supercedes: V1, January 2002 – Australian and New Zealand Version ISRCTN 94984750

PROTOCOL SUMMARY. 3
HYPOTHESIS. 4
BACKGROUND. 4
Incidence of neonatal sepsis, potential impact on mortality and problems in diagnosis. 4 Pathophysiology of neonatal sepsis and potential impact of sepsis on the perinatal brain . 4 Theoretical and clinical basis for immunoglobulin therapy in neonatal sepsis. 5 Other possible adjunctive treatments . 5 Results of previous randomised controlled trials (RCTs) . 6 Non-specific, polyclonal IVIG versus specific, hyper-immune IVIG. 8 SAFETY. 9
Safety: Transmission of blood borne viruses and prion disease. 9 Safety: Haemolysis in relation to T activation of red cells . 9 SUMMARY. 9
RESEARCH PLAN . 10
Trial eligibility . 10 Parental consent. 10 Randomisation. 10 Treatment. 10 Clinical management . 10 OUTCOMES . 10
Primary outcome. 10 Secondary short term outcom es . 10 Secondary long term outcomes. 10 Health service utilisation . 10 Measurement of Outcomes . 10 DATA COLLECTION. 10
STATISTICAL ANALYSES. 10
Subgroup analyses . 10 Interim analyses: the Safety and Data Monitoring Committee . 10 SAMPLE SIZE . 10
FEASIBILITY. 10
ECONOMIC EVALUATION OF IVIG. 10
PUBLICATION POLICY. 10
OUTCOMES AND SIGNIFICANCE . 10
REFERENCES. 10

PROTOCOL SUMMARY

Background
Sepsis is an important, but sometimes undiagnosed, cause of perinatal brain damage and
mortality. In term infants, blood concentrations of inflammatory cytokines are elevated in those
later diagnosed with cerebral palsy. In preterm infants, infection remote from the brain may
predispose to cerebral white matter damage. While effective antibiotic treatment is essential,
resistance to antibiotics is increasing. Adjuvant therapies, such as intravenous immunoglobulin
(IVIG), therefore offer an important additional strategy.
Newborn babies are deficient in immunoglobulins, which enhance and modulate the immune
response to infection. The anti-inflammatory properties of polyclonal IVIG make it of therapeutic
benefit in many auto-immune and inflammatory diseases such as multiple sclerosis and chronic
demyelinating inflammatory polyneuropathy. In laboratory studies, polyclonal IVIG can modulate
the local CNS immune reaction, suppressing phagocytosis and facilitating the re-myelination of
damaged oligodendrocytes. Polyclonal IVIG may therefore be of therapeutic benefit in cerebral
inflammation due to sepsis.
Three recent Cochrane systematic reviews of randomised controlled trials in nearly 6,000
patients suggest that non-specific, polyclonal IVIG is safe, reduces sepsis by about 15% in
prophylaxis and may reduce mortality by 45% in treatment of neonatal sepsis. However, the trials
of treatment were small and lacked long-term follow-up data. This protocol is for a large, simple,
international trial, to assess reliably whether treatment of neonatal sepsis with IVIG reduces
mortality and adverse neuro-developmental outcome. It needs no special expertise and can be
conducted simultaneously with other studies.

Research Plan

Infants are eligible if they have proven or suspected serious infection; AND they have at least
one of the following, either (i) birth weight of less than 1500 g; or (ii) evidence of infection in
blood culture, CSF or usually sterile site body fluid; or (iii) respiratory support via an endotracheal
tube; AND they are receiving antibiotics. Infants are excluded if IVIG has already been given or if
IVIG is thought to be needed or contraindicated.
The treatment group will receive an infusion of IVIG, 500 mg (8.33 ml) per kg, repeated after 48 hours. The control group will receive an infusion of placebo solution, 8.33 ml per kg, repeated after 48 hours. The primary measure of outcome is mortality or major disability at two years, corrected for gestational age. Secondary outcomes include hospital mortality, chronic lung disease or major cerebral abnormality before hospital discharge, significant positive culture after trial entry, pneumonia, necrotising enterocolitis, duration of respiratory support, mortality before two years, major disability at 2 years, non-major disability at 2 years, length of hospital stay and number of hospital admissions. Subgroup analyses will stratify by birthweight, gestation, clinical severity, clinical chorioamnionitis, small for gestation, elevated maternal CRP, duration of membrane rupture, type of infection, and type of IVIG. Recruitment will continue until the end of 2005, with follow-up until early 2008. The total sample
of 5,000 infants worldwide will yield over 90% power with a type I error of 5% (two tailed) to
detect a difference of 4%, from 25% to 21%, in the rate of primary outcome. A moderate
reduction like this would mean that one extra death or disabled survivor could be prevented for
every 25 babies treated. Australian and New Zealand centres will recruit 1500 of the total
sample. Resources are available to train and support part-time local research nurses to facilitate
recruitment and data collection.

Significance
Assessment of neuro-developmental status in survivors is essential if neonatal trials are to
contribute fully to evidence-based policy. If this trial confirms benefit, it could establish the most
cost-effective indication yet for Intragam® P and for other non-specific, polyclonal IVIG products,
changing clinical practice worldwide. If the trial shows no benefit, it will curtail demand for IVIG in
neonatal care and avoid unnecessary costs.

