Clinical trials: healing of erosive oesophagitis with dexlansoprazole MR, a proton pump inhibitor with a novel dual delayed-release formulation – results from two randomized controlled studies

Authors


Dr P. Sharma, Division of Gastroenterology and Hepatology, Department of Medicine, University of Kansas School of Medicine, 3901 Rainbow Blvd, 4035 Delp Bldg, Mail Stop 1023, Kansas City, KS 66160, USA.
E-mail: psharma@kumc.edu

Summary

Background  Dexlansoprazole MR employs a dual delayed-release delivery system that extends drug exposure and prolongs pH control compared with lansoprazole.

Aim  To assess the efficacy and safety of dexlansoprazole MR in healing erosive oesophagitis (EO).

Methods  Patients in two identical double-blind, randomized controlled trials (n = 4092) received dexlansoprazole MR 60 or 90 mg or lansoprazole 30 mg once daily. Week 8 healing was assessed using a closed testing procedure – first for non-inferiority, then superiority, vs. lansoprazole. Secondary endpoints included week 4 healing and week 8 healing in patients with moderate-to-severe disease (Los Angeles Classification grades C and D). Life-table and crude rate analyses were performed. Symptoms and tolerability were assessed.

Results  Dexlansoprazole MR achieved non-inferiority to lansoprazole, allowing testing for superiority. Using life-table analysis, dexlansoprazole MR healed 92–95% of patients in individual studies vs. 86–92% for lansoprazole; the differences were not statistically significant (> 0.025). Using crude rate analysis, dexlansoprazole MR 90 mg was superior to lansoprazole in both studies and 60 mg was superior in one study. Week 4 healing was >64% with all treatments in both studies. In an integrated analysis of 8-week healing in patients with moderate-to-severe EO, dexlansoprazole MR 90 mg was superior to lansoprazole. All treatments effectively relieved symptoms and were well tolerated.

Conclusion  Dexlansoprazole MR is highly effective in healing EO and offers benefits over lansoprazole, particularly in moderate-to-severe disease.

Introduction

Proton pump inhibitors (PPIs) are widely recognized as being the most effective treatments for healing erosive oesophagitis (EO) and have become the mainstay of pharmacological therapy for acid-related disorders.1, 2 Despite the widespread use of PPIs as first-line therapy for acid-related disorders, about 30% of patients with gastro-oesophageal reflux disease (GERD) fail to obtain complete healing and/or symptom resolution after a standard course of conventional PPI therapy.3, 4 GERD affects up to 20% of adults in the US5 and about one-third of GERD patients have EO.6–8 Epidemiological data assessing the percentage of EO patients with severe disease are sparse; however, the ProGERD (Progression of GERD) study, which evaluated a cohort of 3245 EO patients in Europe, estimated that 19% of patients with EO have Los Angeles (LA) grades C or D disease.9 Suboptimal healing rates have been reported in this subgroup of patients following 8 weeks of therapy.10, 11

Failure to control effectively acid reflux in patients with EO has also been associated with increased morbidity and complications, such as oesophageal strictures, bleeding and development of Barrett’s oesophagus with or without dysplasia.1, 12, 13 These findings underscore the need for once-daily medications that can offer a longer duration of acid inhibition, which may effectively control symptoms and heal EO, especially in patients with more severe disease.

Dexlansoprazole MR is a novel modified release formulation of dexlansoprazole, an enantiomer of lansoprazole.14 Dexlansoprazole MR employs an innovative Dual Delayed Release (DDR) technology designed to prolong the plasma concentration–time profile of dexlansoprazole and extend the duration of acid suppression. This technology uses granules with different pH-dependent dissolution profiles designed to optimize drug release initially in the proximal small intestine and then in the distal region of the small intestine several hours later. To prolong drug exposure with a single daily dose, dexlansoprazole MR incorporates higher doses than conventional PPIs.

