Gastroesophageal reflux disease (GERD) is defined as a condition that develops when the reflux of stomach contents causes troublesome symptoms and/or complications. Non-erosive reflux disease (NERD) is defined by the presence of troublesome reflux-associated symptoms and the absence of mucosal breaks in the esophagus at endoscopy; when erosions are present, it is called erosive esophagitis (EE).¹ GERD is a common condition. A recent meta-analysis reported a prevalence of 18.1–27.8% in North America, 8.8–25.9% in Europe, 2.5–7.8% in East Asia, 8.7–33.1% in the Middle East, 11.6% in Australia, and 23.0% in South America. The prevalence of GERD appears to be increasing, especially in Asia, where the rates are beginning to approach those reported in Western countries.^2–4

Patients generally consider mild symptoms occurring 2 or more days a week, or moderate/severe symptoms occurring more than 1 day a week to be troublesome.¹ Frequent or severe GERD symptoms are associated with impaired quality of life and activities of daily living.^5,6 These symptoms also result in decreased work productivity and increased costs.⁷ GERD is also commonly associated with nocturnal symptoms and sleep disturbances, which further contribute to disease burden.^1,8,9

Proton pump inhibitors (PPIs) are the mainstay in the management of GERD.¹⁰ However, a sizeable proportion of patients continue to experience persistent GERD symptoms despite treatment with the current PPIs. In a systematic review of the literature, the prevalence of persistent heartburn despite PPI treatment was 17% in interventional non-randomized studies and 32% in randomized trials.¹¹ The prevalence of persistent GERD symptoms despite treatment was 45% in observational studies.¹¹ This persistence of symptoms results in increased burden, with patients reporting impaired sleep, impaired quality of life, reduced productivity, and increased cost of illness despite PPI treatment.^10,12–14

Dexlansoprazole is a PPI that constitutes > 80% of circulating drug after oral administration of the PPI lansoprazole, and is more stable than lansoprazole. Dexlansoprazole modified-release is a novel modified-release formulation of dexlansoprazole, in which a dual delayed-release technology is used for extended duration of acid suppression. In this technology, 2 types of granules are used to ensure initial release of the drug in the proximal small intestine followed by a delayed release many hours later, in the distal small intestine.¹⁵ The safety and efficacy of dexlansoprazole has been demonstrated for the treatment of symptomatic GERD or NERD and safe and prolonged healing of EE, and it is approved for use in many countries across the world.^15,16

The registration studies for dexlansoprazole mostly involved doses of 60 mg/day and 90 mg/day. In Asian subjects with GERD, the use of dexlansoprazole has not been adequately characterized at the dose regimens of 30 mg/day for NERD and 60 mg/day for EE. This phase 4 study was conducted to evaluate the efficacy and safety of the use of dexlansoprazole delayed-release in Asian subjects with GERD who manifest endoscopic evidence of NERD and EE.

This was a phase 4, open-label, non-randomized, uncontrolled, multicenter, multi-country study. Subjects were enrolled at 12 investigational sites in Asia, including 1 site in Hong Kong, 6 sites in South Korea, and 5 sites in Taiwan. Study sites mostly consisted of referral centers with expertise in GERD and with adequate facilities to perform study-related activities including endoscopy. The study was conducted from March 2015 to July 2016.

Key Eligibility Criteria

Male or female subjects aged ≥ 20 years were eligible for the study if they had experienced persistent typical GERD symptoms (heartburn and/or acid regurgitation) for at least 6 months with the presence of GERD symptoms for at least 4 days within the past 7 days prior to the screening visit. Throughout the screening period the subjects documented the presence and maximum severity of daytime and nighttime heartburn and acid regurgitation symptoms each day in a paper diary. In addition, subjects were assessed for heartburn, acid regurgitation, dysphagia, belching, and epigastric pain as recorded by the investigator (clinician). During screening endoscopy, the subjects either needed to have macroscopically normal esophageal mucosa (NERD group) or have evidence of erosive esophageal reflux disease, Los Angeles (LA) classification grades B to D (EE group).

