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THE AMERICAN JOURNAL OF GASTROENTEROLOGY Vol. 98, No. 12, 2003 2003 by Am. Coll. of Gastroenterology ISSN 0002-9270/03/$30.00 Published by Elsevier Inc.
Gastric Acid Control With Esomeprazole,Lansoprazole, Omeprazole, Pantoprazole, andRabeprazole: A Five-Way Crossover StudyPhilip Miner, Jr., M.D., Philip O. Katz, M.D., Yusong Chen, Ph.D., and Mark Sostek, M.D.
Oklahoma Foundation for Digestive Research, University of Oklahoma Health Sciences Center, OklahomaCity, Oklahoma; Department of Medicine, Graduate Hospital, Philadelphia; and Divisions of Biostatisticsand Clinical Research, AstraZeneca, LP, Wilmington, Delaware OBJECTIVES: Proton pump inhibitors owe their clinical ef-
gastric parietal cells, resulting in suppression of gastric acid ficacy to their ability to suppress gastric acid production.
secretion The amount of time that intragastric pH is The objective of this study was to evaluate and compare greater than 4.0 is a parameter that is frequently used to intragastric pH following standard doses of esomeprazole, evaluate the pharmacodynamics and clinical effects of treat- lansoprazole, omeprazole, pantoprazole and rabeprazole.
ment with PPIs in patients with acid-related diseases Moreover, clinical investigations have confirmed that mu- METHODS: This randomized, open-label, comparative five-
cosal healing rates in erosive esophagitis can be correlated way crossover study evaluated the 24-h intragastric pH profile with the duration for which intragastric pH is maintained of oral esomeprazole 40 mg, lansoprazole 30 mg, omeprazole 20 mg, pantoprazole 40 mg, and rabeprazole 20 mg once daily Previously the effects of PPIs on intragastric pH have in 34 Helicobacter pylori–negative patients aged 18 – 60 yr been investigated in single-comparator studies This with symptoms of gastroesophageal reflux disease. Patients trial was designed to compare the intragastric acid-suppres- were randomly assigned to one of five treatment sequences sive pharmacodynamics of standard doses of the five PPIs and study drug was taken on 5 consecutive mornings 30 currently available in the United States; esomeprazole, lan- minutes prior to a standardized breakfast. A washout period soprazole, omeprazole, pantoprazole and rabeprazole. This of at least 10 days separated each treatment phase.
study is the first published comparative pharmacodynamic RESULTS: Thirty-four patients provided evaluable data for
trial to use a 5-way crossover design and provide the same all five comparators. The mean number of hours of evalu- controlled conditions across all treatment groups.
able pH data was ⱖ23.75 hours. On day 5, intragastric pHwas maintained above 4.0 for a mean of 14.0 h with esome- MATERIALS AND METHODS
prazole, 12.1 h with rabeprazole, 11.8 h with omeprazole,11.5 h with lansoprazole, and 10.1 h with pantoprazole (p ⱕ A randomized, single-center, open-label, multiple-dose, 0.001 for differences between esomeprazole and all other five-way crossover study was conducted at one center in the comparators). Esomeprazole also provided a significantly United States in accordance with the ethical principles of the higher percentage of patients with an intragastric pH greater Declaration of Helsinki and Good Clinical Practice guide- than 4.0 for more than 12 h relative to the other proton pump lines. The study was approved by the local institutional inhibitors (p ⬍ 0.05). The frequency of adverse events was review board at the University of Oklahoma Health Sci- similar between treatment groups.
ences Center and all patients provided signed informedconsent. The randomization scheme was computer gener- CONCLUSIONS: Esomeprazole at the standard dose of 40
ated. A centralized allocation method was used to assign mg once daily provided more effective control of gastric patients to a treatment group. The choice of treatment se- acid at steady state than standard doses of lansoprazole, quences was determined by balanced Latin square.
omeprazole, pantoprazole, and rabeprazole in patientswith symptoms of gastroesophageal reflux disease. (Am J Gastroenterol 2003;98:2616⫺2620. 2003 by Am. Coll.