In a phase 1 pharmacokinetic/pharmacodynamic study of once-daily dexlansoprazole MR 60, 90 and 120 mg,15 the pharmacokinetic profile was characterized by a plasma concentration-time curve with two distinct peaks compared with a single peak with lansoprazole. Dexlansoprazole MR prolonged plasma drug levels as evidenced by a delayed time to maximum drug concentration (Cmax) and substantially higher plasma concentrations during the 3- to 8-h postdose period, without a commensurate overall increase in mean Cmax. Dexlansoprazole MR 60 and 90 mg once daily also produced significant increases in the percentage of time with intragastric pH >4 over 24-h postdose compared with lansoprazole 30 mg once daily (∼70% for dexlansoprazole MR vs. 60% for lansoprazole, < 0.05). As no additional pharmacodynamic benefit was seen for the 120-mg dose, dexlansoprazole MR 60 and 90 mg were investigated for treatment of EO.

The objective of these phase 3 trials was to assess the efficacy and safety of dexlansoprazole MR 60 and 90 mg once daily compared with lansoprazole 30 mg once daily in the healing of patients with EO.

Materials and methods

Patient selection and study design

Adult patients (aged ≥18 years) with endoscopically confirmed EO at screening were eligible to enrol in one of two identically designed 8-week, double-blind, active-controlled, three-armed studies conducted at 188 US centres and 118 non-US centres (http://ClinicalTrials.gov identifiers NCT00251693 and NCT00251719). Patients were required to discontinue use of prescription and nonprescription PPIs during screening and throughout the study. The screening period was up to 21 days. The mean and median screening time was 15 days. Endoscopy was performed by qualified endoscopists to evaluate the presence and severity of EO based on LA Classification grades A–D during the screening period, at the week 4 visit and at the week 8 or final visit (if not healed by week 4). Stratified enrolment ensured that a subgroup of patients with more severe EO (LA grade C and D) would comprise approximately 30% of the study group.

Both studies were conducted in compliance with Institutional Review Board/Ethics Committee regulations and within the ethical principles stated in the 1989 Declaration of Helsinki. All patients voluntarily signed an informed consent form in the region in which the patient was participating and completed any Health Insurance Portability and Accountability Act authorization forms (US sites only) before any study-related procedure was initiated.

Major exclusion criteria included patients who tested positive for Helicobacter pylori based on the result of the CLOtest (urease test; Kimberly-Clark, Roswell, GA, USA), which was mandatory in all countries outside North America and was performed in the US and Canada only for patients with EO who tested H. pylori positive by finger stick or serology at screening, women who were pregnant or lactating and patients who needed to use prescription or nonprescription PPIs or histamine2-receptor antagonists during screening and throughout the study. Patients also were excluded if they used nonsteroidal anti-inflammatory drugs chronically (>12 doses/month); had coexisting diseases that affected the oesophagus, including Barrett’s oesophagus with or without dysplastic changes, Zollinger–Ellison syndrome, oesophageal strictures or a history of dilatation of oesophageal strictures other than a Schatzki’s ring; had either a history of or active gastric or duodenal ulcers within 4 weeks of the first dose of study drug or had acute upper gastrointestinal haemorrhage within 4 weeks of the screening endoscopy. There was no restriction on body mass index at study entry.

Eligible patients were randomized to one of three treatment groups: dexlansoprazole MR 60 or 90 mg or lansoprazole 30 mg. Study drug was administered once daily in the morning before breakfast to comply with the dosing recommendations for lansoprazole. Lansoprazole was chosen as the comparator because dexlansoprazole is an enantiomer of lansoprazole and 30 mg is the approved labelled dose for the healing of EO. Pill counts were performed by study site staff at each visit to assess compliance. Patients were allowed to take up to six tablets of Gelusil (US sites, Pfizer Inc., New York, NY, USA) or an equivalent antacid (non-US sites) in a 24-h period as rescue medication.

