Content Detail

• Content META

  Title	Efficacy and safety of tegoprazan for duodenal ulcers in Chinese patients: a multicenter, randomized, double-blind, non-inferiority, phase III study
  ID	3432093
  External ID	7232828392
  Author	Unknown
  Published Date	Oct. 21, 2024, 11:58 a.m.
  Summary	Tegoprazan represents a newly developed potassium-competitive acid blocker utilized for the treatment of acid-related disorders. The present study aimed to explore the therapeutic effectiveness of teg
  Tags	None
  URL	https://www.tandfonline.com/doi/full/10.1080/03007995.2024.2414090
  Sentiment	Negative: 0.07586    Neutral: 0.76748    Positive: 0.15666
  Relevance	0.00000

• Content Details

  Content ID	1786908
  Key	0428873d-b5d5-4490-bf1c-92881afd962e
  Content	Tegoprazan represents a newly developed potassium-competitive acid blocker utilized for the treatment of acid-related disorders. The present study aimed to explore the therapeutic effectiveness of tegoprazan in Chinese individuals with duodenal ulcers (DU). Methods In the current multicenter, randomized, double-blind, double-dummy, parallel-group, non-inferiority, phase III clinical trial, individuals with DU underwent randomization 1:1 to be administered tegoprazan 50 mg or lansoprazole 30 mg once daily. The primary efficacy endpoint was the 6-week cumulative endoscopic ulcer healing rate. Secondary endpoints included 4-week endoscopic ulcer healing rate and relief of DU-related gastrointestinal symptoms at weeks 2, 4, and 6. Safety analysis encompassed adverse events (AEs) and laboratory indexes. Results The 6-week cumulative endoscopic ulcer healing rates were 96.9% (188/194) and 99.0% (189/191) in the tegoprazan and lansoprazole groups, respectively, indicating a difference of −2.0% (95% confidence interval (CI) = −4.9 to 0.8) in the full analysis set (FAS). The corresponding healing rates were 98.4% (185/188) and 99.5% (183/184) in the per-protocol set, respectively, indicating a difference of −1.1% (95% CI = −3.1 to 1.0). The 4-week healing rates in the tegoprazan and lansoprazole groups were 89.2% (173/194) and 88.5% (169/191) in the FAS, respectively, with a difference of 0.7% (95% CI = −5.6 to 7.0). Treatment-related AEs, all mild-to-moderate, were reported in 38.2% (78/204) and 48.2% (94/195) of participants in the tegoprazan and lansoprazole groups, respectively. Conclusions Tegoprazan 50 mg once daily is effective and non-inferior to lansoprazole 30 mg once daily in Chinese patients with DU, showing a promising safety and tolerability profile. ClinicalTrials.gov registration number NCT05010954. Introduction Peptic ulcer disease represents a group of chronic acid-related diseases (ARDs) and mostly includes gastric ulcers (GU) and duodenal ulcers (DU) . Peptic ulcers occur in 5–10% of humans during their lifetime . In a questionnaire survey conducted in Shanghai, the prevalence of endoscopy confirmed DU (5.8%) was slightly higher than that of GU (2.5%) . Acute upper gastrointestinal bleeding is the commonest complication of peptic ulcer disease and can be life-threatening . Proton pump inhibitors (PPIs), including lansoprazole, omeprazole, rabeprazole, and esomeprazole, are the standard treatment options for peptic ulcers . However, PPIs show a slow onset of action and commonly induce nocturnal acid breakthrough . Therefore, new treatment options with sufficient efficacy and good safety need to be developed. Potassium-competitive acid blockers (P-CABs) represent a new class of gastric acid inhibitors that work by competitively blocking potassium ions from binding to hydrogen-potassium ATPase, providing more robust, steadier, and prolonged acid inhibition compared with currently used PPIs . Furthermore, P-CABs are acid-stable and do not require the complex acid-protective coating employed with PPIs, simplifying their formulation and use . Multiple P-CABs are clinically used for ARDs in different countries or regions, e.g. revaprazan, vonoprazan, tegoprazan, keverprazan and fexuprazan. The Japanese guidelines for peptic ulcer disease (2020) and the Chinese expert consensus on peptic ulcers (2022) suggest that P-CABs can be used as first-line treatment for the suppression of gastric acid secretion and promote ulcer healing. Tegoprazan potently and stably reduces gastric acid amounts and is approved and marketed in China for clinical reflux esophagitis. A phase I study reported fast and steady acid suppression with tegoprazan at doses of 50, 100, 200, and 400 mg . Additionally, phase III