Efficacy and Safety of Keverprazan Compared With Lansoprazole in the Treatment of Duodenal Ulcer: A Phase III, Randomized, Double-Blind, Multicenter Trial : Clinical and Translational Gastroenterology

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Efficacy and Safety of Keverprazan Compared With Lansoprazole in the Treatment of Duodenal Ulcer: A Phase III, Randomized, Double-Blind, Multicenter Trial

Tan, Nian-di MD1; Miao, Xin-pu MD2; Liao, Ai-jun MD3; Liu, Cheng-xia MD4; Wu, Hao MD5; Chen, Hong-hui MD6; Li, Fang-fang MD7; Guo, Qing-hong MD8; Li, Sheng-bao MD9; Tang, Yan-ping MD10; Xia, Min MD11; Liu, You-li MD12; Li, Xing MD13; Chen, Hui-xin MD14; Liu, Xiao-wei MD15; Zhang, Yan MD16; Zhang, Zhen-yu MD17; Chen, Min-hu MD1; Xiao, Ying-lian MD1

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Clinical and Translational Gastroenterology 14(7):p e00602, July 2023. | DOI: 10.14309/ctg.0000000000000602

Abstract

INTRODUCTION: 

Keverprazan is a novel potassium-competitive acid blocker for the treatment of acid-related disorders requiring potent acid inhibition. This study aimed to establish the noninferiority of keverprazan to lansoprazole in the treatment of patients with duodenal ulcer (DU).

METHODS: 

In this phase III, double-blind, multicenter study, 360 Chinese patients with endoscopically confirmed active DU were randomized 1:1 to take either keverprazan (20 mg) or lansoprazole (30 mg) treatment for up to 6 weeks. The primary end point was DU healing rate at week 6. The secondary end point was DU healing rate at week 4. Symptom improvement and safety were also assessed.

RESULTS: 

Based on the full analysis set, the cumulative healing rates at week 6 were 94.4% (170/180) and 93.3% (166/178) for keverprazan and lansoprazole, respectively (difference: 1.2%; 95% confidence intervel: −4.0%–6.5%). At week 4, the respective healing rates were 83.9% (151/180) and 80.3% (143/178). In the per protocol set, the 6-week healing rates in keverprazan and lansoprazole groups were 98.2% (163/166) and 97.6% (163/167), respectively (difference: 0.6%; 95% confidence intervel: −3.1%–4.4%); the 4-week healing rates were respectively 86.8% (144/166) and 85.6% (143/167). Keverprazan was noninferior to lansoprazole in DU healing after the treatment for 4 and 6 weeks. The incidence of treatment-emergent adverse events was comparable among groups.

DISCUSSION: 

Keverprazan 20 mg had a good safety profile and was noninferior to lansoprazole 30 mg once daily for DU healing.

INTRODUCTION

Acid suppression has a crucial role in management of peptic ulcer disease (PUD) (1), which refers to acid peptic injury of the digestive tract with significant morbidity and mortality worldwide. The development of proton-pump inhibitors (PPIs) represented a therapeutic advance for PUD (2). Despite their overall efficacy, PPIs still have their own demerits putting some patients into situations of persistent acid-related damage of gastrointestinal mucosa and symptoms. PPIs need to be activated in the presence of secreted gastric acid and have short plasma half-lives, which can lead to night-time breakthrough symptoms in some individuals (3). Besides, they have a slow onset of action and required several doses to exert their maximum acid suppression and symptom relief effects (4).

From this perspective, there is growing interest in the use of potassium-competitive acid blockers (P-CABs) as an initial therapy for peptic ulcers (5). Keverprazan (H008; previous name as carenoprazan; Supplementary Figure 1, Supplementary Digital Content, https://links.lww.com/CTG/A948), a novel P-CAB synthesized by Jiangsu Carephar Pharmaceutical and marketed in China in February 2023, can produce more rapid and profound suppression of gastric acidity than PPIs in clinically relevant doses. Keverprazan is therefore expected to be an alternative option for acid-related diseases. A phase I clinical trial has shown that keverprazan had very strong, dose-dependent gastric acid suppression at doses of 10–60 mg in healthy volunteers. A recent phase II clinical trial has demonstrated that the treatment of 20 mg and 30 mg of keverprazan up to 6 weeks are noninferior to 30 mg of lansoprazole regarding duodenal ulcer (DU) healing (6).