Efficacy endpoints

The primary efficacy endpoint was the percentage of patients who had complete healing of EO over 8 weeks as assessed by endoscopy. Secondary efficacy endpoints included (i) the percentage of patients who had complete healing of EO over 4 weeks as assessed by endoscopy and (ii) the percentage of patients with baseline EO grade C or D who had complete healing of EO over 8 weeks as assessed by endoscopy. The following additional efficacy variables were assessed: percentage of days with neither daytime nor nighttime heartburn (24-h heartburn-free days), percentage of days (awake time) without daytime heartburn and percentage of nights (sleep time) without heartburn during treatment as assessed by patient’s daily diary; mean severity of heartburn; the percentage of patients who achieved sustained resolution of heartburn (7 consecutive heartburn-free days); percentage of days without rescue medication use as assessed by patient’s diary; and severity of GERD symptoms as assessed by the investigator.

Efficacy and symptom assessment

Efficacy was assessed via endoscopy and patient responses in daily diaries where the presence and maximum severity of daytime and nighttime heartburn, as well as their use of rescue medication were recorded. Heartburn severity was rated using a five-point scale (none, mild, moderate, severe or very severe). Investigators also assessed symptoms (heartburn, acid regurgitation, dysphagia, belching and epigastric pain) using a five-point severity scale during the screening period (on study day −1) and at the week 4 and 8 visits during the treatment period. Similar five-point scales for patient- and investigator-reported symptom severity, although not validated, have been used previously in GERD studies.16–18

Safety and tolerability assessments

Safety was assessed by analysis of physical examinations, vital signs and clinical laboratory tests, including routine laboratory evaluations (haematology, chemistry and urinalysis), fasting serum gastrin results and reported adverse events. All adverse events, whether in response to a query, observed by site personnel or reported spontaneously by the patient, were documented on standardized forms. A treatment-emergent adverse event was defined as an adverse event representing a change from baseline that occurred between the first day of study drug and 30 days after the last dose. The investigator assessed and recorded any adverse event in detail. Investigators evaluated event severity, aetiology, actions taken, if any, and any relationship to study drug.

Statistical analyses

For the primary and secondary efficacy endpoints, analysis using life table as the primary analysis method and crude rates as the additional analysis method were prespecified in the protocol. Crude rate is calculated as a simple proportion of patients whose EO was healed, whereas the life-table method also accounts for the time taken to heal and differs from crude rate analysis in the handling of censored data. Crude rate estimates are more conservative than the life-table estimates and tend to report lower healing rates from the same data.

Assessment of the primary and secondary efficacy endpoints was accomplished through a closed testing procedure by first testing for non-inferiority of the two dexlansoprazole MR doses to lansoprazole 30 mg for the primary efficacy endpoint (week 8 healing rates). Non-inferiority was declared if the lower bounds of the 95% confidence intervals of the differences in healing rates between dexlansoprazole MR doses and lansoprazole at week 8 were greater than −10%. The dexlansoprazole MR doses that were shown to be non-inferior were then tested for superiority to lansoprazole 30 mg for the primary and secondary efficacy endpoints. The multiplicities of the treatment comparisons were controlled by Hochberg’s method in addition to the Hommel–Simes method for the multiplicities of the two secondary efficacy endpoints within a treatment group.

All efficacy analyses were performed on the intent-to-treat (ITT) population, defined as all patients who had documented EO at the screening endoscopy, were randomized and received at least one dose of study drug. For the life-table analysis, ITT patients who did not have any postbaseline endoscopy data were included as censored data. Healing rates were calculated using life-table method considering two intervals. Pairwise treatment comparisons were performed using log-rank tests based on actual day of endoscopy rather than intervals.

For the crude rate analysis, ITT patients who had at least one postbaseline endoscopy within 7 days of the last dose of study drug were included. Patients who were healed at week 4 were considered healed at the week 8 crude rate analysis. Crude healing rates were calculated by dividing the number of healed patients by the total number of ITT patients included in the analysis. Pairwise treatment comparisons were performed using Cochran–Mantel–Haenszel (CMH) tests, with baseline EO grades as strata (LA classification).

