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					PATHOLOGIC GE REFLUX 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
   OUTLINE: FOCUS ON 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
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
          DEFINITIONS


    Gastroesophageal reflux [GER]

                  vs

Gastroesophageal reflux disease [GERD]
COMPLICATIONS OF GE REFLUX

     • Esophagitis
     • Peptic stricture
     • Barrett’s esophagus
     • Failure to thrive
     • Pulmonary /
         ENT disease
     • Sandifer’s syndrome /
        torticollis
      MANAGEMENT GOALS


Gastroesophageal Reflux Disease [GERD]

      • RELIEVE SYMPTOMS

      • PREVENT COMPLICATIONS

      • HEAL ESOPHAGITIS

      • MAINTAIN REMISSION

      • TREAT COMPLICATIONS
   OUTLINE: FOCUS ON 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
                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]
    GE Reflux: Children v Adults
            Natural History

                < 2yr age
• Very often physiological, esp < 6mo

• 90% resolve <12-18mo
                                 Carre
                                 Nelson

         > 2yr age -adulthood
• Vomiting > 2yr age never physiological

• GERD usually a chronic relapsing disease
GE Reflux: Children v Adults
       Presentation

       2 - 4yr age
• Similar symptoms / signs
   to younger children


• Heartburn very unusual*


      > 8 - 10yr age


     • Similar to adults
      * Nelson SP. Arch Ped & Adolesc Med, Feb 00
    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
   OUTLINE: FOCUS ON 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
         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
GE Reflux: Children & Adults
Management of Severe GERD


 • Antireflux Surgery
 • Proton Pump Inhibitors
 • [Endoscopic Rx]
  ANTIREFLUX SURGERY IN CHILDREN


    EXCLUDING ‘MINOR’ PROCEDURES
  [Inguinal herniorrhaphy, central line placement]

  ANTIREFLUX SURGERY IS THE COMMONEST

OPERATION PERFORMED BY PEDIATRIC SURGEONS
   OUTLINE: FOCUS ON 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
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]
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]
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]
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]
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]
   OUTLINE: FOCUS ON 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
                       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
             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
   OUTLINE: FOCUS ON 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
               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?
   OUTLINE: FOCUS ON 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
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
               ‘FEASIBILITY’

= Patient accrual, Retention, Success of Study
  ENDPOINTS, PRESENTING SYMPTOMS / SIGNS


          SUBJECT THESE TO ‘THE TESTS’:

 Vomiting: frequency
                           ? ‘Feeding problems’
 Heartburn
                           ? Respiratory
 Esophagitis
                           ? ENT
? Degree of acid reflux
  - intraesophageal pH     x Dysphagia / odynophagia

? Epigastric pain/        x Apnea
    irritability           x Degree of acid suppression
? Failure to thrive         - intragastric pH
   OUTLINE: FOCUS ON 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
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
                     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?
     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
       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
      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
         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
                 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
TREATMENT OF GE REFLUX

     Medical vs Surgical ?
           ISSUES
 •   Indications
 •   Efficacy
 •   Safety
 •   Durability [longevity]
 •   Compliance
 •   Relative cost
GE Reflux Disease: Differences Between
          Children vs Adults
       Children: <1yr vs >1-2yr



          • Natural history

           • Presentation
             • Approach

           • Management
      GE Reflux: Children
          Approach


INDICATIONS FOR INVESTIGATION

• RECURRENT FORCEFUL VOMITING

• COMPLICATION   AT ANY AGE
         ETIOLOGIES OF ESOPHAGITIS
                IN CHILDREN

• GE reflux                 • Post-sclerotherapy/
• Infections                  banding
  - candida albicans        • Radiation/chemotherapy-
  - herpes simplex
  - cytomegalovirus
                              induced
• Infections                • Collagen vascular
                              disease
• Crohn’s disease
• Idiopathic eosinophilic   • Graft-versus-host
  esophagitis (IEE)           disease
• Pill-induced              • Bullous skin diseases
• Caustic ingestion         • Idiopathic
             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%
GE Reflux: Children & Adults
Management of Severe GERD



  •   Surgery [ARS]

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


   •   Proton Pump Inhibitors
       [omeprazole, lansoprazole]

   • Surgery [ARS]

   • Endoscopic Rx
OMEPRAZOLE: EFFICACY AND SAFETY
  PROSPECTIVE DOSE-FINDING FOR HEALING
              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
ETIOLOGIES OF VOMITING OTHER THAN REFLUX

OTHER ACID PEPTIC DISORDERS

FOOD ALLERGY

EXTRA-INTESTINAL DISORDERS
[UTI, INFECTIONS, METABOLIC]
     ANTIREFLUX SURGERY
    BC CHILDREN’S HOSPITAL
          VANCOUVER

1980 - 1990: ~ 50 new operations/year




1990 - 2002: ~ 10 new operations/year
                                 G.BLAIR MD
                                 Dept Surgery
                                        BCCH
                                       250
                                                                      250
                                                                                               153         167
                                            618          Clinical                 116
                                                                                                                                         136
                                    434                                                                                         97
                           378                            Flare                                                       78

               128
  00                                                                   00
          -2     -2   -1     -1 0     0 1    1 2    23      3           -2        -2 -1         -10        01         1
                                                                                                                      2         2
                                                                                                                                3         3
Anti-DNA abs and C as Candidate Biomarkers for Clinical
                     Trials in SLE

 Clinical laboratory correlation in SLE is a heterogeneous
  relationship
                   Unanswered Questions
 1. Are these serologic parameters useful as predictors of flare
   and/or in assessment of flare and response to therapy?

 2. Which tests are best and are combinations superior?

 3. What is the optimal time interval in which to study a patient?

 4. What is the outcome being measured i.e. definitions of flare, and
   in what organ, renal could be most relevant?
   TABLE 13.4, p252... Dubois Textbook, Chapter: Complement and SLE,
                          Schur and Glickstein

   Ability of Immune Tests to Predict Clinical Exacerbations in SLE

   C3              Anti-DNA        Clinical Evidence

   i               hh              none necessarily

   ii              hhh             active nephritis

   i               hhh             active extrarenal

   iii             h               active nephritis and
                                   extrarenal


" One easily believes what one earnestly hopes for "
                 The Roman dramatist Terrence

				
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