Clinical trial NCT02930824: Genotype-supported Versus Conventional Proton Pump Inhibitor Dosing
Official title: Implementing Genomics in Practice (IGNITE) Proof of Concept Study: CYP2C19 Genotype-supported Versus Conventional Proton Pump Inhibitor Dosing
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Gastroesophageal Reflux Disease
Lead sponsor: University of Florida
Sponsor class: OTHER
Collaborators: name: Nemours Children's Hospital
name: National Human Genome Research Institute (NHGRI)
First posted: 2016-10-12
Enrollment: 185
Sex: ALL
Minimum age (years): 5
Maximum age (years): 100
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: SCREENING

Brief 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.

Eligibility criteria: Pediatric:

Inclusion Criteria:

* 5-17 years of age
* diagnosed with GERD or any other stomach acid mediated condition for which a PPI treatment is provided
* currently under a Proton Pump Inhibitor (PPI) therapy or will start a PPI therapy
* Parents/legal guardians and or child must have access to internet and a valid email address

Exclusion Criteria:

* history of extensive esophageal or gastric surgery
* diagnosed with any major chronic illness or conditions that in the opinion of the gastroenterologist that would interfere with participation in the study
* history of Phenylketonuria (PKU) and patients with a history of previous adverse effects from PPI treatment or sensitivity to aspartame (NutraSweet, Equal)

Adult:

Inclusion Criteria:

* 18 years of age or older
* Gastroesophageal Reflux Disease symptoms
* Being initiated on PPI therapy OR continues to have symptoms despite PPI therapy

Exclusion Criteria:

* Extensive esophageal or gastric surgery
* Any chronic illness that would interfere with the study

Primary outcomes:
measure: Reflux Disease Questionnaire (RDQ)
timeFrame: Change from baseline and 12 weeks
measure: Pediatric Sinonasal Symptom Survey (SN-5)
timeFrame: Week 4 (or next available results)
measure: Safety Questionnaire (SafetyQ)
timeFrame: Over the 12-week period or last date of follow-up
measure: Gastroesophageal Reflux Disease (GERD) Assessment of Symptoms in Pediatrics Questionnaire (Gasp-Q)
timeFrame: Change in score from baseline to the week 4 ± 1-week
measure: Pediatric Quality of Life Inventory (PedsQL) Gastrointestinal Symptoms Module
timeFrame: Change in score from baseline to the week 4 ± 1-week
Secondary outcomes:
Other outcomes:
Locations:
city: Gainesville
country: United States
facility: University of Florida
state: Florida
city: Orlando
country: United States
facility: Nemours Children's Hospital
state: Florida
Study officials:
affiliation: University of Florida
name: Larisa Cavallari, PharmD
role: PRINCIPAL_INVESTIGATOR
affiliation: Nemours Children's Hospital
name: James P Franciosi, MD
role: PRINCIPAL_INVESTIGATOR
References: