Functional dyspepsia (FD) is a common gastrointestinal (GI) disorder characterized by chronic and recurrent symptoms of epigastric pain, burning, postprandial fullness, and early satiation.^1,2 Rome foundation categorizes FD into 2 subtypes, epigastric pain syndrome (EPS) and postprandial distress syndrome (PDS), based on the predominant symptom pattern.² The pathogenesis of FD is complex and involves different underlying mechanisms that contribute to diverse patterns of symptoms. Impaired gastric accommodation, delayed gastric emptying, abnormal clearance of duodenal acid, and visceral hypersensitivity are involved in both the EPS and PDS subtypes.² Many studies have revealed that acid-related mechanisms play a crucial role in FD pathogenesis, including hypersensitivity to acid, reduced duodenal acid clearance, and altered gastric motility induced by duodenal acid,^3-5 and so, acid suppressive medication has been recommended as a good treatment option for FD. Proton pump inhibitors (PPIs) have been shown to be more effective than placebos for symptom improvement in FD in many randomized controlled trials and also in meta-analyses.^6,7 Therefore, PPIs have been recommended as the first-line treatment for FD in many clinical guidelines.^1,8,9

Recently, potassium-competitive acid blockers (P-CABs), which have many advantages over PPIs, have emerged as a new class of acid-suppressive drugs and are in the spotlight for the treatment of many acid-related diseases such as gastroesophageal reflux disease (GERD) and peptic ulcer disease. Tegoprazan is a novel P-CAB that binds to the H⁺/K⁺-ATPase on parietal cells and rapidly and effectively reduces acid secretion.¹⁰ Animal and clinical studies have shown that tegoprazan has a faster and longer-lasting acid inhibitory effect than PPIs.^11,12 Therefore, tegoprazan has the potential to be at least non-inferior to PPIs in improving FD symptoms. However, few studies have investigated the efficacy of P-CABs in the treatment of FD. The aim of this study was to evaluate the efficacy and safety of tegoprazan in patients with FD.

Study Design

This was a prospective, multicenter, open-label, single-arm trial conducted to assess the efficacy and safety of tegoprazan administered once daily for 8 weeks to Korean patients with FD diagnosed using the Rome IV criteria. This study was conducted at 11 referral hospitals in South Korea between January 2021 and June 2022. The study protocol was approved by the institutional review board of each participating institution (3-2020-0176), and the study was registered at cris.nih.go.kr (KCT0005600). Written informed consent was obtained from all patients before enrollment in the study. All authors had access to the study data, and reviewed and approved the final manuscript.

Patient Population

Patients who met the Rome IV criteria for FD were recruited for this study. The EPS was defined as experiencing bothersome epigastric pain, burning, or both, at least 1 day per week. PDS was defined as experiencing bothersome postprandial fullness, early satiety, or both, at least 3 days per week. Those with the overlapping variant fulfilled criteria for both conditions.² All patients underwent upper endoscopy within 4 weeks. The inclusion criteria were as follows: (1) patients aged ≥ 19 years and (2) patients who suffered one or more of the 4 major dyspeptic symptoms (epigastric pain, epigastric burning, early satiety, and postprandial fullness) for ≥ 6 months and had continually experienced dyspeptic symptoms of at least moderate severity within the last 3 months. Patients were excluded for the following: (1) unable to undergo upper endoscopy; (2) presence of esophageal stricture, peptic ulcer obstruction, esophageal varices, Barrett’s esophagus, eosinophilic esophagitis, active peptic ulcer, or bleeding during endoscopy; (3) planning to perform surgery or history of receiving surgery that could affect gastric acid secretion (such as upper gastrectomy and vagotomy); (4) diagnosed with primary esophageal motility disorder, or diabetic gastroparesis; (5) known hypersensitivity to antacids, PPIs, and P-CABs; (6) history of malignancy within 5 years; (7) coexisting diseases; (8) pregnancy or lactation; (9) history of alcohol or drug abuse; (10) human immunodeficiency virus; (11) use of PPI, histamine-2 receptor antagonist (H2RA), prokinetics, nonsteroidal anti-inflammatory drugs, anticholinergics, glucocorticoid, or antidepressants 14 days before enrollment; (12) Hospital Anxiety and Depression Scale ≥ 8; or (13) at the investigator’s discretion.

Study Protocol

Patients who met the inclusion criteria completed the Nepean Dyspepsia Index-Korean (NDI-K), GERD-questionnaire (GERD-Q), and GERD–health-related quality of life (GERD-HRQL) questionnaires. The NDI-K and GERD-HRQL are well-validated questionnaires used to evaluate symptomatic outcomes and therapeutic effects in patients with FD and GERD.^13,14 All patients received 50 mg tegoprazan once a day after breakfast for 8 weeks. Patients visited the hospital 4 weeks and 8 weeks after starting the medication and completed a dyspepsia symptom questionnaire using a 5-point Likert scale: 1 = very aggravated, 2 = aggravated, 3 = no change, 4 = improved, and 5 = very improved. At 4 weeks and 8 weeks, the patients completed the NDI-K and GERD-HRQL questionnaires, and medication compliance and adverse events related to tegoprazan were evaluated at each visit. Patients returned remaining study drugs after 4 weeks and 8 weeks, respectively. The investigator evaluated compliance through the patients’ unused study drugs and returned them to the pharmacist. The use of any medications that could potentially affect the symptoms of FD or GERD, such as PPIs, H2RAs, prokinetics, NSAIDs, anticholinergics, glucocorticoids, or antidepressants, was restricted from 14 days before the study registration until the end of the study.

Endpoints

The primary endpoint was the rate of satisfactory relief of symptoms according to the dyspepsia symptom questionnaire (defined as 5-point Likert scale of ≥ 4 at week 8: improved or very improved). The secondary endpoints were the rate of satisfactory relief of symptoms according to the dyspepsia symptom questionnaire at 4 weeks and differences in the NDI-K and GERD-HRQL scores after 4 weeks and 8 weeks from baseline. Safety was evaluated based on treatment-emergent adverse events (TEAEs) at weeks 4 and 8, physical examinations, vital signs, or laboratory test results.

Sample Size Calculation

A previous study revealed that the rate of symptom relief in patients administered PPI was 31.1%.⁷ We assumed that tegoprazan would not be inferior to PPIs in terms of symptom relief, with a non-inferiority margin of −10%. With a value of 0.05 and a power of 80%, the estimated sample size was 168 patients. Considering a dropout rate of 10%, 187 patients were required.

Statistical Analysis

Efficacy assessments were analyzed primarily in the per-protocol set (PPS). Safety assessments were performed using the safety set. Categorical variables are presented as frequencies and percentages (%) and were analyzed using the chi-square test or Fisher’s exact test. Continuous variables are presented as mean and standard deviation, median, minimum, and maximum. In addition, two-group comparisons were analyzed using the independent t test and Wilcoxon’s rank-sum test, and comparisons of 3 or more groups were analyzed using analysis of variance and the Kruskal-Wallis test. Within-group comparisons were performed using the paired t test, Wilcoxon signed-rank test, and McNemar test. The statistical program SAS (version 9.4; SAS Institute, Cary, NC, USA) was used for the analysis. All tests were performed at a significance level of P < 0.05.

Patient Characteristics

A total of 209 patients were screened, and 187 patients were enrolled. Fourteen patients were excluded due to major protocol violations. As a result, the PPS analysis included 173 patients (Fig. 1). Patient characteristics are summarized in Table 1. The patients had a mean age of 41.3 years, and 71.7% were women. There were no significant differences in baseline characteristics among the different subtypes of FD.

Figure 1. Flow chart.

