A Pilot Randomized Controlled Study of Dexlansoprazole MR-Based Triple Therapy for Helicobacter Pylori Infection

Abstract Dexlansoprazole MR is the R-enantiomer of lansoprazole that is delivered by a dual delayed release formulation. It is effective for symptom control of patients with gastroesophageal reflux disease. However, its efficacy in the treatment of Helicobacter pylori infection remains unclear. This pilot, randomized, controlled, head-to-head study was conducted to investigate whether the efficacy of single-dose dexlansoprazole MR-based triple therapy was noninferior to double-dose rabeprazole-based triple therapy in the treatment of H pylori infection. Consecutive H pylori-infected subjects were randomly allocated to either 7-day dexlansoprazole MR-based standard triple therapy (dexlansoprazole MR 60 mg once daily, clarithromycin 500 mg twice daily, and amoxicillin 1 g twice daily) or rabeprazole-based triple therapy (rabeprazole 20 mg twice daily, clarithromycin 500 mg twice daily, and amoxicillin 1 g twice daily). H pylori status was assessed 6 weeks after the end of treatment. A total of 177 H pylori-infected patients were randomized to receive dexlansoprazole MR-based (n = 90) or rabeprazole-based (n = 87) triple therapy. Intention-to-treat analysis demonstrated no differences between eradication rates of the 2 study groups (83.3% vs 81.6%; P = 0.736). Per-protocol analysis yielded comparable results (85.1% vs 81.2%; P = 0.497). Both groups exhibited similar frequencies of adverse events (7.8% vs 4.6%; P = 0.536) and drug compliance (98.9% vs 97.7%; P = 0.496). Multivariate analysis disclosed that the presence of clarithromycin resistance was the only independent factors predictive of treatment failure with an odds ratio of 6.8 (95% confidence interval: 1.2–37.6). This work demonstrates that single-dose dexlansoprazole MR-based triple therapy yields a similar eradication rate as double-dose rabeprazole-based therapy. Since the pharmaceutical cost of the single-dose dexlansoprazole MR regime is lower than that of the double-dose rabeprazole regimen, dexlansoprazole-based therapy can reasonably be recommended in the first-line treatment of H pylori infection.


INTRODUCTION
H elicobacter pylori (H pylori) infects more than 50% of the adult population globally. The bacterium induces chronic inflammation of gastric mucosa and leads to various gastroduodenal diseases, such as peptic ulcer, gastric adenocarcinoma, and mucosa-associated tissue lymphoma. 1,2 Currently, H pylori eradication has become the standard treatment to cure peptic ulcer disease. 3,4 This therapy is also advocated in the treatment of H pylori-related mucosa associated lymphoid tissue lymphoma. 5 In regions with high incidence of gastric cancer, H pylori eradication is recommended for the prevention of cancer development. 6,7 Proton pump inhibitor (PPI) is one of the key medicines in anti-H pylori regimens. It possesses anti-H pylori activity, 8 and also increases bioavailability and activity of some antibiotics by reducing gastric acid secretion. 9 Dexlansoprazole, an R-enantiomer of lansoprazole, is a PPI with 3 to 5 times greater maximum concentration (C max ), area under the plasma concentration-time curve (AUC), and a longer elimination half-life than S-lansoprazole. 10 Dexlansoprazole modified release (MR) is a novel PPI with a dual delayed release formulation providing 2 separate releases of medication to extend the duration of effective plasma drug concentration. 11 The dual delayed release PPI possesses 2 types of enteric-coated granules with different pH-dependent dissolution characteristics to release an initial drug in the proximal small intestine, at a pH of approximately 5.5, followed several hours later by another drug release at distal small intestine, at a pH of !6.0. 12 It is effective in improving the healing of erosive esophagitis and in the treatment of symptomatic gastroesophageal reflux disease. [13][14][15] However, its efficacy in the treatment of H pylori infection remains unclear.
Our previous study demonstrated that esomeprazole-based triple therapy achieved a higher eradication rate than pantoprazole-based regimen. 16 The difference in eradiation efficacies between the 2 study groups is most likely due to the more powerful acid inhibition effect of esomeprazole compared with pantoprazole. 17 A recent cross over study documented that esomeprazole at standard dose of 40 mg once daily provides more effective control of gastric acid than standard doses of pantoprazole, lansoprazole, and rabeprazole. 17 A comparison study of dexlansoprazole 60 mg with esomeprazole 40 mg showed that dexlansoprazole MR 60 mg achieved a greater acid control than esomeprazole 40 mg (the mean percentage of time with pH >4 between 0 to 24 hours post-dose: 58% and 48%, respectively). 18 Since single-dose esomeprazole (40 mg daily)-based triple therapy has been shown to achieve a similar eradication rate as double-dose esomeprazole (40 mg b.d.)based therapy, 19 dexlansoprazole MR is potentially a promising PPI which can be used in H pylori eradication.
Currently, the efficacy of dexlansoprazole MR-based standard triple therapy is still lacking. We therefore conducted this pilot study to assess the eradication rate of dexlansoprazole MRbased triple therapy for H pylori infection, and to investigate whether the efficacy of single-dose dexlansoprazole MR-based triple therapy is noninferior to double-dose rabeprazole-based triple therapy in the treatment of H pylori infection.