INTRODUCTION
This protocol is for a large, simple-in-design, double-blind, placebo-controlled, pragmatic multi-
centre randomised trial.
HYPOTHESIS
That, in infants receiving antibiotics for clinical sepsis, the addition of non-specific, polyclonal
intravenous immunoglobulin IgG (IVIG) therapy reduces mortality and major disability at 2 years
compared with antibiotics alone.
BACKGROUND
Despite advances in perinatal care, neonatal sepsis remains a major cause of mortality and
morbidity in the first weeks after birth and has been implicated in the causation of perinatal brain
damage and cerebral palsy, both in term and preterm infants.1,2 Although antibiotics are the
mainstay of therapy, increasing numbers of bacteria are resistant to them.3,4 Effective adjunctive
strategies are therefore needed.
Incidence of neonatal sepsis, potential impact on mortality and problems in diagnosis
Prospective Australian studies have reported an incidence of neonatal sepsis, defined as clinical
evidence of infection confirmed by a positive blood culture, of 6.6 per 1000 live births,5 with
approximately threefold greater risk in Aboriginal infants.6 The ratio of sepsis of early onset
(within 48 hours of birth) to late onset sepsis was 1: 2 and the overall hospital mortality rate was
10%. In the Australian and New Zealand Neonatal Network cohort in 2000, the incidence of
clinically proven systemic infection, including early and late onset infection, was 14%, with 15%
all-cause mortality, and 6% mortality due to infection.7 Among a North American cohort of very
low birth weight infants, late onset sepsis occurred in 16%, with 21% hospital mortality.8
Assuming a 15% rate of neurodevelopmental impairment, this translates annually into 250 deaths
and 350 disabled survivors in Australia and New Zealand and over 1 million deaths or disabled
survivors worldwide. However, even these figures may underestimate the true incidence and
impact of clinical sepsis in the newborn, which may often remain undiagnosed.9-12 Sepsis-specific
mortality rates should therefore be interpreted with caution as the diagnosis may often be
inaccurate. More reliable evidence would be provided by randomised comparisons of the effects
of specific interventions on all-cause mortality.
Pathophysiology of neonatal sepsis and potential impact of sepsis on the perinatal brain
Recent evidence suggests that sepsis is also important in the pathogenesis of neuro
developmental impairment of perinatal origin. Neonatal sepsis of early or late onset is associated
with cerebral white matter damage and cerebral palsy13,14 and neurodevelopmental impairment15
or need for special educational resources.14,16-18 In preterm infants, chorioamnionitis and neonatal
sepsis are each independently associated with a fourfold increase in odds of cerebral palsy.2,17
Even in children born at term, cerebral palsy is nine times more likely to develop after antenatal
exposure to maternal infection around the time of birth compared with controls.1 In another case-
control study of term infants, levels of cytokines in neonatal blood spots were consistently higher
in children diagnosed with cerebral palsy at 3 years of age than in controls, suggesting that an
inflammatory response may be important in the aetiology of cerebral impairment.19 Furthermore,
early cerebral lesions on magnetic resonance imaging (MRI) are associated with an inflammatory
response to chorioamnionitis and prenatal infection in preterm infants,20 which may partly reflect
their relative deficiency in anti-inflammatory, endogenous immunoglobulin.21 As antenatal and
postnatal sepsis may predispose to neurodevelopmental impairment and disability in term and
preterm infants, these are essential measures of outcome.
In the immature brain, infection may lead to the release of cytokines, chemokines, adhesins, matrix metallo-proteinases, disruption of the blood brain barrier, activation of microglia and astrocytes and transendothelial migration of circulating leukocytes, leading to disruption of oligodendrocyte myelination, disordered migration of precursors and cellular apoptosis. Other mechanisms of neuronal damage in sepsis may include cerebral hypoperfusion and neurotoxicity from hyperbilirubinaemia. Dammann and Leviton have suggested that infection remote from the preterm brain may predispose to cerebral white matter damage with disruption of oligodendroglial myelination and disordered migration of precursors.22,23 The damage could result partly from inadequate endogenous protection from developmentally regulated factors such as oligotrophins.24 The commonest organisms causing sepsis in neonatal intensive care units (NICUs) in Australia and New Zealand are coagulase negative Staphylococci (CONS), particularly Staphylococcus epidermidis. There is increasing evidence of their pathogenicity.25,26 Perinatal CONS infection is associated with subsequent cerebral palsy.27 Neonatal CONS infection prolongs hospitalisation and increases morbidity and costs.28 No difference has been reported in the rate of neuro-developmental impairment after neonatal meningitis associated with S. Epidermidis versus other organisms.15 Theoretical and clinical basis for immunoglobulin therapy in neonatal sepsis
Newborn infants, particularly those who are born preterm or very low birthweight, are deficient in
IgG.29 This immunoglobulin can bind to cell surface receptors and has many pro-inflammatory
properties such as promoting opsonic activity, fixation of complement, antibody dependent
cytotoxicity, neutrophil chemiluminescence, phagocytosis and release of stored neutrophils.29-34
IgG also has several anti-inflammatory effects35 including down-regulation of inflammatory
cytokines via Fc receptor blockade, provision of anti-idiotype antibodies and interference with the
activation of T-cells, B-cells, the cytokine network and complement.36,37 Of particular interest,
polyclonal IVIG may modulate the local immune reaction in the CNS and may help prevent or
repair damage to oligodendrocytes.38,39 Owing to its anti-inflammatory properties, polyclonal IVIG
is of therapeutic benefit in many autoimmune and inflammatory disorders, such as Kawasaki
Disease and Idiopathic Thrombocytopenic Purpura, and in central nervous system (CNS)
inflammatory diseases such as multiple sclerosis and chronic demyelinating inflammatory
polyneuropathy and others.35,40-44 In randomised controlled trials, polyclonal IVIG decreased
cerebral lesions on serial MRI in relapsing multiple sclerosis 45 and reduced clinical relapses by
30%.40 The immunomodulatory properties of polyclonal IVIG may also partly explain why it
reduces mortality by 36% in adults with sepsis.46 The data support the hypothesis that polyclonal
IVIG may reduce mortality, cerebral inflammatory damage and neurodevelopmental impairment
after neonatal sepsis.
Intravenous immunoglobulin (IVIG) is therefore a theoretically attractive strategy, with multiple
mechanisms of action. Its potential clinical relevance is confirmed by recent evidence from
randomised controlled trials.

Other possible adjunctive treatments

Pentoxifylline
In animal models of sepsis, pentoxifylline, a methylxanthine derivative, inhibits production of
Tumour Necrosis Factor (TNF), preserves micro-vascular blood flow, prevents circulatory failure
and intestinal vaso-constriction and improves survival.47,48 It is well tolerated and decreases TNF
production in adults and preterm infants with sepsis.49,50 Two randomised controlled trials (RCTs)
of pentoxifylline51,52 recruited 140 preterm infants with clinical sepsis. Pentoxifylline was
associated with an 87% reduction in the risk of mortality (RR 0.13, 95% CI 0.02 to 0.69).
Pentoxifylline may be a promising therapy in neonatal sepsis.

Cytokines
Other adjunctive strategies for prophylaxis or treatment of neonatal sepsis are also attractive,
such as use of the recombinant cytokines Granulocyte Colony Stimulating Factor (G-CSF) or
Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) to prevent neutropenia.53
However, no systematic reviews of RCTs of these agents are yet available. In four RCTs of G-
CSF therapy which recruited 125 infants with neonatal sepsis, there was a trend to reduced
mortality which was not statistically significant (OR 0.6, 95% CI 0.2 to 1.8).54-57 Two recent RCTs
of GM-CSF prophylaxis in a total of 339 high risk infants showed no reduction in sepsis or
mortality.58,59 However, these findings do not rule out a moderate benefit.60


Blood products other than immunoglobulin
White cell (granulocyte) transfusions are also a logical approach. Although preliminary clinical
evidence is encouraging,61 there are potential risks from transmission of infection (e.g. HIV or
hepatitis) or from graft-versus-host disease, and the technology is not widely available. Exchange
transfusion with fresh whole adult blood appeared effective in one RCT of 22 septicaemic
infants,62 but may also transmit infection. In another RCT, in 776 infants of less than 32 weeks
gestation, there was no evidence that prophylactic fresh frozen plasma reduced the risks of
mortality from all causes or of disability in survivors at 2 years.63
Overall, therefore, the evidence suggests that IVIG therapy is one of the most promising
strategies in neonatal sepsis and should be assessed in a definitive RCT.
Results of previous randomised controlled trials (RCTs)
A Cochrane systematic review of the prophylactic use of non-specific, polyclonal IVIG in 15 RCTs
with 5,054 preterm or low birthweight infants demonstrated that prophylactic, non-specific IVIG
reduced the risk of sepsis (RR 0.85, 95% CI 0.74 to 0.98) and was safe, with no serious adverse
effects reported, but did not alter mortality (RR 0.89, 95% CI 0.75 to 1.05).64
A Cochrane systematic review65 of reports of RCTs of IVIG therapy for proven or suspected
neonatal sepsis identified nine studies31,66-73 that reported outcomes for 318 infants with
suspected infection and 262 infants with proven infection. IVIG therapy appeared to be safe and
was associated with approximately a 40% reduction in the risk of mortality for both suspected
and proven infection (Tables 1 and 2). However the confidence intervals were wide and the
studies included in the analyses were small and not of high methodological quality. Problems
identified by the reviewers were lack of allocation concealment, lack of blinding of outcome
assessment and high levels of post-randomisation exclusions in some of the trials. The reviewers
concluded that: “The reduced mortality following treatment with IVIG for subsequently proven
infection, the imprecise estimate of the effect size (number needed to treat 11, 95% CI 5.6, 100)
and the borderline statistical significance for the outcome of mortality in neonates with suspected
infection justify further research. Researchers should be encouraged to undertake well-designed
trials to confirm or refute the effectiveness of IVIG”
.65