Table 1 . Baseline Characteristics of Patients

Characteristics	PPS (N = 173)				P-value
	Total (n = 173)	EPS (n = 48)	PDS (n = 75)	Overlapping EPS and PDS(n = 50)
Sex					0.068a
Male	49 (28.32)	8 (16.67)	27 (36.00)	14 (28.00)
Female	124 (71.68)	40 (83.33)	48 (64.00)	36 (72.00)
Age (yr)	41.3 ± 14.0	41.5 ± 15.4	39.4 ± 12.7	43.9 ± 14.5	0.288b
BMI (kg/m2)	22.83 ± 3.35	22.83 ± 3.02	22.42 ± 3.07	23.44 ± 3.98	0.456b
Smoking					0.380c
Yes	8 (4.62)	2 (4.17)	2 (2.67)	4 (8.00)
No	165 (95.38)	46 (95.83)	73 (97.33)	46 (92.00)
Alcohol consumption					0.826a
Yes	40 (23.12)	10 (20.83)	19 (25.33)	11 (22.00)
No	133 (76.88)	38 (79.17)	56 (74.67)	39 (78.00)
Endoscopic finding
Atrophic gastritis	70 (40.46)	19 (39.58)	27 (36.00)	24 (48.00)	0.404a
Erythematous exudative gastritis	31 (17.92)	6 (12.50)	12 (16.00)	13 (26.00)	0.186a
Flat erosive gastritis	13 (7.51)	5 (10.42)	4 (5.33)	4 (8.00)	0.545c
Hemorrhagic gastritis	1 (0.58)	1 (2.08)	0 (0.00)	0 (0.00)	0.278c
Intestinal gastritis	9 (5.20)	3 (6.25)	4 (5.33)	2 (4.00)	0.913c
Raised erosive gastritis	5 (2.89)	0 (0.00)	1 (1.33)	4 (8.00)	0.061c
Anti-Helicobacter pylori IgG antibody (+)	36 (20.81)	10 (20.83)	12 (16.00)	14 (28.00)	0.280c
HADS score
Total	4.10 ± 2.18	4.42 ± 2.09	3.84 ± 2.20	4.18 ± 2.24	0.345b
Depression	2.12 ± 1.46	2.17 ± 1.39	1.87 ± 1.49	2.44 ± 1.45	0.071b
Anxiety	1.98 ± 1.47	2.25 ± 1.21	1.97 ± 1.52	1.74 ± 1.59	0.094b

^aChi-square test.

^bKruskal-Wallis test.

^cFisher’s exact test.

PPS, per-protocol set; EPS, epigastric pain syndrome; PDS, postprandial distress syndrome; BMI, body mass index; HADS, Hospital Anxiety and Depression Scale.

Data are presented as mean ± SD or n (%).

Efficacy Analysis

Primary and secondary endpoints

The efficacy outcomes are summarized in Table 2 and Figures 2 and 3. The satisfactory symptom relief rates based on the dyspepsia symptom questionnaire at 8 weeks were 86.7% (150/173), 83.3% (40/48), 86.7% (65/75), and 90.0% (45/50) for the total, EPS, PDS, and overlapping subtypes, respectively (Fig. 2A). At 4 weeks, the satisfactory symptom relief rates were 74.6% (129/173), 70.8% (34/48), 73.3% (55/75), and 80.0% (40/50) for the total, EPS, PDS, and overlapping subtypes, respectively (Fig. 2B). Also, NDI-K and GERD-HRQL scores significantly improved at 4 weeks and 8 weeks compared to baseline scores (Table 2 and Fig. 3). The detailed NDI-K and GERD-HRQL scores are presented in Supplementary Tables 1 and 2. The satisfactory symptom relief rates and NDI-K and GERD-HRQL scores significantly improved at 8 weeks compared to those at 4 weeks (Fig. 3).

Figure 2. Satisfactory symptom relief rate at 8 weeks (A) and 4 weeks (B). EPS, epigastric pain syndrome; PDS, postprandial distress syndrome.

Figure 3. Change from Baseline in Nepean Dyspepsia Index-Korean (NDI-K) score at 4 weeks and 8 weeks (A). Change from Baseline in gastroesophageal reflux disease–health-related quality of life (GERD-HRQL) score at 4 weeks and 8 weeks (B). GERD-Q, gastroesophageal reflux disease questionnaire.

