INIS Ancillary Studies

1
INIS Ancillary Studies

• Dr Dan Hawcutt
• Clinical Research Fellow
• National Perinatal Epidemiology Unit
• Oxford
• UK

2
Introduction

• Several ancillary trials under consideration by
  trial investigators
• 2 trials within a trial proposed
• INLET
• Increased Financial Support
• 2 Observational Studies
• Dr K. Haque
• Dr R. Carr
• Possible future ancillary studies

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INLET

• INIS Newsletter plus Educational Topic

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INLET

• Background
• Newsletters common in large RCT
• Maintain awareness and recruitment
• Little critical evaluation of effectiveness
• Several RCT / Cohort with promising results
• Health related knowledge
• Health related behaviour
• Some inconclusive results

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INLET

• Methods
• Intervention over 6 months
• Study newsletter cover theme about INIS
• Intervention sites
• Newsletter and Educational Supplement
• Individually addressed to staff
• Control sites
• Newsletter only
• 5 copies posted on noticeboards / staffroom

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INLET

• Educational Supplement
• Explore newsletters theme in more detail
• Designed to interest medical and nursing staff
• Increase understanding and support for INIS
• Invite feedback via
• Discussion list
• INIS website

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INLET

• Proposed themes
• Newsletter
• Why do we need RCTs
• What is current evidence on IVIG
• FAQ from parents
• IVIG and cerebral inflammation
• Data monitoring committee
• Building network of neonatal research nurses

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INLET

• Proposed themes
• Educational Supplement
• Will tie in with previous themes
• E.G. for why do we need RCTs
• James Lind and Lemon Juice
• Type I and Type II errors
• Seminal trials in neo and perinatology
• Content up for discussion

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INLET

• Implementation
• 64 UK and Australian centres
• No funding required
• Awaits investigators approval

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Financial Support

• Full Title
• Randomised trial of increased financial support
  to improve trial recruitment

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Financial Support

• Background
• ORACLE trial developed model for support
• To offset costs to centres
• Staff time discussing trial / consent
• Form filling
• It appears logical that the provision of
  financial support will facilitate recruitment it
  has not yet been evaluated
• Would increased funds improve recruitment?

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Financial Support

• Cluster RCT
• 2 Questions
• Whether provision of increased financial support
  to centres participating in INIS improves
  recruitment to the trial
• Whether the method of payment affects recruitment
• Proportion of nurses salary
• Fixed payment per recruit

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Financial Support

• Cluster randomised 3x2 design
• One of three levels of funding
• Standard, medium or high
• One method of payment
• Proportion of salary or fixed per baby
• All hospitals taking part in Phase II of INIS
  eligible

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Financial Support

• Randomised by INIS co-ordinating centre
• Centre to be informed of
• Amount of payment
• Method of payment
• Recruitment targets
• Explanation of how performance will be measured

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Financial Support

• Data
• Because withdrawing enhanced levels of funding
  from centres would risk a fall in recruitment, it
  is proposed to conduct this study over the last
  18 months of INIS recruitment (Jan 05 Jun 06)
• Record kept by coordinating centre
• Number of recruits per centre
• No extra data collection by centre needed

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Financial Support

• Outcomes
• Recruitment rate
• Adjustment for expected recruitment rate
• Withdrawal of study funding for poor recruitment

17
Financial Support

• MRC application for funding sent Feb 04
• Investigators not yet approved

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T-Lymphocytes and IVIG

• Study proposed by Dr R. Carr
• Aim
• To assess the effect of IVIG administration on
  inflammatory cytokine production by T-lymphocytes
  and monocytes, when given to neonates recruited
  into INIS

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T-Lymphocytes and IVIG

• Measurements
• T lymphocyte cytokine produciton
• IL-2, IL-4, IL-10, IL-13, IFN-?, TNF-a
• Monocytes intracellular cytokine production
• Plasma Cytokines
• Requires 600 - 800µl of blood
• Carried out at Guys Hospital (London)

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T-Lymphocytes and IVIG

• Justification
• Previous work by this group (PROGRAMS babies and
  non-trial preterm infants) is providing a
  reference range for data
• INIS provides a unique opportunity to relate the
  immunological response to objectively identified
  episodes of sepsis, and has the potential to
  provide insight into the pathogenesis of sepsis
  related tissue injury in preterm infants

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T-Lymphocytes and IVIG

• Requires fresh samples
• No information of proposed size
• To be discussed by investigators

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Potential Studies

• Dr Claudio Cavalli (Italy)
• Asked me how to submit an ancillary study
• Heard nothing since
• Will keep you posted

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Cytokines and IVIG

• Ancillary Study proposed by Dr K. Haque
• St Helier Hospital, UK
• Full Title Influence of polyclonal IVIG therapy
  on selected pro-inflammatory cytokines (IL-6,
  IL-8, and TREM-1) in neonatal sepsis

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Cytokines and IVIG

• Background
• Animal and Laboratory evidence IVIG influences
• Synthesis of cytokines
• Release of cytokines
• E.g. decrease IL-2,-6,-10, TNF-alpha production
• E.g. decrease IL-1 neutrophil stimulation

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Cytokines and IVIG

• Background
• TREM-1 triggering receptor expressed on myeloid
  cells
• Member of super family of immunoglobulins
• WCC at sites of infection express high levels
• Some evidence that it mediates acute inflammatory
  response to microbial products that occur in
  sepsis

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Cytokines and IVIG

• Postulation
• Polyclonal IVIG acts as a potent blocker of
  TREM-1 and it is by this action that it reduces
  mortality in sepsis

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Cytokines and IVIG

• Sample Size
• 40 patients
• 20 IVIG
• 20 Placebo
• Blood tests required
• Pre-infusion
• Pre- second infusion
• Daily for five days thereafter

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Cytokines and IVIG

• Costs
• 20,000 for consumables and lab support
• Not yet funded
• Status
• Awaiting trial investigators discussion