Key exclusion criteria related to the gastrointestinal system were as follows: known hypersensitivities to any PPI and component of dexlansoprazole; use of a histamine H2 blocker or a PPI other than dexlansoprazole during screening and throughout the study; previous use of dexlansoprazole before screening; endoscopic Barrett’s esophagus and/or definite dysplastic changes in the esophagus; active gastric or duodenal ulcers within 4 weeks of the first dose of study drug; history of dilation of esophageal strictures other than a Schatzki’s ring; coexisting disease affecting the esophagus, history of radiation therapy or cryotherapy to the esophagus, or caustic or physiochemical trauma; current or historical evidence of Zollinger-Ellison syndrome or other hypersecretory condition; history of gastric, duodenal, or esophageal surgery except simple oversew of an ulcer; and acute upper gastrointestinal hemorrhage within 4 weeks prior to endoscopy.

This study was registered with ClinicalTrials.gov (NCT 02351960; https://clinicaltrials.gov/ct2/show/NCT02351960), and was conducted in accordance with the protocol, the ethical principles that have their origin in the Declaration of Helsinki, the ICH E6 GCP guidance, and all applicable regulations. Each subject (or the subject’s legally authorized representative) signed and dated the informed consent form before undergoing any study participation. The study was reviewed and approved by the Institutional Review Boards/Independent Ethics Committees of all study sites, constituted according to the applicable local requirements of each participating region.

The names and numbers of the Institutional Review Boards are as follows:

• Institutional Review Board of Taichung Veterans General Hospital (SC15048A)

• Chang Gung Medical Foundation Institutional Review Board (104–0906A2)

• Institutional Review Board of The Catholic University of Korea (KC14MSGV0846)

• Asan Medical Center Institutional Review Board (2015–0014)

• Seoul National University Bundang Hospital Institutional Review Board (B-1412/277–008)

• Seoul National University College of Medicine/Seoul National University Hospital Institutional review board (H-1411-076-626)

• Yonsei University Health System, Severance Hospital, Institutional Review Board (4-2014-1023)

• Samsung Medical Center Institutional Review Board (SMC-2014-11-079-001)

• Institutional Review Board, National Cheng Kung University Hospital (AB-CR-104-004)

• Joint CUHK-NTEC Clinical Research Ethics Committee (2014.681-T)

• Kaohsiung Medical University Chung-Ho Memorial Hospital Institutional Review Board (KMUHIRB-F(I)-20150009)

• Research Ethics Committee, National Taiwan University Hospital (201412003MSB)

Study Design

Based on the results of the screening endoscopy, the subjects were assigned to either the NERD study group or the EE study group, and were treated as follows (these regimens were already approved in the countries where this study was conducted):

(1) NERD group: dexlansoprazole delayed-release 30 mg once-daily (QD) for 4 weeks

(2) EE group: dexlansoprazole delayed-release 60 mg QD for 8 weeks

During the study, dexlansoprazole delayed-release was self-administered orally QD in the morning. Approximately 200 subjects were planned to be enrolled in the NERD study group and 100 subjects in the EE study groups. Subjects from Taiwan were to be enrolled in the EE group only because dexlansoprazole 30 mg was not commercially available in the country.

Outcomes

During the study, efficacy was assessed via subject responses in a paper diary provided in local language (twice daily entries), investigator assessment of GERD symptoms (conducted at baseline and end of treatment, with an additional assessment at week 4 for subjects in the EE group), and via endoscopy (conducted at screening and, for subjects in the EE group, repeated at end of treatment).