Men and women aged 18 – 60 yr, who experienced heartburn of Gastroenterology) for an average of at least 2 days per month during the 2months before screening were eligible for enrollment. For those patients with a history of more frequent heartburn(three or more heartburn episodes per week during the 3 Proton pump inhibitors (PPIs) owe their clinical efficacy to months before study entry), esophagogastroduodenoscopy their ability to inhibit H⫹, K⫹-adenosine triphosphatase in was performed if no such evaluation had been performed AJG – December, 2003 Crossover Study with PPIs
within 6 months before study entry. Patients with past or study being conducted on the same day of the week. If a present endoscopic evidence of esophageal erosions, ulcer, patient was unable to attend the clinic one week, they came or any other significant upper GI pathology were excluded back on the same day the following week resulting in from participation. A rapid urease test by gastric biopsy to washout periods of 10, 17 or 24 days.
detect Helicobacter pylori was also performed at the time of An ambulatory 24-h intragastric pH recording was per- esophagogastroduodenoscopy. All other patients underwent a formed beginning on day 5 of each treatment period. A 13CO urea breath test (Meretek, Nashville, TN). Only patients calibrated microelectrode attached to a Medtronics Digitrap- who were H. pylori negative were eligible for enrollment.
per pH data logger (Medtronics, Minneapolis, MN) was Women of childbearing potential were required to use positioned 10 cm below the manometrically located lower acceptable birth control methods. Exclusion criteria were esophageal sphincter and used to evaluate intragastric pH pregnancy, lactation, any clinically significant abnormal every 4 s. Study drug was administered after probe place- laboratory values at entry, or a history of a clinically sig- ment on day 5 of each treatment period. All pH traces were nificant medical disease. In addition, patients were excluded blinded and assessed for evaluability by a single gastroen- from the trial if they smoked or consumed nicotine-contain- terologist, independent of the principal investigator.
ing products of any kind within 3 months before the first The primary pharmacodynamic endpoint of this study dose of study drug or during the study; if they consumed any was the amount of a 24-h period that intragastric pH was alcoholic beverage or an average of more than four cups of maintained above 4.0 by each of the study drugs on day 5 of coffee or caffeine-containing beverages per day within 1 wk treatment. Twenty-four hour mean pH on day 5 was deter- before the first dose of study drug or during the study; or if mined for each treatment group. The percentage of subjects they required chronic anti-inflammatory doses of aspirin who had more than 12 h of intragastric pH greater than 4.0 and/or nonsteroidal anti-inflammatory drugs. Patients were on day 5 was also determined.
also excluded if they had any history of drug or alcohol For the assessment of tolerability, all patients were en- dependence, multiple drug allergies, or other drug-associ- couraged to report adverse events spontaneously or in re- ated adverse events. Discontinuation of any previous PPI sponse to general questioning. Routine laboratory screening, therapy was required at least 10 days before randomization.
which included hematology, clinical chemistry, and urinal- No antisecretory drugs, including H -receptor antagonists ysis, was conducted at the screening visit and at the termi- (prescription strength), prokinetic drugs, or any other agents nation of the study and monitored for any clinically signif- known to alter the pharmacokinetics of PPIs were allowed icant changes.
during the study or within 2 wk before entry.
Pharmacodynamic analyses were performed for evaluable Each patient received either esomeprazole 40 mg, lansopra- patients who received all doses in each of the five treatment zole 30 mg, omeprazole 20 mg, pantoprazole 40 mg, or periods, and who, for each treatment phase, had at least 17 h rabeprazole 20 mg orally once daily, 30 min before a stan- of pH data within the reference range (⬎0.5 to ⬍10.0) and dardized breakfast for 5 consecutive days during each of the not more than one continuous hour outside of this range.
five treatment periods. Each dose of study drug was placed The percentage of time and number of hours (of the 24-h in an opaque envelope and given to the patient by a study interval) with a pH greater than 4.0 on day 5 were analyzed coordinator who observed emptying of the study drug into with a mixed model with effects for subject, period, and the patient's mouth and swallowing of the dose. Patients treatment, in which subject was a random effect. The least were prohibited from examining the study drugs. A stan- square mean and SEM for each treatment was directly dardized breakfast was provided to the patients 30 minutes calculated. Statistical comparisons were performed with following each dose of study drug and patients were dis- analysis of variance. A similar model was developed to missed from the clinic after they had been observed eating evaluate the percentage of subjects with intragastric pH the breakfast. A maximum of six tablets of Gelusil威 (Pfizer greater than 4.0 for more than 12 h. The OR for each pair of Inc., Canada) per day was permitted for heartburn rescue comparators was calculated, along with the 95% CIs. P therapy as needed, except after midnight on day 4 through values were determined with the ␹2 test. Similarly, for each the end of each treatment period. Patients were domiciled at comparison of mean 24-h intragastric pH between esome- the single investigational site during day 5, when 24-h prazole and other PPIs, the least square mean, SEM, 95% intragastric pH monitoring was conducted and standardized CIs, and p value were determined. A p value less than 0.05 meals provided. Each treatment period was separated by a was considered significant.
washout period of ⱖ10 days, during which no PPI was Safety assessments were recorded and tabulated for all taken. This was considered sufficient to avoid any carry- patients who received at least one dose of study drug.
over effects on either gastric acid production or hepaticenzyme activity from the previous drug. The treatment periods were based around a repeated two-week schedule It was estimated that 30 evaluable patients would be re- with the study drug being started and stopped, and the pH quired to provide 95% overall power to detect a difference Miner et al.