Base on the aforementioned data, the purpose of this study was to verify the noninferiority of efficacy of keverprazan to lansoprazole in the treatment of patients with DU in China.

MATERIALS AND METHODS

Study design

This was a phase III, multicenter, randomized, double-blind, and active drug-controlled study (Chictr.org.cn identifier ChiCTR2100043457) involving 46 sites in China to assess the noninferiority of keverprazan to lansoprazole in the treatment of patients with DU from September 2020 to March 2021. The conduct of study was in accordance with the Declaration of Helsinki, the Good Clinical Practice of Pharmaceutical Products, and all other Chinese regulatory requirements. The protocol was approved by the China National Medical Products and the ethics committee of each study site. All subjects provided written informed consent before study participation.

Study population

Male or female patients aged 18–75 years with endoscopically confirmed 1 or 2 active DU measuring ≥3 mm to ≤20 mm of A1 or A2 stage according to the Sakita endoscopic staging system were included in the study (7). The DU should be without active bleeding (Forrest classification IIc or III) within 7 days before the initiation of the study treatment (8).

Patients who had the following conditions would be excluded: acute gastric or duodenal mucosal lesion (sudden onsets of clinical symptoms after probable causes with endoscopic findings of gastroduodenal erosion, ulcer, or bleeding which vary quickly in a short time); suspected malignant ulcer; linear DU; concomitant gastric and DUs (gastric and DUs found in the same patient synchronously); iatrogenic ulcer; ulcer with severe complications (such as bleeding or obstruction); a history of malignancy, Zollinger-Ellison syndrome, esophageal erosion or ulcer, esophageal or gastric varices, or inflammatory bowel disease; a history of serious systemic diseases; a history of surgery which might affect gastric acid secretion; any abnormal laboratory test values at the screening such as alanine aminotransferase or aspartate aminotransferase level >1.5 upper limit of normal [ULN] or serum creatinine > ULN; drug abuse; Helicobacter pylori (H. pylori) eradication therapy within 30 days, previous acid suppressive (PPIs, histamine 2 receptor antagonist, etc.) therapy for ulcer treatment within 7 days before randomization, or currently in use of Atazanavir sulfate or rilpivirine; or persistent use of nonsteroidal anti-inflammatory drugs, antithrombotic (aspirin, clopidogrel, etc), or anticoagulant drugs during the study period. Any female of child-bearing age who was sexually active was required to use adequate contraceptive measures during the study period.

Study protocol

Eligible patients were randomized at the ratio of 1:1 through the interactive web response system program to orally receive either keverprazan tablets (10 mg/tablet, 20 mg once daily) or lansoprazole enteric-coated capsules (30 mg/capsule, 30 mg once daily). All randomization information was securely stored and could be accessed by authorized personnel only. A double-dummy blinding method involving matched placebo tablets of keverprazan and placebo capsules of lansoprazole was used. Subjects were instructed to take 2 tablets and 1 capsule once daily 30 min before eating breakfast. Treatment was completed after 4 weeks or 6 weeks if DU not healed at week 4.

There were 3 phases including up to 7 visits (Figure 1). At the start of the screening period, patient demographics and baseline characteristics were recoded, along with physical examination, laboratory tests, electrocardiogram, and 13C urea breath test, to confirm the condition of H. pylori. At weeks 2, 4, and 6, physical examination, laboratory tests, and electrocardiogram were performed. At week 2, CYP2C19 genotype was tested. Endoscopy was performed at screening and at week 4 in all patients as well as at week 6 in those with unhealed DU at week 4. Staging of DU was defined based on the Sakita endoscopic staging system. Active ulcer was defined as an ulcer in the active stage (A1 or A2 stage). Healed ulcer was defined as an ulcer in the scarring stage or disappeared after treatment (S1 or S2 stage). When the DU healing was endoscopically confirmed, patients with an elevated serum gastrin (SG) level from baseline were required to enter the SG follow-up period, which was up to 4 weeks.

F1
Figure 1.:
Flow diagram showing the study design.

Changes of DU-related clinical symptoms (epigastric pain, epigastric burning sensation, regurgitation, nausea, vomiting, belching, and abdominal distension) were assessed at screening and at weeks 2, 4, and 6. Patients rated the frequency and severity of symptoms according to the 5-level numeric rating scale from 0 to 4 (a higher score indicating a more frequent or worse symptom) using daily diaries. Symptom improvement meant at least 1 point decreased from baseline and symptom remission indicated the decrease of symptom score to 0. The overall remission meant the frequency and severity scores of all symptoms changed to 0 after treatment. In addition, concomitant medication, treatment-emergent adverse events (TEAEs), patients' diary, and treatment compliance were checked throughout the study.