clinical trials showed that tegoprazan is effective and safe for managing erosive esophagitis , non-erosive reflux disease , and GU . However, no clinical studies have investigated the use of tegoprazan for the treatment of DU. Therefore, the present study aimed to examine the therapeutic effectiveness of tegoprazan in Chinese individuals with DU. The results could provide another treatment option for DU in China. Methods Study design and patients This was a multicenter, randomized, double-blind, double-dummy, parallel-group, non-inferiority, phase III study. Lansoprazole 30 mg once daily was selected as the active control. Patients with DU were screened in 41 Chinese centers from 29 September 2021 to 28 September 2022. The study was designed and carried out per the Declaration of Helsinki and other relevant regulations. The study had approval from the Ethics Committees of various participating centers and is registered at ClinicalTrials.gov (NCT05010954). Signed informed consent was obtained from each patient prior to enrolment. Cases aged 18–70 years with one or two endoscopically-confirmed active DU of 0.3–2.0 cm in diameter staged A1 or A2 per the Sakita-Miwa staging system within 2 weeks prior to first administration of the study drug were enrolled. Key exclusion criteria were (1) prior use of P-CABs; (2) iatrogenic ulcers caused by endoscopic procedures; (3) a history of upper gastrointestinal surgeries, Zollinger-Ellison syndrome, inflammatory bowel diseases, or other severe gastrointestinal diseases; (4) endoscopically-confirmed gastrointestinal bleeding, esophageal stenosis, ulcerative stenosis, pyloric stenosis, gastroesophageal varices, Barrett's esophagus >3 cm, confirmed gastroesophageal reflux disease, acute gastric mucosal lesion (with or without duodenal involvement), active gastric or refractory ulcer, ulcer perforation, or suspected malignancies; (5) use of any agents for peptic ulcer treatment within 2 weeks before the first administration of the study drug, including PPIs, anticholinergic drugs, gastrin receptor antagonists, H receptor antagonists, prostaglandins, mucosal protective agents, prokinetics, or antacids; (6) continuous need for nonsteroidal anti-inflammatory drugs in the trial period; or (7) alanine (ALT) or aspartate (AST) aminotransferase amounts higher than their respective upper limits of normal (ULNs), or creatinine >1.5 × ULN at screening. Randomization and blinding Eligible patients were randomly grouped into the tegoprazan and lansoprazole groups at 1:1 using block randomization and the interactive web response system (IWRS) for the trial. A label containing a random number was attached to the outer package of each box of the study drugs, which were identical in appearance except for the number. The study drugs and matching placebos were also identical in appearance. The participants and study personnel involved in this clinical trial or clinical evaluation remained blinded throughout the trial. Intervention Study drugs were administered in the morning before breakfast once daily. Each administration included one tablet and one capsule. Participants in the tegoprazan group received a tegoprazan 50 mg tablet plus a capsule of lansoprazole-matching placebo. Those of the lansoprazole group received a tablet of tegoprazan-matching placebo plus a lansoprazole 30 mg capsule. The participants who achieved endoscopic ulcer healing after 4 weeks per the Sakita-Miwa staging system terminated the study treatment, while those who failed to achieve endoscopic ulcer healing continued the study treatment for another 2 weeks. Efficacy assessment Upper gastrointestinal endoscopy was conducted at enrolment and weeks 4–5 (day 29 ± 3) for all participants. The participants who completed the 6-week treatment period underwent an additional upper gastrointestinal endoscopy at weeks 6–7 (day 43 ± 3). In participants who discontinued the treatment early, upper gastrointestinal endoscopy was performed within 7 days after the last study drug administration. Efficacy endpoints The primary efficacy endpoint was the 6-week cumulative endoscopic ulcer healing rate, i.e. the proportion of cases achieving ulcer healing by upper gastrointestinal endoscopy after 4 or 6 weeks of therapy. Healing was reflected by alleviation of mucosal defects to stage S1 or S2 according to the Sakita-Miwa classification Secondary efficacy endpoints included 4-week endoscopic ulcer healing rate; overall remission rates of DU-related gastrointestinal symptoms at 2, 