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P ATHOLOGIC GE R EFLUX IN C HILDREN Age-Related Characteristics: Effect on Design of Clinical Trials

P ATHOLOGIC GE R EFLUX IN C HILDREN Age-Related Characteristics: Effect on Design of Clinical Trials. FDA / CDER Pediatric Advisory Committee Bethesda, MD 11 June ‘02. E RIC H ASSALL MD Division of Gastroenterology BC Children’s Hospital / University of British Columbia

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P ATHOLOGIC GE R EFLUX IN C HILDREN Age-Related Characteristics: Effect on Design of Clinical Trials

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  1. PATHOLOGIC GEREFLUX IN CHILDREN Age-Related Characteristics: Effect on Design of Clinical Trials FDA / CDER Pediatric Advisory Committee Bethesda, MD 11 June ‘02 ERIC HASSALL MD Division of Gastroenterology BC Children’s Hospital / University of British Columbia Vancouver, BC, CANADA

  2. OUTLINE: FOCUSON AGE-RELATED DIFFERENCES BACKGROUND Difficulties in ped studies, Definitions, Complications, Goals of Rx, Prevalence, Natural history, Available treatments PATHOPHYSIOLOGY Etiologies, Mechanisms, Acid secretion, Underlying diseases PHARMACOKINETICS ENDPOINTS: PRESENTING SYMPTOMS / SIGNS FEASIBILITY REQUIREMENTS FOR PERFORMANCE OF SUCCESSFUL STUDY

  3. DIFFICULTIES IN DOING PEDIATRIC STUDIES Ethics: Placebo controls, etc Age-related differences in disease manifestations Fears of parents / investigators Feasibilities: What’s practicable? Time- and labor-intensiveness Need for flexibility: Optional tests Inexperience of centers: Uniformity of approach

  4. DEFINITIONS Gastroesophageal reflux [GER] vs Gastroesophageal reflux disease [GERD]

  5. COMPLICATIONSOF GE REFLUX • Esophagitis • Peptic stricture • Barrett’s esophagus • Failure to thrive • Pulmonary / • ENT disease • Sandifer’s syndrome / • torticollis

  6. MANAGEMENT GOALS Gastroesophageal Reflux Disease [GERD] • RELIEVE SYMPTOMS • PREVENT COMPLICATIONS • HEAL ESOPHAGITIS • MAINTAIN REMISSION • TREAT COMPLICATIONS

  7. OUTLINE: FOCUSON AGE-RELATED DIFFERENCES BACKGROUND Difficulties in ped studies, Definitions, Complications, Goals of Rx, Prevalence, Natural history, Available treatments PATHOPHYSIOLOGY Etiologies, Mechanisms, Acid secretion, Underlying diseases PHARMACOKINETICS ENDPOINTS: PRESENTING SYMPTOMS / SIGNS FEASIBILITY REQUIREMENTS FOR PERFORMANCE OF SUCCESSFUL STUDY

  8. PREVALENCE, NATURAL HISTORY Nelson SP, et al. Prevalence of symptoms of GE reflux during infancy. Arch Pediatr Adolesc Med 1997;151:569-72 • X-sectional, community practice-based • 948 healthy children <13mo • Infant GER Questionnaire [IGER-SF], shortened, revised [5min] * • Main outcome measure: Reported frequency of vomiting • RESULTS • Vomiting at least 1/ day: 50% at 0-3mo • Vomiting at least 1/ day: 5% at 10-12mo • Peak frequency: 4mo • Decrease from 61% to 21%: between 6-7mo • Peak frequency of vomiting reported as ‘problem’: • - 23% at 6mo to 14% at 7mo * Based on IGER, Orenstein SR, et al. Clin Pediatr 1993;32:472-84 [20min]

  9. GE Reflux: Children v Adults Natural History < 2yr age • Very often physiological, esp < 6mo • 90% resolve <12-18mo • Vomiting > 2yr age never physiological • GERD usually a chronic relapsing disease Carre Nelson > 2yr age -adulthood

  10. GE Reflux: Children v Adults Presentation 2 - 4yr age • Similar symptoms / signs • to younger children • Heartburn very unusual* • Similar to adults > 8 - 10yr age * Nelson SP. Arch Ped & Adolesc Med, Feb 00

  11. GE Reflux: Children v Adults Presentation NATURE OF VOMITING Effortless vs Forceful / ‘Projectile’ DISPOSITION OF CHILD ‘Fat happy spitters’ / thriving vs Unhappy, irritable child / poor wt gain