Table 2 . Change From Baseline in Nepean Dyspepsia Index-Korean and Gastroesophageal Reflux Disease–Health-related Quality of Life Scores at Week 4 and Week 8

Parameters	Week 4					Week 8
	EPS (n = 48)	PDS (n = 75)	Overlapping EPS and PDS (n = 50)	P-valuea		EPS (n = 48)	PDS (n = 75)	Overlapping EPS and PDS (n = 50)	P-valuea
NDI-K score	27.00 ± 17.60	22.13 ± 17.85	30.38 ± 22.24	0.036	20.38 ± 21.06		12.64 ± 13.90	18.18 ± 18.78	0.078
Change from baseline	–27.98 ± 25.14	–24.97 ± 24.31	–47.20 ± 29.89	< 0.001	–34.60 ± 26.33		–34.47 ± 24.52	–59.40 ± 31.94	< 0.001
GERD-HRQL total score	5.42 ± 4.97	4.37 ± 4.08	6.14 ± 5.63	0.281	3.44 ± 4.80		2.36 ± 2.69	3.42 ± 4.10	0.839
Change from baseline	–7.19 ± 7.61	–3.84 ± 4.94	–9.98 ± 8.46	< 0.001	–9.17 ± 7.60		–5.85 ± 5.26	–12.70 ± 8.79	< 0.001

^aKruskal-Wallis test.

EPS, epigastric pain syndrome; PDS, postprandial distress syndrome; NDI-K, Nepean Dyspepsia Index-Korean; GERD-HRQL, gastroesophageal reflux disease–health-related quality of life.

Data are presented as mean ± SD.

Subgroup analysis

Although the subtype (EPS, PDS, or overlapping) and Helicobacter pylori status are important background factors for FD, these characteristics did not significantly influence the efficacy of tegoprazan. No apparent differences in the efficacy of tegoprazan were observed among the FD subtypes (Table 3). Subgroup analysis was performed for the patients with overlapping FD-GERD (GERD-Q ≥ 8). Although there was no significant difference in the satisfactory symptom relief rate, patients with overlapping FD and GERD experienced greater improvements in the NDI-K and GERD-HRQL scores than those with only FD symptoms (Supplementary Table 3).

Table 3 . Baseline Characteristics According to Satisfactory Symptom Relief

Characteristics	PPS (N = 173)
	Total (n = 173)	Symptom relief (n = 150)	No symptom relief(n = 23)	P-value
Sex
Male	49 (28.32)	43 (28.67)	6 (26.09)	0.798a
Female	124 (71.68)	107 (71.33)	17 (73.91)
Age (yr)	41.3 ± 14.0	41.5 ± 14.1	40.4 ± 14.1	0.849b
BMI (kg/m2)	22.83 ± 3.35	22.90 ± 3.32	22.38 ± 3.63	0.246b
Smoking				> 0.999c
Yes	8 (4.62)	7 (4.67)	1 (4.35)
No	165 (95.38)	143 (95.33)	22 (95.65)
Alcohol consumption				0.372a
Yes	40 (23.12)	33 (22.00)	7 (30.43)
No	133 (76.88)	117 (78.00)	16 (69.57)
Syndrome subtype				0.624a
EPS	48 (27.74)	40 (26.67)	8 (34.78)
PDS	75 (43.35)	65 (43.33)	10 (43.48)
Overlapping EPS and PDS	50 (28.90)	45 (30.00)	5 (21.74)
Main endoscopic finding
Atrophic gastritis	70 (40.46)	65 (43.33)	5 (21.74)	0.049a
Erythematous exudative gastritis	31 (17.92)	27 (18.00)	4 (17.39)	> 0.999c
Flat erosive gastritis	13 (7.51)	13 (8.67)	0 (0.00)	0.221c
Hemorrhagic gastritis	1 (0.58)	1 (0.67)	0 (0.00)	> 0.999c
Intestinal metaplasia	9 (5.20)	8 (5.33)	1 (4.35)	> 0.999c
Raised erosive gastritis	5 (2.89)	4 (2.67)	1 (4.35)	0.514c
Anti-Helicobacter pylori IgG antibody (+)	36 (20.81)	32 (21.33)	4 (17.39)	0.751c

^aChi-square test.

