In patients with gastroesophageal reflux disease (GERD), esomeprazole, the S-isomer of omeprazole, has demonstrated pharmacological and clinical benefits beyond those seen with the racemic parent compound. This study was designed to further evaluate the efficacy and tolerability of esomeprazole relative to that of omeprazole in healing erosive esophagitis and resolving accompanying symptoms of GERD.
Esomeprazole 40 mg was compared with omeprazole 20 mg once daily in 2425 patients with erosive esophagitis (Helicobacter pylori negative by serology) in an 8-wk, multicenter, randomized, double-blind, parallel-group study conducted in 163 centers throughout the US. The primary efficacy endpoint was the proportion of patients with healed esophagitis at wk 8. Secondary endpoints were the proportion of patients healed at wk 4, resolution of heartburn at wk 4, time to first resolution and sustained resolution of heartburn, and proportion of heartburn-free days and nights. Safety and tolerability were also assessed.
Significantly more patients were healed with esomeprazole versus omeprazole at wk 8 (93.7% vs 84.2%, p < 0.001; life table estimates, intention-to-treat analysis). Healing rates at wk 4 were 81.7% and 68.7%, respectively. Esomeprazole was superior to omeprazole for all secondary measures and had a similar safety profile. The most common adverse events in both treatment groups were headache, diarrhea, and nausea.
Esomeprazole demonstrates significantly greater efficacy than omeprazole in the treatment of GERD patients with erosive esophagitis. The tolerability and safety of esomeprazole are comparable to that of omeprazole.
Gastroesophageal reflux disease (GERD) symptoms affect an estimated 20–40% of the adult population in Western countries (1, 2, 3, 4). The disease can have a major impact on quality of life and be associated with substantial morbidity (5, 6, 7). Between 40% and 60% of patients presenting with symptoms of GERD have erosive esophagitis (2, 3, 4), the severity of which is largely related to the extent and duration of exposure to refluxed gastric acid (8, 9). Erosive esophagitis has been associated with complications such as esophageal stricture, ulceration and bleeding, and Barrett's esophagus (1, 10).
Proton pump inhibitors (PPIs) represent the most effective treatment option for the short- and long-term management of GERD and are recommended first-line agents (11). Since the introduction of omeprazole in 1989, PPIs have been shown to be clinically superior to histamine2 receptor antagonists (H2RAs) in terms of healing of esophagitis and resolution of GERD symptoms (5, 12, 13). Controlled trials have shown that treatment with omeprazole for 8 wk heals 70–96% of patients with erosive esophagitis (13, 14, 15, 16). Similar healing rates have been demonstrated with the subsequently marketed PPIs, lansoprazole, pantoprazole, and rabeprazole (17, 18, 19, 20).
Esomeprazole, the S-isomer of omeprazole, was developed to further improve the management of acid-related disease. This optical isomer is subject to less first-pass metabolism and lower plasma clearance than omeprazole, thereby offering higher systemic bioavailability. In patients with symptoms of GERD, the area under the plasma concentration-time curve (AUC) of esomeprazole 20 mg was two-fold higher than that of omeprazole 20 mg (p < 0.001). At a 40-mg dose, esomeprazole had a five-fold higher AUC than omeprazole 20 mg (p < 0.001) (21). This improvement in bioavailability has been shown, in patients, to translate into greater and more prolonged acid suppression with esomeprazole versus omeprazole. Esomeprazole 40 mg administered for 5 days produces a 60% increase in the percentage of the day with pH >4 versus omeprazole 20 mg (21) and a 10% increase in the percentage of the day with pH >4 versus omeprazole 40 mg (each p < 0.001) (21, 22).
