Clinical Trial Design Related to Studies of PPIs in Premature and Term Newborns - PowerPoint PPT Presentation

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Clinical Trial Design Related to Studies of PPIs in Premature and Term Newborns

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Oxygen and RLF Surfactant therapy: 1960s Surfactant therapy: 1980s Vitamin E and ROP Light and ROP Steroids Nitric oxide Cisapride COMMENTARY ON INTENSIVISTS ... – PowerPoint PPT presentation

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Title: Clinical Trial Design Related to Studies of PPIs in Premature and Term Newborns


1
Clinical Trial Design Related to Studies of
PPIs in Premature and Term Newborns
  • Mark Hudak M.D.
  • University of Florida at Jacksonville

2
ASSIGNMENT
  • Delineation of controversy re association of
    gastroesophageal reflux (GER) and apnea
  • Current management of reflux associated apnea
    is there a standard?
  • General issues in designing clinical trials in
    premature and term neonates
  • Specific issues in designing clinical trials of
    PPIs in premature and term neonates clinically
    meaningful outcome measures of extraesophageal
    manifestations of GER and assessments of short
    and longer term efficacy

3
GASTROESOPHAGEAL REFLUX Premature infants and
neonates
  • Retrograde movement of gastric contents into the
    esophagus or mouth lumpers vs. splitters
  • Usually associated with transient relaxations in
    tone of lower esophageal sphincter (TLESRs)
  • Physiologic phenomena
  • Natural history regurgitation resolves
    spontaneously by 1 year GER continues into
    adulthood

4
GASTROESOPHAGEAL REFLUX Risk factors
  • Positioning/posturing
  • Increased gastric pressure
  • Decreased LES tone
  • Abnormal esophagus
  • Neurological abnormalities
  • Delayed gastric emptying

5
GASTROESOPHAGEAL REFLUX Diagnostic studies
  • Clinical observation of regurgitation
  • Barium swallow / UGI series
  • pH probe
  • Manometry
  • Multiple intraluminal impedance

6
GER AND APNEA MECHANISMS
  • Healthy spitters / eructators / burpers
  • Laryngeal chemoreflex
  • ??? Associated with esophageal reflux (acidic vs.
    non-acidic)

7
GER AND APNEA ONE READING OF THE LITERATURE
  • Apnea and GER occur commonly in premature infants
  • Older studies associating apnea with GER
    generally did not perform temporal analyses of
    the two phenomena
  • More recent studies of the universe of premature
    infants have found no temporal correlation of
    apnea (as determined clinically or by research
    methodology) with acid GER (pH probe), all GER
    (MII), or clinical regurgitation
  • In selected subsets of patients with GER (severe
    symptoms xanthine-resistant apnea), medical and
    surgical anti-reflux therapies appear to have
    improved symptoms

8
PRESUMED GER IN PRETERM INFANTS CURRENT
MANAGEMENT PRACTICES
  • Positioning / postural therapy universal
  • Feeding manipulations
  • Decreased volume per unit time (continuous
    feedings) universal
  • Decreased osmolarity common
  • Thickening of formula / breast milk variable
  • Medical therapy
  • H2 acid blockade (ranitidine) common
  • Prokinetics
  • Cisapride (prior to withdrawal) very common
  • Metoclopramide common

9
CLINICAL TRIALS IN PRETERM INFANTS General
considerations
  • Extremely vulnerable population
  • Risk / benefit considerations
  • Rational physiologic basis of treatment
  • Long term follow-up may be essential
  • Multiple co-morbidities / confounders
  • Clinical equipoise / therapeutic skepticism
  • Natural history of disease / condition
  • Meaningful clinical endpoints
  • Optimal population selection identification of
    treatment effect

10
CLINICAL TRIALS IN PRETERM INFANTS Population
selection
  • Surfactant therapy was not consistently shown to
    decrease chronic lung disease
  • Suppose risk factors for CLD are gestational age
    and air leak syndrome
  • Surfactant decreases incidence of air leak from
    20 to 10 (n400)
  • If rates of CLD are 75 and 50 in air leak and
    non-air leak populations, surfactant decreases
    CLD from 55 to 52.5 (n10,400)

11
HISTORY OF NEONATOLOGY
  • Innovative therapy introduced without due
    process
  • Graduates to standard practice (or is quickly
    abandoned)
  • Later skeptics demonstrate lack of efficacy or
    frank adverse effect (or a therapeutic benefit)
    in well-designed trials

12
NEONATOLOGY PROGRESS?
  • Oxygen and RLF
  • Surfactant therapy 1960s
  • Surfactant therapy 1980s
  • Vitamin E and ROP
  • Light and ROP
  • Steroids
  • Nitric oxide
  • Cisapride

13
COMMENTARY ON INTENSIVISTS
  • Once the rockets are up,
  • who cares where they come down?
  • Thats not my department,
  • says Werner von Braun
  • Tom Lehrer, That Was the Year That Was (1965)

14
CLINICAL TRIALS IN PRETERM INFANTS Specific
considerations for PPIs
  • No evidence that GER in healthy preterm infants
    is associated with long-term esophageal or
    supraesophageal morbidity
  • No evidence that acid GER produces more frequent
    or more severe supraesophageal symptoms than
    non-acid GER (studies not done)
  • Paucity of evidence that other anti-reflux
    medications (ranitidine, metoclopramide) mitigate
    symptoms in general population of preterm infants
    with apnea

15
CLINICAL TRIALS IN PRETERM INFANTS Specific
considerations for PPIs
  • Clinically relevant efficacy endpoints
  • Primary significant apnea or bradycardia or
    desaturation and type of nursing intervention
  • Secondary length of hospital stay, use of home
    monitors, discharge medications
  • Safety endpoints include growth, infection,
    feeding tolerance, liver function, drug
    interactions 2 year neurodevelopmental outcome
  • Careful selection of study population
  • Study design placebo-controlled vs. randomized
    withdrawal
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