^bWilcoxon rank sum test.

^cFisher’s exact test.

PPS, per-protocol set; EPS, epigastric pain syndrome; PDS, postprandial distress syndrome; BMI, body mass index.

Data are presented as n (%).

Safety Analysis

The incidence of adverse events was 14.1% (26/185) in the 185 patients in the safety analysis set and that of drug-related TEAE was 1.6% (3/185). No serious drug-related TEAE or deaths occurred during the study period. Additional details are provided in Supplementary Table 4.

This is the first study to demonstrate the efficacy of P-CAB in patients with FD. In our study, tegoprazan 50 mg daily showed a satisfactory symptom relief rate of 86.7% after 8 weeks and 74.6% after 4 weeks. These results were not influenced by the FD subtype or presence of H. pylori infection. Patients with overlapping FD and GERD demonstrated an even greater improvement in symptoms than those with only FD symptoms.

Acid-related mechanisms, such as acid hypersensitivity, reduced duodenal acid clearance, and altered gastric motility induced by duodenal acid, have been identified as having an important role in FD pathogenesis.^3-5 So, PPIs have been shown to be more effective than placebo in relieving symptoms in patients with FD and have been recommended as the first-line treatment in recent guidelines.^1,7-9 Traditionally, PPIs were believed to be effective for FD patients with the EPS subtype, and several guidelines suggested tailored PPI treatment based on the FD subtype.^15-17 However, recent studies and meta-analyses have reported no significant difference in treatment response to PPIs based on FD subtype.^1,7,18,19 These findings are consistent with the results of our study. In our study, tegoprazan demonstrated a high efficacy in symptom improvement in patients with FD regardless of the subtype (EPS subtype, 83.3%; PDS subtype, 86.7%; overlapping subtype, 90.0%; P = 0.624). The reason for these results remains unclear. It is known that gastric acid plays a role in generating dysmotility symptoms such as feelings of heaviness in the stomach and satiety through gastric and/or duodenal hypersensitivity.²⁰ The findings of our study may reflect these perceptions, which are consistent with recent evidence.^1,6,7

Tegoprazan, a novel P-CAB, was approved for the treatment of GERD and gastric ulcers and for H. pylori eradication in South Korea in 2018. It is known to rapidly inhibit acid secretion from the time of initial administration and has demonstrated sustained acid suppression in experimental and clinical studies.^10-12 Despite its potential as a first-line treatment option for patients with FD, no previous studies have investigated its efficacy in these patients. Iwakiri et al⁶ reported that rabeprazole 20 mg for 8 weeks in FD patients resulted in symptom improvement rates of 45.3%, which were significantly better than those of the placebo group (28.2%). Recent meta-analyses have also reported an overall symptom improvement rate of 31.1% for PPI treatment in FD, with no significant correlation observed between PPI dosage or treatment duration.⁷ Moreover, PPIs were found to significantly improve FD symptoms compared to placebo (risk ratio, 0.88; 95% CI, 0.82-0.94; P < 0.001).⁷ In our study, after 4 weeks of tegoprazan administration, symptom improvement rate was 74.6%, and it further increased to 86.7% at 8 weeks, demonstrating a higher efficacy in symptom improvement compared to conventional PPI treatment. Based on the results of this study, tegoprazan showed a remarkable improvement in FD symptoms regardless of the FD subtype or H. pylori status. No serious drug-related TEAEs were observed during the study period. Although additional large-scale randomized controlled trials are necessary, the findings of this study suggest that tegoprazan could be considered a first-line treatment option for patients with FD.