4, and 6 weeks after treatment; and time to the first overall relief of the aforementioned symptoms for 7 consecutive days. The participants completed a daily diary to assess their DU-related gastrointestinal symptoms for the previous day. Symptoms were assessed on a 4-point scale, with 0–3 reflecting no, mild, moderate, and severe symptoms, respectively. Safety assessment Safety assessments comprised vital signs, physical exams, electrocardiography, laboratory assays (complete blood count, blood chemistry, coagulation, and urinalysis), and serum gastrin analysis. Adverse events (AEs), e.g. treatment-emergent (TEAEs), treatment-related (TRAEs), and serious (SAEs) AEs, were determined using Medical Dictionary for Regulatory Activities (MedDRA) version 25.1, with their severity graded as mild, moderate, or severe by the investigator. Treatment compliance was assessed for each study drug as actually used amount/scheduled amount × 100%. Statistical analysis Based on previous reports in DU, the 4–6 week endoscopic ulcer healing rate in the lansoprazole group was estimated to be 93% . The 6-week endoscopic ulcer healing rate in the tegoprazan group was expected to be similar. With a one-sided α set at 0.025, 160 cases in each arm were needed to provide a power of over 80% for non-inferiority detection between treatment groups (non-inferiority margin, −8%) . Considering a 20% dropout rate, 200 patients were required per group. The 6-week and 4-week endoscopic ulcer healing rates were examined in the full analysis set (FAS). Subgroup analyses of cumulative endoscopic ulcer healing rates at 6 weeks were performed according to baseline ulcer stage in the FAS. Baseline patient features were summarized for the FAS, and symptom relief was analyzed in participants with the corresponding symptoms at baseline. The per-protocol set (PPS) was used for sensitivity analysis of 6-week and 4-week endoscopic ulcer healing rates. Drug safety was analyzed in the safety set (SS). The FAS consisted of all randomized participants who took one or more doses of the study drug with one or more post-enrolment efficacy assessments. The PPS encompassed all participants who had all test results required for the evaluation of the primary efficacy endpoint and no important protocol deviations affecting the efficacy assessment. The SS comprised all patients who were administered a study drug one or more times after randomization and had a safety evaluation. Last observation carried forward (LOCF) was applied to analyze 6-week and 4-week endoscopic ulcer healing rates. All analyses were conducted using SAS 9.4. Continuous variables with normal distribution are mean ± standard deviation (SD) and were compared by Student's t-test; those with skewed distribution were reported as median (interquartile range [IQR]) and compared using the Mann-Whitney U-test. Categorical variates were expressed as number (percentage) and compared using the chi-square test or Fisher's exact test. The 95% confidence interval (CI) of the difference in healing rates between groups was calculated by the Wald method. A lower limit for the two-sided 95% CI of between-group difference above the set non-inferiority margin of −8% would indicate that the 6-week cumulative endoscopic ulcer healing rate of tegoprazan 50 mg shows non-inferiority versus that of lansoprazole 30 mg. The time between treatment start and the first relief of symptoms was estimated by Kaplan-Meier curve analysis, comparing groups by the log-rank test. Two-sided p < 0.05 was deemed statistically significant. Results Disposition and demographics In total, 569 subjects were screened, of whom 400 were randomized, including 205 and 195 in the tegoprazan and lansoprazole groups, respectively. One participant in the tegoprazan group was excluded from the SS for not receiving the study drug after randomization. Fourteen patients were excluded from the FAS due to no post-baseline efficacy assessment. Four participants were excluded from the PPS because of no primary efficacy endpoint assessment, while nine were excluded for important protocol deviations. In the tegoprazan group, 191 (93.2%) patients completed the study and 14 (6.8%) withdrew early, including six informed consent withdrawals, five voluntary withdrawals, one for safety reasons, and two for other reasons. In the lansoprazole group, 190 (97.4%) completed the study and five (2.6%) withdrew early, including one informed consent withdrawal, two for safety reasons, and two due to loss to