Study end points

The primary efficacy end point was the cumulative healing rate of DU at week 6 as confirmed by endoscopy. The secondary efficacy end points were the DU healing rate at week 4 and the improvement of DU-related symptoms.

Safety profile was assessed by physical examinations and the analysis of adverse events, laboratory test values, electrocardiogram findings, and SG levels.

Statistical analysis

Sample size was determined according to the primary end point. Previous studies showed the DU healing rate in lansoprazole-treated patients at week 6 was about 95% (9). Based on the assumptions of 95% DU healing rate in 2 groups and a significant level of 0.025 (1-sided), a sample size of 146 patients per treatment group would have a power of more than 80% to detect noninferiority for the difference of DU healing rate between the treatment groups (with a noninferiority margin of 8% at the lower limit of 2-sided 95% CIs in the proportion difference). Taking into account of a 20% dropout rate, 180 randomized patients would be required for each treatment group. The noninferiority margin of −8% was selected based on previous studies of lansoprazole (10,11).

Efficacy assessments were performed through the per protocol set (PPS) and full analysis set (FAS). Following intent-to-treat principles, the FAS included all patients who were randomized and received at least 1 dose of a study drug. PPS included all FAS patients who were randomized to a study treatment, completed study treatment, and had an evaluable primary end point and no major protocol deviation. The safety set, which was used for safety assessments, was defined as all patients who received at least 1 dose of a study drug.

All statistical analyses were performed using SAS software version 9.4 (SAS Institute, Cary, NC). The percentages of patients with healed DU and symptoms were analyzed by calculating frequencies, point estimates, and 2-sided 95% CIs by treatment group. Noninferiority was assessed using the Miettinen-Nurminen test. If the lower bound of the 95% confidence intervel (CI) was ≥−8%, the DU healing rate for keverprazan was considered to be noninferior to that of lansoprazole.

RESULTS

Demographic characteristics

Of the 407 outpatients screened, 360 eligible patients were randomized to receive either keverprazan (n = 180) or lansoprazole (n = 180). A total of 337 subjects completed the study. The allocating details of each treatment group are shown in Figure 2. Demographics and baseline characteristics of the randomized patients are described in Table 1, with no obvious differences between treatment groups. The overall compliance rate exceeded 95% in all the treatment groups.

F2
Figure 2.:
Flow diagram showing progression through the trial. FAS, full analysis set; PPS, per protocol set; SS, safety set.
Table 1. - Patient demographics and baseline characteristics (full analysis set)
Keverprazan (n = 180) Lansoprazole (n = 178) P Value
Age (yr) 44.2 ± 12.4 44.4 ± 11.8 0.9046
Male sex (n) 111 (61.7) 108 (60.7) 0.8472
Height (cm) 165.5 ± 8.5 165.2 ± 8.9 0.7144
Weight (kg) 64.9 ± 11.6 63.0 ± 11.1 0.1104
Maximum diameter of ulcers (cm) 0.8 ± 0.3 0.8 ± 0.3 0.8906
Stage of ulcers (n)
 A1 110 (61.1) 108 (60.7) 0.9929
 A2 32 (17.8) 33 (18.5)
 A1 and A1 29 (16.1) 27 (15.2)
 A1 and A2 1 (0.6) 0 (0.00)
 A1 and H2 0 (0.00) 1 (0.6)
 A2 and A2 7 (3.9) 8 (4.5)
 A2 and H1 1 (0.6) 1 (0.6)
Helicobacter pylori positive (n) 151 (83.9) 153 (86.0) 0.5850
Serum gastrin (pg/mL) 42.4 ± 32.6 41.6 ± 29.7 0.8053
CYP2C19 genotypes (n)a
 Slow metabolizer 22 (12.4) 21 (12.1) 0.7795
 Intermediate metabolizer 76 (42.7) 79 (45.4)
 Normal metabolizer 78 (43.8) 70 (40.2)
 Fast metabolizer 2 (1.1) 4 (2.3)
Data are represented as mean ± standardized deviation or number of subjects with percentages in parentheses.
aData were missing in 2 and 4 patients for the keverprazan and lansoprazole group, respectively.