Patients
This study was a prospective, noninferiority, randomized, controlled trial. Consecutive adult patients with endoscopically proven H pylori-related peptic ulcer diseases or gastritis were recruited for the study. The diagnosis of H pylori was based on at least 2 positive results of histology, rapid urease test, and culture. 20 Criteria for exclusion criteria were as follows: age younger than 20 years; previous H pylori-eradication therapy, ingestion of antibiotics or bismuth within the prior 4 weeks, presence of severe comorbidities, allergy to any of the medications used in the trial, and pregnant woman. The study protocol was approved by the Ethics Committee of the Kaohsiung Medical University Hospital (IRB number: KMUH-IRB-E (I)-20150107). It was registered as a standard randomized Clinical Trial (ClinicalTrials.gov.identifier: NCT02541786).

Randomization and Treatment
We randomly allocated patients at a 1:1 ratio to receive either a DCA (dexlansoprazole MR [Dexilant delayed release; Takeda, Osaka, Japan] 60 mg once daily, clarithromycin 500 mg twice daily, and amoxicillin 1 g twice daily) or RCA (rabeprazole [Pariet; Eisai, Misato, Japan] 20 mg twice daily, clarithromycin 500 mg twice daily, and amoxicillin 1 g twice daily) therapy according to a computer-generated number sequence. All medicines were taken 1 hour before breakfast and dinner. The random number sequence was generated by an independent study assistant. The treatment allocation was concealed in an opaque envelope until anti-H pylori therapy was assigned. After informed consents were obtained from the participants, a study nurse assigned anti-H pylori therapies according to the treatment allocations in the envelopes.

Study Design
All recruited patients were requested to complete a questionnaire that contained questions regarding demographic data and history of smoking, alcohol drinking, nonsteroidal antiinflammatory drug use, and underlying diseases.
The patients were informed of the common adverse events of anti-H pylori therapy and were requested to record the side effects during treatment. The severity of adverse events was recorded according to a 4-point scale (none; mild; moderate; severe) system as previous description. 21 Drug compliance was determined via pill counts. Good compliance was defined as participants taking at least 80% of eradication drugs, and poor compliance was defined as participants taking less than 80% of drugs. 22 Because a gastric cancer presenting with an ulcerative lesion might be missed by initial biopsy at endoscopy on enrollment, a follow-up endoscopy with histological examination, urease test, and culture was performed for the patients with gastric ulcers to assess the eradication outcome and the healing status of ulcers 6 weeks following anti-H pylori therapy. Patients with gastritis or duodenal ulcer underwent a urea breath test to assess final H pylori status. The urea breath test was conducted by a staff who was blind to the eradication arm. The cutoff value of urea breath test was set at 4.8% of d 13 CO 2 . 23 Cure of H pylori infection was defined as negative results of all histology, urease test and bacterial culture, or a negative result of urea breath test.
An antral gastric biopsy specimen was obtained for H pylori culture, using previously described methods. 15 H pylori culture was performed by rubbing the specimens on the surface of a Campy-BAP agar plate (Brucella agar þ IsoVitalex þ 10% whole sheep blood). Then, they were incubated at 378C with microaerobic condition for 4 to 5 days. The results of culture were regarded as positive if at least 1 colony of gram-negative bacilli with positive oxidase, catalase, and urease tests was found. The resistance to antibiotics was assessed by E-test (AB Biodisk, Solna, Sweden), and antibiotic resistances for clarithromycin, amoxicillin, and metronidazole were considered positive if the minimum inhibitory concentration values were >1, >0.5, and >8 mg/mL, respectively. 24

