International Neonatal International Neonatal Immunotherapy StudyImmunotherapy Study

Co-ordinating Centre

National Perinatal Epidemiology Unit

Oxford

www.npeu.ox.ac.uk/inis

INIS

is funded by the

Medical Research Council

INIS - hypothesis

The addition of non-specific polyclonal immunoglobulin reduces death and major disability in infants receiving antibiotics for

serious sepsis

International randomised controlled International randomised controlled trial evaluating the use of trial evaluating the use of

intravenous immunoglobulin (IVIG) intravenous immunoglobulin (IVIG) for the reduction of death or disability for the reduction of death or disability

in infants with sepsisin infants with sepsis

INIS – the reality

Current Status

• 5th year of study

• 3286 babies recruited (at 27/03/07)

• 48 centres in UK

• 21 Argentina

• 17 Australia

• 2 New Zealand

• 8 Europe

Future

• MRC funding awarded to extend recruitment until Summer 2007

• 97 centres worldwide

• Target of at least 3500 babies

Background

Neonatal sepsis

• Incidence 6.6 per 1000 live births 1

15.4 per 1000 VLBW 2

• Death VLBW 14% -21% 3

All 10 -14%

Sepsis and neurodevelopment

• Studies show a strong association between intrauterine sepsis and both cPVL and cerebral palsy 5

• In addition there is evidence to show a link between postnatal infection and cerebral palsy 6

Intrauterine sepsis and neurodevelopment

• Babies born to mothers with clinical chorioamnionitis have a statistically significant higher risk of developing cerebral palsy 5

– Term infants – RR 4.7 (1.3,16.2)– Preterm infants – RR 1.9 (1.4-2.5)

Postnatal sepsis and neurodevelopment

• Postnatal infection is associated with an increased risk of cerebral palsy (after adjustment for gestational age) 6

• OR 3.6 (1.8, 7.4)

Treatment for sepsis• Newborn infants, especially if small or preterm,

may be deficient in immunoglobulin (IgG)

• IVIG provides IgG which has potent anti-inflammatory and immuno-modulatory properties

• This makes it an attractive adjunctive treatment for sepsis in all babies, not just the preterm population

Evidence

Systematic Reviews• Intravenous immunoglobulin for preventing infection in

preterm and low birth weight infants Ohlsson A, Lacy JB. In: The Cochrane Library, Issue 1, 2003.

• Intravenous immunoglobulin for suspected or subsequently proven infection in neonate

Ohlsson A, Lacy JB. In: The Cochrane Library, Issue 1, 2003.

• Intravenous immunoglobulin for treating sepsis and septic shock Alejandria MM, Lansang MA, Dans LF, Mantanng JBV. In The Cochrane Library, 2003.

Cochrane systematic review– IVIG for prevention of infection

• 19 RCTs, 5054 infants

• Results:– Reduction in sepsis - RR 0.85 (0.74-0.98)– No effect on death

• No major adverse effects from immunoglobulin

Cochrane systematic review– IVIG for treatment of infection

• Suspected infection

• 6 RCTs, n=318• Reduction in death

not statistically significant

• RR 0.63 (0.4,1.00)

• Proven infection• 7 RCTS, n=262• Statistically significant

reduction in death

• RR 0.55 (0.31,0.98)

Cochrane systematic review– IVIG for treatment of infection

• Criticisms of RCTs based on :– Small size; 22-82 infants per study– Poor study designs – Lack of placebo group– Absence of blinding

Cochrane SR – suspected infection

Cochrane SR– proven infection

Cochrane systematic review – IVIG for treatment of sepsis or septic shock

• 11 RCTs, 492 patients (any age)• Results:

– All ages - reduction in all cause death – RR 0.64 (95% CI 0.51-0.80)– Neonates – no statistically significant

difference– RR 0.70 (0.42,1.18)

Summary of evidence

• Insufficient and weak evidence to support use of immunoglobulin for prevention or treatment of sepsis

• Large RCT needed to test hypothesis

Study Design

Study design

• ‘The randomised double-blind controlled trial is usually taken as the ‘gold standard’ against which to judge the quality of the design of a trial.’

• The design of INIS adheres to these principles

Study design

• Randomisation:

– Controls for known and unknown confounders

– Ensures treatment allocation is unbiased at the start of the trial

Study design

• Randomisation– Drug packs are pre-randomised and kept on

unit– So no phone calls to randomise an eligible

baby!– Selecting the lowest numbered drug pack will

ensure randomisation is intact

Study design• Placebo-controlled

– The placebo is a weak solution of albumin– It is identical in appearance to the IVIG both in

its reconstituted form and in its packaging

Study design• Blindness

– INIS is a double-blind trial– Neither the attending medical staff nor those

evaluating outcomes will know which treatment has been given

– This avoids any bias whilst the study is

being run

Eligibility Criteria

Receiving antibiotics and suspected or proven serious sepsisAND

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

There is substantial uncertainty that IVIG is indicated

Eligibility

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 Patient Information Leaflet– This is for relevant for all parents whose baby is

admitted to NICU– It gives a simple and accurate description of the study

• Direct parents to website or INIS contact

InterventionIVIG group• Intravenous infusion of IVIG 500 mg / kg

(10ml/kg) over 4 - 6 hours, repeated 48 hours later

Control group• Intravenous infusion of 10 ml / kg of placebo

(0.2% albumin solution), repeated 48 hours later

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

• Death or

• Major disability at 2 years corrected age

Primary Outcome

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

• Parent questionnaire

• Paediatrician questionnaire

• Completed at 2 year appointment

Follow-up

If you have any queries please contact :

Clare Shakeshaft INIS Study Co-ordinator

01865 289741inis@npeu.ox.ac.uk

www.npeu.ox.ac.uk/inis