Table 1:

Mortality in trials of IVIG for suspected infection in neonates
IVIG in neonatal infection
Comparison: IVIG vs placebo or no intervention for suspected infection
Outcome:

Mortality from any cause
Mortality in trials of IVIG for proven infection in neonates
IVIG in neonatal infection
Comparison: IVIG vs placebo or no intervention for proven infection
Outcome:

Mortality from any cause

Using slightly different selection criteria and methods for analysis, Jenson and Pollock published
a systematic review of three RCTs of IVIG in neonatal sepsis in which 55 infants received IVIG
and 55 received placebo or no infusion.74 The odds ratio for mortality in treated versus control
infants was 0.17 (95% CI 0.03-0.75). These authors reached a conclusion which many would
consider premature, namely that ‘IVIG should be considered as part of the routine therapy of
neonatal sepsis’
. Nevertheless, it remains true that, among all interventions currently reviewed in
the Cochrane Library, IVIG therapy in neonatal sepsis is associated with one of the largest
reductions in the odds of death. A further RCT of IVIG in neonatal sepsis in Brazilian neonatal
units is being conducted. One of the applicants (K Haque) is an investigator of this trial. Its results
will be incorporated into the current meta-analysis as soon as they are available.
Another recent Cochrane systematic review and meta-analysis of IVIG in treating sepsis and
septic-shock in all patients (adults, children and neonates) with non-specific, polyclonal IVIG from
a variety of sources suggested a beneficial effect on all-cause mortality (OR 0.64, 95% CI 0.51 –
0.80)46 (Table 3).
Table 3.
Mortality in trials of IVIG for proven sepsis/septic shock in adults & children
Intravenous immunoglobulin for treating sepsis and septic shock
Comparison: IVIG vs placebo or no intervention
Outcome:

All-cause mortality (ACM), by age group, polyclonal IVIG

Polyclonal IVIG vs placebo, adults, ACM


Polyclonal IVIG vs placebo, neonates, ACM


There was significant heterogeneity between studies, which makes this summary measure
difficult to interpret. A sensitivity analysis of studies of good and fair quality, however, did not
detect any heterogeneity and also suggested a decreased risk of mortality in septic patients
(n=332; RR 0.55 95% CI 0.40-0.79). The same Cochrane review also explored the effect of
monoclonal antibodies: the relative risks for both anti-endotoxins and anti-cytokines were similar
and were of borderline statistical significance (anti-endotoxins RR 0.93, 95% CI 0.85 to 1.02;
anti-cytokines RR 0.92, 95% CI 0.86 to 0.99). The authors concluded that although there was
evidence that non-specific IVIG appears to be beneficial ‘Large, multi-centre studies are needed
to confirm the effectiveness of polyclonal IVIG in reducing mortality in patients with sepsis.
These are particularly indicated for neonatal sepsis, where evidence for benefit is still conflicting
’.
Duration of hospitalisation was reported as a secondary outcome measure in seven polyclonal
IVIG trials. There was a significant reduction in number of days in hospital in the IVIG group
(weighted mean difference -1.36; 95% CI -2.51,-0.22).
Non-specific, polyclonal human IVIG appears to be generically effective, in keeping with multi-
factorial actions, and its impact does not appear limited to any one IVIG product. As no trial used
repeated IVIG treatment for subsequent episodes of neonatal sepsis, repeated treatments are
not proposed in this study. While there is evidence that polyclonal IVIG may reduce mortality in
neonates, its effects on specific organisms may vary.75 The INIS trial will therefore provide
reliable comparisons among subgroups by pathogen. Detailed follow up of survivors is
mandatory as there are no reliable data on disability, which is a major determinant of costs. The
trial is unique in proposing systematic follow-up in a large sample of survivors to provide reliable
comparisons of health status and disability at two years between the treated and control groups.

Non-specific, polyclonal IVIG versus specific, hyper-immune IVIG
This trial will use non-specific, polyclonal IVIG (normal human IgG immunoglobulin) (Intragam®
P) produced by CSL, Melbourne, Australia, from voluntary donors in each country (Australian
donors for Australian IVIG and New Zealand donors for New Zealand IVIG). It was decided that
specific, hyper-immune IVIG would not be used and that there was no necessity to characterise
the specific antibacterial profile of non-specific, polyclonal IVIG, for several reasons:
(i) Previous RCTs of non-specific, polyclonal IVIG in neonates and adults did not characterise any specific aspects of antibacterial function in the products used. There is therefore no reference laboratory data against which to judge the possible antibacterial efficacy of polyclonal IVIG. (ii) As the mechanism of action of IVIG is likely to be multifactorial, the precise aspects of antibacterial function that should be assessed are speculative. Much of the therapeutic benefit of polyclonal IVIG may be related to its anti-inflammatory properties, which are multi-factorial and non-specific. (iii) Despite production of monoclonal antibodies with demonstrable in vitro and in vivo antibacterial function in laboratory studies, they have not been associated with reductions in mortality in RCTs.46 There is no evidence that laboratory studies to characterise specific antibacterial function in IVIG would be more predictive of clinical efficacy than the evidence from RCTs for non-specific, polyclonal IVIG therapy. The UK Medical Research Council commissioned three referees to examine this issue. They concluded that hyper-immune IVIG for specific pathogens was theoretically preferable but unavailable and unanimously endorsed use of non-specific, polyclonal IVIG in this study.
Safety: Transmission of blood borne viruses and prion disease
The risk of transmissible infection by blood products remains a potent source of anxiety for
clinicians and patients. However, Intragam® P, for use in Australia and New Zealand, is
produced to the most modern standards of quality control using only plasma donated by healthy,
unpaid, local volunteers screened for viruses such as HIV and Hepatitis. The process includes
alcohol fractionation, partitioning, microfiltration and two specific virus inactivation steps:
pasteurisation (heating at 600C for 10 hours) and low pH incubation (for 14 days at 270C).
Intragam® P and its predecessor, Intragam®, have an excellent safety record, with no
documented cases of transmissible infection. The manufacturer estimates the risk of
transmission of a virus, such as Hepatitis or HIV, as less than 1 in 10 million IVIG infusions,
approximately 100 times lower than the risk associated with blood transfusions (Australian Red
Cross Blood Service, Jan 2001). Leucocytes are the main source of infectivity in Creutzfeld-
Jacob disease. Owing to the physico-chemical characteristics of the abnormal prion protein, the
process of partitioning and filtration of leucocytes during fractionation of Intragam® P reduces
any theoretical risk of prion transmission in IVIG.76 Fractionation pools are also tested with PCR
(polymerase chain reaction) for blood borne viruses. The residual theoretical risk of transmissible
infection must be balanced against the estimated actual 25% risk of mortality or major morbidity
in infants eligible for the trial and against potential benefits that may include a 30% reduction in
mortality.
Safety: Haemolysis in relation to T activation of red cells
Bacteria such as Clostridia can strip neuraminic acid residues from the red cell membrane,
exposing the T antigen (T activation). Adult plasma contains anti-T antibodies, so transfusing
newborn infants whose red cells are T activated with whole blood, unwashed red cells or
unselected plasma may lead to polyagglutination and haemolysis.77 However, anti-T antibodies
are predominantly IgM immunoglobulins, a fraction which is removed from the IVIG products
used in this study (CSL Intragam® P product literature). In the published literature, no significant
neonatal haemolysis has been noted with IVIG. Neither the Adverse Drug Reactions Advisory
Committee in Australia nor the UK Committee on Safety of Medicines have received any reports
of haemolysis or other serious adverse reactions in association with neonatal IVIG treatment
(personal communication, Sept 1999). T activation is thus not a contraindication for these IVIG
products in neonatal sepsis.
SUMMARY
There is good preliminary evidence that IVIG therapy may reduce mortality and cerebral inflammatory damage in neonatal sepsis. However, there is no information on longer term quality of survival, the number of babies included in the existing systematic reviews is small and the effect size seems larger than would be anticipated. As a consequence a reliable multicentre trial is needed to test whether IVIG therapy is of benefit, with survival free from major morbidity in early childhood as the outcome. IVIG is not yet widely used as routine therapy. There remains, therefore, a window of opportunity for a reliable trial before an inadequately assessed intervention may be introduced into practice. The trial results will be generalisable to other IVIG products, commercial and non-commercial. Most importantly, they will provide reliable evidence on whether neonatal sepsis should constitute a new indication for IVIG therapy in Australia and New Zealand.
RESEARCH PLAN