A large trial has compared once daily esomeprazole 20 and 40 mg with omeprazole 20 mg in GERD patients with erosive esophagitis. Results indicated that both esomeprazole 40 and 20 mg were significantly (p < 0.05) more effective than omeprazole 20 mg for healing of erosive esophagitis, but the 40-mg dose was the most effective (p < 0.001) (23). Compared with omeprazole 20 mg, symptom resolution was also greater with esomeprazole 40 mg (p < 0.05) but only tended to be better with esomeprazole 20 mg. Thus, the body of data accumulated in early pharmacological and clinical trials establishes esomeprazole 40 mg to be the optimal dose for the acute management of patients with GERD and erosive esophagitis. The current trial was conducted in a large population of patients with erosive esophagitis to further evaluate the efficacy and safety of esomeprazole 40 mg relative to that of omeprazole 20 mg, the standard FDA-approved dosage for this patient population.
Materials and methods
This was a multicenter, double-blind, randomized, parallel-group, comparative trial conducted at 163 centers in the US. The study was consistent with the principles of the Declaration of Helsinki and conducted in compliance with Good Clinical Practices regulations and guidance issued by the FDA; the protocol was approved by the Institutional Review Board of each center before enrolling patients. Before entry, patients underwent a complete history and physical examination. Routine blood and urine samples were obtained and Helicobacter pylori (H. pylori) serology screening was conducted. A commercially available in-office rapid serology test kit was used (FlexSure, SmithKline Beecham, Philadelphia, PA).
Patients included in the study were male and female adults aged between 18 and 75 yr. All had photographically documented erosive esophagitis confirmed by esophagogastroduodenoscopy (EGD), and graded according to the Los Angeles (LA) Classification (Table 1), within 1 wk before randomization to treatment. The LA Classification was used because of the high level of interobserver reliability it allows among experienced endoscopists (24, 25).
All patients provided written informed consent before entry into the study. Female patients were required to be nonpregnant, nonlactating, postmenopausal, surgically sterilized, or using a medically acceptable form of birth control, as determined by the investigator. Women of child-bearing potential received a pregnancy test.
Those individuals who tested positive for H. pylori during serological screening were excluded to eliminate a potentially confounding variable when assessing the efficacy of the study medications. Patients who were later found to be H. pylori positive when the histological results from gastric biopsies were available were allowed to remain in the study. These patients were included in the overall data analysis as part of the intention-to-treat (ITT) population. Efficacy in healing was also tabulated separately for these patients, although the study was not powered to detect a statistical difference by H. pylori status.
Patients with any bleeding disorder or signs of gastrointestinal bleeding at the time of the baseline EGD or within 3 days before randomization were also excluded from the study, as were those with a history of gastric or esophageal surgery. Other exclusion criteria were: current or historical evidence of Zollinger-Ellison syndrome, primary esophageal motility disorders, esophageal stricture, endoscopic Barrett's esophagus (>3 cm) or significant dysplastic changes in the esophagus, duodenal or gastric ulcer, inflammatory bowel disease, upper gastrointestinal malignancy, unstable diabetes mellitus, or other severe concomitant disease.
Treatment with a PPI within 28 days before baseline was prohibited, as was daily therapy with an H2RA during the 2 wk before baseline EGD. Patients with known hypersensitivity to any component of esomeprazole (Nexium), omeprazole (Prilosec), or aluminum/magnesium hydroxide (Gelusil), as well as patients previously participating in a clinical trial of esomeprazole, were excluded from the study. Concomitant use of the following medications was not permitted during the study: anticholinergics, antineoplastic agents, diazepam, diphenylhydantoins, H2RAs, nonsteroidal anti-inflammatory drugs (NSAIDs), PPIs (except study medication), promotility drugs, prostaglandin analogs, quinidine, salicylates (except low-dose prophylactic antithrombotic therapy), steroids (oral or intravenous), sucralfate, and warfarin.
Eligible patients were randomly assigned in double-blind fashion to one of two treatment groups: esomeprazole 40 mg or omeprazole 20 mg administered once daily in the morning before breakfast for up to 8 wk. Randomization was performed at each center using blinded blocks of four allocation numbers. Treatment allocation for each patient was provided in individually sealed and blinded randomization envelopes that were collected and checked by the monitor at the end of the study to ensure the integrity of the blinding. To maintain blinding, the drugs were given in capsules identical in appearance.