For each study, a sample size of 520 patients per group would provide at least 95% power at the 0.025 level of significance to meet the non-inferiority criteria between a dexlansoprazole MR group and lansoprazole 30 mg, assuming equal EO healing rates (87%) at week 8. This sample size would also provide at least 80% power at the 0.025 level of significance to detect a 6% difference for superiority between a dexlansoprazole MR dose (93%) and lansoprazole 30 mg (87%) in the EO healing rates at week 8. The lansoprazole healing rate was estimated from previous lansoprazole studies.19, 20 The enrolment of nearly 30% of patients with moderate-to-severe EO was intended to gather more data in this important subset of patients.

The presence and severity of heartburn and use of rescue medication were analysed from diary data and summarized by treatment group. Comparisons between treatment groups were made using Wilcoxon rank-sum tests. For investigator-assessed GERD symptoms, comparisons between treatment groups were made using a CMH test for ordered responses with baseline severity as strata.

Results

Patient characteristics

Study 1 was conducted from 2 December 2005 to 30 January 2007 and study 2 was conducted from 16 December 2005 to 22 January 2007. A total of 4092 patients were enrolled in the two studies: 2038 in study 1 and 2054 in study 2 (Figure 1). There were no statistically significant differences between randomized treatment groups for any baseline demographic characteristic (Table 1). Study drug compliance was >97% for each treatment in both studies.

Figure 1.

 Diagram of trial randomization and completion for studies 1 and 2. q.d.s., once daily.

Table 1.   Baseline demographics (intent-to-treat population)
VariableStudy 1Study 2
DEX MR 60 mg q.d.s. (n = 680)DEX MR 90 mg q.d.s. (n = 668)LAN 30 mg q.d.s. (n = 690)DEX MR 60 mg q.d.s. (n = 694)DEX MR 90 mg q.d.s. (n = 687)LAN 30 mg q.d.s. (n = 673)
  1. All baseline demographics  0.05.

  2. BMI, body mass index; DEX MR, dexlansoprazole MR; EO, erosive oesophagitis; LA, Los Angeles; LAN, lansoprazole; q.d.s., once daily; s.d., standard deviation.

  3. * These evaluations were performed outside the prescribed screening window.

Gender, n (%)
 Men380 (55.9)366 (54.8)365 (52.9)377 (54.3)352 (51.2)362 (53.8)
Race, n (%)
 White602 (88.5)580 (86.8)601 (87.1)598 (86.2)588 (85.6)584 (86.8)
Age (years)
 Mean ± s.d.47.8 ± 13.7147.3 ± 13.9347.3 ± 13.7448.7 ± 13.5347.7 ± 13.8047.3 ± 13.65
 Minimum–maximum18–8418–8518–8720–8519–9018–85
BMI (kg/m2), n (%)
 ≥30287 (42.2)277 (41.5)277 (40.1)289 (41.6)266 (38.7)288 (42.8)
Baseline LA grade of EO, n (%)
 A236 (34.7)242 (36.2)231 (33.5)234 (33.7)271 (39.4)222 (33.0)
 B247 (36.3)233 (34.9)248 (35.9)257 (37.0)221 (32.2)257 (38.2)
 C163 (24.0)148 (22.2)170 (24.6)156 (22.5)152 (22.1)150 (22.3)
 D33 (4.9)45 (6.7)40 (5.8)46 (6.6)42 (6.1)44 (6.5)
 Not available*1 (0.1)01 (0.1)1 (0.1)1 (0.1)0

Healing

Dexlansoprazole MR 60 and 90 mg achieved non-inferiority to lansoprazole in both studies, allowing further testing for superiority. Both doses produced consistently higher week 8 healing rates than lansoprazole 30 mg in both studies (Table 2). Using life-table analysis, dexlansoprazole MR healed 92–95% of patients in the individual studies vs. 86–92% for lansoprazole; the differences did not reach statistical significance (> 0.025). For the more conservative crude rate analysis, both dexlansoprazole MR 60 mg (= 0.004) and 90 mg (= 0.001) provided significantly higher healing rates at week 8 than lansoprazole 30 mg in study 1, with therapeutic gains (difference in healing rates) of 6 and 7 percentage points respectively. Dexlansoprazole MR 90 mg (= 0.019) also provided a significantly higher crude healing rate at week 8 than lansoprazole 30 mg in study 2 with a therapeutic gain of 5 percentage points.