Trial eligibility
Hospitals are eligible to join the International Neonatal Immunotherapy Study (INIS) if they
provide neonatal intensive or special care, can achieve satisfactory rates of follow-up at 2 years
and would be able to institute the routine use of adjuvant IVIG for babies with sepsis if the trial
demonstrates evidence of benefit.
Infants are eligible if:
They have proven or suspected serious infection They have at least one of the following: • birth weight less than 1500 g
OR
• evidence of infection in blood culture, or CSF or usually sterile body fluid
OR
• respiratory support via an endotracheal tube
They are receiving antibiotics and there is substantial uncertainty that IVIG is indicated IVIG has already been given or is thought necessary or contra-indicated
Over 50 clinical and laboratory criteria have been described for neonatal sepsis,78-82 which may
present with subtle changes, so a precise definition is not practicable. A pragmatic approach will
therefore be adopted, based on the clinicians’ own judgement that there is serious infection.
However, specific, previously validated clinical and laboratory criteria (see Statistical Analysis)
will be recorded at trial entry to grade the clinical severity (low, moderate, high) of all infants for
subsequent analysis. Clinicians normally have a low threshold for antibiotic treatment, which
should begin quickly, as infected infants can quickly deteriorate. However, the threshold for IVIG
therapy in this study is greater than for simply starting a course of antibiotics. For entry into INIS
there should be a clinical suspicion that the baby has infection and/or be considered at
significantly increased risk.83 Once an infant is considered to be eligible, it is important that
enrolment takes place as soon as practically possible.
The trial is designed to include all neonatal infections, including bacterial, viral and fungal
infections. Both early and late onset infections are also included. Babies remain eligible at any
age during their first hospitalisation. If they have been readmitted from home, they are eligible up
until their EDD (estimated date of delivery) plus 28 days.

Parental consent
Recruitment will depend on good teamwork, knowledge and confidence among all clinicians,
particularly front line nursing and medical staff, so that parents receive appropriate information
about the study before entry and throughout their baby’s stay. Experience from the ORACLE
trials,84,85 which recruited over 11,000 women from 161 centres, suggests that it is helpful if
nurses and doctors understand the study background, see clinical research as an integral part of
clinical care contributing to future quality, and if a named nurse is appointed and trained as a
local trial coordinator. If those caring for the baby are well informed about the study, they can
discuss it without transmitting anxiety. Indeed, parents are likely to feel less anxious if given the
opportunity to discuss options for their baby’s treatment in the context of the study with
knowledgeable staff. The named nursing and medical representative in each unit will therefore
receive opportunities for training, regular information and support to enable them to orientate and
update new and established nursing and medical staff. The protocol, printed materials and
relevant new research will be widely available and staff will be kept informed by newsletters,
personal visits and the study website (ANZ: INIS website is being developed at the NHMRC
Clinical Trials Centre; UK: www.npeu.ox.ac.uk/INIS).

Parents should routinely be given an Information Sheet about INIS by the nursing staff when their
baby is admitted to the neonatal unit, or when appropriate time. This will include details of their
local medical and nursing contact with whom they can discuss the study. If an infant becomes
eligible for INIS it is necessary to gain parental consent and start treatment with the study drug as
soon as possible. Therefore, informing the parents about INIS early may help them to be able to
decide about participation in INIS quickly, if the need arises. If their baby becomes eligible they
will be asked for consent to participate in the study and later follow up, by the most appropriate
member of staff available, in person or by telephone. If telephone consent is considered
necessary and appropriate by the recruiting clinician, a ‘Telephone consent’ form will be
completed and the parent will be asked to sign the consent form on their next visit to the hospital.
A copy of the Information Sheet and consent form will be given to parents. Nursing and medical
staff will be asked to encourage parents to ask any questions they may still have about the study
during their baby’s continuing care and follow up. Regular newsletters will inform parents about
the study after discharge and, eventually, about its results.
Randomisation
The randomisation will be a stratified block design, stratified by site, with randomly varied block
sizes. The computer-generated randomisation lists will be prepared by an independent
statistician at the NHMRC Clinical Trials Centre, University of Sydney. The randomisation list will
be held by the clinical trials pharmacist or other appropriate third party at each participating
hospital, and will be accessed only by authorised staff not involved in the baby’s daily clinical
care.

Treatment
Infants will be randomly allocated to the treatment and control groups. The treatment group will
receive an intravenous infusion of IVIG (Intragam® P), 500 mg/kg (8.3 ml per kg) over 4–6 hours,
repeated after 48 hours. The control group will receive 8.3 ml per kg, normal saline (placebo
solution) over 4–6 hours, repeated after 48 hours. The study is double-blind, i.e. treatment
allocation will be concealed from investigators, clinicians and parents. To maintain the blinding,
the pharmacist or other appropriate third party person will prime the extension line, mask the
syringe with yellow tape and ensure that no bubbles are present.
Clinical management
After the second dose, no further IVIG or placebo, nor open label IVIG should be given, in this or
any subsequent episodes of clinical sepsis. Other aspects of management are left to the
neonatologist responsible for care. No special investigations and no delays of discharge will be
required.
IVIG may lessen the immune response to live virus vaccines (e.g. MMR and polio) up to 3
months after treatment with IVIG. However this will not interfere with the infants’ polio
vaccinations (National Centre for Immunisation Research and Surveillance of Vaccine
Preventable Diseases, The Children’s Hospital at Westmead, Sydney; and NSW Health;
personal correspondence, May 2003).
OUTCOMES
Primary outcome
1. Mortality or major disability at two years, corrected for gestational age.

Secondary short term outcomes

2. Mortality, chronic lung disease or major cerebral abnormality before hospital discharge,
significant positive culture after trial entry, pneumonia, necrotising enterocolitis, duration of
respiratory support.

