Erosive Esophagitis: Rabeprazole vs Esomeprazole
Background Current PPIs may not achieve desired outcomes in some GERD patients due to limited duration of acid inhibition.
Aim To evaluate a novel rabeprazole extended release (ER), which provides longer duration of drug exposure and acid suppression, in healing and symptomatic resolution of moderate-severe erosive oesophagitis.
Methods Patients with LA grade C or D oesophagitis were randomised to rabeprazole-ER 50 mg or esomeprazole 40 mg once daily in two identical 8-week double-blind trials (N = 2130). Two primary endpoints were tested sequentially: (1) healing by 8 weeks [hypothesis: rabeprazole-ER non-inferior to esomeprazole (non-inferiority margin = 8%)], (2) healing by 4 weeks [hypothesis: rabeprazole-ER superior to esomeprazole (P < 0.05)]. The secondary endpoint was sustained heartburn resolution at 4 weeks.
Results Rabeprazole-ER was non-inferior to esomeprazole in week-8 healing (80.0% vs. 75.0%; 77.5% vs. 78.4%). Week-4 healing (54.8% vs. 50.3%; 50.9% vs. 50.7%) and sustained heartburn resolution (48.3% vs. 48.2%; 53.2% vs. 52.5%) were not significantly different. Post hoc combined results for grade D revealed rabeprazole-ER vs. esomeprazole differences in week-8 healing = 10.4% (95% CI: –1.4%, 22.2%) and week-4 healing = 12.0% (P = 0.048).
Conclusions Rabeprazole-ER is as effective as esomeprazole in healing moderate-severe oesophagitis and achieves similar rates of heartburn resolution. Subgroup analysis suggests the possibility of benefit in severe oesophagitis, but this requires further evaluation.
Proton pump inhibitors (PPIs) provide healing of erosive oesophagitis and relief of symptoms in most patients with gastro-oesophageal reflux disease (GERD). However, a sizable minority of patients have persistent erosions and/or symptoms despite PPI therapy. Patients with more severe erosive oesophagitis [e.g. Los Angeles (LA) grade C-D] have lower rates of healing than those with milder oesophagitis (LA grade A-B) when given the same dose of a PPI, with differences up to ~25%.
Increasing severity of erosive oesophagitis is associated with a longer duration of oesophageal acid exposure, and intragastric acid suppression, assessed as proportion of a 24-h period gastric pH >4.0, is positively correlated with healing of erosive oesophagitis. These data suggest that a longer duration of acid suppression may provide greater efficacy in healing of erosive oesophagitis especially in patients with more severe disease. However, it remains uncertain if there is a threshold beyond which further acid suppression will not further improve healing rates. The relief of GERD symptoms is not as clearly associated with the duration of acid suppression and hence the benefit of increasing the duration of acid suppression on relief of GERD symptoms remains uncertain.
A new extended-release formulation of rabeprazole was developed to provide longer duration of acid suppression with the goal of improving the efficacy of GERD therapy, especially in patients with more severe oesophagitis. Each rabeprazole-extended release (rabeprazole-ER) 50 mg capsule contains a single 10 mg enteric-coated tablet and four identical 10 mg pulsatile release tablets. The enteric-coated tablet is designed to release rabeprazole in the proximal small intestine and the pulsatile release tablets to release the drug in the distal small intestine and the colon in a non-pH-dependent manner. Rabeprazole-ER 50 mg provides prolonged plasma concentration without increased peak concentration as compared with the currently available rabeprazole delayed-release 20 mg. In a pharmacodynamic study in healthy volunteers, a rabeprazole-ER 50 mg prototype formulation once daily for 5 days showed a mean time gastric pH >4.0 during a 24-h period of 79% compared with 66% for esomeprazole 40 mg and 63% for rabeprazole delayed-release 20 mg. These differences were driven mainly by the effect during the nighttime period (10 pm–8 am), when rabeprazole-ER 50 mg showed gastric pH >4.0 for 63% of the nighttime vs. 33% in the esomeprazole 40 mg group and 34% in the rabeprazole delayed-release 20 mg group.
Two phase 3 studies were designed to evaluate the efficacy and safety of rabeprazole-ER 50 mg in patients with moderate-to-severe erosive oesophagitis (defined as LA grade C or D) and to determine if longer duration of acid suppression with rabeprazole-ER 50 mg would translate into improved healing in patients with moderate-to-severe erosive oesophagitis when compared with esomeprazole 40 mg.