As 2 patients in the lansoprazole group did not take the study drugs after the randomization, the FAS comprised 180 patients in the keverprazan group and 178 patients in the lansoprazole group.

Efficacy

The 6-week healing rates in keverprazan and lansoprazole groups were respectively 94.4% and 93.3% in the FAS (difference: 1.2%; 95% CI: −4.0% to 6.5%) as shown in Table 2 and were respectively 98.2% and 97.6% in the PPS analysis (difference: 0.6%; 95% CI: −3.1% to 4.4%). Noninferiority of keverprazan compared with lansoprazole for the DU healing rate at week 6 was confirmed and thus the primary efficacy end point was met.

Table 2. - Healing rates of duodenal ulcers
Keverprazan Lansoprazole
Week 6
 Full analysis set n = 180 n = 178
 No. (%) of healed patients 170 (94.4) 166 (93.3)
 Difference from LPZ with 95% CI 1.19 (−4.0, 6.5)
P Value 0.6404
Per protocol set n = 166 n = 167
 No. (%) of healed patients 163 (98.2) 163 (97.6)
 Difference from LPZ with 95% CI 0.6 (−3.1, 4.4)
P Value 1.0000
Week 4
 Full analysis set n = 180 n = 178
 No. (%) of healed patients 151 (83.9) 143 (80.3)
 Difference from LPZ with 95% CI 3.6 (−4.5, 11.6)
P Value 0.3805
Per protocol set n = 166 n = 167
 No. (%) of healed patients 144 (86.8) 143 (85.6)
 Difference from LPZ with 95% CI 1.1 (−6.4, 8.7)
P Value 0.7675
Noninferiority was assessed using the Miettinen-Nurminen method with a noninferiority margin of −8%.
LPZ, lansoprazole.

At week 4, the healing rate was 83.9% in the keverprazan group and 80.3% in the lansoprazole group (P = 0.3805) in the FAS. The healing rate at week 4 was 86.8% for keverprazan and 85.6% for lansoprazole (P = 0.7675) in the PPS analysis. Treatment differences regarding the 4-week healing rate were not statistically significant.

Besides, subgroup analysis showed similar DU healing rates at weeks 4 and 6 between H. pylori serology subgroups and among CYP2C19 genotype subgroups (Table 3).

Table 3. - Subanalysis of ulcer healing rates by CYP2C19 genotype and Helicobacter pylori serology (full analysis set)
Keverprazan (n = 180) Lansoprazole (n = 178) P Value
No. (%) of healed patients at week 6
 CYP2C19 genotype
  Slow metabolizer 20 (90.9) 19 (90.5) 1.0000
  Intermediate metabolizer 74 (97.4) 72 (91.1) 0.1675
  Normal metabolizer 74 (94.9) 69 (98.6) 0.3702
  Fast metabolizer 1 (50.0) 3 (75.0) 1.0000
Helicobacter pylori positive 142 (94.0) 145 (94.8) 0.7814
H. pylori negative 28 (96.6) 21 (84.0) 0.1704
No. (%) of healed patients at week 4
 CYP2C19 genotype
  Slow metabolizer 19 (86.4) 17 (81.0) 0.6981
  Intermediate metabolizer 65 (85.5) 62 (78.5) 0.2544
  Normal metabolizer 65 (83.3) 59 (84.3) 0.8753
  Fast metabolizer 1 (50.0) 3 (75.0) 1.0000
Helicobacter pylori positive 126 (83.4) 124 (81.1) 0.5844
H. pylori negative 25 (86.2) 19 (76.0) 0.4852
CYP2C19 genotype data were missing in 2 and 4 patients for the keverprazan and lansoprazole group, respectively.

Improvement of the DU-related clinical symptoms was obtained in both keverprazan and lansoprazole arms. Overall, keverprazan had better efficacy for belching symptom than lansoprazole, otherwise there were no marked difference between groups in other symptoms (see Supplementary Tables S1–S3, Supplementary Digital Content, https://links.lww.com/CTG/A949).

Safety

Safety analysis was performed in 358 patients (keverprazan: 180; lansoprazole: 178). On the whole, the safety profile of keverprazan was similar to that of lansoprazole (Table 4). The 5 most frequently reported drug-related TEAEs by preferred term in the keverprazan group were hyperlipemia (2.2%), diarrhea (2.2%), hyperuricemia (2.2%), detected urine protein (1.7%), and arrhythmia (1.7%). A total of 2 patients experienced 3 drug-related TEAEs that led to study drug discontinuation: 1 patient in the keverprazan group reported nausea and 1 patient in the lansoprazole group reported rash and abnormal liver function test. No severe drug-related TEAE was reported in either group.