Table 2.   Percentage of patients with complete erosive oesophagitis healing at week 8 (intent-to-treat population)
Week 8 healing rate (%) (95% CI), nStudy 1Study 2
DEX MR 60 mg q.d.s.DEX MR 90 mg q.d.s.LAN 30 mg q.d.s.DEX MR 60 mg q.d.s.DEX MR 90 mg q.d.s.LAN 30 mg q.d.s.
  1. DEX MR, dexlansoprazole MR; LAN, lansoprazole; q.d.s, once daily.

  2. < 0.05 vs. lansoprazole 30 mg after adjusting for multiplicity.

Life-table analysis92.3 (90.0–94.7), 67392.2 (89.8–94.6), 66586.1 (83.0–89.2), 68493.1 (90.9–95.3), 68594.9 (92.9–96.8), 68091.5 (89.0–93.9), 672
Crude rate analysis85.3* (82.3–87.9), 63985.8* (82.8–88.4), 63479.0 (75.6–82.0), 65686.9 (84.1–89.4), 65789.4* (86.8–91.7), 65284.6 (81.6–87.3), 648

Week 4 healing was >64% in all treatment groups in both studies by both life-table and crude rate analyses. There were no statistically significant differences between the treatment groups.

Healing rates at week 8 for patients with baseline LA grade C or D EO are shown in Table 3. Dexlansoprazole MR 60 mg was statistically superior to lansoprazole in study 1 by both life-table and crude rate analyses. In this study, dexlansoprazole MR 90 mg also was superior to lansoprazole by life-table analysis. As the two studies were identical in design and the baseline demographics were similar, results from these studies were combined to allow for adequately powered post hoc analyses to evaluate differences between treatment groups for healing in patients with baseline LA grade C or D. In this post hoc integrated analysis, both statistical methods demonstrated superiority of dexlansoprazole MR 90 mg to lansoprazole in healing of moderate and severe EO, with therapeutic gains of 7 percentage points by life-table analysis and 8 percentage points by crude rate analysis (Figure 2). Healing rates with dexlansoprazole MR 60 mg were not significantly higher than lansoprazole 30 mg in this integrated analysis.

Table 3.   Percentage of patients with baseline grades C or D erosive oesophagitis healed at week 8 (intent-to-treat population)
Week 8 healing rate (%) (95% CI), nStudy 1Study 2
DEX MR 60 mg q.d.sDEX MR 90 mg q.d.s.LAN 30 mg q.d.s.DEX MR 60 mg q.d.s.DEX MR 90 mg q.d.s.LAN 30 mg q.d.s.
  1. DEX MR, dexlansoprazole MR; LAN, lansoprazole; q.d.s., once daily.

  2. *P < 0.05 vs lansoprazole 30 mg after adjusting for multiplicity.

Life-table analysis88.9* (83.7–94.2), 19183.8* (77.4–90.1), 19174.5 (67.3–81.6), 20887.6 (82.2–92.9), 19993.3 (89.2–97.3), 19187.7 (82.4–93.0), 194
Crude rate analysis79.7* (73.1–85.3), 18274.1 (67.1–80.2), 18565.0 (58.0–71.6), 20077.8 (71.3–83.5), 19486.3 (80.4–90.9), 18278.9 (72.5–84.5), 190
Figure 2.

 Erosive oesophagitis integrated healing rates at week 8 in patients with baseline grade C or D (intent-to-treat population). *P < 0.05 vs. lansoprazole.