AJG – Vol. 98, No. 12, 2003 Table 1. Baseline Demographic and Clinical Characteristics
Table 2. The Mean Number of Hours of pH Data for Each Treat-
(Evaluable Cohort; N ⫽ 34) hour (three patients). Evaluable traces for all five PPIs were required for a patient to be considered in the efficacy anal- summarizes the baseline demographic and clin- ical characteristics of the 34 patients in the evaluable cohort.
Approximately three quarters of the patients were women, Body mass index (kg/m2) and the majority had a history of three or more episodes of heartburn per week during the 3 months before screening.
History of heartburn ⱖ3 times/wk Of the 136 washout periods (four for each patient), most during the last 3 mo, n (%) were 10 days (n ⫽ 113), although some were 17 (n ⫽ 20)or 24 (n ⫽ 3) days. Table 2 summarizes the mean numberof hours of evaluable pH data for each treatment group. Of of 12.4% between esomeprazole 40 mg once daily and any the 170 evaluable traces, although the protocol considered one of the other four PPI treatments, assuming the within- ⬎17 hours of data acceptable, only one trace contained less patient SD to be 10.5 and the significance level to be 0.05.
than 22 hours data. The mean number of hours of pH data The trial was designed to randomize 45 patients to compen- for each treatment group ranged between 23.75 and 23.86.
sate for an expected 33% dropout rate, or non-evaluable rate The mean number of hours for each treatment group that due to the complexity of trial methodology and stringent intragastric pH was greater than 4.0 on day 5 is shown in requirements for evaluability.
Treatment with esomeprazole provided signifi-pH greater than 4.0, compared with all other PPIs.
The percentage of time on day 5 that intragastric pH was Forty-five patients were randomized to form the intent-to- greater than 4.0 and the mean 24-h intragastric pH for each treat and safety cohorts. The first patient entered the study treatment group are shown in There was a statis- on December 4, 2001, and the last patient completed the tically significant difference between esomeprazole and all study on June 23, 2002. Eleven patients were excluded from of the other PPIs for the percentage of the 24-h period that the evaluable group. Two withdrew consent. Three discon- intragastric pH was greater than 4.0 and for mean pH.
tinued because of adverse events. In the remaining six The percentage of patients with intragastric pH greater patients, their pH measurements were not evaluable because than 4.0 for more than 12 h is presented in A of miscalibration (one patient), Digitrapper failure (one pa- significantly higher percentage of patients treated with es- tient), premature removal of the pH probe (one patient), or omeprazole had intragastric pH greater than 4.0 for more a pH outside the reference range for more than 1 continuous than 12 h relative to treatment with all other PPIs. Compar- Table 3. Percent Time (Least Square Mean) That Intragastric pH
Was 4.0 and Mean 24-Hr Intragastric pH on Day 5 by Treatment
Group (N ⫽ 34)
Esomeprazole 40 mg Rabeprazole 20 mg Lansoprazole 30 mg Pantoprazole 40 mg * p ⱕ 0.0001 for comparison of esomeprazole versus lansoprazole, omeprazole, andpantoprazole; p ⫽ 0.001 for comparison between esomeprazole and rabeprazole.
Figure 1. Mean number of hours on day 5 that intragastric pH was
p ⬍ 0.0001 for comparison of esomeprazole versus lansoprazole, omeprazole, ⬎4.0 by treatment group (N ⫽ 34).
and pantoprazole; p ⫽ 0.003 for comparison between esomeprazole and rabeprazole.
AJG – December, 2003 Crossover Study with PPIs
Until now, it has been difficult to compare the pharma- codynamic properties of each of these five PPIs directlybecause previous trial designs involved a single comparator.
