Title: Clinical Trial Design Related to Studies of PPIs in Premature and Term Newborns
1Clinical Trial Design Related to Studies of
PPIs in Premature and Term Newborns
- Mark Hudak M.D.
- University of Florida at Jacksonville
2ASSIGNMENT
- 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
3GASTROESOPHAGEAL 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
4GASTROESOPHAGEAL REFLUX Risk factors
- Positioning/posturing
- Increased gastric pressure
- Decreased LES tone
- Abnormal esophagus
- Neurological abnormalities
- Delayed gastric emptying
5GASTROESOPHAGEAL REFLUX Diagnostic studies
- Clinical observation of regurgitation
- Barium swallow / UGI series
- pH probe
- Manometry
- Multiple intraluminal impedance
6GER AND APNEA MECHANISMS
- Healthy spitters / eructators / burpers
- Laryngeal chemoreflex
- ??? Associated with esophageal reflux (acidic vs.
non-acidic)
7GER 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
8PRESUMED 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
9CLINICAL 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
10CLINICAL 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)
11HISTORY 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
12NEONATOLOGY PROGRESS?
- Oxygen and RLF
- Surfactant therapy 1960s
- Surfactant therapy 1980s
- Vitamin E and ROP
- Light and ROP
- Steroids
- Nitric oxide
- Cisapride
13COMMENTARY 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)
14CLINICAL 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
15CLINICAL 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