Ignite Creation Date:
2024-05-05 @ 4:56 PM
Last Modification Date:
2024-10-26 @ 9:26 AM
Study NCT ID:
NCT00354757
Status:
COMPLETED
Last Update Posted:
2012-12-03
First Post:
2006-07-18
Brief Title:
CYP2C19 Genetic Polymorphism on the Accuracy of Proton-Pump Inhibitor Testing
Sponsor:
National Taiwan University Hospital
Organization:
National Taiwan University Hospital
Study Overview
Official Title:
The Influence of CYP2C19 Genetic Polymorphism and Dosage of Rabeprazole on the Accuracy of Proton-Pump Inhibitor Testing in Chinese Patients With Gastroesophageal Reflux Disease
Status:
COMPLETED
Status Verified Date:
2012-11
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
BackgroundAim To evaluate the optimal dosage of rabeprazole for proton-pump inhibitor PPI testing of gastroesophageal reflux disease GERD and to test the influence of cytochrome P CYP 2C19 polymorphism in a population with a high prevalence of people who poorly metabolize PPIs
Patients and Methods In this randomized open-label trial patients with symptoms suggestive of GERD were randomized to receive a two-week test with 20-mg or 40-mg rabeprazole after diagnostic endoscopy Symptom response was assessed with a four-grade daily record in addition DNA from peripheral blood leukocytes was genotyped for CYP2C19 polymorphism with polymerase chain reaction-restrict fragment length polymorphism PCR-RFLP technique
Patients and Methods In this randomized open-label trial patients with symptoms suggestive of GERD were randomized to receive a two-week test with 20-mg or 40-mg rabeprazole after diagnostic endoscopy Symptom response was assessed with a four-grade daily record in addition DNA from peripheral blood leukocytes was genotyped for CYP2C19 polymorphism with polymerase chain reaction-restrict fragment length polymorphism PCR-RFLP technique
Detailed Description:
INTRODUCTION A broad spectrum of symptoms are commonly associated with gastroesophageal reflux disease GERD which has an incidence of roughly 20 in the general population1 Despite recent substantial advances in understanding GERDs pathogenesis diagnosis still presents many challenges A rapid symptomatic response to proton pump inhibitors PPIs in patients with a presumptive diagnosis of GERD is useful to validate diagnosis which is known as the PPI test Studies addressing diagnostic PPI testing have produced valuable estimates for Western populations regarding prediction of GERD in individual patients234 Some population-specific features distinguish Asian patients from their Western counterparts First the majority 75-90 of Asian reflux patients have endoscopy-negative reflux disease ENRD15 Not all of them demonstrate a favorable response to PPI treatment because the pathogenesis of ENRD is in part associated with psychosomatic pathways67 Second PPIs are eliminated by a hepatic route with a polymorphically expressed cytochrome P CYP 2C19 primarily responsible for the rate of metabolism8 Compared with people who have a homozygous wild-type genotype people with a variant CYP2C19 allele exhibit lower rates of PPI degradation higher plasma PPI concentrations 3-to-13 times higher and a lesser degree of gastric acid secretion9 The prevalence of people who are poor metabolizers ie have a homozygous variant genotype has been cited as 12 to 38 for Caucasian-European populations but 126 to 225 for Asian populations10 Lower gastric parietal cell mass is also prevalent in Asians These characteristics may augment the therapeutic effect of PPIs in Asian patients
When considering the pros and cons of PPI testing in an Asian population the major pro is that there will be a high prevalence of poor or intermediate metabolizers who may have an increased serum level of PPI resulting in a higher sensitivity lower required dose of PPI and less cost in testing The con is mainly related to the increased proportion of ENRD patients Up to 50 of ENRD patients whose condition is termed functional heartburn report sufficient heartburn relief with PPI treatment611 Therefore a higher proportion of false positive cases may occur which can lead to a decrease in test specificity
The prediction of intra-esophageal damage is of paramount importance because patients with erosive and non-erosive disease have distinctive manifestations and prognosis12 Therefore in this study we tested the hypothesis that the PPI test can be used as a valid tool for diagnosis of esophagitis in a Chinese population Validation of the accuracy of PPI testing would provide important information for comparison of diagnosis with the traditional endoscopy-first approach We selected rabeprazole as the PPI test agent because it is well tolerated and can effectively prevent pathological and symptomatic GERD relapse1314 Another potential benefit is that a variable proportion of rabeprazole degradation proceeds through a non-enzymatic pathway1516 Thus a decrease in inter-individual variability in serum PPI level may prove the rabeprazole-based regimen to be a diagnostic test with stable accuracy
PATIENTS METHODS Patients A consecutive series of patients with symptoms suggestive of GERD were enrolled from the Gastroenterology outpatient clinic in our institution The typical GERD symptom was defined as heartburn andor acid regurgitation of at least three episodes per week for a minimum of three months Patients who received concurrent PPI treatment had a medical contraindication to rabeprazole therapy reported a history of peptic ulcer disease or gastrointestinal surgery peptic ulcer disease or malignancy proven by endoscopy the presence of alarm features eg dysphagia weight loss bleeding abdominal mass andor anemia or who were unwilling or unable to provide informed consent were excluded from the study Participants provided informed consent and the Ethics Committee of National Taiwan University Hospital approved the study protocol prior to implementation no 940711