Aluminum/magnesium hydroxide was permitted as a rescue medication for breakthrough GERD symptoms, to a maximum of six tablets per day. At each visit, patients were asked to return all unused study and rescue medication from the previous visit. Compliance with study medication and rescue medication usage was calculated by counting unused capsules. Patients who discontinued from the study for any reason were asked to return for a follow-up visit at the time of, or soon after, discontinuation.
Assessment of efficacy
Patients were evaluated using EGD at baseline, at wk 4, and at wk 8 (if erosions were still present at wk 4). Patients healed at wk 4 were considered to have completed the study as treatment successes and were discontinued from the study after endpoint evaluations; the final visit was at wk 8 for remaining patients. At baseline, gastric biopsies were collected during the EGD procedure from patients confirmed to have erosive esophagitis. Biopsy samples of the gastric mucosa were taken from the body of the corpus, the antrum, and the incisura angularis. Histopathological slides for baseline biopsy specimens were prepared at The Gastrointestinal Mucosa Laboratory (Veterans Administration Medical Center, Houston, TX). Biopsy samples from the antrum were evaluated for H. pylori by one pathologist using the Genta stain. Biopsies from the other sites were evaluated for possible gastritis, atrophy, and intestinal metaplasia only in those patients who enrolled in a subsequent extension study that evaluated the efficacy of esomeprazole in the maintenance of healing of erosive esophagitis.
At baseline, wk 4 and wk 8 (if erosions were still present at wk 4) visits, investigators assessed the severity of the worst episode of heartburn to occur during the preceding 7-day period. Each morning during the first 4 wk of treatment, patients also recorded in diary cards the severity of the most intense episode of heartburn during the preceding 24-h period. Patients also indicated the presence of nocturnal heartburn during the previous night. Heartburn was defined as a burning feeling, rising from the stomach or lower part of the chest towards the neck. Severity of heartburn was classified by both investigators and patients as none (no heartburn), mild (awareness of heartburn, but easily tolerated), moderate (discomforting heartburn sufficient to cause interference with normal activities, including sleep), or severe (incapacitating heartburn, with inability to perform normal activities, including sleep). A heartburn rating of “none” on the 4-point scale was considered resolution, whereas 7 consecutive days with a rating of “none” was considered sustained resolution (the first day of the 7 was used for analysis).
The primary efficacy endpoint was complete healing of esophageal erosions on EGD examination (LA Classification of “not present”) at wk 8. Secondary efficacy endpoints were complete healing of esophageal erosions on EGD at wk 4, and complete resolution of heartburn (severity of “none”) at wk 4 and 8. Time to first resolution and sustained resolution of heartburn, and the percentage of days and nights free from heartburn were calculated from diary card data.
Assessment of adverse events
The population for the analysis of safety consisted of all patients who received at least one dose of study medication. The safety and tolerability of study medication were assessed using physical examination at final visit (wk 4 or 8), review of adverse events as reported by patients at wk 4 and 8, and clinical laboratory evaluations at baseline and at the final visit. Clinical laboratory tests included serum chemistry, hematology, and urinalysis. Clinical laboratory testing was conducted by SmithKline Beecham Clinical Laboratories, Inc. (Van Nuys, CA). At each follow-up visit, all adverse events reported during investigators’ interviews with patients were recorded. Open nonsuggestive questioning was used to solicit adverse events. The causal relationship of an adverse event to the study drug was classified by investigators as being probable, possible, or unlikely, and the intensity of the adverse event was rated as mild, moderate, or severe. The action taken with study drug in response to the adverse event (none, treatment temporarily stopped, treatment discontinued) was also recorded.
Adverse events were described using preferred terms encompassing 31 system organ classes. Standard terminology for the classification of adverse events was based on a modified version of the WHO Adverse Reaction Terminology (WHOART) developed by the WHO Collaborating Centre for International Drug Monitoring in Uppsala.
