Genotype-supported Versus Conventional Proton Pump Inhibitor Dosing

Gastroesophageal Reflux Disease Clinical Trial

Official title:

Implementing Genomics in Practice (IGNITE) Proof of Concept Study: CYP2C19 Genotype-supported Versus Conventional Proton Pump Inhibitor Dosing

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02930824
• Other study ID #: IRB201601774-N
• Secondary ID: U01HG007269
• Status: Completed
• Phase: N/A
• Start date: December 2016
• Est. completion date: July 17, 2019

Study information

• Verified date: May 2024
• Source: University of Florida
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 185
• Est. completion date: July 17, 2019
• Est. primary completion date: July 17, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 5 Years to 100 Years

Eligibility

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

Related Conditions & MeSH terms

• Gastroesophageal Reflux
• Gastroesophageal Reflux Disease

Intervention

Genetic:
• 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.

Locations

Country	Name	City	State
United States	University of Florida	Gainesville	Florida
United States	Nemours Children's Hospital	Orlando	Florida

Sponsors (3)

Lead Sponsor	Collaborator
University of Florida	National Human Genome Research Institute (NHGRI), Nemours Children's Hospital, Orlando

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Reflux Disease Questionnaire (RDQ)	The RDQ was developed to monitor treatment response over time and evaluates 6 symptoms (12 items) covering 3 domains: heartburn, regurgitation, and upper abdominal pain. Each symptom is evaluated using a 6-point Likert scale to assess frequency and severity over the previous week. Each symptom is rated from 1 (did not have) to 6 (severe), and the RDQ mean score is calculated as the mean response to the 12 items. The RDQ mean score thus ranges from 1 to 6 and has been psycho-metrically validated.	Change from baseline and 12 weeks
Primary	Pediatric Sinonasal Symptom Survey (SN-5)	The Pediatric Sinonasal Symptom Survey (SN-5) is a validated 5-item scale with each item rated on a scale of worsening symptoms from 1 (none of the time) through 7 (all of the time). Items were averaged to yield a single total score ranging from 1 (better outcomes) to 7 (worse outcomes). The total SN-5 scores were compared between the conventional and genotype-guided dosing groups to determine if one group reported worsening symptoms over the other.	Week 4 (or next available results)
Primary	Safety Questionnaire (SafetyQ)	Occurrence of adverse events over the 12 weeks was captured by the Safety Questionnaire (SafetyQ), which was to be completed on a weekly basis by the parents. The Safety Questionnaire (SafetyQ) asked about the presence of seven different respiratory symptoms since their last visit; upper respiratory infection, sore throat, strep throat, bronchitis, pneumonia, ear infection, and acute sinusitis. If a symptom was selected as being present since the last visit, the date of onset and patient-reported explanation of the symptom was recorded. The number of participants who reported infections were compared between each group.	Over the 12-week period or last date of follow-up
Primary	Gastroesophageal Reflux Disease (GERD) Assessment of Symptoms in Pediatrics Questionnaire (Gasp-Q)	Gastroesophageal reflux disease (GERD) Assessment of Symptoms in Pediatrics Questionnaire (Gasp-Q) is a validated patient-reported outcome questionnaire that evaluated proton pump inhibitor therapy efficacy. Gasp-Q inquired about the severity and frequency of belly pain, chest pain, difficulty swallowing, choking, burping, nausea, pain after eating, night pain, and vomiting. If the symptom was present, the patient was asked to score the severity of the symptom ranging from 1 (Not at all severe) to 7 (Most severe). A composite score was then calculated based on the scoring of the 9 symptoms and ranged from 9 to 63.	Change in score from baseline to the week 4 ± 1-week
Primary	Pediatric Quality of Life Inventory (PedsQL) Gastrointestinal Symptoms Module	Pediatric Quality of Life Inventory (PedsQL) Gastrointestinal Symptoms Module is a validated patient-reported outcome questionnaire and Likert response scale, to evaluate proton pump inhibitor therapy efficacy. The gastrointestinal problems included in the PedsQL were stomach pain and hurt, stomach upset, food and drink limits, trouble swallowing, heartburn and reflux, gas and bloating, constipation, diarrhea, and worry. Participants were asked to rate the symptoms from 0 (never a problem) to 4 (almost always a problem).	Change in score from baseline to the week 4 ± 1-week