FD is often accompanied by GERD in 9-76% of all cases.^21-23 Patients who have both FD and GERD tend to experience a lower quality of life compared to those who only have FD symptoms.²⁴ In the present study, satisfactory symptom relief rate as well as the improvement for NDI-K and GERD-HRQL scores were higher in patients with overlapping FD-GERD than in those with only FD symptoms. The symptomatic therapeutic effects of tegoprazan were more pronounced in patients with overlapping FD and GERD than in those without GERD. The exact reason for the better symptom relief with tegoprazan in patients with overlapping FD-GERD remains unclear, but there are several possible explanations. First, it is possible that the more severe baseline symptoms experienced by patients with overlapping FD-GERD make it easier to detect symptom improvement after tegoprazan treatment. Secondly, the role of gastric acid in the development of GERD may be more important, leading to a greater therapeutic effect of tegoprazan. Finally, there could be unknown confounding factors contributing to the differential therapeutic effects. Based on our results, tegoprazan treatment is expected to be effective in patients with overlapping FD and GERD.

The optimal duration of PPI use for the treatment of patients with FD has not yet been established. According to recent guidelines, an 8-week course of PPI treatment demonstrated a significant improvement in symptoms compared to a 4-week course of PPI treatment when compared to a placebo.¹ However, another meta-analysis did not find any significant relationship between the duration of PPI treatment and the improvement of FD symptoms.⁷ In our study investigating the efficacy of tegoprazan, the symptom improvement rate was found to be significantly higher after an 8-week treatment period than after a 4-week treatment period. The exact reason for this discrepancy is unclear and requires further large-scale randomized trials.

This study has several limitations that must be considered. First, there may be biases related to the “reassuring effects.” These biases may occur when patients feel reassured after being informed about the absence of worrisome endoscopic findings at the beginning of the study. Additionally, patients may expect to receive cutting-edge medical care, which can also contribute to “reassuring effects.” Second, this was a single-arm, open-label study, which means it lacked a control group. This design could be influenced by confounding factors and biases, including possible placebo effects. In the case of FD, placebo effects have been reported to be as high as 30-39%.^7,25 This high placebo response in FD is attributed not only to psychological and neurobiological effects but also to the natural history of FD.²⁶ Therefore, our single-arm design presents a significant limitation in addressing these “placebo response” considerations. Consequently, further randomized controlled trial with an appropriate sample size for placebo comparison are warranted. Third, we did not investigate the actual amount of gastric acid secreted through pH monitoring. Fourth, we could not include all the questionnaires related to FD such as patient assessment of upper gastrointestinal disorders-symptom severity index or self-evaluation questionnaire for dyspepsia.²⁷ Fifth, since the symptom questionnaires were administered at 4 weeks and 8 weeks, there is a potential for recall bias. Finally, our results are restricted to South Korea and cannot be generalized to other ethnicities or countries. Nevertheless, this is the first study to demonstrate the efficacy of P-CAB in patients with FD. We conducted upper endoscopy, a H. pylori test, and various laboratory tests to identify any potential confounding factors that could influence symptom improvement. Moreover, we evaluated symptom improvement from different perspectives using a variety of questionnaires, thereby providing a comprehensive assessment of the treatment impact.

In conclusion, tegoprazan 50 mg once daily provided satisfactory symptom relief in patients with FD, irrespective of the FD subtype or H. pylori status. Moreover, the efficacy of tegoprazan was more pronounced in patients with overlapping FD-GERD than in those without GERD. Although further large-scale randomized controlled trials are needed, the results of our study suggest that tegoprazan could be considered a first-line treatment option for patients with FD.

Note: To access the supplementary tables mentioned in this article, visit the online version of Journal of Neurogastroenterology and Motility at http://www.jnmjournal.org/, and at https://doi.org/10.5056/jnm23150.

This study was supported by HK inno.N Corp, Seoul, Republic of Korea. HK inno.N Corp provided financial support and study drug, however no role in the design of this study, study conduct, data analysis, and interpretation of the data.

None.

Cheal Wung Huh and Young Hoon Youn: study design, data collection and analysis, interpretation of the data, and drafting of the manuscript; Da Hyun Jung, Ra Ri Cha, Yeon Ji Kim, Kyoungwon Jung, Ki Bae Bang, Chung Hyun Tae, Soo In Choi: data collection, analysis, and interpretation of the data, and editing of the final version of the manuscript; and Kyung Ho Song and Cheol Min Shin: study design, data collection, and critical review of the manuscript for important intellectual content. All authors have approved the final draft of the manuscript.