A sample size of 1040 subjects per treatment arm was calculated to have 95% power to detect a difference in complete healing rates of 88% for omeprazole 20 mg once daily and 93% for esomeprazole 40 mg once daily. This calculation assumed a two-sided test, using the arcsine transformation, and an alpha level of 0.05. All summaries and analyses were performed with the statistical software package SAS, Version 6.12 (SAS Institute, Cary, NC).
The primary efficacy endpoint of complete healing of erosive esophagitis at wk 8 included data carried forward from patients exhibiting complete healing at wk 4, based on the assumption that if such patients continued treatment they would remain healed at wk 8. Thus, the primary efficacy endpoint was a cumulative healing rate. This rate was calculated based on a life table approach. Statistical comparisons between treatment groups for the primary analysis were performed using a log-rank test, which is sensitive to the magnitude of difference between treatment groups and compensates for the time of healing. The primary efficacy endpoint was also analyzed using a Cochran-Mantel-Haenszel (CMH) test with stratification for baseline severity of erosive esophagitis (i.e., LA Classification). This crude rate represents a more conservative approach than the log-rank test as all patients who did not contribute “appropriate” data were considered to be treatment failures. The CMH test was performed separately at wk 4 and 8.
The proportion of patients experiencing resolution of GERD symptoms according to investigators was analyzed at wk 4 using a CMH test, stratified by baseline severity of the particular symptom. An analysis of GERD symptoms was not performed on wk 8 as patients could complete the study at wk 4 with healed erosive esophagitis even if symptoms were present. A log-rank test was used to analyze the diary-recorded number of days until first resolution and sustained resolution of heartburn. Differences between treatments in the mean percentage of heartburn-free days and the mean percentage of patients with heartburn-free nights were compared using analysis of variance.
Two populations were defined for purposes of analysis of efficacy data: the ITT population, defined as all patients randomized to treatment, and the per protocol (PP) population, a subset of patients meeting certain predefined inclusion/exclusion criteria and compliance measures. The primary efficacy endpoint was analyzed for both the ITT and PP populations. All secondary endpoints were analyzed for the ITT population only.
No inferential statistics were used in comparing any safety variables. Incidence rates for adverse events were calculated using the number of patients having one or more occurrences of an adverse event and the number of patients who received that treatment.
A total of 4798 patients were screened for study entry; the main reasons for excluding screened subjects from the study were: 1) no evidence of esophageal mucosal breaks on endoscopy, and 2) positive serology for H. pylori (Fig. 1). Overall, 2425 patients were randomized to receive either esomeprazole 40 mg once daily (n = 1216) or omeprazole 20 mg once daily (n = 1209) for up to 8 wk (Fig. 1). Thus, the ITT population comprised 2425 patients, including a small percentage (8%) who were H. pylori positive by histology. The PP and safety populations consisted of 2132 patients and 2405 patients, respectively. Baseline demographics and other characteristics for patients evaluable for efficacy (ITT population) were similar across the two treatment groups (Table 2).
A total of 24 patients failed to complete the study because of an adverse event (Fig. 1). A further 85 patients did not complete the study for other reasons, including withdrawal of consent (n = 31), lost to follow-up (n = 25), and discontinued at the request of the investigator (n = 25). Compliance with medication was high in general and similar in patients treated with esomeprazole compared with those receiving omeprazole. Over 90% of patients in each treatment group had a compliance rate of ≥90%.
Esomeprazole was significantly (p < 0.001) more effective than omeprazole with regard to endoscopic healing rates for esophagitis (LA Classification “not present”) at wk 8 according to life table rates (ITT population). Graphic presentation of the cumulative healing rates for life table estimates at wk 4 and 8 are given in Figure 2. A total of 93.7% (95% CI 92.3–95.1%) of patients treated with esomeprazole once daily experienced healing of esophagitis at wk 8, compared with 84.2% (95% CI 82.1–86.3%) of patients treated with omeprazole. Similar results were observed in the PP population (life table rates of 93.8% and 84.4%, respectively, p < 0.001). Crude healing rates were also significantly higher with esomeprazole 40 mg than with omeprazole 20 mg at both wk 4 (78.6% vs 66.6%) and wk 8 (89.9% vs 80.9%) (CMH test; p = 0.001 at both wk). The greater efficacy of esomeprazole over omeprazole was consistent when adjusted for baseline severity of esophagitis according to the LA Classification at both wk 4 and 8 (Fig. 3).