Secondary long term outcomes

3. Mortality before two years, major disability at 2 years, non-major disability at 2 years.

Health service utilisation

4. Length of hospital stay and number of hospital admissions.
Measurement of Outcomes
All examinations will be blinded to treatment allocation. Hospital mortality, chronic lung disease,
major cerebral abnormality and length of stay will be assessed from case notes. Major disability
at two years will be assessed by questionnaires sent to the child’s parents and health care
professionals. Major disability will be defined according to the criteria set out in the National
Perinatal Epidemiology Unit (NPEU) and Oxford Regional Health Authority document and will
include any major disability in the following domains: neuromotor function, seizures, auditory
function, communication, visual function, cognitive function and other physical disability.86-88 The
parental questionnaire incorporates the parent report component of the Parent Report of
Children’s Abilities (PARCA), which was used in the 2 year follow up of the MRC funded UKOS
trial. This shortened version of the PARCA was acceptable to parents, with a high response rate
in UKOS, and is currently being validated by the UKOS team. The PARCA score (both parent
report and parent administered components) has been validated and was found to predict
performance on the Mental Development Index of the Bayley Scales of Infant Development II
(BSID II).89,90 The overall score for the modified PARCA will give a measure of verbal and non-
verbal cognitive abilities. The parents’ questionnaire also includes questions about temperament,
which may give an early indication of behavioural and attentional difficulties, and also includes
questions about respiratory function, hearing, vision, hospital admissions, relevant diagnoses and
current function in a number of domains, allowing categorisation of disability as major or non-
major.
In addition a BSID II89 assessment will be undertaken at 2 years of age in all infants recruited in
New Zealand centres and a number of infants recruited in Australian centres. The BSID-II is a
gold standard test for evaluating disability and developmental status, administered by a certified
psychologist or paediatrician, which can reliably differentiate major, moderate and mild disability
and normal development. The Bayley assessments in Australia and New Zealand will allow
further validation of the PARCA parent questionnaires, and for the first time in these countries.
These data will also be used to perform a sensitivity analysis within the economic evaluation by
reliably classifying the surviving infants into major, moderate, mild or no disability at 2 years of
age. While parental questionnaires have generally been shown to be predictive of major disability
versus no disability, they tend to be less predictive of more subtle disabilities.91 The Bayley
assessments will also enable evaluation of whether IVIG has subtle beneficial effects on
cognitive and psychomotor development, by comparing their mean test scores in pre-specified
subgroups who are at high risk of a poor outcome, such as preterm infants born after clinical
chorioamnionitis, preterm, prolonged rupture of membranes and high maternal CRP.
Loss to follow-up will be minimised by collecting comprehensive contact details, distribution of
parent newsletters, contact with the hospital follow-up clinic and use of the Health Insurance
Commission address database in Australia where appropriate.
DATA COLLECTION
Data collection will be the responsibility of the local trial coordinator. Data forms will be provided by the INIS Coordinating Centre, to prospectively collect data relating to the baby’s baseline factors, clinical condition at trial entry, hospital-based outcomes and comprehensive contact details for follow-up. Data will be collected for the baby’s entire stay in hospital, up until discharge to home or death. Infants transferred to other hospitals prior to discharge home will be tracked by the local trial coordinator and data about the baby’s care in each unit will be collected to ensure that data regarding outcomes are complete. Ongoing mortality data will be collected from the Australian Institute of Health and Welfare mortality register. Data relating to subsequent health service use and hospitalisations will be collected retrospectively using 1-yr and 2-yr parent questionnaires. Follow-up data collected at 1 and 2 years of age is the responsibility of the local trial coordinator, although the INIS Coordinating Centre will provide logistical and coordination
support. Data collection will be subjected to stringent quality control at the ANZ INIS Coordinating
Centre, NHMRC Clinical Trials Centre, University of Sydney.

Serious adverse events
Unexpected serious adverse events occurring during the period of hospitalisation will be notified
to the ANZ INIS Coordinating Centre within 24 hours of the event becoming known to the
Investigator. The Aust/NZ Study Coordinating Centre will then notify the UK INIS Coordinating
Centre of these events within 24 hours. The UK Coordinating Centre will activate a notification
cascade, which includes notifying the Safety and Data Monitoring Committee, Trial Steering
Committee, multi-centre research ethics committee, Scottish Blood Transfusion Service and
Medicines Control Agency if appropriate. In Australia, the ANZ INIS Coordinating Centre will
notify the TGA of reportable unexpected serious adverse events as specified in TGA regulations.
The Investigator or delegate at each participating institution is responsible for reporting serious
adverse events to their Health Research Ethics Committee (HREC) as specified in each HREC’s
guidelines. Adverse events will be monitored by the Safety and Data Monitoring Committee (UK)
at least once per year.

STATISTICAL ANALYSES

An intention to treat analysis will be performed comparing the outcome of all infants allocated
IVIG with all those allocated placebo, regardless of what treatment was received, or how
complete the treatment was. Statistical analysis will calculate the relative risk of an outcome in
the IVIG group compared with the placebo group, with a 95% confidence interval. For subgroup
analyses, 99% confidence intervals will be calculated to take account of the number of
comparisons.

Subgroup analyses
Nine subgroup analyses will also be undertaken, stratifying by the factors described below.
1. Birth weight: Infants of very low birth weight (VLBW: < 1500g) vs infants with birth weight =
2. Small for gestational age infants (< 10th centile) vs infants = 10th centile. 3. Gestational age at birth: < 26 weeks, 26+0 to 27+6 weeks, 28+0 to 29+6 weeks, 30+0 weeks 4. Maternal chorioamnionitis: infants born at < 30 weeks gestation to women with clinical chorioamnionitis vs infants born at < 30 weeks gestation with no clinical chorioamnionitis vs infants born at = 30 weeks. 5. Elevated maternal CRP: infants born at < 30 weeks gestation to women with elevated CRP (> 80mg/l) vs infants born at < 30 weeks gestation with no elevated maternal CRP vs infants born at = 30 weeks. 6. Preterm birth and duration of membrane rupture: Born at < 37 weeks and membranes ruptured for < 24 hours, 24-48 hours or > 48 hours vs born at = 37 weeks. 7. Clinical markers of mortality risk:78-82 (i) Clinical evidence of high mortality risk: looking seriously ill or inactive, and has: (a) capillary refill time >3 seconds OR (b) bowel perforation or definite necrotising enterocolitis OR (c) prolonged bleeding from puncture sites OR (d) ventilated, SaO2/FiO2 ratio or PaO2/FiO2 ratio consistent with >15% mortality risk for (e) pH consistent with >15% mortality risk for gestation. [SaO2/FiO2 ratio, PaO2/FiO2 ratio and pH consistent with >15% mortality risk will be extrapolated from oxygenation and pH data in a prospective cohort of 14,000 infants (UK Neonatal Staffing Study)92 by methods similar to that used in the development of the MRC funded CRIB score.] (ii) Intermediate mortality risk: not satisfying criteria for high risk, but has: (a) Total white cell count < 5 x 109/l OR (b) CRP above 15 mg/l OR (c) platelet count < 50 x 109/l OR (d) organism(s) isolated in blood or usually sterile site OR (e) pneumonia on chest X-ray OR (f) CSF consistent with bacterial meningitis. (iii) Other: not satisfying criteria for high or intermediate risk. 8. Type of infection: (i) Early onset infection (non contaminant organisms isolated from culture sent before 48 a) group B streptococcal disease b) other pathogens c) indeterminate aetiology (ii) Late onset infection (non contaminant organisms isolated from culture sent after 48 hours) a) gram positive organisms except Staphylococcus epidermidis b) staphylococcus epidermidis c) other pathogens d) indeterminate aetiology (iii) Post surgery
9. Type of IVIG. This subgroup analysis will analyse separately babies recruited in hospitals
using the different IVIG products included in INIS. This subgroup analysis will include baseline
characteristics and treatments after randomisation as well as outcomes.