Table 4. - Treatment-emergent adverse events and serious adverse events (safety analysis set)
Keverprazan (n = 180) Lansoprazole (n = 178) P Value
TEAEs, patients (%) 104 (57.8) 105 (59.0) 0.8309
 Mild 92 (51.1) 101 (56.7)
 Moderate 11 (6.1) 4 (2.3)
 Severe 1 (0.6) 0 (0.0) 1.0000
Study drug related 46 (25.6) 58 (32.6) 0.1627
Leading to study drug discontinuation 3 (1.7) 2 (1.1) 1.0000
Leading to study drug discontinuation (study drug related) 1 (0.6) 1 (0.6) 1.0000
Serious adverse events 3 (1.7) 1 (0.06) 0.6229
Serious adverse events (study drug related) 1 (0.6) 0 1.0000
TEAEs, treatment-emergent adverse events.

Incidences of drug-related liver injury were 3.9% (7/180) in the keverprazan group and 8.4% (15/178) in the lansoprazole group, mainly including elevated alanine aminotransferase, aspartate aminotransferase, bilirubin, and glutamic dehydrogenase. Two patients experienced the level of liver enzymes increasing to more than 3 ULN: 1 patient (related to study drug) in the lansoprazole group and 1 (related to acute pancreatitis, unrelated to study drug) in the keverprazan group, both of whom recovered after treatment.

Serious AEs were experienced by 3 patients in the keverprazan group and 1 in the lansoprazole group: 1 patient with acute pancreatitis (unrelated to keverprazan); 1 patient with gastric polyps (possibly related to keverprazan); 1 patient with hypertension and chronic otitis media simultaneously (unrelated to keverprazan); and 1 patient with acute endocarditis, Staphylococcus sepsis, and ventricular septal defect simultaneously (unrelated to lansoprazole). No deaths were reported in either group.

Serum gastrin concentration

The increase in SG levels at the end of treatment was evident in 125 keverprazan-treated patients and in 56 lansoprazole-treated patients. The increase of SG levels was markedly higher in the keverprazan group than the lansoprazole group (195.2 ± 175.3 pg/mL vs 63.9 ± 61.3 pg/mL, P < 0.0001). However, SG levels returned to preadministration levels 4 weeks after completion of treatment except 1 case in the keverprazan group and 3 cases in the lansoprazole group. The changed gastrin levels from baseline during treatment and follow-up phases are provided in Table 5.

Table 5. - Gastrin levels from baseline (pg/mL) during treatment and follow-up phases (safety analysis set)
Keverprazan (n = 180) Lansoprazole (n = 178) P Value
N Mean (SD) N Mean (SD)
Treatment phase
 Baseline 180 42.4 (32.6) 177 41.6 (29.7) 0.8053
 Week 4 174 236.5 (188.9) 172 100.6 (62.3) <0.0001
 Week 6 24 240.7 (200.2) 26 133.9 (71.4) 0.0139
 End of treatment 176 237.6 (187.7) 172 105.1 (67.0) <0.0001
Follow-up phase
 Week 2 116 51.4 (48.0) 50 71.5 (55.6) 0.0197
 Week 4 6 56.5 (39.4) 8 98.7 (35.4) 0.0567

DISCUSSION

In this phase III clinical trial, the noninferiority of keverprazan to lansoprazole regarding endoscopic healing of DU after 6 weeks of treatment was verified, and the tolerability of keverprazan was similar to that of lansoprazole.

PUD is a worldwide prevalent disease with significant morbidity and mortality (1). Despite the good efficacy of PPIs, the complicated PUD was still reported as one of the leading causes of death (12). Symptomatic PUD remained as an important reason for hospitalization (13). Timely treatment of PUD with longer-acting acid suppressors is crucial to minimize the associated morbidity and mortality.

