Real-world-evidence, prospective-observational study to evaluate safety and effectiveness of rabeprazole dual-delayed-release capsules in patients with gastroesophageal reflux disease

Abstract

BACKGROUND

Abnormal gastric acid reflux into the esophagus causes symptoms of gastroesophageal reflux disease (GERD) such as heartburn and regurgitation and also leads to mucosal damage. This damage can further lead to complications such as Barrett’s esophagus and esophagitis. Conventional proton pump inhibitors (PPIs) often fail to reduce nocturnal acid production, leaving patients with unresolved symptoms that worsen at night and decreased satisfaction. Happi ER, a novel dual delayed-release (DDR) formulation of rabeprazole, aims to address these limitations by providing both immediate and prolonged acid suppression.

AIM

To evaluate the safety and effectiveness of rabeprazole DDR 20 mg capsule in patients with GERD.

METHODS

This study involved a multicenter, real-world, prospective, observational design over an eight-week period. A total of 1022 GERD patients were treated with rabeprazole DDR 20 mg capsules (Happi ER), as prescribed by their physicians. We included adult patients with confirmed GERD and persistent heartburn symptoms despite prior PPI use. Outcome measures included heartburn severity, frequency of night-time awakenings, use of rescue medications, and overall patient satisfaction.

RESULTS

Rabeprazole DDR 20 mg capsules (Happi ER) were shown to be highly effective in treating GERD symptoms. At the end of the study, the mean heartburn score improved significantly from 2.46 ± 0.67 at baseline to 0.16 ± 0.39 (P < 0.0001). The median number of night-time awakenings decreased to 0 (P < 0.0001). More than 93% of patients rated the therapy as “excellent” or “very good”, reflecting high satisfaction. No significant adverse effects were reported, and the safety profile was comparable to that of traditional PPIs.

CONCLUSION

By providing both rapid and sustained acid suppression, Happi ER effectively treats GERD, particularly with respect to night-time symptoms. Its safety and efficacy profile make it a viable option for individuals with mild-to-moderate GERD, significantly improving the quality of life and symptom management.

Key Words: Gastroesophageal reflux disease; Heartburn; Acid reflux; Rabeprazole; Dual delayed-release

Core Tip: The novel dual delayed-release formulation of rabeprazole, Happi ER, addresses the unmet needs of gastroesophageal reflux disease (GERD) management by offering both immediate and sustained acid suppression. This real-world evidence study demonstrated significant improvements in heartburn severity, reduced night-time awakenings, and enhanced patient satisfaction, particularly in patients with mild-to-moderate GERD. With a safety profile comparable to that of traditional proton pump inhibitors and superior efficacy in managing nocturnal symptoms, Happi ER provides a comprehensive and reliable solution for long-term GERD management.

