International Neonatal Immunotherapy Study

National Perinatal Epidemiology Unit

Oxford

www.npeu.ox.ac.uk

Co-ordinating centre

• INIS is run by the National Perinatal Epidemiology Unit, Oxford

• Please visit our site at www.npeu.ox.ac.uk

• If you have any queries please contact – Barbara Farrell (Trial Director) – Clare Shakeshaft (Study Co-ordinator)

INIS – current status

• Start of trial 2001

• Participating centres 97

• Participating countries 9

• Babies recruited 3,292 (March 07)

– See www.npeu.ac.uk/inis for current update

INIS Co-ordinating Team

Peter Brocklehurst Chief InvestigatorBarbara Farrell Trial DirectorClare Shakeshaft Study Co-ordinatorCaroline Wilson Follow up Co-ordinatorAndy King ProgrammerRui Zhao Data AssistantEllie Morgan-Jones Administrative Assistant

INIS - future

• Aim– To reach a target of at least 3500 babies by

end of recruitment 31st May 2007

INIS hypothesis

• That, in infants receiving antibiotics for clinical sepsis, the addition of non-specific immunoglobulin (IVIG) reduces mortality and major morbidity compared with antibiotics alone

INIS - study design

• Gold standard for treatment trials

• Double-blind

• Randomised

• Placebo -controlled

Receiving antibiotics and proven or

suspected serious infection

Mortality or major disability

IVIG

at 2 years

Placebo

Eligibility criteria

1.Receiving antibiotics and suspected or proven serious infection

AND ………

Eligibility criteria2. At least one of the following:

birth weight less than 1500greceiving respiratory support via an

endotracheal tube evidence of infection in blood culture, CSF or

usually sterile body fluid

AND………

Eligibility criteria

AND ………

3. There is substantial uncertainty that IVIG is indicated

Exclusion criteria

• IVIG already given*

• IVIG thought to be needed or contraindicated

*specific IVIG

Specific IVIG

• IVIG for specific indications should be given as per hospital policy and these infants will still be eligible

– Hepatitis B immunoglobulin– Varicella-Zoster immunoglobulin

Eligibility - age

• Babies at any age whilst resident on NICU

• After discharge babies are eligible until EDD plus 28 days

Consent

• Consent must be fully informed and obtained before randomisation

• Use the Information Leaflet

• Direct parents to website or INIS contact

Randomisation

• Simple, no phone call required

• Drug boxes in pre-randomised sequence

• Use lowest numbered box

IVIG

• Plasma from non-UK donors

• Produced by Scottish National Blood Transfusion Service

• Tested for HIV 1 ,2 and Hepatitis A,B,C

• Excellent safety record

• Few adverse reactions

Placebo

• 0.2% albumin

• Identical appearance to IVIG

• Safety record as for IVIG

Follow-up

• Parent questionnaire

• Paediatrician questionnaire

• Completed at 2 year corrected age

Primary outcomes

• Death or

• Major disability at 2 years corrected age

Secondary outcomes• Short term

– Death, chronic lung disease or major cerebral abnormality before hospital discharge

– Significant positive culture after trial entry– Pneumonia– NEC– Duration of respiratory support

Secondary outcomes

• Long term– Death before 2 years– Major disability at 2yrs– Non-major disability at 2yrs

Case scenarios

Eligible?

• 29 weeks gestation• Deterioration day 34• Recurrent apnoeic episodes• Prolonged cap. refill time• CRP 66• Commenced on antibiotics • CNS in blood culture

Eligible?

Remember

• It is NOT TOO LATE to randomise an infant after a positive blood culture has been reported

• IVIG may be of benefit after the inflammatory process has begun

Eligible?

• 27 weeks gestation, 1.3kg

• PROM 27 hrs

• GBS on maternal HVS

• Intrapartum antibiotics not given

• Asymptomatic infant

• Antibiotics commenced as hospital policy

Eligible?

But

• If there was offensive liquor, raised inflammatory markers or this baby was to become unwell

This baby would be eligible for INIS

Eligible?

• Term infant

• Cyanotic episodes at 2hrs age

• Apnoeic requiring ventilation

• CXR patchy consolidation both lung fields

• Commenced on antibiotics

• CRP 19

Any Questions?

Please contact us:

Tel: 01865 289741 Email: inis@npeu.ox.ac.uk

References

1. Murphy DJ, Hope PL, Johnson A. Neonatal risk factors for cerebral palsy in very preterm babies: case-control study. BMJ 1997;314:404.

1. Yoon BH, Romero R, Park JS et al. Fetal exposure to an intra-amniotic inflammation and the development of cerebral palsy at the age of 3 years. Am J Obstet Gynecol 182:675-681.

2. Wu YW. Systematic Review of Chorioamnionitis and Cerebral Palsy. Mental Retard Dev Disabilities Research Reviews 2002;8: 25-29.

3. Damman O, Leviton A. Infection remote from the brain, neonatal white matter damage, and cerebral palsy in the preterm infant. Semin Pediatr Neurol 1998;5:190-201.