Interim analyses: the Safety and Data Monitoring Committee
For the trial a Data Monitoring and Ethics Committee (DMEC) [Safety and Data Monitoring
Committee (SDMC)] has been established. This is independent of the trial organisers and meets at
least once per year. During the period of recruitment to the trial, interim analyses will be supplied, in
strict confidence, to the DMEC, together with any other analyses the DMEC may request. In the light
of interim data, and other evidence from relevant studies (including updated overviews of the
relevant randomised controlled trials), the DMEC will inform the Trial Steering Committee, if in their
view (i) there is proof beyond reasonable doubt that any part of the protocol under investigation is
either clearly indicated or contra-indicated, for all infants or for a particular subgroup of trial
participants; or (ii) it is evident that no clear outcome will be obtained. Decision to inform the Trial
Steering Committee in either of these circumstances will in part be based on statistical
considerations.
Appropriate criteria for proof beyond reasonable doubt cannot be specified precisely. A difference of
at least 3 standard deviations in the interim analysis of a major endpoint may be needed to justify
halting, or modifying, such a study prematurely. If this criterion were to be adopted, it would have the
practical advantage that the exact number of interim analyses would be of little importance, and so
no fixed schedule is proposed.93
Unless modification or cessation of the protocol is recommended by the DMEC, the Trial Steering
Committee, collaborators and administrative staff (except those who supply the confidential
information) will remain ignorant of the results of the interim analysis. Collaborators and all others
associated with the study may write through the trial office to the DMEC to draw attention to any
concern they may have about the possibility of harm arising from the treatment under study, or
about any other matters that may be relevant.
The membership of the DMEC is:

Professor Adrian Grant: Director, Health Services Research Unit, Foresterhill, Aberdeen AB25
2ZD. Email: a.grant@abdn.ac.uk
Professor Forrester Cockburn: Royal Hospital for Sick Children, Yorkhill NHS Trust, Glasgow G3
8SJ. Email: f.cockburn@clinmed.gla.ac.uk
Professor Deborah Ashby: Wolfson Institute of Preventive Medicine, Charterhouse Square,
London WC1M 6BQ. Email: d.ashby@mds.qmw.ac.uk
Mrs Hazel Thornton: ‘Saionara’, 31 Regent Street, Rowhedge, Colchester CO5 7EA. Email:
hazelcagct@ol.com
Dr Neena Modi: Reader in Neonatal Medicine, Imperial College Faculty of Medicine, 4th Floor,
Chelsea & Westminster Hospital, 369 Fulham Road, London, SW10 9NH. Email:
n.modi@imperial.ac.uk
Dr Brian McClelland: Consultant, Scottish National Blood Transfusion Service, Edinburgh Royal
Infirmary, Edinburgh EH3 9YW. Email: brian.mcclelland@snbts.csa.scot.nhs.uk
The membership of the Trial Steering Committee is:
Professor Richard Cooke: Professor of Neonatal Medicine, Neonatal Intensive Care Unit,
Liverpool Women’s Hospital, Crown Street, Liverpool L8 7SS. Email: mc19@liverpool.ac.uk
Professor C Anthony Hart: Head of Department, Medical Microbiology, University of Liverpool,
Liverpool L69 3BX. Email: cahmm@liv.ac.uk
Dr Gorm Greisen: Department of Neonatology, Rigs – Hospitalet, DK 2100 Koppenhagen,
Denmark. Email: greisen@rh.dk
Professor Douglas G Altman: ICRF Medical Statistics Group, Centre for Statistics in Medicine,
Institute of Health Sciences, Old Road, Headington, Oxford OX3 7LF. Email:
doug.altman@cancer.org.uk
Chief Executive of BLISS: 68 South Lambeth Road, London SW8 1RL.
Dr William Tarnow-Mordi: Department of Neonatology, Westmead Hospital, Sydney, New South
Wales 2122, Australia. Email: williamt@westgate.wh.usyd.edu.au
Dr Peter Brocklehurst: NPEU, Institute of Health Sciences, Old Road, Headington, Oxford OX3
7LF. Email: peter.brocklehurst@perinat.ox.ac.uk
SAMPLE SIZE
The total sample of 5,000 infants worldwide will yield over 90% power with a type I error of 5% (two tailed) to detect an absolute risk difference of 4%, from 25% to 21%, in the rate of primary outcome. A moderate reduction of this magnitude would mean one death or case of major disability prevented for every 25 children treated. This would provide the most cost-effective clinical indication for IVIG ever reported. The study will also have over 85% power with a type 1 error of 5% (two-tailed) to detect a 3% difference in permanent disability (from 15% to 12%), and over 80% power and a type I error of 5% (two tailed) to detect important differences in the primary measure of outcome in each of the three subgroups stratified by clinical severity at presentation (see Table 4). The estimate of the incidence of the outcome (the event rate) for the trial is imprecise, particularly as the threshold at which clinicians will enter patients cannot be precisely estimated. If clinicians enter babies where the likelihood of serious sepsis is lower then the event rate will also be lower. If clinicians restrict entry to only those babies who are very sick, then the event rate will be high. Either of these two scenarios is reasonable because it will define a population to which the trial result can be generalised. However, it does mean that until the trial has recruited sufficient numbers of babies it will not be possible to determine the optimum trial sample size with any certainty. As a consequence the trial sample size currently represents the minimum size desirable. The DMEC (see above) will review the data and advise the Trial Steering Committee whether the trial has answered the clinical question being addressed. If not, the trial will continue to recruit until 5,000 babies have been recruited, or until funding is exhausted.
Table 4. Sample sizes and power in subgroups randomised into the trial with different levels of
severity at presentation (Arcus Quickstat: Longman Software)
Clinical severity at
No of
Rate of primary
Difference in outcome
Power to
entry to the study
patients adverse outcome
between IVIG &
demonstrate this
expected
control group
difference at 2p=0.05