Abstract and Introduction
Abstract
Background Current PPIs may not achieve desired outcomes in some GERD patients due to limited duration of acid inhibition.
Aim To evaluate a novel rabeprazole extended release (ER), which provides longer duration of drug exposure and acid suppression, in healing and symptomatic resolution of moderate-severe erosive oesophagitis.
Methods Patients with LA grade C or D oesophagitis were randomised to rabeprazole-ER 50 mg or esomeprazole 40 mg once daily in two identical 8-week double-blind trials (N = 2130). Two primary endpoints were tested sequentially: (1) healing by 8 weeks [hypothesis: rabeprazole-ER non-inferior to esomeprazole (non-inferiority margin = 8%)], (2) healing by 4 weeks [hypothesis: rabeprazole-ER superior to esomeprazole (P < 0.05)]. The secondary endpoint was sustained heartburn resolution at 4 weeks.
Results Rabeprazole-ER was non-inferior to esomeprazole in week-8 healing (80.0% vs. 75.0%; 77.5% vs. 78.4%). Week-4 healing (54.8% vs. 50.3%; 50.9% vs. 50.7%) and sustained heartburn resolution (48.3% vs. 48.2%; 53.2% vs. 52.5%) were not significantly different. Post hoc combined results for grade D revealed rabeprazole-ER vs. esomeprazole differences in week-8 healing = 10.4% (95% CI: –1.4%, 22.2%) and week-4 healing = 12.0% (P = 0.048).
Conclusions Rabeprazole-ER is as effective as esomeprazole in healing moderate-severe oesophagitis and achieves similar rates of heartburn resolution. Subgroup analysis suggests the possibility of benefit in severe oesophagitis, but this requires further evaluation.
Introduction
Proton pump inhibitors (PPIs) provide healing of erosive oesophagitis and relief of symptoms in most patients with gastro-oesophageal reflux disease (GERD). However, a sizable minority of patients have persistent erosions and/or symptoms despite PPI therapy. Patients with more severe erosive oesophagitis [e.g. Los Angeles (LA) grade C-D] have lower rates of healing than those with milder oesophagitis (LA grade A-B) when given the same dose of a PPI, with differences up to ~25%.
Increasing severity of erosive oesophagitis is associated with a longer duration of oesophageal acid exposure, and intragastric acid suppression, assessed as proportion of a 24-h period gastric pH >4.0, is positively correlated with healing of erosive oesophagitis. These data suggest that a longer duration of acid suppression may provide greater efficacy in healing of erosive oesophagitis especially in patients with more severe disease. However, it remains uncertain if there is a threshold beyond which further acid suppression will not further improve healing rates. The relief of GERD symptoms is not as clearly associated with the duration of acid suppression and hence the benefit of increasing the duration of acid suppression on relief of GERD symptoms remains uncertain.
A new extended-release formulation of rabeprazole was developed to provide longer duration of acid suppression with the goal of improving the efficacy of GERD therapy, especially in patients with more severe oesophagitis. Each rabeprazole-extended release (rabeprazole-ER) 50 mg capsule contains a single 10 mg enteric-coated tablet and four identical 10 mg pulsatile release tablets. The enteric-coated tablet is designed to release rabeprazole in the proximal small intestine and the pulsatile release tablets to release the drug in the distal small intestine and the colon in a non-pH-dependent manner. Rabeprazole-ER 50 mg provides prolonged plasma concentration without increased peak concentration as compared with the currently available rabeprazole delayed-release 20 mg. In a pharmacodynamic study in healthy volunteers, a rabeprazole-ER 50 mg prototype formulation once daily for 5 days showed a mean time gastric pH >4.0 during a 24-h period of 79% compared with 66% for esomeprazole 40 mg and 63% for rabeprazole delayed-release 20 mg. These differences were driven mainly by the effect during the nighttime period (10 pm–8 am), when rabeprazole-ER 50 mg showed gastric pH >4.0 for 63% of the nighttime vs. 33% in the esomeprazole 40 mg group and 34% in the rabeprazole delayed-release 20 mg group.
Two phase 3 studies were designed to evaluate the efficacy and safety of rabeprazole-ER 50 mg in patients with moderate-to-severe erosive oesophagitis (defined as LA grade C or D) and to determine if longer duration of acid suppression with rabeprazole-ER 50 mg would translate into improved healing in patients with moderate-to-severe erosive oesophagitis when compared with esomeprazole 40 mg.
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