follow-up. Finally, 399, 385, and 372 patients were included in the SS, FAS, and PPS, respectively ( Figure 1. Study flowchart. Abbreviations. AE, adverse event; FAS, full analysis set; PPS, per protocol set; SS, safety set. Baseline patient features were similar in both treatment groups ( ). Mean patient age was 43.3 ± 12.39 years, and there were 59.5% males. Most participants had only one ulcer, and 61.8% had ulcers with a diameter of 0.5–1 cm. Most patients had an A1 stage ulcer according to the Sakita-Miwa system (A1: 76.9%; A2: 23.1%). Treatment compliance rates were 98.32% and 98.84% in the tegoprazan and lansoprazole groups, respectively. Table 1. Baseline patient characteristics (full analysis set). Primary endpoint The 6-week cumulative endoscopic ulcer healing rates in the FAS were 96.9% (188/194) and 99.0% (189/191) in the tegoprazan and lansoprazole groups, respectively, indicating a between-group difference of −2.0% (95% CI = −4.9 to 0.8). Subgroup analysis showed 6-week cumulative endoscopic ulcer healing rates for ulcers with baseline stage A1 of 97.4% and 98.6% in the tegoprazan and lansoprazole groups, respectively; ulcers with baseline stage A2 had rates of 95.1% and 100.0%, respectively. Ulcer stage showed no significant effect on the cumulative endoscopic ulcer healing rate at 6 weeks in both groups (all p > 0.05). In the PPS, 6-week cumulative endoscopic ulcer healing rates were 98.4% (185/188) and 99.5% (183/184), respectively (between-group difference of −1.1% [95% CI = −3.1 to 1.0]). As the lower limit of the 95% CI was greater than the prespecified −8.0% threshold, the non-inferiority of tegoprazan to lansoprazole for 6-week cumulative endoscopic ulcer healing rate was demonstrated in both FAS and PPS ( Table 2. Endoscopic ulcer healing rates. Secondary endpoints The 4-week endoscopic ulcer healing rates were 89.2% (173/194) and 88.5% (169/191) in the tegoprazan and lansoprazole groups of the FAS, respectively, indicating a difference of 0.7% (95% CI = −5.6 to 7.0); these rates were 91.5% (172/188) and 90.2% (166/184) in the PPS, respectively (difference of 1.3% [95% CI = −4.6 to 7.1]) ( Tegoprazan and lansoprazole were comparable in alleviating DU-related gastrointestinal symptoms. The overall relief of symptoms was achieved in 57 (57.6%) and 67 (58.8%) patients in the tegoprazan and lansoprazole groups at week 2, respectively, 71 (71.7%) and 79 (69.3%) at week 4, respectively, and 69 (69.7%) and 82 (71.9%) at week 6, respectively (all p > 0.05). Median times between treatment initiation and first overall relief of symptoms were 4 (95% CI = 3.0 to 7.0) and 4 (95% CI = 3.0 to 6.0) days in the tegoprazan and lansoprazole groups, respectively ( p = 0.173). The relief rates of individual symptoms, including daytime upper abdominal pain, nocturnal upper abdominal pain, and heartburn and/or regurgitation were also comparable at weeks 2, 4, and 6 between groups, as well as median times between treatment initiation and first relief (all p > 0.05) ( Table 3. Overall and individual relief of DU-related gastrointestinal symptoms. Safety Median durations of drug exposure were 29 (range = 1–48) days for tegoprazan and 29 (range = 5–50) days for lansoprazole. There were 127 (62.3%) and 130 (66.7%) participants with TEAEs in the tegoprazan and lansoprazole groups, respectively, while TRAEs were recorded in 78 (38.2%) and 94 (48.2%) cases, respectively. The commonest TEAEs included blood gastrin increase/hypergastrinemia (17.2% vs. 27.2%), upper respiratory tract infection (5.9% vs. 3.1%), and hypercholesterolemia (4.4% vs. 0.5%) (Supplementary Table S1). The vast majority of TEAEs were mild, and only one (0.5%) patient in the tegoprazan group had a severe TEAE, which was hematemesis. The latter patient had a bulb ulcer (1 cm diameter, grade A2) and a history of chronic non-atrophic gastritis, hypertension, and type 2 diabetes at enrolment. The patient had concluded treatment with tegoprazan at the time of hematemesis. This hematemesis was considered by the investigator to be unrelated to tegoprazan as the patient had undergone surgery for a gastric space-occupying lesion, and the hematemesis occurred on the first postoperative day. The commonest TRAEs were blood gastrin increase/hypergastrinemia (17.2% vs. 27.2%), blood uric acid increase (2.0% vs. 1.5%), alanine aminotransferase increase (2.0% vs. 1.0%), aspartate aminotransferase increase (2.0% vs. 1.0%), hyperlipidemia (2.0% vs. 4.1%), and diarrhea (1.0% vs. 3.1%) ( ). All TRAEs were