Statistical Analysis
The primary endpoint of the study was eradication rate of H pylori. It was evaluated by intention-to-treat (ITT) and perprotocol (PP) analyses. ITT analysis included all participants enrolled in the study regardless of drug compliance. Participants without follow-up tests for final H pylori status were assumed to have been treated unsuccessfully. PP analysis only included patients with good drug compliance who received follow-up examinations for eradication outcomes. The second outcomes were the frequency of adverse events and compliance to medications. Differences in baseline characteristics, eradication rates, and adverse events between groups were determined by x 2 test or Fisher exact test, as appropriate. The Student t test was used for the comparison of continuous data. SPSS (version 12.0 for Microsoft Windows) were used for all statistical analyses. A P value of <0.05 was regarded as significant difference.
According to our previous study, the eradication rate of standard triple therapy by conventional PPI is 82%. 16 If there is a true difference in favor of the DCA treatment of 8%, at least 176 patients are required to be 90% sure that the upper limit of a 1-sided 95% confidence interval will exclude a difference in favor of the control group of more than 8%, assuming 10% loss to follow-up.
Thirteen clinical and bacterial parameters including age, sex, smoking habit, alcohol consumption (<80 or !80 g/day), drug compliance, and antibiotic resistance were examined by univariate analysis to search the factors related to eradication rate. A stepwise logistic regression method was then applied to search the independent factors influencing eradication outcome.

Characteristics of the Study Groups
A total of 177 H pylori-infected participants were recruited for the study and randomly allocated to DCA (n ¼ 90) or RCA (n ¼ 87) therapy. The baseline demographic data and clinical parameters of the 2 treatment groups are listed in Table 1. There were no differences in all factors between groups. The flow of patients through the study is shown in Figure 1. In the recruited patients, 4 (DCA group: 2 patients; RCA group: 2 patients) with poor compliance and 1 (DCA group: 1 patient; RCA group: 0 patient) with incomplete follow-up were excluded from PP analysis.

Adverse Events and Compliances
Overall, 7.8% of the patients in the DCA group and 4.6% of those in the rabeprazole group suffered from at least 1 adverse event (P U 0.536). Table 3 lists the profiles of adverse events during eradication treatment. The 2 therapeutic groups shared similar adverse events during eradication therapy (Table 3). In the DCA group, 1 patient discontinued medicines owing to the development of skin rash. A patient in the rabeprazole group stopped treatment due to dizziness.
The 2 treatment arms showed comparable compliance rates (97.8% vs 97.7%, P ¼ 1.000). Two patients in the DCA group and another 2 in the RCA group had poor drug compliance.

Factors Influencing Efficacy of Anti-H Pylori Therapy
Univariate analysis showed that clarithromycin was a factor related to the eradication outcome (P ¼ 0.046; Table 4). The other factors including smoking, alcohol consumption, type of PPI, and drug compliance did not influence eradication rate. Multivariate analysis confirmed that clarithromycin resistance was an independent factor determining eradication outcome of standard triple therapy (odds ratio: 6.75; 95% confidence interval [CI], 1.21-37.64; P ¼ 0.029; Table 5).