Keverprazan is a novel, potent, and highly selective P-CAB with an acting mechanism different from PPIs. Unlike PPIs, keverprazan competes with potassium to inhibit H+/K+-ATPase more potently. Keverprazan can produce strong and sustained acid-inhibitory effects with the first dose. Preclinical studies and phase I clinical trials of keverprazan had shown that it was comparable to vonoprazan in safety and efficacy (14–17). After a single dose of keverprazan, its Tmax was about 1–4 hours and t1/2 was about 7 hours in healthy adults. The 24-h pH > 3 holding time ratio (HTR) for keverprazan 20 mg was 85.5% and 99.6% in Chinese healthy volunteers after 1 and 7 days of dosing, respectively. Corresponding results for the pH > 4 HTR was 85.0% and 98.3% after 1 and 7 days of dosing, which was comparable to vonoprazan 40 mg/d (18). These vital data matched the fact that peptic ulcer healing occurs above a pH of 3 (19,20). Furthermore, keverprazan does not require acid-induced activation and is stable in the acid. As a result, keverprazan does not need to be given 30 min before a meal and does not require enteric-coated preparation, in which situation patients' compliance to keverprazan would be better than PPIs. Besides, it is known that most PPIs are primarily metabolized by CYP2C19, the genotype of which has been linked to PPI efficacy and adverse effects. The CYP2C19 genotype data are required to guide PPI therapy in some cases (21). Considering the metabolism of keverprazan does not depend on the polymorphism of CYP2C19, patients with CYP2C19 fast metabolizer or refractory genotype to PPI therapy would take advantages from the treatment of keverprazan. Therefore, keverprazan may have some potential advantages over PPIs and improve clinical outcomes of PUD.

By far, the known P-CABs approved in clinical use are vonoprazan, revaprazan, and tegoprazan (22–24). The efficacy of the former 2 drugs in healing DU was already evaluated in randomized controlled trials. But the efficacy data of revaprazan have not been published. A randomized controlled trial performed in China and Korea showed vonoprazan was noninferior to lansoprazole as for the 6-week healing rate of DU (96.9% vs 96.5%) (9), which were slightly higher than that of both keverprazan and lansoprazole groups in our study. This might be interpreted by the different treatment protocols for H. pylori-positive subjects used in 2 trials. In the above study (9), H. pylori-positive participants received study drugs for the first 2 weeks along with bismuth-containing quadruple therapy. But in our study, eradication therapy was not performed for H. pylori-positive patients during the trial. Another randomized controlled trial performed in Japan showed 95.5% of vonoprazan-treated patients and 98.3% of lansoprazole-treated patients achieved healed DU at week 6, although noninferiority to lansoprazole was not confirmed (P = 0.0654) (25). It seemed that keverprazan achieved comparable efficacy to vonoprazan for endoscopic DU healing rates. Based on valid evidence from clinical trials, vonoprazan and revaprazan are already licensed for the indication of DU in some countries outside China. But the indication of vonoprazan approved in China was limited to erosive esophagitis. Therefore, keverprazan is anticipated to be a viable alternative treatment option for DU as a novel P-CAB.

Because H. pylori infection plays a key role in both the cause and documented temporal variations of PUD, a test-and-treat strategy has been advocated (26). As the strength and duration of acid inhibition are related to the eradication rate of H. pylori, it is concluded that intragastric pH > 4 should be maintained for 24 h during eradication therapy (27,28). Unfortunately, treatment with PPI at standard dose twice a day does not meet the above criteria. However, vonoprazan 20 mg twice a day effectively inhibits acid secretion across 24 h (pH ≥ 4 HTR is 100%) (29). And a meta-analysis has showed the H. pylori eradication rates of vonoprazan-containing triple therapy were significantly higher than that of PPI-containing triple therapy (30). Vonoprazan has been clinically used in Japan for short-term treatment of PUD and H. pylori infection based on its effectiveness in the eradication of clarithromycin-resistant H. pylori strains (31). A daily dose of keverprazan 20 mg could effectively maintain gastric acid inhibition throughout the 24 h: the pH > 4 and > 5 HTR was 98.3% and 97.4%, respectively. Therefore, similar to vonoprazan, an H. pylori eradication regimen containing keverprazan is expected to improve the eradication rate when compared to conventional regimens that use a standard dose of PPI. In addition, keverprazan would have an advantage in achieving near 100% pH > 4 HTR, which may be necessary for individuals with severe erosive esophagitis or gastrointestinal bleeding.