Subgroup analysis of results for the primary endpoint of endoscopic healing of erosive esophagitis found no clinically meaningful effect for gender, age, race, or H. pylori status. A total of 186 patients had histological evidence of H. pylori infection. In this group, 88.9% of esomeprazole-treated patients and 77.1% of omeprazole-treated patients were healed at wk 8. In the H. pylori-negative group, 89.9% of esomeprazole-treated patients and 81.2% of omeprazole-treated patients were healed at wk 8.
Esomeprazole was also significantly more effective than omeprazole for all secondary endpoints evaluating heartburn resolution (Table 3). According to patients’ diary cards, the proportion of patients having sustained resolution of heartburn (a rating of “none” for 7 consecutive days) was significantly higher (p = 0.0005; log-rank test) with esomeprazole than with omeprazole every day of the first 4 wk of treatment (Fig. 4).
Use of aluminum/magnesium hydroxide was slightly lower in the group treated with esomeprazole once daily than in the omeprazole group at wk 4 (mean 0.6 and 0.7 tablets/day, respectively) and at wk 8 (mean 0.5 and 0.8 tablets/day, respectively).
There was a relatively high concurrence between healing of erosive esophagitis at wk 4 and resolution of GERD symptoms: of those patients with resolution of heartburn at wk 4, 85.2% of the esomeprazole group and 76.8% of the omeprazole group had healing of erosive esophagitis. Of those who were asymptomatic but not healed, the preponderance of patients had grade A or B esophagitis, i.e., 95.8% in the esomeprazole group had grade A (79.8%) or B (16.0%) esophagitis, whereas 98% in the omeprazole group had grade A (76.1%) or B (22.0%) esophagitis. Because most patients had healing by wk 4, concurrence data could not be accurately determined for wk 8.
Safety and tolerability
Of the 2425 patients with erosive esophagitis randomized to study medication, 2405 patients received at least one dose of either esomeprazole (n = 1205) or omeprazole (n = 1200) and were included in the safety and tolerability analysis. Overall, the incidence and profile of adverse events were similar between the two treatment groups. At least one adverse event was reported in 32.2% of patients treated with esomeprazole compared with 34.3% of patients treated with omeprazole. A similar proportion of patients in each group (15.3% and 15.1%, respectively) had an adverse event considered to be treatment related. Adverse events occurring in at least 2.0% of patients in the esomeprazole group are presented in Table 4, along with the corresponding values for omeprazole.
Approximately 1% of patients in each treatment group discontinued treatment because of an adverse event. Less than 1% of patients in each group experienced a serious adverse event, and none were considered by the investigator to be treatment related. There were no clinically meaningful differences between treatment groups in the profile of serious adverse events. No deaths were reported during the study among patients treated with esomeprazole. One death, secondary to stab wounds, was reported in the omeprazole group and was not considered to be related to treatment.
There were no clinically meaningful changes in vital signs over the course of the study. Mean changes from baseline in laboratory test results were small and generally similar for the two treatment groups. As expected, serum gastrin levels increased, but mean post-treatment gastrin levels remained within the normal range (0–99 pg/ml) for both treatments.
The results of this 8-wk, multicenter, randomized, double-blind study in more than 2400 patients with EGD-verified erosive esophagitis indicate that esomeprazole has several advantages over omeprazole. Most importantly, the healing rate at wk 8 with esomeprazole (93.7%) represents a significant therapeutic gain of 9.5% compared with that of omeprazole (84.2%). Healing rates at wk 4 were also higher with esomeprazole (81.7%) than omeprazole (68.7%) suggesting that esomeprazole provides more rapid healing than omeprazole. Indeed, healing rates at wk 4 with esomeprazole were similar to those reported with omeprazole at 8 wk. When considering how these results impact on clinical practice, the primary endpoint of healing rates at wk 8 (ITT analysis) can be used to show that for every 11 patients treated with esomeprazole instead of omeprazole for 8 wk, one treatment failure would be prevented. Similarly, esomeprazole could prevent one treatment failure for approximately every eight patients after 4 wk of treatment. Because the confidence intervals for healing rates for both treatments were tight, these results are likely to be highly reproducible.
