Genotype-supported Versus Conventional Proton Pump Inhibitor Dosing
Condition: Gastroesophageal Reflux Disease
MeSH terms: Gastroesophageal Reflux
Study type: Interventional

Summary: 
      Investigators will conduct a comparative effectiveness study of genotype-supported vs.
      conventional PPI dosing. Adults and children presenting with Gastroesophageal Reflux Disease
      (GERD) or dyspepsia symptoms and either 1) being initiated on proton pump inhibitor (PPI)
      therapy or 2) with continued symptoms on current PPI therapy will be recruited from
      gastroenterology clinics and randomized to a genotype-supported versus conventional PPI
      therapy management strategy.
    

Detailed description: 
      The efficacy of proton pump inhibitors (PPIs) is highly dependent on plasma concentrations
      achieved following drug administration. All PPIs are metabolized in part by the CYP2C19
      enzyme, which is encoded by the highly polymorphic CYP2C19 gene. Depending on the CYP2C19
      genotype, individuals are classified into different metabolizer phenotypes: poor metabolizers
      (PM, 2 loss-of-function CYP2C19 alleles); intermediate metabolizers (IM, one loss-of-function
      allele); normal metabolizers (NM, no loss or gain-of-function alleles); rapid metabolizer
      (RM; one gain-of-function allele) and ultra-rapid metabolizers (UM, two gain-of
      function-alleles). Genetic variants in CYP2C19 are known to profoundly influence PPI plasma
      concentrations and consequently, response to PPI therapy. For example, individuals classified
      as either RM or UM have lower PPI concentrations compared to NM or loss-of-function (LOF)
      allele carriers, respond poorly to PPI therapy, and some fail to respond even when the PPI
      dose is increased. The investigators hypothesize that genotype-supported PPI dosing will lead
      to better GERD control and improvement in severity of dyspepsia symptoms compared to
      conventional dosing. The investigators will conduct a comparative effectiveness study of
      genotype-supported vs. conventional PPI dosing. Patients presenting with GERD or dyspepsia
      symptoms and either 1) being initiated on PPI therapy or 2) with continued symptoms on
      current PPI therapy will be recruited from gastroenterology clinics and randomized to a
      genotype-supported versus conventional PPI therapy management strategy. The investigators
      will integrate individual CYP2C19 genotype information into dosing decisions for the
      genotype-supported arm and compare change in symptom control from baseline to the end of the
      study between study arms. Given that PPI efficacy is related to PPI exposure and to
      metabolizer phenotype, individualizing treatment using CYP2C19 genotype-supported dosing is
      expected to improve symptom management. The investigators will also evaluate patient and
      clinician knowledge and attitudes about pharmacogenetics testing and physician acceptance of
      genetic information into clinical practice. Finally, the investigators will collect
      preliminary data on the potential impact of CYP2C19-supported PPI dosing on adverse event
      rates.
    

Intervention name(s): CYP2C19 genotyping
Intervention type(s): Genetic
Intervention description(s): All proton pump inhibitors are metabolized in part by the CYP2C19 enzyme, which is encoded by the highly polymorphic CYP2C19 gene. Based on variations within this gene the effectiveness of the drug may be reduced.
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Screening