mild-to-moderate. SAEs were detected in two (1.0%) patients administered tegoprazan and one (0.5%) administered lansoprazole, among whom only one case of moderate pain in the extremity in the tegoprazan group was considered to be treatment-related per investigators' judgment. TEAEs leading to permanent drug discontinuation were recorded in one (0.5%) participant administered tegoprazan and two (1.0%) treated with lansoprazole. No TEAEs leading to death were detected in this study ( Table 4. Adverse events (safety set). Discussion This was the first randomized, double-blind, phase III trial that explored tegoprazan's therapeutic efficacy and safety in Chinese patients with DU. This trial met its primary endpoint of 6-week cumulative endoscopic ulcer healing rate, which was 96.9% with tegoprazan 50 mg versus 99.0% with lansoprazole 30 mg in the FAS, with a lower 95% CI for the difference of −4.9%, which surpasses the set non-inferiority threshold of −8%. PPS data were consistent with FAS findings. Therefore, tegoprazan 50 mg once daily is effective and non-inferior to lansoprazole 30 mg once daily in Chinese patients with DU. All TRAEs were mild-to-moderate in severity. Only one (0.5%) participant permanently discontinued tegoprazan treatment due to TEAEs, and no TEAEs leading to death were detected, indicating a favorable safety profile. Meta-analyses support using PPIs for DU . A network meta-analysis revealed that PPIs have a higher efficacy against DU compared with H receptor antagonists, and the efficacy and tolerance of different PPIs were similar . In the present study, endoscopic healing rates for DU at 4 and 6 weeks with lansoprazole 30 mg (88.5% at week 4 and 99.0% at week 6) were similar to previously reported data (83.9–93.8% at week 4 and 94.4–96.9% at week 6) . Previous studies examining DU treated with P-CABs reported 6-week endoscopic ulcer healing rates of 95.5–96.9% for vonoprazan , 94.4% for keverprazan 20 mg, and 93.3% for keverprazan 30 mg , similar to 96.9% observed with tegoprazan 50 mg in the present study. We also found similar 6-week cumulative endoscopic ulcer healing rates in the tegoprazan and lansoprazole groups for either stage A1 or A2 ulcers. Therefore, tegoprazan 50 mg for DU following 4 or 6 treatment weeks is similar in efficacy to other P-CABs and non-inferior to lansoprazole 30 mg. In the current study, endoscopic ulcer healing rates at 4 weeks were similar in the tegoprazan and lansoprazole groups (89.2% vs. 88.5%). This result aligns with findings from randomized phase III clinical studies of vonoprazan (89.2% vs. 88.4%) and keverprazan (83.9% vs. 80.3%) , which also showed comparable ulcer healing rates with P-CABs and PPIs after 4 treatment weeks. Additionally, the tegoprazan and lansoprazole groups had similar overall relief of DU-related gastrointestinal symptoms at 2, 4, and 6 weeks. At 4 weeks, the overall symptom relief rate was greater in the tegoprazan group (71.7%) compared with the lansoprazole group (69.3%), but this difference was not statistically significant. The relief of individual symptoms, e.g. nocturnal upper abdominal pain (78.8% vs. 74.4%) and heartburn or regurgitation (71.4% vs. 62.2%), followed a similar trend, with no significant difference between the two groups. The majority (over 55%) of patients in the tegoprazan group achieved gastrointestinal symptom relief within 2 weeks, with slight increases up to 6 weeks. Similar results were observed for the relief of individual symptoms. More than half of the examined patients achieved first overall symptom relief after 4 days of treatment. Tegoprazan was comparable to lansoprazole regarding DU symptom relief rates and time from treatment initiation to first relief of symptoms. The incidence rates of TEAEs (62.3% vs. 66.7%) and TRAEs (38.2% vs. 48.2%) were numerically lower in the tegoprazan group compared with the lansoprazole group; however, TEAEs were not statistically significant. This is consistent with findings from a phase 3, double-blind, active-controlled, multicenter trial conducted in Korea, where lower rates of TEAEs (17.65% vs. 25.00%) and TRAEs (9.80% vs. 12.00%) were also reported with tegoprazan 50 mg compared with lansoprazole 30 mg . The commonest TEAEs in the tegoprazan group included increased blood gastrin (hypergastrinemia) and upper respiratory tract infections, corroborating previous reports of P-CABs . The low or absent gastric acid state caused by acid-suppressing medications can lead to a reactive increase in serum gastrin