Esomeprazole demonstrated greater consistency of efficacy across patient groups when baseline severity of erosive esophagitis was considered. In addition, differences in healing rates were consistently greater with esomeprazole across all grades of baseline severity (LA Classification) of erosive esophagitis at both wk 4 and wk 8. Further, baseline H. pylori status did not appear to affect healing rates with esomeprazole, although the study was not powered to detect a statistical difference by H. pylori status.
Esomeprazole also produced significantly superior control of heartburn compared with omeprazole based on evaluation of very rigorous endpoints. Significantly more patients treated with esomeprazole than omeprazole had complete resolution of heartburn (a rating of “none”) and sustained resolution of heartburn (7 consecutive days with a rating of “none”). Time to sustained resolution of heartburn, and the proportion of heartburn-free days and nights were also significantly greater than corresponding results with omeprazole.
In concurrence with a recent consensus report (26) freedom from heartburn, the predominant symptom of GERD, was predictive of healing of erosive esophagitis: 85.2% of patients with resolution of heartburn at wk 4 also had healing of erosive esophagitis. Thus, a treatment effect of esomeprazole on sustained resolution of heartburn in patients with erosive esophagitis can be used as a strong indicator of healing of esophageal erosions.
The results of the current study are consistent with the findings of the earlier 8-wk study that compared esomeprazole 20 mg and 40 mg with omeprazole 20 mg in GERD patients with erosive esophagitis (23). In that study by Kahrilas et al. (23), both dosages of esomeprazole were significantly more effective than omeprazole for healing of erosive esophagitis, with esomeprazole 40 mg providing the greatest healing. Healing rates with esomeprazole 40 mg were very similar in each of these trials: 93.7% at wk 8 in the current trial and 94.1% in the earlier trial.
The greater efficacy of esomeprazole compared with omeprazole demonstrated in this clinical trial and in that of Kahrilas et al. (23) is related to the pharmacokinetic and pharmacodynamic profile of the drug (21, 27). Esomeprazole is more slowly cleared and therefore has a greater bioavailability than omeprazole. Esomeprazole also appears to have more consistent pharmacokinetic properties than omeprazole, with less interpatient variability in terms of AUC, plasma concentrations, and gastric acid inhibition. Esomeprazole maintained intragastric pH above 4.0 for 6 h longer than omeprazole and produced a higher median 24-h intragastric pH than did omeprazole in patients with GERD. This difference was most apparent between 12 and 20 h after a morning dose (21), which probably accounts for the greater reduction of night-time heartburn achieved with esomeprazole in both trials. Ninety-two percent of esomeprazole 40 mg recipients maintained pH >4 for 12 to 24 h in the pharmacodynamic study; in comparison, only 44% of omeprazole 20 mg achieved this result (21).
At present, clinical management guidelines for GERD recommend that the most effective treatment should be instituted as early as possible. Currently marketed PPIs offer similar healing rates to the standard, and usually recommended, dosage of omeprazole (20 mg) at 4 and 8 wk (17, 18, 19, 20, 28, 29, 30, 31, 32). Healing rates were significantly higher with once daily esomeprazole 40 mg than with omeprazole 20 mg in the two clinical trials conducted in patients with GERD and erosive esophagitis. In one trial, esomeprazole 20 mg also produced significantly higher healing rates than omeprazole 20 mg, but the higher dose of esomeprazole (40 mg) was better and was therefore the preferred and further investigated dose.