Study Protocol All enrolled patients underwent an initial diagnostic evaluation with upper endoscopy and were classified with erosive or non-erosive disease After endoscopy patients in the two groups were randomly assigned to receive either one tablet of rabeprazole 20mg before breakfast or two tablets of rabeprazole before breakfast and dinner for 2 weeks The random allocation was performed by choosing cards in sealed envelopes Patient response to PPI treatment was recorded in a diary illustrated below Patients were notified about endoscopy results only at study completion
Endoscopy After an overnight fast all subjects were placed in the left lateral decubitus position Endoscopy was performed by experienced endoscopists at our academic institution During the procedure the stomach and duodenum were inspected to exclude possible lesions The distal portion of the esophagus was evaluated carefully to determine the presence of any mucosal injury The definition of reflux esophagitis rested on demonstration of diffuse or streaking erythema mucosal friability and the presence of erosions or ulcers ie mucosal breaks Severity was assessed according to the Los Angeles LA classification with standard comparator photos a reference standard in diagnosis of GERD17
Symptom Assessment Patients kept a daily diary record of the severity of their reflux symptoms for the 14 days of PPI therapy The evaluation scale was adapted from the scale used in the Dickman trial 18 and was translated into Chinese The scale was as follows 1 mild symptoms that were easily tolerated and did not last long 2 moderate symptoms that caused some discomfort but did not interfere with usual activities 3 severe symptoms that caused much discomfort and interfered with usual activities and 4 disabling symptoms that were unbearable and interfered considerably with usual activities
Analyses of CYP2C19 Genotypes For genotype analysis each patients peripheral blood leukocytes were obtained and their DNA was extracted Genotyping procedures that identified the CYP2C19 wild-type allele and the two known mutant alleles CYP2C19m1 in exon 5 and CYP2C19m2 in exon 4 were carried out by polymerase chain reaction-restriction fragment length polymorphism PCR-RFLP technique with allele-specific primers19 On the basis of their ability to metabolize PPI individuals were classified as extensive metabolizers homEM homozygous for wild-type allele heterozygous extensive metabolizers hetEM carrier of only one mutant allele or poor metabolizers PM homozygous for variant allele All laboratory procedures were performed blind to the patients randomization status
Statistical Analysis Quantitative data were summarized as mean standard deviation SD and categorical variables were summarized as percentages Between study groups categorical variables were compared with the 2 test quantitative data with the independent t-test and ordinal data with Wilcoxons two-sample test To identify the best cutoff value of symptom reduction for prediction of GERD we compared three levels for a positive response 25 50 and 75 symptom reduction from baseline by calculating the areas under the receiver-operating curve ROC in a prediction model In this model the dependent variable was diagnosis of GERD and a positive therapeutic response was treated as the main independent variable Covariants included age male gender body mass index BMI and social habits eg smoking and alcohol all of which are known to be associated with risk of GERD1 According to the best definition for positive response diagnostic parameters were calculated for sensitivity specificity positive predictive value PPV negative predictive value NPV and accuracy To assess the effect of CYP2C19 polymorphic genotype results were stratified and compared according to carrier status eg homEM hetEM and PM The Cochran-Armitage trend test assessed whether there was a therapeutic difference across the three genotype classes All P values were two sided and P 005 indicated statistical significance Analyses were performed with statistical software SAS version 80 SAS Institute Inc Cary NC
When considering the pros and cons of PPI testing in an Asian population the major pro is that there will be a high prevalence of poor or intermediate metabolizers who may have an increased serum level of PPI resulting in a higher sensitivity lower required dose of PPI and less cost in testing The con is mainly related to the increased proportion of ENRD patients Up to 50 of ENRD patients whose condition is termed functional heartburn report sufficient heartburn relief with PPI treatment611 Therefore a higher proportion of false positive cases may occur which can lead to a decrease in test specificity