FEASIBILITY

This study reflects the philosophy that the only practicable way to achieve comparisons which are
sufficiently large to minimise the risk of being seriously misled by the play of chance is to design
trials that are extremely simple and flexible.94 Experience in the OSIRIS and ORACLE84,85,95
study suggest that a large, simple trial of this scale of a potentially important intervention is
feasible. It is expected that approximately 2500 infants will be recruited in the UK, 1500 infants in
Australia and New Zealand, and 1000 infants from other European and Asian centres; making a
total of 5000 infants from 150 centres worldwide.
Approximately 25 centres in Australia and New Zealand will participate in the study. Assuming
recruitment at the rate of 2 patients per centre per month [24 per centre per year], 600 infants will
be recruited in each year of 2004 and 2005. With the addition of the estimated 300 babies
recruited in Australia by the end of 2003, the target of 1500 babies is feasible by the end of 2005.
The average parental consent rate has been 75% in Australian centres to date. Furthermore, a
prospective antibiotic audit conducted in 18 ANZ neonatal units in 2002 showed that 7-8 infants
per centre per month on average received antibiotics for 5 or more days (which may indicate a
serious infection), further suggesting that the target sample size is feasible.
Funding (as at July 2003) has been obtained from the UK Medical Research Council, Financial
Markets Foundation for Children, University of Sydney (Sesqui Grant), NHMRC Clinical Trials
Centre, New Zealand Health Research Council, Telstra Foundation, and the Ian Potter
Foundation (travel grant). The Australian Red Cross Blood Service and New Zealand Blood
Service will distribute the IVIG for free to participating centres, and the Commonwealth
Government has guaranteed a free and reserved supply of IVIG (Intragam® P) from the National
Reserve for the trial in Australia.
Funding is provided for a part-time local research nurse at each participating centre. Evidence
that this strategy is effective comes from several large trials: ORACLE,84,85,96 the UK Neonatal
Staffing Study,92 the LIPID Study,97 and is recommended by The British Association of Perinatal
Medicine (http://www.bapm-london.org/publications/mchtn3.pdf). Experience suggests that a
large, simple trial of a potentially important intervention supplied free, with local part-time
research nurse co-ordinators in participating centres will be feasible.
ECONOMIC EVALUATION OF IVIG
The methods for the economic evaluation of neonatal intensive care will follow those employed previously in Australia.98,99 The cost of IVIG will be varied in a sensitivity analysis from $25 per g to $125 per gram, to simulate non-commercial and commercial prices (2 doses of 3 gram vials are administered). Hospitalisations between discharge and 2 years of age will be added assuming that they cost one third of a patient-day of respiratory support. Up to 2 years specialist care for paediatrics, speech, hearing and physiotherapy outside of hospital admissions will be retrospectively reported and costed where significant differences between trial arms are found. The additional cost of long term care for a child with a severe disability will be assumed to be $50,000 ($A 1997) per year,100 and varied in sensitivity analysis, with ranges to include alternative costs of permanent
disability in Australia.100 To estimate cost per Quality Adjusted Life Year (QALY) saved, utility
weights will be assigned as 0 for dead, 0.4 for severe disability, 0.6 for moderate disability, 0.8 for
mild disability and 1 for no disability. Utilities at 2 years will be aggregated for each group and
divided by the number of children to calculate quality adjusted survival rates at 2 years. Within study
life years differences will be calculated with cumulative life years derived from Kaplan Meier survival
curves. For both treatment and control groups, life years gained and quality adjusted life years
gained per child after age 2 will be calculated incrementally by multiplying the survival rate and the
quality adjusted survival rate at 2 years, respectively, by life expectancy at age 2. The difference
between groups will be evaluated. A life expectancy at age 2 of 70 years will be assumed, except
for multiply severely disabled children, whose life expectancy at age 2 will be assumed to be 40
years. A discount rate of 5% will be applied and cost effectiveness and cost utility ratios for IVIG will
be calculated. To assess the robustness of the conclusions, sensitivity of the incremental cost per
QALY saved will be calculated with 95% confidence intervals around the treatment effects using a)
the paediatric and PARCA parental reports, and b) the BSID-II assessment, and the underlying
assumptions about costs of hospital care, costs of permanent disability, assignment of utilities and
life expectancy.98,99 A 3% reduction in permanent disability would annually prevent 60 cases in
Australia alone (each costing a conservatively estimated $800,000 in discounted lifetime care
costs).100 This would lead to net discounted cost savings of over $48 million, mainly attributable
to the lifetime costs of care for the 60 cases of disability prevented. Hence participation in INIS
could save Australian Health Services in one year substantially more than the cost of the study.

PUBLICATION POLICY
To safeguard the scientific integrity of the trial, data from this study should not be presented in
public or submitted for publication without requesting consent from the Trial Steering Committee.
The success of the trial depends on the collaboration of a large number of doctors, nurses and
researchers. For this reason, chief credit for the results will be given not to the committees or
central organisers but to all who have collaborated in the study. Acknowledgement will include all
members of the trial committees, the data coordinating centre, trial staff, and local coordinators at
all collaborating centres. Authorship at the head of the paper will take the form: “The INIS
Collaborative Group”. This is the preferred option, as it avoids giving undue prominence to any
individuals. All contributors to the study will be listed at the end of the report, with their
contribution to the study identified. Publications based on trial data collected at individual centres
or in subgroups of centres which address ancillary research questions may be authored by the
individual investigators responsible, but will not be submitted for publication until after the main
trial manuscript has been submitted. All ancillary studies must have prior approval of the Steering
Committee to ensure that these studies will not interfere with the main study.
The investigators will acknowledge all sources of support in publications arising from the study.
However, the conduct, analysis, scientific interpretation and publication of the results of the study
will be independent of the sponsors.