Thus, for the first time, a PPI, esomeprazole, has been shown to offer significant advantages over omeprazole in terms of healing of erosive esophagitis. Resolution of heartburn also occurred faster and in a greater percentage of patients treated with esomeprazole compared with omeprazole.
The results of this study indicate that esomeprazole provides a significant advantage over omeprazole in terms of esophageal healing and relief of heartburn in GERD patients with erosive esophagitis, irrespective of baseline severity of disease.
We gratefully acknowledge the assistance of David J. Magner, M.S.Hyg., with statistical analyses, Robert Genta, M.D., with evaluating biopsy samples, as well as the diligent efforts of the study coordinators at the investigation sites.
This study was supported by a grant from AstraZeneca LP, Wayne, PA.
The esomeprazole study investigators
D. R. Abrahm, Newport Beach Gastroenterology Associates; M. Ali, A. Arora, Sierra Medical Research; K. Ashby, Harriman Jones Medical Group; R. D. Baerg, Tacoma Digestive Disease Center; C. F. Barish, Wake Research Associates; M. Barreiro, United Medical Associates, PC; I. Bassan, J. G. Beckwith, R. W. Bennetts, Northwest Gastroenterology Clinic; C. Berggreen, W. R. Berry, Longmont Clinic, PC; T. Bianchi, Southern Drug Research Network; D. Biery, C. A. Birbara, Clinical Pharmacology Study Group; P. C. Bird, Research Associates of Norman, Inc.; V. A. Botoman, J. Breiter, Center for Medical Research; J. R. Caldwell, A. Caos, S. Carlson, Coastal Medical Research Group, Inc.; R. Chasen, A. Y. Chen, Monroe Clinic; R. Chiprut, D. C. Chua, Summit Digestive and Liver Disease Specialists; N. Cirillo, L. B. Cohen, C. Colip, Portland Medical Associates; D. W. Collins, Western States Clinical Research, Inc.; D. Dalke, Gastroenterology Specialties, PC; V. A. DeLuca, Jr., Griffin Hospital; J. W. Dimitroff, St. Louis Center for Clinical Research; M. R. Dosch, Clinical Studies, Boynton Beach; J. Doyle, D. W. Dozer, Advanced Clinical Research, LLC; S. L. Duckor, AGMG Clinical Research; M. Efrusy, Olympia Fields Osteopathic Hospital; M. Eisner, Florida Medical Clinic; M. Epstein, Medlantic Investigators Network Inc.; J. F. Ervin, The Center for Pharmaceutical Research; C. Fausel, The Oregon Clinic; S. H. Feldman, Gastroenterology Associates of Fairfield County; R. Finlaw, Southern Colorado Clinic; R. Fogel, Henry Ford Hospital; R. D. Folan, Gastroenterology Association of CO; F. C. Fowler, University Gastroenterology; S. R. Freeman, Mile High Gastroenterology, PC; S. Gaddam, G. Gibbons; H. Giller, Digestive and Liver Disease Consultants, PC; O. D. Gilliam, Health Advance Institute, Inc.; E. Gillie, Medical Studies, Florida; P. B. Goldberg, M. Goldhamer, J. Goldstein, Brachfield Medical Associates; J. Goldstein, University of Illinois at Chicago Medical Center; M. Gorsky, A. Gottesman, Hill Top Research, Inc.; A. Harris, New York Hospital Medical Center; A. Harrison, E. H. Hirsh, R. B. Hogan, II, Mississippi Center for Clinical Research, LLC; J. J. Hsu, The Genesee Hospital; D. S. James, J. Johanson, Rockford Gastroenterology; R. B. Johnson, Sharp Rees Stealy Medical Group; D. A. Johnson, Gastrointestinal and Liver Specialists of Tidewater, PLLC; J. Jolley, J. V. Jones, Jr., Green Clinic; R. Kamyar, Institute of HealthCare Assessment, Inc.; R. D. Kaplan, LeBauer Health Care; S. Katz, Long Island Clinical