Genotype-supported Versus Conventional Proton Pump Inhibitor Dosing

NCT ID: NCT02930824

Last Updated: 2024-05-16

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 185 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-12-31
• Study Completion Date: 2019-07-17

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.

Conditions

Gastroesophageal Reflux Disease

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: SCREENING
• Blinding Strategy: NONE

Study Groups

Adult Genotype guided treatment

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

Group Type: EXPERIMENTAL

CYP2C19 genotyping

Intervention Type: GENETIC

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.

Adult Conventional treatment

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

Group Type: NO_INTERVENTION

No interventions assigned to this group

Pediatric Genotype guided treatment

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

Group Type: EXPERIMENTAL

CYP2C19 genotyping

Intervention Type: GENETIC

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.

Pediatric Conventional treatment

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

Group Type: NO_INTERVENTION

No interventions assigned to this group

Interventions

CYP2C19 genotyping

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.

Intervention Type: GENETIC

Eligibility Criteria

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

• 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

• 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:

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

• Minimum Eligible Age: 5 Years
• Maximum Eligible Age: 100 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Nemours Children's Hospital

OTHER

Sponsor Role: collaborator

National Human Genome Research Institute (NHGRI)

NIH

Sponsor Role: collaborator

University of Florida

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Larisa Cavallari, PharmD

Role: PRINCIPAL_INVESTIGATOR

University of Florida

James P Franciosi, MD

Role: PRINCIPAL_INVESTIGATOR

Nemours Children's Hospital

Locations

University of Florida

Gainesville, Florida, United States

Nemours Children's Hospital

Orlando, Florida, United States

Countries

United States

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Document Type: Informed Consent Form

View Document

Other Identifiers

U01HG007269

Identifier Type: NIH

Identifier Source: secondary_id

View Link

IRB201601774-N

Identifier Type: -

Identifier Source: org_study_id