levels, which is a known and expected outcome. Since the study protocol did not predefine that an increase in gastrin levels should not be reported as an AE, the investigators reported it as an AE based on their judgment. No new safety concerns were identified in this study. Only one severe TEAE, hematemesis after a gastric operation, was detected in the tegoprazan group, but was determined to be unrelated to a study drug or endoscopic procedure, as judged by the investigator. All other TRAEs were mild-to-moderate in terms of severity, and no TEAEs led to death. The incidence rate of TEAEs leading to permanent drug discontinuation was low (0.5%). These results suggest that tegoprazan 50 mg is safe and well tolerated, as supported by previous studies . Additionally, the once-daily oral dosing regimen was convenient for patients, with compliance rates exceeding 98% in both groups. This study had limitations. First, the status of H. pylori infection was not analyzed, which may restrict the clinical applicability of these findings, as H. pylori infection status may influence the treatment approach for DU. Additionally, the presence of H. pylori could act as a confounding factor in the interpretation of results. However, as H. pylori -infected individuals (if any) would have been randomized into both treatment groups, the potential effects of H. pylori infection would be equally distributed between the tegoprazan and lansoprazole groups. Despite this limitation, high endoscopic ulcer healing rates were obtained in both groups, suggesting that the impact of H. pylori infection on the overall study outcome is likely minimal. Second, slightly more patients withdrew early in the tegoprazan group compared with the lansoprazole group, but early withdrawals were mostly related to the severe COVID-19 pandemic during the study period in China, which led to a relatively low enthusiasm in patients to continue the study and visit the hospital. Finally, only Chinese patients were enrolled, which might limit the generalizability of the findings. Conclusion In conclusion, tegoprazan 50 mg once daily is effective and non-inferior to lansoprazole 30 mg once daily in Chinese patients with DU, with promising safety and tolerability. The novel P-CAB tegoprazan has a fast onset of action and achieves high rates of ulcer healing and symptom relief. Therefore, it could be an option for the treatment of DU. Transparency Declaration of funding This study was sponsored by Shandong Luoxin Pharmaceutical Group Stock Co., Ltd., which provided all the drugs used, participated in study design and data collection, analysis and interpretation, and paid for medical writing assistance. Declaration of financial/other relationships Chanyan Hu is an employee of Shandong Luoxin Pharmaceutical Group Stock Co., Ltd. The remaining authors declared no conflict of interest. A reviewer on this manuscript has disclosed that they are a consultant and speaker for Phathom. Peer reviewers on this manuscript have no other relevant financial or other relationships to disclose. Author contributions Ye Zong: Conceptualization; investigation; writing – review and editing. Cheng Lan, Xing Li, Weixing Chen, Honghui Chen, Aijun Liao and Side Liu: Investigation; writing – review and editing. Chanyan Hu: Conceptualization; investigation; supervision; writing – original draft; writing – review and editing. Yongdong Wu: Conceptualization; investigation; supervision; writing – review and editing. Shutian Zhang: Conceptualization; investigation; supervision; writing – review and editing. Supplemental material Supplementary Table S1-clean.docx Supplementary Table S1-clean.docx Site Ethical Approval Number.pdf Site Ethical Approval Number.pdf Acknowledgements The authors would like to thank all the patients and investigators who participated in this trial. Data availability statement The data supporting the findings of the current study are available from the corresponding author on reasonable request. Ethics statement This study had approval from the Ethics Committees of various participating centers. Signed informed consent was provided by each patient before enrollment. Related research
  Content Reference URL	None

• Publisher

  None

• Data Source

  Data Source Name	Quantexa News (#5)
  Data Source Type	news
  Data Source URL	https://app.aylien.com/dashboard
  Description	Welcome to Quantexa News API — the most powerful way to aggregate, filter, and integrate global news data into your apps and models.
  Weight	10