  12. OUTLINE: FOCUSON AGE-RELATED DIFFERENCES BACKGROUND Difficulties in ped studies, Definitions, Complications, Goals of Rx, Prevalence, Natural history, Available treatments PATHOPHYSIOLOGY Etiologies, Mechanisms, Acid secretion, Underlying diseases PHARMACOKINETICS ENDPOINTS: PRESENTING SYMPTOMS / SIGNS FEASIBILITY REQUIREMENTS FOR PERFORMANCE OF SUCCESSFUL STUDY

  13. GE Reflux: Children & Adults Management • Explanation, reassurance • Diet, lifestyle • Position • Antacids • Anticholinergics [e.g., XbethanecolX] • Prokinetics [XmetoclopramideX, XcisaprideX] • H2-Receptor Antagonists • Prayer/Meditation/Vega therapy/‘Can-deeda’ Rx

  14. GE Reflux: Children & Adults Management of Severe GERD • Antireflux Surgery • Proton Pump Inhibitors • [Endoscopic Rx]

  15. ANTIREFLUX SURGERY IN CHILDREN EXCLUDING ‘MINOR’ PROCEDURES [Inguinal herniorrhaphy, central line placement] ANTIREFLUX SURGERY IS THE COMMONEST OPERATION PERFORMED BY PEDIATRIC SURGEONS

  16. OUTLINE: FOCUSON AGE-RELATED DIFFERENCES BACKGROUND Difficulties in ped studies, Definitions, Complications, Goals of Rx, Prevalence, Natural history, Available treatments PATHOPHYSIOLOGY Etiologies, Underlying diseases, Mechanisms, Acid secretion, PHARMACOKINETICS ENDPOINTS: PRESENTING SYMPTOMS / SIGNS FEASIBILITY REQUIREMENTS FOR PERFORMANCE OF SUCCESSFUL STUDY

  17. Conditions Predisposing to Severe GE Reflux in Children • Neurologic impairment [NI] • Repaired esophageal atresia • Chronic lung disease [eg CF, BPD] • Hiatal hernia • Transient lower esophageal • sphincter relaxation [TLESR]

  18. Conditions Predisposing to Severe GE Reflux in Children • Neurologic impairment [NI] • Repaired esophageal atresia • Chronic lung disease [eg CF, BPD] • Hiatal hernia • Transient lower esophageal • sphincter relaxation [TLESR]

  19. Conditions Predisposing to Severe GE Reflux in Children • Neurologic impairment [NI] • Repaired esophageal atresia • Chronic lung disease [eg CF, BPD] • Hiatal hernia • Transient lower esophageal • sphincter relaxation [TLESR]

  20. Conditions Predisposing to Severe GE Reflux in Children • Neurologic impairment [NI] • Repaired esophageal atresia • Chronic lung disease [eg CF, BPD] • Hiatal hernia • Transient lower esophageal • sphincter relaxation [TLESR]

  21. Conditions Predisposing to Severe GE Reflux in Children • Neurologic impairment [NI] • Repaired esophageal atresia • Chronic lung disease [eg CF, BPD] • Hiatal hernia • Transient lower esophageal • sphincter relaxation [TLESR]

  22. OUTLINE: FOCUSON AGE-RELATED DIFFERENCES BACKGROUND Difficulties in ped studies, Definitions, Complications, Goals of Rx, Prevalence, Natural history, Available treatments PATHOPHYSIOLOGY Etiologies, Underlying diseases, Mechanisms, Acid secretion PHARMACOKINETICS ENDPOINTS: PRESENTING SYMPTOMS / SIGNS FEASIBILITY REQUIREMENTS FOR PERFORMANCE OF SUCCESSFUL STUDY

  23. ACID SECRETION • Healthy term infants • Relative hypochlorhydria for 0-5hrs age, nl by 6-8hrs • [normal BAO 25+/-10 mol/kg/hr  in adults] • Hypergastrinemia, despite nl acid secretion • Euler, Gastro 1977 • Enteral feedings necessary for nl oxyntic mucosal secretion • - purely TPN-fed relatively hypochlorhydric • Hyman, Gastro 1983 • Meal-stim secretion occurs, but weaker than older infants [>6mo] • Hyman, J Peds 1984 • Healthy pre-term infants • BAO by 7days 12 mol/kg/hr, incr over 4wks to 30 [nl] • A few infants are achlorhydric [pentagastrin-fast] in first wk • Hyman, J Peds 1985