OUTCOMES AND SIGNIFICANCE

This study will establish or refute the role of non-specific, polyclonal, human IVIG as an adjunctive treatment for neonatal sepsis. The trial will demonstrate for the first time whether or not IVIG can reduce the risk of death or severe disability at two years. If the intervention is shown to be effective, it is likely to be the most cost effective indication for IVIG yet described. The results of the trial could be rapidly adopted into clinical practice, as Intragam P is available in Australia and New Zealand.
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Lancet 1996;348:229-32. 64. Ohlsson A,.Lacy JB. Prophylactic intravenous immunoglobulin (IVIG) in preterm and/or low-birth- weight neonates (Cochrane Review). In: The Cochrane Library, Issue 2.Oxford Update Software, 2003. 65. Ohlsson A,.Lacy JB. Intravenous immunoglobulin for suspected or subsequently proven infection in neonates (Cochrane Review). In: The Cochrane Library, Issue 2.Oxford Update Software, 2003. 66. MancillaRamirez J, GonzalezYunes R, CastellanosCruz C, GarciaRoca P, SantosPreciado JI. [Intravenous immunoglobulin in the treatment of neonatal septicemia]. [Spanish]. Boletin Medico del Hospital Infantil de Mexico. 1992;49:4-11. 67. Weisman LE, Stoll BJ, Kueser TJ, Rubio TT, Frank CG, Heiman HS et al. Intravenous immune globulin therapy for early-onset sepsis in premature neonates. Journal of Pediatrics. 1992;121:434-43. 68. Chen JY. Intravenous immunoglobulin in the treatment of full-term and premature newborns with sepsis. Journal of the Formosan Medical Association. 1996;95:839-44. 69. Erdem G, Yurdakok M, Tekinalp G, Ersoy F. The use of IgM-enriched intravenous immunoglobulin for the treatment of neonatal sepsis in preterm infants. Turk J Pediatr 1993;35:277-81. 70. Haque KN, Zaidi MH, Bahakim H. IgM-enriched intravenous immunoglobulin therapy in neonatal sepsis. Am J Dis Child 1988;142:1293-6. 71. Sidiropoulos D, Boehme U, von Muralt G, Morell A, Barandun S. Immunoglobulin supplementation in prevention or treatment of neonatal sepsis. Pediatr Infect Dis 1986;5 PMID- 3714523 DCOM- 19860707:S193-S194. 72. Shenoi A, Nagesh NK, Maiya PP, Bhat SR, Subba Rao SD. Multicenter randomized placebo controlled trial of therapy with intravenous immunoglobulin in decreasing mortality due to neonatal sepsis. Indian Pediatrics 1999;36:1113-8. 73. Samatha S, Jalalu MP, Hegde RK, Vishwanath D, Maiya PP. [Role of IgM enriched intravenous immunoglobulin as an adjuvant to antibiotics in neonatal sepsis]. Karnataka Pediatr J 1997;11:1-6. 74. Jenson HB,.Pollock BH. Meta-analyses of the effectiveness of intravenous immune globulin for prevention and treatment of neonatal sepsis. Pediatrics 1997;99:E2. 75. Fischer GW. Use of intravenous immune globulin in newborn infants. Clin Exp Immunol 1994;97 76. Foster PR. Assessment of the potential of plasma fractionation processes to remove causative agents of transmissible spongiform encephalopathy. [Review]. Transfusion Medicine 1999;9:3-14. 77. Osborn DA, Lui K, Pussell P, Jana AK, Desai AS, Cole M. T and Tk antigen activation in necrotising enterocolitis: manifestations, severity of illness, and effectiveness of testing. Arch Dis Child Fetal Neonatal Ed 1999;80:F192-F197. 78. Bonadio WA, Hennes H, Smith D, Ruffing R, Melzer-Lange M, Lye P et al. Reliability of observation variables in distinguishing infectious outcome of febrile young infants. Pediatr Infect Dis J 1993;12:111-4. 79. Harrell FE, Jr., Margolis PA, Gove S, Mason KE, Mulholland EK, Lehmann D et al. Development of a clinical prediction model for an ordinal outcome: the World Health Organization Multicentre Study of Clinical Signs and Etiological agents of Pneumonia, Sepsis and Meningitis in Young Infants. WHO/ARI Young Infant Multicentre Study Group. Stat Med 1998;17:909-44. 80. Dear PF. Infection in the newborn. In Rennie JM, Roberton NRC, eds. Textbook of Neonatology, pp 1109-202. Edinburgh: Churchill Livingstone, 1999. 81. Ronfani L, Vilarim JN, Dragovich D, Bacalhau AF, Cattaneo A. Signs of severe bacterial infection in neonates. J Trop Pediatr 1999;45:48-51. 82. Singhi S,.Chaudhuri M. Functional and behavioral responses as marker of illness, and outcome in infants under 2 months. Indian Pediatr 1995;32:763-71. 83. Stevens SM, Richardson DK, Gray JE, Goldmann DA, McCormick MC. Estimating neonatal mortality risk: an analysis of clinicians' judgments. Pediatrics 1994;93:945-50. 84. Kenyon SL, Taylor DJ, Tarnow-Mordi W. Broad-spectrum antibiotics for spontaneous preterm labour: the ORACLE II randomised trial. ORACLE Collaborative Group. Lancet 2001;357:989-94. 85. Kenyon SL, Taylor DJ, Tarnow-Mordi W. Broad-spectrum antibiotics for preterm, prelabour rupture of fetal membranes: the ORACLE I randomised trial. ORACLE Collaborative Group. Lancet 2001;357:979-88. 86. Disability and perinatal care: measurement of health status at two years. A report of two working groups convened by the National Perinatal Epidemiology Unit and the former Oxford Regional Health Authority. 1994. NPEU: Oxford. 87. Johnson A. Follow up studies: a case for a standard minimum data set. Arch Dis Child Fetal 88. Field D, Draper ES, Gompels MJ, Green C, Johnson A, Shortland D et al. Measuring later health status of high risk infants: randomised comparison of two simple methods of data collection. BMJ 2001;323:1276. 89. Bayley N. Bayley Scales of Infant Development - 2nd Edition. The Psychological Corporation. San 90. Saudino KJ, Dale PS, Oliver B, Petrill SA, Richardson V, Rutter M et al. The validity of parent- based assessment of the cognitive abilities of two-year olds. British Journal of Developmental Psychology 1998;16:349-63. 91. Fooks J, Mutch L, Yudkin P, Johnson A, Elbourne D. Comparing two methods of follow up in a multicentre randomised trial. Arch Dis Child 1997;76:369-76. 92. Tucker J,.The UK Neonatal Staffing Study Group. Patient volume, staffing, and workload in relation to risk-adjusted outcomes in a random stratified sample of UK neonatal intensive care units: a prospective evaluation. The Lancet 2002;359:99-107. 93. Peto R, Pike MC, Armitage P, Breslow NE, Cox DR, Howard SV et al. Design and analysis of randomized clinical trials requiring prolonged observation of each patient. I. Introduction and design. Br J Cancer 1976;34:585-612. 94. Peto R,.Baigent C. Trials: the next 50 years. Large scale randomised evidence of moderate 95. The OSIRIS Collaborative Group (open study of infants at high risk of or with respiratory insufficiency--the role of surfactant. Early versus delayed neonatal administration of a synthetic surfactant--the judgment of OSIRIS. Lancet. 1992;340:1363-9. 96. Kenyon, S. L. and et al. Training and support of local part-time midwives as a key to improving and maintaining recruitment to a large multicentre trial (ORACLE). 2000. Proceedings 7th Annual Congress of the Perinatal Society of Australia and New Zealand. 97. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. New England Journal of Medicine. 1998;339:1349-57. 98. The Victorian Infant Collaborative Study Group. Economic outcome for intensive care of infants of birthweight 500-999 g born in Victoria in the post surfactant era. J Paediatr Child Health 1997;33:202-8. 99. Boyle MH, Torrance GW, Sinclair JC, Horwood SP. Economic evaluation of neonatal intensive care of very-low-birth-weight infants. N Engl J Med 1983;308:1330-7. 100. Australian Institute of Health and Welfare (AIHW). Demand for Disability support services in Australia: size, cost and growth. AIHW Cat. no. DIS 8. 1997. Canberra:AIHW.
? Sepsis - consider
INIS
ELIGIBILITY
They have proven or suspected serious infection The have at least one of the following:
birth weight less than 1500g
OR
evidence of infection in blood culture, CSF or in usually sterile body fluid
OR
respiratory support via an endotracheal tube They are receiving antibiotics and there is substantial uncertainty that IVIG is indicated *Serious infection cannot be defined precisely but might include any of: ? white cells <5,000/µl (5 x 109/l)
? unresponsiveness ? platelets <50,000/µl (50 x 109/l)
? prolonged bleeding ? will definitely need antibiotics EXCLUSIONS:
• IVIG has already been given • IVIG is thought to be needed or contra-indicated On or before admission, or when appropriate, all parents receive an Information
Leaflet from the neonatal unit staff, outlining this study.
If a baby becomes eligible, the parents are asked as soon as possible, in person or
by telephone, for consent to participate in the study and later follow up.
Parents who participate will receive a leaflet thanking them, with the name of a senior
doctor and research co-ordinator they can contact about the study.
Randomisation
(study entry)

Phone pharmacist (or on-call pharmacist after hours) who will randomise baby and
draw up 1st and 2nd study infusions
Treatment
500 mg/ kg (8.33 ml/ kg) of Intragam® P or placebo (normal saline) over 4-6 hours,
repeated 48 hours later. No more study drug can be given.
At Discharge • Short Discharge Form and Contact Details Form to complete.
Follow-up
• 1 year short parental questionnaire, and 2 year parental and paediatrician questionnaires, plus Bayley II Scales assessments (in some units).

Source: http://inis.ctc.usyd.edu.au/assets/files/study_docs/Protocol%20ANZ%20version%202%20July%202003.pdf

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