In our study, keverprazan had better efficacy than PPIs in improving the symptom of belching. The effect of PPIs on reflux symptoms might stop air swallowing as a response to chest or abdominal discomfort (32). Several studies have demonstrated the efficacy of PPI therapy in improving belching symptoms. Significantly better improvement of belching symptom in the keverprazan group might be due to its stronger acid inhibition. This finding highlighted the additional benefit for patients with both PUD and associated symptoms, particularly belching.

Our study has a limitation in that patients who tested positive for H. pylori did not receive the recommended eradication therapy during the study period but rather after its completion. In addition, the results of the eradication therapy were not tracked.

In conclusion, this study was designed with a randomized, double-blind, double-dummy, and multisite approach and had a large sample size to compare the efficacy of keverprazan and lansoprazole in DU healing in a Chinese population. Our study demonstrated that a 20 mg dose of keverprazan was noninferior to 30 mg of lansoprazole in healing DU after 4–6 weeks treatment and had a favorable safety profile.

CONFLICTS OF INTEREST

Guarantor of the article: Ying-lian Xiao and Min-hu Chen.

Specific author contributions: Y.-l.X., M.-h.C.: took a major lead in study conception and design, analysis and interpreting the data, critical revision of the article for important intellectual content and final approval of the article. N.-d.T.: played a major role in acquisition of data, interpretation of data, drafting and finalizing the manuscript. The other authors took part in interpretation of data and critical revision of final manuscript. All authors approved the final version of the manuscript.

Financial support: This study was supported in full by Jiangsu Carephar Pharmaceutical Co. Ltd. China

Potential competing interests: None to report.

IRB approval statement: The study protocol was approved by the State Food and Drug Administration and was approved by the ethics committee of each study site. URL: http://www.chictr.org.cn/showproj.aspx?proj=120380.

Trial identification number: ChiCTR2100043457.

Study Highlights

WHAT IS KNOWN

  • ✓ Despite PPIs' overall efficacy in duodenal ulcer, they still have their own demerits putting some patients into situations of persistent acid-related damage of gastrointestinal mucosa and symptoms.
  • ✓ Potassium-competitive acid blockers (P-CABs) have high pKa values, potent acid inhibition effects, and are stable at low pH.

WHAT IS NEW HERE

  • ✓ Keverprazan is a novel P-CAB and displays a longer half-life than current PPIs (6.0–7.2 vs 1.5–2.0 hour).
  • ✓ Keverprazan 20 mg was noninferior to lansoprazole 30 mg once daily for duodenal ulcer healing with a good safety profile.

ACKNOWLEDGMENTS

The authors thank all patients and all investigators including Xiao-yan Wang (the Third Xiangya Hospital of Central South University), Bing-qiang Zhang (The First Affiliated Hospital of Chongqing Medical University), Wei-ming Xiao (Yangzhou First People's Hospital), Dong-xing Su (The Second Nanning People's Hospital), Zhi-li Wen (The Second Affiliated Hospital of Nanchang University), Rui-hua Shi (Zhongda Hospital, Southeast University), Yong Yao (Suining Central Hospital), Yang Wang (The First People's Hospital of Changzhou), He-kun Yin (Jiangmen Central Hospital), Tian-wei Deng (Chongqing University Three Gorges Hospital), Bin Yang (Jiangsu Taizhou People's Hospital), Sheng-bing Wang (Meizhou People's Hospital), Yong-jian Zhou (Guangzhou First People's Hospital), Rong-yuan Qiu (The Second People's Hospital of Yueyang), Wei-jie Dai (Huai’an First People's Hospital), Ling-yun Wang (Sun Yat-sen Memorial Hospital of Sun Yat-sen University), Pei-fen Zheng (Affiliated Zhejiang Hospital Zhejiang University School of Medicine), Min Xu (Affiliated Hospital of Jiangsu University), Lei Gong (The Second People's Hospital of Wuxi), Wei-ping Li (Huzhou Central Hospital), De-liang Liu (The Second Xiangya Hospital Central South University), Bing Zou (Peking University Shenzhen Hospital), Xin Ma (Gansu Provincial Hospital), Bi-guang Tuo (Affiliated Hospital of Zunyi Medical University), Hai-tao Tang (Huzhou Central Hospital), Yan-bo Zhen (Central Hospital Affiliated to Shandong First Medical University), Si-chen Wei (Cangzhou Central Hospital), Yong-dong Wu (Beijing Friendship Hospital), and Hua-hong Wang (Peking University First Hospital).

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Keywords:

keverprazan; potassium-competitive acid blocker; lansoprazole; duodenal ulcer

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