INTRODUCTION

Gastroesophageal reflux disease (GERD) refers to symptoms or mucosal injury caused by the abnormal reflux of gastric acid into the esophagus or, in some cases, into the lungs or oral cavity (including the larynx)[1]. In India, the prevalence of GERD ranges from 7.6% to 30%[2]. Heartburn, which affects 20%–40% of patients, is the most common symptom of GERD; however, the condition can present with a wide variety of symptoms. If left untreated, GERD can lead to serious complications such as Barrett’s esophagus (intestinal metaplasia of the esophagus) and esophagitis[3]. In the treatment of GERD, proton pump inhibitors (PPIs) are a crucial component of the pharmacological regimen. PPIs are modified benzimidazoles that bind covalently to the H⁺/K⁺-ATPase in the parietal cells of the stomach, inhibiting the enzyme and blocking the final stage of acid secretion[4]. Despite over two decades of remarkable efficacy and safety in GERD management, certain medication-related challenges such as night-time acid reflux, which is caused by nocturnal acid breakthrough (NAB), pose a significant challenge to effective GERD control. Patients experiencing NAB face a substantially higher risk of developing GERD-related complications[5,6]. After taking a typical once-daily PPI dosage, 40% of patients with GERD report either a partial or total lack of symptom response[7]. Evidence shows that the rate of effective healing of erosive esophagitis is positively correlated with the rate of intragastric acid suppression, particularly when the 24-hour gastric pH is maintained above 4.0[8]. Consequently, a subset of GERD patients, especially those with moderate-to-severe esophagitis or persistent heartburn, may have unmet needs that require a PPI offering prolonged acid suppression. Current PPI formulations, such as rabeprazole Gastro-Resistant Tablets IP available in India, are characterized by relatively short plasma elimination half-lives[9]. As PPI plasma levels decline, newly synthesized and activated proton pumps are not inhibited, leading to reduced gastric acid suppression, particularly during night-time if the PPI is dosed once daily in the morning[10]. To enhance acid control throughout the 24-hour period, extended plasma exposure of the PPI is essential, potentially improving clinical outcomes such as sustained relief from night-time heartburn, more frequent 24-hour heartburn-free days, and effective healing of moderate-to-severe erosive esophagitis[11]. To address this need, a novel dual delayed-release (DDR) formulation of rabeprazole was analyzed. This innovative DDR formulation comprises five minitablets within a single capsule, each coated with two distinct pH-dependent release polymers to ensure prolonged acid suppression. Initially, two of the five minitablets dissolve to release 40% of the drug, while the remaining three dissolve later in the intestine, delivering the remaining 60% of the drug to achieve a secondary peak. This dual-release mechanism is designed to offer both immediate acid suppression, akin to that of delayed-release tablets, and extended plasma exposure over a 24-hour period, providing a prolonged pharmacodynamic effect. The formulation manufacturing has been approved for marketing in India. A current real-world evidence study aims to evaluate the safety and effectiveness of the 20-mg rabeprazole DDR capsules (Cap. Happi ER) in patients with GERD (HERCULES Study).

MATERIALS AND METHODS

Research objective

The primary objective of the real-world prospective observational study was to evaluate the safety and effectiveness of rabeprazole DDR 20 mg capsule in patients with GERD.

Study design and participants

This was a real-world, prospective, observational, single-arm study conducted in the outpatient departments of multiple centers across India over an eight-week period. Approximately 1022 participants were enrolled to receive rabeprazole DDR 20 mg capsules (Cap. Happi ER, manufactured by Zydus Healthcare Ltd., India) at the discretion of the treating physician.

Inclusion and exclusion criteria

Inclusion criteria: The study included male and female patients aged 18–60 years who had a confirmed diagnosis of Gastric Acid Reflux Disorder determined through endoscopy and presented with symptoms of heartburn according to the Four-Graded Scale for Severity for Heartburn[12]. Eligible patients were those who had not received any PPIs in the 4 weeks that preceded enrollment and were prescribed rabeprazole DDR 20 mg (Cap. Happi ER) with the discretion of the treating physician.

Exclusion criteria: Patients were excluded if they were pregnant or lactating, had a known hypersensitivity to rabeprazole, or were deemed unsuitable to receive rabeprazole DDR 20 mg by the treating physician. Additionally, nonconsenting individuals and those who did not comply with the study requirements were not included.

Baseline examination and study follow-up

The study commenced after obtaining informed consent from all participants. Participants were prescribed rabeprazole DDR 20 mg capsules (Cap Happi ER) by their attending physicians. At baseline, each participant’s demographic details and medical history were recorded, followed by a thorough general and systematic examination. The intensity of the heartburn was assessed, and any concomitant medications were documented. Participants were instructed to take the study medication daily at the prescribed time and for the duration determined by the physician. During the first follow-up (2–4 weeks), routine clinical examinations were performed, including the assessment of heartburn scores, frequency of night-time awakenings due to heartburn, and the number of rescue antacid medications taken. These assessments were repeated at the final follow-up (6–8 weeks), along with a global assessment of treatment effectiveness by the treating physician and the patient. All data were recorded in case report forms and later transferred into a Microsoft Excel spreadsheet.

Dosing procedure

At enrollment, all patients were treated with rabeprazole DDR 20 mg capsules, which they purchased from the pharmacy. Patients were allowed to take antacid tablets as needed during the GERD treatment course. However, no other medications specifically for GERD or heartburn were permitted during the study period. Patients requiring additional GERD medications were excluded from the final analysis, with only rescue antacids prescribed for breakthrough heartburn symptoms being included in the study. Concomitant medications for managing other conditions unrelated to GERD or heartburn were permitted.