The primary endpoints were as follows:

(1) The percentage of 24-hour heartburn and acid regurgitation-free days over 4 weeks in NERD subjects following study drug treatment, as assessed by subject entries in a daily paper diary (completed twice a day)

(2) The percentage of 24-hour heartburn and acid regurgitation-free days over 8 weeks in EE subjects following study drug treatment, as assessed by subject entries in a daily paper diary (completed twice a day)

Other efficacy endpoints included the assessment of the individual symptoms of heartburn and acid regurgitation separately, assessment for 24-hour and nighttime symptoms separately, investigator assessment of GERD symptoms, assessment of subject-rated severity of nighttime symptoms, and (in the EE group) the percentage of study subjects with endoscopically evaluated macroscopic healing of their esophagus, with at least 1 LA grade classification grade improvement, at end of treatment.

Statistical Methods

No formal sample size calculation was performed for this study; a total of approximately 300 subjects were considered sufficient to achieve the study endpoints.

The percentage of 24-hour heartburn and acid regurgitation-free days were calculated for each subject with at least 1 daytime or nighttime heartburn and/or regurgitation result (yes or no) during treatment.

Summary statistics of percentage for the efficacy endpoints were generated for subjects in the full analysis set (all subjects who received at least 1 dose of study drug and had post-baseline data for the appropriate efficacy variable) over 4 weeks in the NERD group and over 8 weeks in the EE group.

The safety analysis set included all subjects who received at least 1 dose of study drug. For subjects in the safety analysis set, the adverse event (AE) data and data on clinical laboratory tests, vital signs, physical examinations, and 12-lead electrocardiogram were summarized.

The Statistical Analysis System 9.2 or higher system for the UNIX operating system was used to perform the statistical analyses. Statistical review of the study was performed by a biomedical statistician.

A total of 445 subjects were screened for the study: 208 subjects were enrolled into the NERD group and 88 subjects were enrolled into the EE group (Fig. 1).

Demographic and Baseline Characteristics

The key baseline and demographic characteristics, including baseline subject-rated heartburn and regurgitation scores are shown in Table 2.

The mean age of the subjects was 53.6 years in the NERD group and 51.7 years in the EE group. The mean body mass index was 23.00 kg/m² in the NERD group and 25.11 kg/m² in the EE group. In both the NERD and EE groups, for the 7 days prior to treatment with study drug, subjects experienced 24-hour heartburn or acid regurgitation for a median of 7 days. In both groups, daytime heartburn and acid regurgitation were more prevalent than nighttime heartburn and acid regurgitation.

Efficacy Results

The results of the subject-rated heartburn and acid regurgitation assessments following treatment with dexlansoprazole are shown in Figures 2 and 3 (Table 3). The median percentage of days that subjects did not experience any 24-hour heartburn and acid regurgitation was 26.92% in the NERD group and 65.45% in the EE group. The median percentage of days that subjects did not experience any nighttime heartburn and acid regurgitation was 59.26% in the NERD group and 83.33% in the EE group. For individual symptoms, the median percentage of days without nighttime heartburn was 73.08% and 92.73% respectively, and without nighttime acid regurgitation was 88.00% and 92.59% respectively, in the NERD and EE groups. The median severity (Table 3) of nighttime heartburn and of acid regurgitation ranged from 0.1 to 0.3 in the 2 groups.

Regarding investigator assessment, in the NERD group, the percentage of subjects who experienced an at least 1-category improvement in the severity of the symptom was 69.7% for acid regurgitation, 66.7% for heartburn severity, 64.3% for belching, 33.8% for epigastric pain, and 14.6% for dysphagia. Similarly, in the EE group, the percentage of subjects who experienced an at least 1-category improvement in the severity of the symptom was 71.0% for acid regurgitation, 63.2% for heartburn severity, 42.1% for epigastric pain, 40.8% for belching, and 17.1% for dysphagia.

The detailed endoscopy results are shown in Table 4. Of the subjects in the EE group, 77.3% experienced at least a 1 LA grade improvement in EE from baseline to week 8, with 27 subjects (30.7%) having no EE at week 8.

Safety, Tolerability, and Compliance

The median exposure to treatment was 27 days in the NERD group and 56 days in the EE group. In the NERD group, 96.2% of subjects showed > 90.0% drug compliance, while in the EE group, 94.3% of subjects showed > 90.0% drug compliance.