  24. ACID SECRETION • SUMMARY • Pre-term and term infants make acid • Acid secretion increases quickly to adult ranges • [mol/kg/hr] • Pentagastrin-responsive by 1-4wks • Increase in secretion depends on postnatal age • not gestational age • Require enteral feeds for nl acid output

  25. OUTLINE: FOCUSON AGE-RELATED DIFFERENCES BACKGROUND Difficulties in ped studies, Definitions, Complications, Goals of Rx, Prevalence, Natural history, Available treatments PATHOPHYSIOLOGY Etiologies, Underlying diseases, Mechanisms, Acid secretion PHARMACOKINETICS ENDPOINTS: PRESENTING SYMPTOMS / SIGNS FEASIBILITY REQUIREMENTS FOR PERFORMANCE OF SUCCESSFUL STUDY

  26. PHARMACOKINETICS • FOR OMEPRAZOLE • Ontogeny [CY2C19, 3A]: metabolic capacity • [AUC, AUC normalized, t-half, Cmax, Cmax nl-ized] • - highest 1-6yrs, • - gradual decline with increasing age • NL adult values by ~12yrs • Much higher doses [per kg basis] reqd in older • Andersson, Am J Gastro 2000 • Hassall, J Pediatr 2000 • PK similar to benzodiazepines…..extrapolate to <1yr?

  27. OUTLINE: FOCUSON AGE-RELATED DIFFERENCES BACKGROUND Difficulties in ped studies, Definitions, Complications, Goals of Rx, Prevalence, Natural history, Available treatments PATHOPHYSIOLOGY Etiologies, Underlying diseases, Mechanisms, Acid secretion PHARMACOKINETICS ENDPOINTS: PRESENTING SYMPTOMS / SIGNS FEASIBILITY REQUIREMENTS FOR PERFORMANCE OF SUCCESSFUL STUDY

  28. ENDPOINTS, PRESENTING SYMPTOMS / SIGNS • For purposes of study…. • SYMPTOM/SIGN SHOULD BE: • Definitely causally related to GERD • Most relevant to patient improvement • Common in the age group under study • Measurable / ‘hard’ / objective • ‘Safely accessible’ in the given age group

  29. ‘FEASIBILITY’ = Patient accrual, Retention, Success of Study

  30. ENDPOINTS, PRESENTING SYMPTOMS / SIGNS SUBJECT THESETO ‘THE TESTS’: • Vomiting: frequency • Heartburn • Esophagitis • ?Degree of acid reflux • - intraesophageal pH • ? Epigastric pain/ irritability • ?Failure to thrive ?‘Feeding problems’ ?Respiratory ?ENT xDysphagia / odynophagia xApnea xDegree of acid suppression - intragastric pH

  31. OUTLINE: FOCUSON AGE-RELATED DIFFERENCES BACKGROUND Difficulties in ped studies, Definitions, Complications, Goals of Rx, Prevalence, Natural history, Available treatments PATHOPHYSIOLOGY Etiologies, Underlying diseases, Mechanisms, Acid secretion PHARMACOKINETICS ENDPOINTS: PRESENTING SYMPTOMS / SIGNS FEASIBILITY REQUIREMENTS FOR PERFORMANCE OF SUCCESSFUL STUDY

  32. REQUIREMENTS FOR PERFORMANCE OF SUCCESSFUL STUDY • Availability of other, equal or better treatments • [Can’t offer placebo] • Question worth asking • Protocol simple • Tests reliable • Tests not ‘overly invasive’ given the child’s illness • Willingness of parents to enrol • Willingness of docs to discuss enrolment with parents • Pediatric centers qualified to carry out protocol

  33. QUESTIONS • Age Group: <1yr vs >1-2yr ….. Up to 17yr? • Is this a sufficiently sensitive age breakdown? • Do we need others? What should they be? • Are there indications for PPI use in all age groups? • Efficacy: Can we study it in all age groups? • If not, can we impute efficacy from other studies? • What are the appropriate study endpoints • in each age group? • What are the dosages in each age group?

