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% (n=400) • If rates of CLD are 75% and 50% in air leak and non-air leak populations, surfactant decreases CLD from 55% to 52.5% (n=10,400)

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? That’s 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