Table 5 shows the frequency of AEs in the 2 groups. In the NERD group, 16.8% of subjects reported treatment-emergent AEs (TEAEs), with a small proportion of subjects (6.7%) experiencing TEAEs related to the study drug. In the EE group, 35.2% of subjects reported TEAEs, with 5.7% experiencing TEAEs related to the study drug. Most TEAEs were mild in intensity in both groups. No TEAEs were reported in ≥ 5.0% of subjects in either group. TEAEs that occurred in 2.0% or more subjects were headache in the NERD group (2.4%) and diarrhea in the EE group (2.3%).

TEAEs that led to study drug discontinuation were reported by 6 subjects in the NERD group and 3 subjects in the EE group. In the NERD group, there were no reports of serious AEs or deaths. In the EE group, 1 subject experienced a serious AE of mild urticaria on day 1, which was considered related to study drug; in addition, 1 subject experienced a treatment-emergent serious AE (SAE) leading to death. The death occurred in a 68-year-old male subject who experienced metastatic adenocarcinoma, diagnosed on omental nodule biopsy. The SAE start date was on day 66 (10 days after the last study treatment), and it lasted for 106 days. The patient also had comorbid hypertension, diabetes mellitus, and hyperlipidemia. The outcome of the metastatic adenocarcinoma was fatal and was considered not related to the study drug.

No clinically important findings were noted in the clinical laboratory, vital sign, or physical examination data.

GERD is a common condition with an increasing prevalence in Asia. GERD symptoms can be troublesome and are associated with impaired daily living, poorer quality of life, decreased work productivity, and increased costs. A substantial proportion of patients continue to experience troublesome GERD symptoms despite treatment with the current PPIs. Dexlansoprazole delayed-release is a recently developed PPI with the novel dual delayed-release technology for extended duration of acid suppression. In Asian patients who require treatment for GERD, the effectiveness of the use of dexlansoprazole delayed-release has not been sufficiently characterized at the dose regimens of 30 mg/day for NERD and 60 mg/day for EE.

In this large multicenter study conducted in 3 Asian countries, in subjects with NERD, dexlansoprazole delayed-release 30 mg QD for 4 weeks relieved both daytime and nighttime heartburn and acid regurgitation. Symptom improvement was observed on both subject self-report and investigator ratings of GERD symptoms. For all the outcomes (except percentage of days without 24-hour heartburn and acid regurgitation), most patients reported relief for at least 50.0% of the days in the study. This finding should be understood in the context of the baseline status of the patients, during which the vast majority of the patients reported near-daily 24-hour heartburn or acid regurgitation symptoms (mean 6.3 days and median 7 days of heartburn or acid regurgitation in the 7 days prior to treatment). In subjects with EE, whose baseline GERD symptom frequency was broadly comparable to that of subjects with NERD, dexlansoprazole delayed-release 60 mg QD for 8 weeks relieved both daytime and nighttime heartburn and acid regurgitation on self- and investigator-ratings; most patients reported relief for at least 50.0% of the days on all outcomes. Three in 4 patients in this group experienced at least 1 LA grade improvement in esophagitis, with approximately one-third of the patients showing no evidence of EE at the end of treatment. The mean severity of nighttime heartburn and nighttime regurgitation was also numerically lower at end of treatment than baseline status in both groups. An improvement in the frequency and severity of these symptoms can be expected to translate to better quality of life and productivity.¹⁷

The EE healing rate in this study (30.7%) was lower than that seen in the dexlansoprazole pivotal trials in which the EE healing rate was higher than 80.0% after 8 weeks of treatment with dexlansoprazole.¹⁸ These pivotal trials were conducted mainly in North American and European centers. A review of studies with PPIs showed that EE healing rates were significantly lower in non-white patients than in white patients.¹⁹ A similar difference between Asian and non-Asian patients was reported in a pragmatic trial with pantoprazole for GERD.²⁰ Low EE healing rates were also reported in a Chinese study, in which 75.8% of patients experienced complete symptom resolution but only 48.0% showed complete healing of esophagitis after 8 weeks of treatment with esomeprazole 20 mg.²¹

