Genotype-supported Versus Conventional Proton Pump Inhibitor Dosing

University of Florida

Status: Completed

Conditions: Gastroesophageal Reflux Disease

Treatments: Genetic: CYP2C19 genotyping

Study type: Interventional

Funder types: Other; NIH

Identifiers

NCT02930824

IRB201601774-N

U01HG007269 (U.S. NIH Grant/Contract)

Details and patient eligibility

About

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.

Full 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.

Enrollment: 185 patients

Sex: All

Ages: 5 to 100 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion 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

Trial design

Primary purpose: Screening

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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185 participants in 4 patient groups

Adult Genotype guided treatment

Experimental group

Description:

For adults randomized to the genotype-supported arm a CYP2C19 genotype will be provided to physicians to assist in dosing.

Treatment:

Genetic: CYP2C19 genotyping

Adult Conventional treatment

No Intervention group

Description:

For adults randomized to the conventional arm no genotype will be provided to physicians to assist in dosing.

Pediatric Genotype guided treatment

Experimental group

Description:

For children randomized to the genotype-supported arm a CYP2C19 genotype will be provided to physicians to assist in dosing.

Treatment:

Genetic: CYP2C19 genotyping

Pediatric Conventional treatment

No Intervention group

Description:

For children randomized to the conventional arm no genotype will be provided to physicians to assist in dosing.