Effectiveness and safety assessment

In this study, we assessed the effectiveness based on several parameters: (1) The heartburn score; (2) The number of rescue antacid medications used; (3) The rate of night-time awakenings due to heartburn; and (4) A global assessment of the effectiveness by the physician and the patient. Heartburn was evaluated using a four-graded scale: (1) “None”for no symptoms; (2) “Mild” for awareness of symptoms that were easily tolerated; (3) “Moderate” for discomfort that interfered with normal activities; and (4) “Severe” for incapacitation. This score was measured at the baseline, first follow-up, and final follow-up visits. Additionally, the number of rescue antacids used in the week prior to each follow-up visit was recorded, along with the rate of night-time awakenings due to heartburn. The physician provided a global assessment of the effectiveness of Cap Happi ER at the end of the treatment, rating it as excellent, very good, good, fair, or poor. Similarly, patients rated their symptomatic relief on a scale from 0 to 10, where 0 represented no relief and 10 represented complete relief. Safety was assessed by recording any adverse events reported by patients or noted during clinical examinations at follow-up visits[13].

Statistical analysis

After verifying the completed case report forms, data entry was initiated. The relevant data were entered in Microsoft Excel spreadsheets and analyzed using Statistical Package for the Social Sciences version 25.0. Quantitative variables were presented as the mean and SD for normally distributed data or the median and interquartile range for skewedly distributed data. Categorical variables were presented as frequencies and percentages. P values less than 0.05 were considered statistically significant.

Ethical considerations

The study received approval from the Independent Ethics Committee of Suraksha Ethics Committee, Dombivli (No. ECR/644/Inst/MH/2014/RR-20). The study was conducted in accordance with the principles outlined in the Declaration of Helsinki and its subsequent revisions, good clinical practice guidelines, and other applicable national regulatory guidelines.

RESULTS

A total of 1022 patients were enrolled in the study, with a mean age of 44.94 years ± 10.38 years and a mean body mass index of 25.43 kg/m² ± 3.79 kg/m². The majority of the patients were male (612, 59.88%). The mean number of mild-to-moderate heartburn episodes was 7 ± 6.3 and 2.91 ± 3.3, respectively, with a mean treatment duration of 4.6 weeks ± 1.71 weeks (Table 1). The majority of these patients had diabetes mellitus (16.54%) and other comorbid conditions (Table 2). This suggests a higher prevalence of GERD in patients with diabetes mellitus and highlights that patients with GERD tend to have elevated blood pressure and irregular cholesterol levels. The consumption of Happi ER in the study showed that 84.54% of patients took the medication once daily, while 15.46% took it twice daily. Regarding the timing of the doses, 89.24% of patients took the medication before breakfast, while 27.98% took it before dinner. Additionally, 18.59% of patients reported using antacids during the course of treatment, and 31.31% of patients were on other concurrent treatments (Table 3). At baseline, the mean heartburn score was 2.46 ± 0.67, which significantly decreased to 0.16 ± 0.39 by visit 3 (P < 0.0001). The number of night-time awakening episodes due to heartburn, which was initially reported as a median of 2 (range: 1–2), reduced to 0 (none) by visit 3 (P < 0.0001). These results, based on the paired t-test, indicate a statistically significant improvement in both heartburn symptoms and sleep disturbance due to GERD following treatment with Happi ER (Table 4). Based on the global assessment of Happi ER, 60.6% of patients rated the treatment as “excellent”, 32.9% as “very good”, followed by 5.9% rating it as “good”, and 0.7% as “fair” (Table 5). When assessing the adverse events, the most common occurrences were diarrhea (26.09%), constipation (17.39%), and giddiness (13.04%), among others. The association of these adverse events with the treatment showed that 65.22% were considered related to Happi ER use, 30.43% were classified as unrelated, and 4.35% were deemed possibly related (Table 6).

Table 1 Baseline characteristics.

