INIS - Frequently Asked Questions
Should all infants on antibiotics or with respiratory distress be recruited into the study?
No it would be reasonable to recruit any infant who makes a poor response to surfactant, or who is ventilated with suspected pneumonia. Otherwise infants who respond to surfactant with no further evidence of sepsis should not be recruited.
Will IVIG be expensive?
Non-specific IVIG will be supplied free of charge during the study. It currently costs about &20 per gram to produce. If this study shows that it is effective in reducing mortality, and between 5-200 infants need to be treated to save one life, then the cost (of IVIG alone) might vary between &100 - &4000 per life saved. This compares favourably with many other interventions but does not take into account any additional hospital costs.
The eligibility criteria for INIS will result in very different types of baby being recruited, for example VLBW and term. How do you know that there will be enough babies recruited in any of these groups for the study results to give useful information?
The eligibility criteria are deliberately inclusive of a wide spectrum of babies who may benefit from IVIG. Sub group analyses will be performed for the VLBW and larger babies to determine outcomes in each group. However the number of babies in any of these groups may be lower than needed to give sufficient power to provide useful information. So if clinicians think it important to know the outcome for such a group then they should ensure recruitment is encouraged for such babies.
What is considered evidence of infection in CSF?
A positive CSF culture or leucocytosis compatible with bacterial infection are both considered evidence of infection.
Why has the eligibility criterion been altered from 'severe and life-threatening infection' to 'serious infection'?
Interim analysis for INIS has revealed a mortality rate of 24% (UK figures) which suggests that the majority of recruited infants have been extremely sick. INIS is aiming to increase coverage of those infants who may benefit from intravenous immunoglobulin (IVIG) by encouraging clinicians to recruit early those infants who have suspected or proven serious infection.
If a baby is mistakenly randomised to INIS is it still necessary to complete entry and discharge forms and arrange follow up?
A baby is considered randomised to INIS once the drug pack has been opened, regardless of whether any drug is infused. All such babies should have complete data collection including a 2 year follow-up because analysing study subjects in the groups to which they were initially randomised (intention to treat analysis) is the safest way of dealing with protocol violations that would otherwise bias the results.
What are the X and Y drug packs for (UK only)?
The X and Y drug packs are spares containing either placebo or IVIG. They are ONLY to be used if the second bottle of INIS drug is found to be broken or damaged AFTER a baby has received the first dose. In this event the coordinating centre must be contacted so that they can reveal which of the packs should be used to provide the second infusion.
Our neonatal unit would be interested in participating in INIS but we occasionally use open-label immunoglobulin in the very sickest babies. Can we still be included?
Yes. We stress that babies randomised to INIS should NOT receive any open-label IVIG for the duration of stay on the unit as this has the potential to contaminate the study results.
Clinicians who wish to use open label IVIG for babies outside of the study should first check whether the baby is eligible for INIS. There is insufficient evidence to support the use of IVIG otherwise, hence the justification for the study.
Will intravenous immunoglobulin (IVIG) interfere with routine infant vaccinations?
The half life of IVIG is approximately 1 month and remains in the body for up to 3 months, similar to maternal IgG. According to studies maternal IgG does not seem to interfere with immunisations so it is very unlikely that IVIG will interfere with routine immunisations. All babies should be immunised on schedule according to each country's policy.
Until what age are babies eligible for INIS?
Babies are eligible at any age whilst they are resident on the neonatal unit. Once they have been discharged they are eligible until 28 days post EDD (estimated date of delivery).
Will admissions to the paediatric ward be eligible?
Yes, up to 28 days postnatal age as long as they fulfil the eligibility criteria.
What is generalisability (in RCTs)?
Generalisability in RCTs refers to how applicable the results are to the target population - the use of different IVIGs (Australia is using Intragam) will increase generalisabilty across countries. This means should INIS show that immunoglobulin causes a statistically significant reduction in mortality or major disability different brand forms can be used to treat the local population.
What is the safety record of the INIS immunoglobulin?
The INIS immunoglobulin is one of the safest blood products known. It is sourced from voluntary donor plasma from the US and Germany after screening by medical history then PCR testing for HIV 1, 2 and Hepatitis A, B and C. In addition it is processed via recognised virus inactivation steps.
It has an excellent safety record with only a small proportion of patients experiencing mild adverse reactions.
Reference: Scottish National Blood Transfusion Service; Information pamphlet human immunoglobulin for intravenous administration, 2001.
Are babies with fungal infection eligible for INIS?
Yes. Any baby with bacterial or fungal sepsis, commenced on antibiotics or antifungals, is eligible for the study.
Will intravenous immunoglobulin (IVIG) interfere with the BCG vaccine?
No. Immunity to TB from the BCG vaccine is mediated by T-cells not antibody, so IVIG should have no effect on BCG.
How should the INIS drug be infused?
The INIS drug can be infused through a pre-existing IV cannula or long line but should not be used at the same time as other infusions. Lines should be flushed before and after the INIS drug. See the drug infusion posters for more information.
Do we have to plan extra visits for the 2 yr follow-up?
No, it is normal practice to follow up pre-term babies for at least 2 years. Sick term babies need to be followed as well but their numbers are likely to be smaller.
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