Symptom assessment

Patients in all three treatment groups in each study reported significant improvement from baseline in heartburn relief as assessed by daily diary during treatment. The median percentage of 24-h heartburn-free days was 82.1% for dexlansoprazole MR 60 mg, 84.2% for dexlansoprazole MR 90 mg and 80.0% for lansoprazole 30 mg in study 1 and 83.0%, 80.8% and 78.3% respectively, in study 2. All three treatment groups were highly effective at relieving nighttime symptoms. The percentage of patients who achieved sustained resolution of heartburn was >80% in all treatment groups; there were no statistically significant differences between groups. The median percentage of days without rescue medication usage was also similar among treatment groups (P > 0.05).

Safety and tolerability

A total of 4092 patients who were randomized and received at least one dose of study medication were included in the safety analyses. The percentage of patients with ≥1 treatment-emergent AE was similar among the three treatment groups in the combined studies: 30.4%, 28.1% and 27.8% in the dexlansoprazole MR 60-mg, dexlansoprazole MR 90-mg and lansoprazole 30-mg treatment groups respectively. There were no treatment-emergent adverse events occurring in ≥5% of patients in any treatment group. The 10 most frequently reported treatment-emergent adverse events in any treatment groups in the two studies are shown in Table 4. The percentages of patients with adverse events leading to premature discontinuation of study drug ranged from 1.3% to 2.3% across treatment groups. The most common adverse event leading to premature discontinuation in dexlansoprazole MR and lansoprazole patients was diarrhoea (0.5% and 0.2% respectively). No dose-related increase in adverse events with dexlansoprazole MR was observed.

Table 4.   The 10 most frequently reported treatment-emergent adverse events in the two studies in any treatment group
MedDRA high-level term, n (%)Dexlansoprazole MRLansoprazole
60 mg q.d.s. (n = 1374)90 mg q.d.s. (n = 1355)Total (n = 2729)30 mg q.d.s. (n = 1363)
  1. q.d.s., once daily; NEC, not elsewhere classified.

Diarrhoea (excluding infective)57 (4.1)55 (4.1)112 (4.1)44 (3.2)
Nausea and vomiting symptoms36 (2.6)42 (3.1)78 (2.9)36 (2.6)
Gastrointestinal and abdominal pain38 (2.8)41 (3.0)79 (2.9)35 (2.6)
Headache37 (2.7)41 (3.0)78 (2.9)32 (2.3)
Upper respiratory tract infections34 (2.5)29 (2.1)63 (2.3)36 (2.6)
Flatulence, bloating and distension25 (1.8)20 (1.5)45 (1.6)32 (2.3)
Diaphragmatic hernias25 (1.8)25 (1.8)50 (1.8)22 (1.6)
Gastritis (excluding infective)23 (1.7)14 (1.0)37 (1.4)16 (1.2)
Gastrointestinal atonic and hypermotility disorders NEC17 (1.2)13 (1.0)30 (1.1)20 (1.5)
Viral Infections NEC14 (1.0)18 (1.3)32 (1.2)13 (1.0)

A total of 22 patients (0.5%) reported nonfatal serious adverse events. Of these, four patients had events considered possibly related to study medication by the investigators (noncardiac chest pain in one patient on dexlansoprazole MR 60 mg, arteriospasm coronary in one patient on dexlansoprazole MR 90 mg and paralysis and facial palsy respectively in two patients on lansoprazole 30 mg). Three patients died in these two studies of causes unrelated to study drug.

No clinically significant differences were observed in the percentage of patients experiencing shifts outside the normal range for clinical laboratory parameters in the dexlansoprazole MR treatment groups compared with the lansoprazole treatment group. Mean increases in serum gastrin were higher in the dexlansoprazole MR groups compared with lansoprazole, but were within ranges expected with PPI treatment.21, 22

Discussion

Dexlansoprazole MR is the first PPI to use DDR technology designed to maintain pharmacologically effective drug concentrations over a longer period of time with a single daily dose. Data from these two identical, randomized controlled studies in more than 4000 EO patients show that dexlansoprazole MR 60 and 90 mg once daily were non-inferior to lansoprazole 30 mg and were then tested for superiority to lansoprazole 30 mg for the primary and secondary efficacy endpoints. Both doses were highly effective in healing all grades of EO.