Variables	mean ± SD
Age (years)	44.94 ± 10.38
Body mass index (kg/m2)	25.43 ± 3.79
Number of moderate heartburn episodes	7 ± 6.3
Number of severe heartburn episodes	2.91 ± 3.3
Duration of Happi ER treatment (weeks)	4.6 ± 1.71

Table 2 Associated comorbidities in the enrolled participants.

Comorbid condition	Frequency	Percentage
Diabetes mellitus	169	16.54
Hypertension	152	14.87
Dyslipidemia	16	1.57
Chronic obstructive pulmonary disease	10	0.98
Hypothyroidism	9	0.88
Arthritis	8	0.78
Asthma	8	0.78
Obesity	6	0.59
Migraine	3	0.29
Osteoarthritis	3	0.29
Allergic asthma	2	0.20
COPS	2	0.20
Hyperlipidemia	2	0.20
Pulmonary tuberculosis	2	0.20
Rheumatoid arthritis	2	0.20
Systemic hypertension	2	0.20
Chronic pancreatitis	1	0.10
Common bile duct stone	1	0.10
Cholelithiasis	1	0.10
Chronic kidney disease	1	0.10
Chronic liver disease	1	0.10
Renal calculi	1	0.10
Lumbar spondylitis	1	0.10
Cardiovascular diseases	1	0.10
Grade II fatty liver	1	0.10
Uterine fibroid	1	0.10

Table 3 Timing and frequency of Happi ER prescribed, antacid consumption, and other ongoing treatments.

Variables	Frequency	Percentage
Timing of Happi ER prescribed
Before breakfast	912	89.24
Before lunch	04	0.39
Before dinner	286	27.98
Frequency of Happi ER
Once daily	864	84.54
Twice daily	158	15.46
Antacid consumption in previous week
Yes	190	18.59
No	832	81.41
Other ongoing treatments
Yes	320	31.31
No	702	68.69

Table 4 Comparison of heartburn score and number of awakening episodes at baseline and visit 3.

Variables	At baseline	At visit 3	Paired t-test
Heartburn score	2.46 ± 0.67	0.16 ± 0.39	P < 0.0001
Number of episodes of awakening	2 (1–2)	0 (0)	P < 0.0001

Table 5 Effectiveness assessment of Happi ER.

Effectiveness	Frequency	Percentage
Excellent	619	60.6
Very good	336	32.9
Good	60	5.9
Fair	7	0.7
Total	1022	100.0

Table 6 Nature and association of adverse events during the study.

Variables	Frequency	Percentage
Nature of adverse event
Diarrhea	6	26.09
Constipation	4	17.39
Giddiness	3	13.04
Headache	2	8.70
Acidity	2	8.70
Polydipsia	1	4.35
Loose motion	1	4.35
Polyphagia	1	4.35
Fatigue	1	4.35
Dry mouth	1	4.35
Vomiting	1	4.35
Association of adverse events using causality assessment criteria
Related	15	65.22
Unrelated	7	30.43
Possible	1	4.35