Treatment with dexlansoprazole delayed-release 30 mg/day in subjects with NERD for 4 weeks and 60 mg/day in subjects with EE for 8 weeks was well tolerated. AEs related to the study drug were uncommon (6.7% in the NERD group and 5.7% in the EE group), and AEs resulting in study drug discontinuation were reported in fewer than 4.0% of the subjects in each group. In the NERD group, over 4 weeks, no SAEs or deaths were reported. In the EE group, 1 SAE leading to death was reported and it was not considered related to dexlansoprazole.

In subjects with EE, the data suggested that further improvements in efficacy with treatment occurred during the period from 4 weeks to 8 weeks. As an example, the median severity of nighttime acid regurgitation was 0.14 at 4 weeks and 0.09 at 8 weeks. Similar numerical differences between week 4 and week 8 were seen for the other nighttime symptom parameters in subjects with EE. It is possible that subjects with NERD may also have continued to show further improvement with a longer treatment period extending to 8 weeks or longer.

A comparison of outcomes between patients with NERD and EE shows that, at 4 weeks, the efficacy was consistently higher in EE patients than in NERD patients. While no statistical comparisons were conducted, efficacy was numerically higher in EE for both daytime and nighttime symptoms, and for both heartburn and regurgitation symptoms; differences between EE and NERD were less pronounced for regurgitation symptoms. As an example, after 4 weeks of treatment, the mean percentage of days that subjects did not experience any nighttime heartburn was 70.0% in the EE group compared with 59.6% in the NERD group; for regurgitation symptoms, the respective percentages were 69.2% in the EE group and 67.4% in the NERD group. As noted earlier, GERD severity in both groups was broadly similar at baseline. While the dose of dexlansoprazole was lower in NERD patients than in EE patients, this is unlikely to explain the observed difference in outcomes; in NERD, the 30 mg and 60 mg doses of dexlansoprazole have showed comparable efficacy.¹⁵ This differential efficacy between EE and NERD appears to be related to the disease process itself, and is in keeping with the reported literature in which efficacy rates are consistently higher in EE than in NERD.^22,23

The demonstration of improvement in both daytime and nighttime symptoms with a single daily dose of dexlansoprazole is encouraging. In a large recent survey (the GERD in Asia Pacific Survey), 45.0% of patients reported limited improvement in nocturnal symptoms despite regular treatment with PPIs.²⁴ Therefore, dexlansoprazole, which has shown high response rates, 24-hour pH control, and reduction in nocturnal symptoms with once-daily dosing in this study, can be expected to meet an important medical need in Asian patients.²⁵

A key limitation of this study was the absence of a comparator arm. No formal sample size calculation was performed for this study, and all patients received treatment with dexlansoprazole. Therefore, efficacy and safety of dexlansoprazole in comparison with placebo or an active comparator could not be established in this study. However, the overall efficacy and safety of dexlansoprazole delayed-release have been established in previous studies, and this treatment is already approved in Hong Kong, South Korea, and Taiwan. Therefore, an open-label uncontrolled study was sufficient to characterize the use of dexlansoprazole in the studied doses. Notably, the efficacy of dexlansoprazole was demonstrated not only on subjective assessments but also on endoscopic evaluations in subjects with EE. Another limitation of this study was that the statistical analyses were generally restricted to summary statistics; therefore, a detailed assessment of the factors associated with efficacy could not be conducted.

Future studies should focus on a longer duration of treatment with more frequent assessments to understand the trajectory of improvement with dexlansoprazole; studies should also attempt to identify those subgroups that are most likely to benefit with treatment with this drug.

In summary, in Asian patients with GERD, treatment with dexlansoprazole delayed-release 30 mg/day for 4 weeks in subjects with NERD and 60 mg/day for 8 weeks in subjects with EE indicated a favorable efficacy and safety profile in relieving both daytime and nighttime heartburn and acid regurgitation symptoms.