Life-table healing rates were consistently high in the individual studies 92–93% for dexlansoprazole MR 60 mg and 93–95% for dexlansoprazole MR 90 mg vs. 86–92% for lansoprazole 30 mg; the differences were not statistically significant. Life-table methodology generally produces higher healing rates than the more conservative crude rate analyses. Also, life-table methods are more commonly reported in recent PPI literature.10, 23–27

The therapeutic gains were similar using both analyses. However, in the crude rate analysis, dexlansoprazole MR 60 mg was superior to lansoprazole 30 mg in one study (85% vs. 79% respectively, < 0.05) and dexlansoprazole MR 90 mg was superior to lansoprazole 30 mg in both studies (86% vs. 79% and 90% vs. 85% respectively, < 0.05).

As the two studies were identical in design and the baseline demographics were similar, results from these studies were combined to allow for adequately powered post hoc analyses to evaluate differences between treatment groups for healing in patients with baseline LA grade C or D, who comprised approximately 30% of the randomized patients in these studies. Integrated data from these two trials show that dexlansoprazole MR 90 mg was significantly more effective than lansoprazole 30 mg in patients with moderate-to-severe EO (LA grades C/D) and produced a therapeutic gain of 8 percentage points using crude rate analyses. This therapeutic gain suggests that an additional 25–30% of patients with moderate-to-severe EO who were not healed with lansoprazole at week 8 may be healed with dexlansoprazole MR 90 mg. This therapeutic gain may be important in clinical practice, where it is estimated that about 20% of the EO population have more severe disease9 and where empiric therapy is often initiated in patients with reflux symptoms without knowledge of whether EO is present or, if present, how severe the disease may be. In these studies, the number needed to treat to prevent one treatment failure on therapy with dexlansoprazole MR was 13 for patients with moderate-to-severe EO and 17 for patients with all grades of EO.

In addition to providing consistently high healing rates, dexlansoprazole MR 60 and 90 mg produced highly effective relief for all symptom endpoints, although no statistical differences were observed among the treatment arms in the individual studies. More than 80% of patients in all three treatment groups achieved sustained resolution of heartburn, i.e. 7 consecutive heartburn-free days, in both studies.

The DDR formulation of dexlansoprazole MR provides a substantially larger area under the curve and prolonged plasma drug levels compared with a conventional release PPI, lansoprazole. Furthermore, dexlansoprazole MR 60 and 90 mg were well tolerated with no dose-dependent adverse events and with a side effect profile in these studies similar to that of lansoprazole 30 mg, which has a long-established history of use in patients with GERD and other acid-related disorders.21, 28 The side effects observed with dexlansoprazole MR are typical both in character and severity of those observed with other PPIs.29–32 While the current randomized trials may not have adequate power to demonstrate very rare side effects, their large size, as well as the rigorous follow-up of the patients, suggests that the compound has an excellent safety profile.

Based on its efficacy and tolerability, dexlansoprazole MR offers potential benefits over lansoprazole in patients with EO. In choosing the appropriate therapy for a patient, there are other factors to consider, e.g. PPI efficacy can be influenced by food and the time of dosing relative to a meal. In separate trials, the absorption and bioavailability of lansoprazole, omeprazole and esomeprazole were diminished when these PPIs were administered with a meal29, 30, 33–37 and product labelling for these PPIs recommend administering them before eating (1 h before meals for esomeprazole).29, 30, 35 However, it has been reported that nearly two thirds of patients have difficulty remembering to take their acid suppression medication 30 min prior to a meal and 68% of patients stated a preference for taking their medication with a meal.33, 38

Whereas food may compromise the bioavailability of some PPIs, the plasma exposure for dexlansoprazole has been shown to increase after administration of dexlansoprazole MR under fed conditions compared with the fasting state with no relevant differences in the fed or fasting intragastric pH profile of dexlansoprazole MR observed.39 As poor compliance is a leading cause of treatment failure,3, 40 the ability to administer dexlansoprazole MR with or without food offers convenience not available with PPIs that exhibit a negative food effect and may improve the effectiveness of PPI treatment in the real-world setting.