The prediction of intra-esophageal damage is of paramount importance because patients with erosive and non-erosive disease have distinctive manifestations and prognosis12 Therefore in this study we tested the hypothesis that the PPI test can be used as a valid tool for diagnosis of esophagitis in a Chinese population Validation of the accuracy of PPI testing would provide important information for comparison of diagnosis with the traditional endoscopy-first approach We selected rabeprazole as the PPI test agent because it is well tolerated and can effectively prevent pathological and symptomatic GERD relapse1314 Another potential benefit is that a variable proportion of rabeprazole degradation proceeds through a non-enzymatic pathway1516 Thus a decrease in inter-individual variability in serum PPI level may prove the rabeprazole-based regimen to be a diagnostic test with stable accuracy
PATIENTS METHODS Patients A consecutive series of patients with symptoms suggestive of GERD were enrolled from the Gastroenterology outpatient clinic in our institution The typical GERD symptom was defined as heartburn andor acid regurgitation of at least three episodes per week for a minimum of three months Patients who received concurrent PPI treatment had a medical contraindication to rabeprazole therapy reported a history of peptic ulcer disease or gastrointestinal surgery peptic ulcer disease or malignancy proven by endoscopy the presence of alarm features eg dysphagia weight loss bleeding abdominal mass andor anemia or who were unwilling or unable to provide informed consent were excluded from the study Participants provided informed consent and the Ethics Committee of National Taiwan University Hospital approved the study protocol prior to implementation no 940711
Study Protocol All enrolled patients underwent an initial diagnostic evaluation with upper endoscopy and were classified with erosive or non-erosive disease After endoscopy patients in the two groups were randomly assigned to receive either one tablet of rabeprazole 20mg before breakfast or two tablets of rabeprazole before breakfast and dinner for 2 weeks The random allocation was performed by choosing cards in sealed envelopes Patient response to PPI treatment was recorded in a diary illustrated below Patients were notified about endoscopy results only at study completion
Endoscopy After an overnight fast all subjects were placed in the left lateral decubitus position Endoscopy was performed by experienced endoscopists at our academic institution During the procedure the stomach and duodenum were inspected to exclude possible lesions The distal portion of the esophagus was evaluated carefully to determine the presence of any mucosal injury The definition of reflux esophagitis rested on demonstration of diffuse or streaking erythema mucosal friability and the presence of erosions or ulcers ie mucosal breaks Severity was assessed according to the Los Angeles LA classification with standard comparator photos a reference standard in diagnosis of GERD17
Symptom Assessment Patients kept a daily diary record of the severity of their reflux symptoms for the 14 days of PPI therapy The evaluation scale was adapted from the scale used in the Dickman trial 18 and was translated into Chinese The scale was as follows 1 mild symptoms that were easily tolerated and did not last long 2 moderate symptoms that caused some discomfort but did not interfere with usual activities 3 severe symptoms that caused much discomfort and interfered with usual activities and 4 disabling symptoms that were unbearable and interfered considerably with usual activities
Analyses of CYP2C19 Genotypes For genotype analysis each patients peripheral blood leukocytes were obtained and their DNA was extracted Genotyping procedures that identified the CYP2C19 wild-type allele and the two known mutant alleles CYP2C19m1 in exon 5 and CYP2C19m2 in exon 4 were carried out by polymerase chain reaction-restriction fragment length polymorphism PCR-RFLP technique with allele-specific primers19 On the basis of their ability to metabolize PPI individuals were classified as extensive metabolizers homEM homozygous for wild-type allele heterozygous extensive metabolizers hetEM carrier of only one mutant allele or poor metabolizers PM homozygous for variant allele All laboratory procedures were performed blind to the patients randomization status
Statistical Analysis Quantitative data were summarized as mean standard deviation SD and categorical variables were summarized as percentages Between study groups categorical variables were compared with the 2 test quantitative data with the independent t-test and ordinal data with Wilcoxons two-sample test To identify the best cutoff value of symptom reduction for prediction of GERD we compared three levels for a positive response 25 50 and 75 symptom reduction from baseline by calculating the areas under the receiver-operating curve ROC in a prediction model In this model the dependent variable was diagnosis of GERD and a positive therapeutic response was treated as the main independent variable Covariants included age male gender body mass index BMI and social habits eg smoking and alcohol all of which are known to be associated with risk of GERD1 According to the best definition for positive response diagnostic parameters were calculated for sensitivity specificity positive predictive value PPV negative predictive value NPV and accuracy To assess the effect of CYP2C19 polymorphic genotype results were stratified and compared according to carrier status eg homEM hetEM and PM The Cochran-Armitage trend test assessed whether there was a therapeutic difference across the three genotype classes All P values were two sided and P 005 indicated statistical significance Analyses were performed with statistical software SAS version 80 SAS Institute Inc Cary NC
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| 940711 | None | None | None |