DISCUSSION

Night-time heartburn significantly affects the quality of life, leading to fatigue, decreased productivity, and mental health issues related to poor sleep quality. This condition is exacerbated by prolonged supine positioning, which increases the risk of esophageal injury[14]. Uncontrolled nocturnal acid reflux disrupts sleep and increases the risk of complications like esophagitis or Barrett’s esophagus due to prolonged acid exposure. Effective night-time heartburn management is crucial to reduce these risks and enhance patient well-being. In this context, a once-daily rabeprazole 20 mg regimen has demonstrated superior efficacy compared with a once-daily lansoprazole 30 mg regimen in patients with cluster GERD and severe heartburn[15]. Studies comparing pantoprazole and rabeprazole for nocturnal gastric acidity control, when administered prior to breakfast, confirmed the efficacy of both drugs[16]. However, rabeprazole DDR showed exceptional results in the present study, providing sustained acid suppression during the critical night-time period. The dual-release mechanism of Happi ER is crucial to its effectiveness. It provides an initial release of rabeprazole shortly after ingestion, followed by a second release several hours later. This formulation ensures sustained plasma levels of the drug throughout the 24-hour cycle, effectively managing nocturnal symptoms, which conventional PPIs often fail to address adequately[17]. Unlike standard formulations that may not extend their acid-suppressing effects into the night, Happi ER consistently maintained an intragastric pH of > 4 for 14.8 hours, resulting in significant reductions in night-time heartburn symptoms, improved sleep quality, and a higher rate of complete symptom relief, particularly for patients with mild-to-moderate GERD. Long-term studies have shown that both 10 mg and 20 mg doses of rabeprazole are as effective as omeprazole 20 mg in maintaining esophageal erosion healing for up to 5 years[18]. Rabeprazole consistently demonstrates rapid and sustained acid control, offering effective relief from GERD symptoms and promoting acute healing of erosive esophagitis with continued healing for at least one year[18,19]. The current study reveals that Happi ER, with its DDR formulation, achieves superior 24-hour acid suppression and extended plasma exposure, significantly reducing nocturnal GERD symptoms and improving symptom relief, especially in patients with mild-to-moderate erosive esophagitis. Happi ER provides a more comprehensive and long-lasting solution for managing GERD by improving control over stomach acidity throughout the night. This may help slow the progression of GERD-related complications and enhance overall symptom relief. Its safety profile is comparable to that of conventional PPIs, with manageable side effects like constipation and diarrhea reported in a small proportion of patients, and no serious life-threatening adverse effects observed[20]. Although rare, longer-term PPI users have been linked to more significant hazards such as Clostridium difficile infection, osteoporosis-related fractures, and chronic renal disease[21]. Compared with the broader PPI class, Happi ER’s DDR mechanism does not increase the frequency or severity of side effects, making it a safe and effective option for long-term GERD management, particularly for patients requiring enhanced night-time acid suppression. In addition, GERD has been linked to metabolic and cardiovascular conditions such as diabetes and hypertension, which may exacerbate symptoms, especially night-time heartburn. Factors like obesity, delayed gastric emptying in diabetic individuals, and medications for hypertension may exacerbate GERD[22]. Future research could explore how these comorbidities impact GERD severity and treatment efficacy, potentially evaluating if Happi ER’s DDR formulation offers better acid control for patients with these conditions, leading to more personalized GERD treatments. Overall, the novel rabeprazole DDR formulation has demonstrated safety and efficacy in managing GERD, supported by data from 1022 patients. One limitation of this study is the potential confounding effect of dietary modifications and lifestyle habits on the observed outcomes. Many GERD patients adopt dietary changes alongside medication, which could have contributed to the improvements in symptom control observed in this study. While this study did not explicitly record dietary habits, the effectiveness of rabeprazole DDR was consistently demonstrated across a broad patient population, suggesting that the observed benefits are could be attributed to the pharmacological properties of the medication. Despite the large sample size and multicenter nature of the trial, the study’s limitations include patient selection bias, the lack of investigation into the impact of concomitant medications and antacids on Happi ER’s effectiveness, and the absence of nocturnal symptom scoring evaluation. Future research should compare Happi ER with other conventional PPIs to predict successful patient and prescriber satisfaction.

CONCLUSION

Rabeprazole’s new DDR formulation, Happi ER, demonstrated safety and effectiveness in treating GERD symptoms. It showed significant reductions in heartburn severity, fewer night-time awakenings, and higher levels of patient satisfaction compared with traditional PPIs. The dual-release mechanism of Happi ER, offering both rapid and extended acid suppression, effectively managed night-time symptoms, an area where traditional PPIs often fall short, by maintaining the intragastric pH for long enough. Happi ER’s safety profile was comparable to that of conventional PPIs, with no serious adverse effects reported and side effects being manageable. This study highlights Happi ER’s potential as a superior treatment option for GERD, especially for patients with mild-to-moderate symptoms and night-time acid reflux, offering a comprehensive solution for long-term management and symptom relief.

ACKNOWLEDGEMENTS

We sincerely thank all participants and the treating physicians at the participating centers for their contributions to this study. We are also grateful to Zydus Healthcare Ltd. for providing the Rabeprazole DDR 20 mg capsules (Cap. Happi ER) and to the Suraksha Ethics Committee, Dombivli, for their ethical oversight.