Research Associates; H. Kavin, Advocate Medical Group-Gastroenterology; P. Kaye, C. S. Kelsey, San Diego Center for Research; P. Kiyasu, The Portland Clinic, LLP; R. Kommor, Health Advance Institute; T. Kovacs, CURE Clinic/West Los Angeles VAMC; G. Koval, West Hills Gastroenterology Associates, PC; R. Krause, The Center for Digestive Disorders and Clinical Research; S. Krumholz, D. Kruss, F. T. Kucer, M. Lamet, F. Lanza, Houston Institute for Clinical Research; J. Leavitt, Gastroenterology Care Center; M. S. Levine, SouthEast Research Associates, Inc.; T. Liebermann, Center for Clinical Research-Austin; L. Lifton, J. Linne, Community Research Management Associates, Inc.; W. R. Lumry, D. M. Maccini, Spokane Digestive Disease Center; M. K. Maden, H. N. Maimon, Dayton Area Research Associates; D. G. Mangels, TQM Research Center; S. Marcuard, Carolina Physicians, PA; R. D. Marks, Alabama Digestive Research Center, LLC; P. Maton, Digestive Disease Research Institute; J. L. Mauldin, ClinSites/SORRA Research Center; R. McCallum, University of Kansas Medical Center; A. McElroy, Multi-Specialty Clinical Research of NE Tennessee; P. Meier, VA Medical Center; T. Mendolia, Medical Park; P. J. Milman, P. B. Miner, Jr., Oklahoma Foundation for Digestive Research; L. Morton, S. Moussa, Advanced Clinical Therapeutics; R. V. Movva, Midwest Clinical Research Associates Ltd.; Z. Munk, Breco Research, Inc.; L. Newell, North Carolina Clinical Research, Inc.; T. Nichols, Jr., Center for Nutrition and Digestive Disorders; J. S. Novick, Charm City Research; C. Olson, Gould Medical Foundation; D. J. Pambianco, Charlottesville Gastroenterology Associates; P. M. Pardoll, Center for Digestive Diseases; W. A. Pearce, Rainier Clinical Research Center, Inc.; L. Peters, B. H. Plotnick, RUSH North Shore Medical Center; J. M. Provenza, Gastrointestinal Specialists, AMC; A. Reddy, Gastroenterology Research and Development Center; D. S. Riff, AGMG Clinical Research; M. A. Ringold, Lynn Health Science Institute; A. Rodriguez, Digestive Disease Clinic; R. D. Rothstein, University of Pennsylvania Hospital; H. A. Rubin, D. A. Ruff, Healthcare Discoveries, PA; V. Rustgi, S. Safavi, M. Safdi, Consultants for Clinical Research, Inc.; B. Sahba, California Research Foundation; B. Salzberg, P. Schleinitz, Gastroenterology Consultants, PC; C. M. Schmitt, Southeastern Clinical Research; J. Schneier, H. Schwartz, J. Schwartz, Northwest Gastroenterologists, SC; M. E. Schwartz, Jupiter Research Associates; A. Shah, U. K. Shah, Philip J. Bean Medical Center; R. Shaker, Medical College of Wisconsin; J. C. Shallcross, Jr., ClinSites/SORRA Research Center; B. Shivakumar, D. Siegel, Doctors Research Associates of Maryland; T. Simmons, S. Singh, W. J. Snape, Jr., E. J. Spiotta, D. B. Stanton, Community Clinical Trials; R. Steller, Long Island Gastroenterology Group, PC; L. Strong, Aspen Medical Group; R. W. Tobin, Seattle Gastroenterology Associates, PS; J. Turse, Health Advance Institute; N. B. Vakil, Sinai Samaritan Medical Center; J. B. Wagonfeld, Digestive Health Specialists; L. M. Weiss, Clinical Research of West Florida; S. Wilkofsky, Metroplex Clinical Research Center; P. E. Williams, Little Rock Diagnostic Clinic; J. A. Winder, Toledo Center for Clinical Research; B. D. Winston, Houston Medical Research Associates; P. Witt, Greeley Medical Clinic; R. A. Wohlman, Northwest Gastroenterology Associates.