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| ID | Type | Description | Link |
|---|---|---|---|
| U01HG007269 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| Nemours Children's Hospital | OTHER |
| National Human Genome Research Institute (NHGRI) | NIH |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Adult Genotype guided treatment | Experimental | For adults randomized to the genotype-supported arm a CYP2C19 genotype will be provided to physicians to assist in dosing. |
|
| Adult Conventional treatment | No Intervention | For adults randomized to the conventional arm no genotype will be provided to physicians to assist in dosing. | |
| Pediatric Genotype guided treatment | Experimental | For children randomized to the genotype-supported arm a CYP2C19 genotype will be provided to physicians to assist in dosing. |
|
| Pediatric Conventional treatment | No Intervention | For children randomized to the conventional arm no genotype will be provided to physicians to assist in dosing. |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| CYP2C19 genotyping | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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 |
| 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) |
| 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 |
| 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. |
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Pediatric:
Inclusion Criteria:
Exclusion Criteria:
Adult:
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Larisa Cavallari, PharmD | University of Florida | Principal Investigator |
| James P Franciosi, MD | Nemours Children's Hospital | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Florida | Gainesville | Florida | 32610 | United States | ||
| Nemours Children's Hospital |
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| ID | Title | Description |
|---|---|---|
| FG000 | Adult Genotype Guided Treatment | For adults randomized to the genotype-supported arm a CYP2C19 genotype will be provided to physicians to assist in dosing. 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. |
| FG001 | Adult Conventional Treatment | For adults randomized to the genotype-supported arm no genotype will be provided to physicians to assist in dosing. |
| FG002 | Pediatric Genotype Guided Treatment | For children randomized to the genotype-supported arm a CYP2C19 genotype will be provided to physicians to assist in dosing. 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. |
| FG003 | Pediatric Conventional Treatment | For children randomized to the genotype-supported arm no genotype will be provided to physicians to assist in dosing. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
Adult and children ages 5-100 with gastroesophageal reflux disease symptoms expected to take a proton pump inhibitor
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| ID | Title | Description |
|---|---|---|
| BG000 | Adult Genotype Guided Treatment | For adults randomized to the genotype-supported arm a CYP2C19 genotype will be provided to physicians to assist in dosing. 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. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | Adult patients enrolled that have a CYP2C19 Rapid or Ultra-rapid metabolizer result. | Posted | Mean | Standard Deviation | score on a scale | Change from baseline and 12 weeks |
|
Adult Arms: 24 months after enrollment Pediatric Arms: 12 weeks from baseline
The study was a minimal risk study and all-cause mortality and serious adverse events were not assessed.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Adult Genotype Guided Treatment | For adults randomized to the genotype-supported arm a CYP2C19 genotype will be provided to physicians to assist in dosing. 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. |
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Pilot study with small sample size and endpoints analyzed in RM/UM subset; no pharmacokinetic analyses done; pragmatic design where any PPI medication could be prescribed; did not account for over-the-counter antacid medications
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Larisa Cavallari | University of Florida | (352) 273-8245 | LCavallari@cop.ufl.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Feb 28, 2017 | May 6, 2020 | Prot_SAP_000.pdf |
| ICF | No | No | Yes | Informed Consent Form | Oct 18, 2017 | Apr 15, 2024 | ICF_001.pdf |
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| ID | Term |
|---|---|
| D005764 | Gastroesophageal Reflux |
| ID | Term |
|---|---|
| D015154 | Esophageal Motility Disorders |
| D003680 | Deglutition Disorders |
| D004935 | Esophageal Diseases |
| D005767 | Gastrointestinal Diseases |
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| Change in score from baseline to the week 4 ± 1-week |
| 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 |
| Orlando |
| Florida |
| 32827 |
| United States |
| BG001 | Adult Conventional Treatment | For adults randomized to the conventional arm no genotype will be provided to physicians to assist in dosing. |
| BG002 | Pediatric Genotype Guided Treatment | For children randomized to the genotype-supported arm a CYP2C19 genotype will be provided to physicians to assist in dosing. 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. |
| BG003 | Pediatric Conventional Treatment | For children randomized to the conventional arm no genotype will be provided to physicians to assist in dosing. |
| BG004 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| OG001 | Adult Conventional Treatment | For adults randomized to the genotype-supported arm no genotype will be provided to physicians to assist in dosing. |
| OG002 | Pediatric Genotype Guided Treatment | For children randomized to the genotype-supported arm a CYP2C19 genotype will be provided to physicians to assist in dosing. 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. |
| OG003 | Pediatric Conventional Treatment | For children randomized to the genotype-supported arm no genotype will be provided to physicians to assist in dosing. |
|
|
|
| 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. | Children aged 5-17 years old with gastric-acid-related conditions and a completed SN-5 questionnaire at week 4 (or next available results) | Posted | Mean | Inter-Quartile Range | score on a scale | 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. | Children aged 5-17 years old with gastric-acid-related conditions with completed SafetyQ assessment over the 12-week period or last date of follow-up | Posted | Number | % of participants reporting infections | 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. | Children aged 5-17 years old with gastric-acid-related conditions and a completed Gasp-Q questionnaire at baseline and week 4 ± 1-week | Posted | Mean | Inter-Quartile Range | median (IQR) composite score | 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). | Children aged 5-17 years old with gastric-acid-related conditions with a completed PedsQL questionnaire at baseline and week 4 ± 1-week | Posted | Mean | Inter-Quartile Range | score on a scale | Change in score from baseline to the week 4 ± 1-week |
|
|
|
|
| 0 |
| 0 |
| 0 |
| 0 |
| 0 |
| 0 |
| EG001 | Adult Conventional Treatment | For adults randomized to the conventional arm no genotype will be provided to physicians to assist in dosing. | 0 | 0 | 0 | 0 | 0 | 0 |
| EG002 | Pediatric Genotype Guided Treatment | For children randomized to the genotype-supported arm a CYP2C19 genotype will be provided to physicians to assist in dosing. 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. | 0 | 0 | 0 | 0 | 0 | 0 |
| EG003 | Pediatric Conventional Treatment | For children randomized to the conventional arm no genotype will be provided to physicians to assist in dosing. | 0 | 0 | 0 | 0 | 0 | 0 |
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| D004066 | Digestive System Diseases |