DISCUSSION
In the current study, we conducted the first, head-to-head, randomized, controlled trial to investigate whether the efficacy of single-dose dexlansoprazole MR-based triple therapy was noninferior to double-dose rabeprazole-based triple therapy in the treatment of H pylori infection. Both ITT and PP analyses demonstrated that the eradication rate of dexlansoprazole MRbased triple therapy was similar to that of rabeprazole-based triple therapy (83.3% vs 81.6% and 85.1% vs 81.2%, respectively). Additionally, both therapies had similar frequencies of adverse events and drug compliance. The data clearly indicate that single-dose dexlansoprazole MR is noninferior to doubledose rabeprazole-base triple therapy in the treatment of H pylori infection.  Currently, lansoprazole 30 mg twice daily is widely used in clinical practice. In this study, single-dose of dexlansoprazole MR 60 mg daily was applied for H pylori eradication. In terms of cost-effective view, the pharmaceutical costs of 7-day dexlansoprazole MR-and rabeprazole-based triple therapies in Taiwan were $19.4 and $20.4, respectively. The former was cheaper than the latter. Dexlansoprazole MR-based therapies can therefore be recommended in the first-line treatment of H pylori infection for Taiwanese and probably most people in the world.
In the current study, the frequencies of adverse events in the dexlansoprazole-MR and rabeprazole group were 7.8% and 4.6%, respectively. The 2 therapeutic groups had comparable frequency of adverse events. Additionally, they shared similar drug compliance (97.8% vs 97.7%). In the dexlansoprazole MR group, 1 patient discontinued eradication therapy due to skin rash. On the other hand, a patient in the rabeprazole group stopped anti-H pylori therapy owing to severe dizziness.
The main reasons for eradication failure for H pylori infection include antibiotic resistance, poor compliance, CYP2C19 genotypes, and smoking. [25][26][27] In the current study, the eradication rate in the patients with clarithromycin-resistant strains was lower than that in those with clarithromycinsusceptible strains (66.7 vs 93.1%). Multivariate analysis    confirmed that the presence of clarithromycin was an independent factor predictive of treatment failure (odds ratio: 6.75). Our findings were consistent with several previous studies that demonstrated clarithromcyin as a key factor influencing eradication outcome of standard triple therapy. [28][29][30] The prevalence of H pylori strains harboring amoxicillin resistance in Taiwan ranged from 0% to 2.3% in previous reports. 19,20,23,24,31,32 In the current trial, the rate of resistant strains to amoxicillin 0%. Since none of the H pylori strains were resistant to amoxicillin, assessing the impact of amoxicillin resistance on eradication outcome of standard triple therapy was precluded. It merits further studies to investigate whether amoxicillin resistance is another independent factor predicting treatment failure of the therapy. This study was an open-label, noninferior, randomized controlled trial. We recruited 197 patients for the study assuming 8% of eradication difference and 10% loss of follow-up. The statistic power and type 1 error of this analysis were 90% and 5%, respectively. The strengths of this study included providing the data regarding antibiotic resistance. Additionally, this study investigated the impacts of antibiotic resistances on eradication rate of standard triple therapy. However, the study has several limitations. First, the current study was conducted only in a single country. The results should therefore be confirmed in other countries with different patterns of antibiotic resistances. Second, antibiotic susceptibility data were only available in some of the patients because most of the patients were referred from other gastroenterologists and culture was not performed at initial endoscopy. Additionally, the genetic factors of hosts such as CYP2C19 genotypes determining eradication were not examined in this study. Nonetheless, this study is the pilot study to investigate the eradication rate of dexlansoprazole MR-based triple therapy. In addition, the study confirms that dexlansoprazole MR-and conventional PPI-based triple therapies have comparable eradication rates for H pylori infection.
In conclusion, our study demonstrates that dexlansoprazole MR-based triple therapy can achieve a similar eradication rate as rabeprazole-based therapy. Since the cost of the singledose dexlansoprazole MR (60 mg) regimen is lower than that of the double-dose rabeprazole (20 mg) regimen, single-dose dexlansoprazole-based triple therapy can reasonably be recommended for the first-line eradication of H pylori.