The five-way crossover study that we performed providedan opportunity for a direct comparison between PPIs. Theseresults support those from the single-comparator studies,which showed that esomeprazole 40 mg provided moreeffective control of gastric acid than omeprazole 40 mg ondays 1 and 5, as measured by the mean percentage of a 24-hperiod that intragastric pH was greater than 4.0 In otherstudies using single comparators, standard-dose esomepra- Figure 2. Percent of subjects with intragastric pH ⬎4.0 for ⬎12
zole maintained intragastric pH greater than 4.0 for a longer hours (N ⫽ 34).
percentage of a 24-h period at day 5 than did standard dosesof lansoprazole, pantoprazole, or rabeprazole isons between the other pairs of PPIs did not reach statistical In our study, esomeprazole maintained intragastric pH significance; all showed efficacy comparable to each other greater than 4.0 on day 5 for 58.4% of the 24-h period. In for this parameter.
other studies, the percentage of a 24-h interval that intra- The number and frequency of adverse events, serious gastric pH was greater than 4.0 after 5 days of esomeprazole adverse events, and discontinuations due to adverse events ranged between 57.7% and 69.8% . Although this are presented in There were four serious adverse narrow range might in part be attributable to less interpatient events, none considered treatment-related, but two resulted variability, as assessed by the area under the plasma con- in study withdrawal. A third patient withdrew because of a centration–time curve with esomeprazole compared with nonserious adverse event (nausea). The types of adverse omeprazole it also emphasizes the importance of head- events that were observed were similar to those previously to-head comparisons within one and the same study.
reported and most frequently included headache, nausea, There are limitations to this study. Although an open- diarrhea, flatulence, or abdominal pain.
label design is standard practice for pH studies, this com-parative crossover study would ideally have a double-blindmethodology. However, introducing a double-blind design would have required over-encapsulation, which could affect All five PPIs investigated in our study provided gastric acid dissolution, bioavailability and other pharmacokinetic pa- suppression (pH⬎4) for at least 10 hours in a 24 hour rameters of the study drugs. We did adopt a "masked dos- period. Esomeprazole (40 mg once daily) provided an in- ing" technique that ensured patients were blinded to the tragastric pH greater than 4.0 for a significantly greater study drug they took on any particular occasion.
amount of a 24-h period at steady state (day 5) compared Although our study did not investigate the effect of the with standard-dose lansoprazole, omeprazole, pantoprazole, five PPIs on any clinical endpoints, small studies with ci- or rabeprazole in patients with symptoms of gastroesopha- metidine and/or omeprazole have correlated duration and geal reflux disease. Similarly, the percentage of patients degree of esophageal acid exposure with clinical endpoints with an intragastric pH greater than 4.0 for more than 12 h such as healing of esophageal erosions Other was significantly greater with esomeprazole relative to the authors have also suggested that a clear relationship exists other PPIs. Although the study was not specifically designed between the degree of esophageal acid exposure and healing to detect differences in this parameter between the other of erosive esophagitis The more effective gastric pairs of PPIs, no statistical differences were found. For all efficacy endpoints, the results were numerically lowest with might contribute to its improved clinical efficacy compared pantoprazole, although statistically the differences were with other PPIs. In well-designed clinical trials, esomepra- only significant compared with esomeprazole.
zole 40 mg once daily produced significantly higher rates of Table 4. Adverse Events and Discontinuations Because of Adverse Events
Treatment-related AE Discontinuation of study treatment Data are presented as n (%). AE ⫽ adverse events.
Miner et al.
AJG – Vol. 98, No. 12, 2003 healing and symptom resolution in patients with erosive 4. Katz PO, Hatlebakk JG, Castell DO. Gastric acidity and acid esophagitis relative to lansoprazole 30 mg or omeprazole 20 breakthrough with twice-daily omeprazole or lansoprazole.
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8. Lind T, Rydberg L, Kyleback A, et al. Esomeprazole provides improved acid control vs omeprazole in patients with symp-toms of gastro-oesophageal reflux disease. Aliment Pharmacol 9. Katz PO, Castell DO, Chen Y, et al. Esomeprazole 40 mg The authors would like to acknowledge Christopher Rains, twice daily maintains intragastric pH ⬎ 4 for more than 80% Karen van Hoeven, and Caroline Spencer for their assis- of a 24-hour time period. Am J Gastroenterol 2002;97:S20 –1.
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Reprint requests and correspondence: Philip Miner, Jr., M.D.,
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Tropical Medicine and International Health Evaluation of the SPf66 vaccine for malaria control whendelivered through the EPI scheme in Tanzania C. J. Acosta1,2, C. M. Galindo1,2, D. Schellenberg1,2, J. J. Aponte1, E. Kahigwa3, H. Urassa2, J. R. M. ArmstrongSchellenberg2,5, H. Masanja2, R. Hayes6, A. Y. Kitua2,4, F. Lwilla7, H. Mshinda2, C. Menendez1, M. Tanner5 andP. L. Alonso1