  34. GE Reflux: Children v Adults Presentation < 2yr age • Vomiting • - commonest • - very often physiological, esp <12mo • Failure to thrive • Irritability • Food refusal / ‘feeding problems’ • Chronic pulmonary symptoms • Anemia 2o blood loss • Hematemesis

  35. GE Reflux in Children Approach < 2yrs age INDICATIONS FOR INVESTIGATION Suspicion of Complication • Irritability with feeds • Recurrent pneumonias / chronic cough • Generally unhappy baby • Failing to thrive • Torti collis [?Sandifer’s syndrome] • Persistent vomiting at 18-24mo

  36. GE Reflux in Children Approach > 2yrs age INDICATIONS FOR INVESTIGATION • Persistence of vomiting since < 2yrs • New onset recurrent vomiting • Suspicion of a complication • - undiagnosed anemia • - dysphagia / odynophagia • - recurrent pneumonias, cough • - nonseasonal asthma

  37. GE Reflux in Children What tests to do / What they mean • CBC • URINALYSIS & CULTURE • UPPER GI CONTRAST STUDY • - not a test for reflux • - stricture / achalasia / mass • -road map • UPPER GI ENDOSCOPY, BIOPSIES • 24HR INTRAESOPHAGEAL pH • ESOPHAGEAL MANOMETRY • GASTRIC EMPTYING STUDY

  38. PREVALENCE, NATURAL HISTORY Nelson SP, et al. One-year follow-up of symptoms of GE reflux during infancy PEDIATRICS Dec 1998; e-publication • Follow-up survey of parents of 63 children with vomiting • identified at 6-12 mo, vs 92 controls • IGER-SF & Children’s Eating Behavior Inventory [CEBI] • RESULTS • None of 63 cases was vomiting >1/day vs 1 of controls • Parents of cases reported more • - feeding refusals [odds ration 4.2] times • - longer eating times [>1hr] • - their own anxiety re feeding • No difference in ENT complaints / wheezing between groups

  39. TREATMENT OF GE REFLUX Medical vs Surgical ? ISSUES • Indications • Efficacy • Safety • Durability [longevity] • Compliance • Relative cost

  40. GE Reflux Disease: Differences Between • Children vs Adults • Children: <1yr vs >1-2yr • Natural history • Presentation • Approach • Management

  41. GE Reflux: Children Approach • INDICATIONS FOR INVESTIGATION • RECURRENT FORCEFUL VOMITING • COMPLICATION ATANY AGE

  42. GE reflux Infections - candida albicans - herpes simplex - cytomegalovirus Infections Crohn’s disease Idiopathic eosinophilic esophagitis (IEE) Pill-induced Caustic ingestion Post-sclerotherapy/ banding Radiation/chemotherapy-induced Collagen vasculardisease Graft-versus-hostdisease Bullous skin diseases Idiopathic ETIOLOGIES OF ESOPHAGITIS IN CHILDREN

  43. PREVALENCE, NATURAL HISTORY Nelson SP, et al. Prevalence of symptoms of GE reflux during infancy. Arch Pediatr Adolesc Med 1997;151:569-72 • X-sectional, community practice-based, Chicago area • 948 parents of healthy children <13mo • Main outcome measure: Reported frequency of vomiting • RESULTS • Vomiting at least 1/ day: 50% at 0-3mo • Vomiting at least 1/ day: 5% at 10-12mo • Peak frequency: 4mo • Decrease from 61% to 21%: between 6-7mo • Peak frequency of vomiting reported as ‘problem’: • - 23% at 6mo to 14% at 7mo • Perception of ‘problem’: • - freq, volume; crying, fussiness, discomfort, back arching • Rx: • - formula change 8%, thickened 2%, stop breast 1%, med 0.2%

  44. GE Reflux: Children & Adults Management of Severe GERD • Surgery [ARS] • Proton Pump Inhibitors • [Endoscopic Rx]

  45. GE Reflux: Children & Adults Management of Severe GERD • Proton Pump Inhibitors • [omeprazole, lansoprazole] • Surgery [ARS] • Endoscopic Rx

  46. OMEPRAZOLE: EFFICACY AND SAFETY PROSPECTIVE DOSE-FINDING FOR HEALING

  47. PREVALENCE, NATURAL HISTORY Nelson SP, et al. Prevalence of symptoms of GE reflux during childhood. Arch Pediatr Adolesc Med 2000;154:150-4 • X-sectional, community practice-based, Chicago area, 3-17yrs • 566 parents 3-9yrs, 584 parents of 10-17yrs, 615 10-17yrs • Infant GER Questionnaire [IGER-SF], shortened, revised [5min] * • Main outcome measure: Reported frequency of vomiting

  48. ETIOLOGIES OF VOMITING OTHER THAN REFLUX OTHER ACID PEPTIC DISORDERS FOOD ALLERGY EXTRA-INTESTINAL DISORDERS [UTI, INFECTIONS, METABOLIC]

  49. ANTIREFLUX SURGERY BC CHILDREN’S HOSPITAL VANCOUVER 1980 - 1990: ~ 50 new operations/year 1990 - 2002: ~ 10 new operations/year G.BLAIRMD Dept Surgery BCCH

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