SUMMARY
ASTRAZENECA PHARMACEUTICALS
FINISHED PRODUCT: Nexium™
Development Phase: I
First Subject Recruited: 15 February 2006
Last Subject Completed: 19 July 2006
Approval Date: 01 December 2006
Trial Title: An Open, Single-Centre, Randomized, 6-way Crossover, Dose-Response Comparative Study of Esomeprazole 20, 40 and 80 mg and Pantoprazole 20, 40 and 80 mg regarding 24-hour Intragastric pH following 5 Days Repeated Oral Dose Administration in Patients with Symptoms of Gastroesophageal Reflux Disease.
OBJECTIVES:
The primary objective of this study was to investigate the dose-response relationship of esomeprazole and pantoprazole following repeated once daily (od) administration of 20, 40 and 80 mg esomeprazole and 20, 40 and 80 mg pantoprazole in patients with symptoms of Gastroesophageal Reflux Disease (GERD), by assessment of the percentage of time with intragastric pH>4 over the 24-hour period on study day 5.
The secondary objectives were:
1. To compare 20, 40 and 80 mg esomeprazole versus 20, 40 and 80 mg pantoprazole following repeated od administration in patients with symptoms of GERD, by assessment of the percentage of time with intragastric pH>4 over the 24-hour period, the 24-hour median pH and the area under the H+ versus time curve on study day 5.
2. To investigate the dose-response relationship of esomeprazole and pantoprazole following repeated od administration of 20, 40 and 80 mg esomeprazole and 20, 40 and 80 mg pantoprazole in patients with symptoms of GERD, by assessment of the 24-hour median pH and the area under the H+ versus time curve on study day 5.
3. To evaluate safety and tolerability of esomeprazole 20, 40 and 80 mg.
METHODS
Study design
The study was conducted as a single-centre, open, randomized, 6-way crossover study in which patients with symptoms of GERD received 20, 40 or 80 mg esomeprazole or 20, 40 or 80 mg pantoprazole od for 5 days.
Target patient population and sample size
Thirty-nine (39) male and female patients with symptoms of GERD, with a minimum of 30% of either gender, were included in the study in order for at least 30 patients to complete the study.
With 30 evaluable patients, a two-sided 95% confidence interval (CI) for the difference in percentage of time with pH>4 between two doses, was to extend no more than 6.5% points from the observed mean difference, with 80% probability, assuming that the true standard deviation for the difference was 15.6% points. This assumption was based on data from previous studies.
Investigational products: dosage, mode of administration and batch numbers
Esomeprazole 20 mg capsules (batch number: H1189-04-01-09) and 40 mg capsules (batch number: H1222-04-01-15) given orally od for 5 days.
Esomeprazole 80 mg, given as two 40 mg capsules (batch number: H1222-04-01-15) orally od for 5 days.
Pantoprazole 20 mg tablets (batch number: H1560-01-02-01) and 40 mg tablets (batch number: H1131-04-02-01) given orally od for 5 days.
Pantoprazole 80 mg, given as two 40 mg tablets (batch number: H1131-04-02-01) orally od for 5 days.
Duration of treatment
Six (6) treatment periods of 5 days each. Each treatment period was separated by a wash-out period of at least 13 days.
Variables
The percentage of time with intragastric pH>4 during the 24-hour period (primary variable), the 24-hour median intragastric pH and the area under the H+ versus time curve.
Adverse events, laboratory variables, blood pressure (BP), pulse and electrocardiogram (ECG).
Statistical methods
Consecutive doses of esomeprazole and pantoprazole respectively were compared regarding the percentage of time with intragastric pH>4, the 24-hour median pH and the area under the H+ versus time curve during the 24-hour period following drug administration on day 5. A mixed model ANOVA (Analysis of variance) with fixed effects for period, sequence and treatment and a random effect for patient within sequence was used. The mean for each treatment and the mean difference between treatments (esomeprazole 40 mg vs. esomeprazole 20 mg, esomeprazole 80 mg vs. esomeprazole 40 mg, pantoprazole 40 mg vs. pantoprazole 20 mg and pantoprazole 80 mg vs. pantoprazole 40 mg) were estimated and stated with symmetric 95% CIs and p-values.
The same ANOVA model as above was used to compare esomeprazole vs. pantoprazole regarding the percentage of time with intragastric pH>4, the 24-hour median pH and the area under the H+ versus time curve during the 24-hour period following drug administration on day 5. The mean for each treatment and the mean difference between treatments (esomeprazole 20 mg vs. pantoprazole 20 mg, esomeprazole 20 mg vs. pantoprazole 40 mg, esomeprazole 40 mg vs. pantoprazole 40 mg, esomeprazole 40 mg vs. pantoprazole 80 mg and esomeprazole 80 mg vs. pantoprazole 80 mg) were estimated and stated with symmetric 95% CIs. The p-value for each treatment comparison was calculated.
Adverse events (AEs), laboratory variables, BP, pulse and ECG are presented descriptively.
A Per Protocol approach was used for the statistical analysis.
Analysis and evaluation of safety variables were done in the safety population, defined as all patients who received at least one dose of randomized treatment with the investigational product and for whom post-dose data are available.
Patient population
In total, 53 patients from a single centre were enrolled into the study, of whom 39 were randomized (22 males and 17 females). Thirty-six (36) patients, 21 males and 15 females, completed the study. Forty (40) patients were planned to be included in the study in order to have 30 evaluable patients completing the study. However, 42 patients came for the baseline testing, of whom 3 dropped out on the baseline day. Therefore, a total of 39 patients were randomized into the study. Enough patients completed the study to fulfill the aim of 30 patients completing the study, as defined in the Clinical Study Protocol (CSP).
One (1) patient discontinued participation in the study due to AE (urticaria) in the wash-out period after treatment period 2. Two (2) patients discontinued the study after treatment periods 1 and 4, respectively, with the reason “not willing to continue”. These patients are included in the statistical analysis where data from two comparing study periods are available.
Thirty-nine (39) patients are included in the safety analysis.
Table S1 gives descriptive statistics of the demographic data for the patients included in the safety population. All randomized patients were Caucasians.
RESULTS:
Summary of pharmacodynamic results
Increasing doses from 20 mg to 40 mg and from 40 mg to 80 mg of both esomeprazole and pantoprazole provided significantly increased acid control in terms of percentage of time with intragastric pH>4 over the 24-hour period (Table S2 and Table S3).
Esomeprazole 20 mg was shown to provide significantly greater acid control than both pantoprazole 20 mg and 40 mg, and esomeprazole 40 mg provided significantly greater acid control than both pantoprazole 40 mg and 80 mg. Also, esomeprazole 80 mg provided a significantly longer time with intragastric pH>4 than pantoprazole 80 mg (Table S4).
The 24-hour median pH and the area under the H+ versus time curve showed a similar pattern of effect to that for the percentage of time with intragastric pH>4, regarding the comparisons both within each drug and between the drugs.
Summary of safety results
The occurrence of AEs was similar in the different treatment groups. There were no serious adverse events (SAEs) and all pregnancy tests were negative. There was no discontinuation of investigational product due to AE but one patient discontinued participation in the study due to an AE (urticaria) in a wash-out period. No patients had any clinically significant laboratory abnormalities and there were no clinically significant changes in laboratory values or vital signs.
No safety concerns were raised in the study.
As with any comprehensive clinical trial programme, individual studies may include both approved and non-approved treatment regimens, including doses higher than those approved for clinical use. Before prescribing Nexium™ (esomeprazole), Healthcare Professionals should view their specific country information.