There were some limitations to these trials. The five-point heartburn severity rating used in these studies has not been validated. Nonetheless, it is similar to scales used in previous studies.16–18 In addition, compliance in the artificial setting of a clinical trial may be higher than real world use. In clinical practice, some patients discontinue PPI therapy when symptoms subside. In a large population-based survey, only 55% of GERD patients continued to take their PPI once daily for 4 weeks as prescribed.3, 41 Patients entering the current trials were also carefully screened and allowed to participate based on specific inclusion and exclusion criteria, an approach not consistent with the clinical setting. Such issues are common to most clinical trials and should not affect the general applicability of the study results. Whether the findings of the current trials are generalizable to other groups of patients with GERD excluded from these studies including those with Barrett’s oesophagus and strictures, is unclear. Furthermore, although the analysis of moderate-to-severe grades was a prespecified endpoint, the integrated analysis was performed post hoc. Nevertheless, dexlansoprazole MR did show clinical and statistical benefit over lansoprazole in this difficult-to-treat population.

As in other PPI studies,23, 24 patients who tested positive for H. pylori infection were excluded from the present study to eliminate a potentially confounding variable. The role of H. pylori infection in GERD patients, however, is still controversial.42 A study by Holtmann et al.43 showed that patients infected with H. pylori experienced better healing rates and symptom relief, whereas other studies did not demonstrate an association between healing rates and H. pylori infection.44, 45 In the absence of definitive data regarding the effect of H. pylori infection on clinical outcomes of therapy with PPIs, it would not be unreasonable to expect that the results of the current study would be similar had patients infected with H. pylori been enrolled.

In conclusion, dexlansoprazole MR 60 and 90 mg administered once daily for up to 8 weeks were highly effective for healing all grades of EO. The absolute difference in healing rates between dexlansoprazole MR and lansoprazole was most pronounced in patients with more severe EO, where the unmet patient need is the greatest. dexlansoprazole MR 60 and 90 mg also were highly effective in relieving symptoms and were well tolerated in this large population of EO patients. Both doses demonstrated similar tolerability profiles that were comparable to that of lansoprazole 30 mg, with no dose-related increase in adverse events observed. Overall, dexlansoprazole MR offers potential benefits over lansoprazole in patients with EO, especially in those with more severe grades of disease.

Acknowledgements

Declaration of personal interests: M. Claudia Perez, MD, Betsy Pilmer, RN, BSN and Stuart Atkinson MB ChB are employees of Takeda Global Research & Development Center, Inc., Deerfield, IL, USA. (At the time of manuscript preparation, they were employees of TAP Pharmaceutical Products Inc., Lake Forest, IL, now a part of Takeda Global Research & Development Center, Inc.). Misun Lee, PhD, was an employee of TAP Pharmaceutical Products Inc. at the time of the study conduct and analysis. Prateek Sharma, MD, has served as an investigator and consultant for Takeda Global Research & Development Center, Inc., an investigator for BARXX Medical and Olympus Inc. and a speaker for AstraZeneca, Wyeth and Santarus. Nicholas J. Shaheen, MD, MPH, has served as an investigator and consultant for Takeda Global Research & Development Center, Inc., an investigator and consultant for AstraZeneca, LLP and as an investigator for Procter & Gamble, BARRX Medical, and CSA Medical. David A. Peura, MD, has served as a speaker, consultant and an advisory board member for Takeda Global Research & Development Center, Inc. and a speaker for AstraZeneca and Santarus. In addition to the authors, initial data analyses were undertaken by Galen Witt, an employee of Takeda Global Research & Development Centre, Inc. The authors wish to thank all the investigators who contributed to these studies. Declaration of funding interests: Writing support and assistance was provided by Eileen Gallagher of Complete Healthcare Communications, Inc., Chadds Ford, PA, and was funded by Takeda Global Research & Development Center, Inc. These studies were funded by Takeda Global Research & Development Center, Inc.

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