Randomised Clinical Trial

Comparison of Tegoprazan and Placebo in Non-erosive Reflux Disease

Seung Han Kim; Kwang Bum Cho; Hoon Jai Chun; Sang Woo Lee; Joong Goo Kwon; Dong Ho Lee; Sang Gyun Kim; Hwoon-Yong Jung; Ji Won Kim; Joon Seong Lee; Hyojin Park; Suck Chei Choi; Sam Ryong Jee; Hyun-Soo Kim; Kwang Hyun Ko; Seun Ja Park; Yong Chan Lee; Soo Heon Park; Ah Rong Kim; Eun Ji Kim; Hyun Wook Park; Bong Tae Kim; Geun Seog Song

Disclosures

Aliment Pharmacol Ther. 2021;54(4):402-411. 

In This Article

Discussion

This was the first randomised, double-blind, controlled phase 3 study that evaluated the effectiveness of tegoprazan, a novel P-CAB, in 324 Korean patients with NERD. Four weeks of treatment with tegoprazan 50 and 100 mg once daily significantly increased the resolution rate of major symptoms (both heartburn and regurgitation) compared with placebo administration.

Tegoprazan 50 and 100 mg also achieved significantly higher complete heartburn resolution rates at weeks 2 and 4 and proportion of heartburn-free days during 4-week of treatment period compared with the placebo. The responses for complete resolution rates of heartburn observed in this study were comparable with those previously obtained with PPIs in patients with NERD.[25,26]

NERD, characterised by the presence of typical GERD symptoms without oesophageal erosion at upper endoscopy, negatively influences the QoL of patients.[6,8] PPIs are currently used as the most effective treatment for GERD, but reflux symptoms are not completely controlled in a significant number of patients with NERD.[7] Additionally, the responses to PPI therapy were higher in patients with ERD than those with NERD,[12,27,28] which suggested that these two disorders might have different underlying pathogeneses.[7,13] The characteristics and pathophysiology of NERD led to administration of higher dose of tegoprazan than the approved ones for treatment of ERD in this study. Our data showed that an increased dose of tegoprazan was more helpful to patients with NERD if it provided a significant relief of the major symptoms, in cases where typical GERD symptoms were not achieved with the standard dose.

Differences from placebo for complete resolution rates of heartburn in tegoprazan groups (14.3% and 16.2% for tegoprazan 50 and 100 mg, respectively) were higher than those for the major symptoms, both heartburn and regurgitation (5.9% and 13.1%, respectively) at week 2, whereas the differences were comparable at week 4. Moreover, complete resolution rates of regurgitation were higher in tegoprazan groups compared with the response of placebo but those differences were not statistically significant, which was consistent with previous reports that regurgitation was less responsive to acid suppression than heartburn in patients with GERD.[29] Interestingly, responses to tegoprazan 50 and 100 mg were comparable in terms of heartburn but not for the complete resolution of major symptoms. Because regurgitation was less responsive to acid suppressant, the complete resolution rate of the major symptoms at week 2 was not significantly different between administration of tegoprazan 50 mg and placebo.

Even though several attempts to improve the development of P-CAB and thus overcome the major disadvantages of PPIs have been made, the evidence of the P-CAB therapeutic potential in the treatment of NERD is limited. Recently, two randomised, placebo-controlled phase 3 studies reported that vonoprazan was not significantly superior to the placebo in achieving the primary efficacy outcome (proportion of days without heartburn during the 4-week treatment period) in the FAS of patients with NERD.[30,31] It is unexpected that vonoprazan did not achieve the superiority in the primary efficacy outcome for treatment of NERD compared with placebo, although it was reported the superior inhibition of gastric acid secretion by P-CAB did not translate into an improved clinical benefit over PPI (active comparator) in patients with NERD.[32] Yoshikazu et al explained that the partial response of vonoprazan monotherapy may be due to the heterogeneous pathophysiology of NERD.[30,31] Additionally, Ryota et al and Satoshi et al reported that vonoprazan was effective in relieving the gastroesophageal reflux symptoms in patients with PPI-resistant NERD.[33,34] These studies do not discard the possibility that P-CAB could be effectively used in NERD; however, these results should be confirmed in larger randomised controlled trials.

Tegoprazan was approved in Korea for the treatment of ERD, NERD, gastric ulcer and eradication of Helicobacter pylori[35,36] and became the first P-CAB clinically available for patients with NERD. Because tegoprazan exhibited a rapid acid inhibition and long-lasting effect in previous studies,[18,19] it is plausible that tegoprazan may have a better therapeutic effect in acid-related diseases. This study confirmed that tegoprazan was superior to the placebo in the achieving the primary efficacy outcome and heartburn-related secondary efficacy outcomes (complete resolution rates of heartburn for the last 7 days of weeks 2 and 4, and proportion of days without heartburn during the 4-week treatment period) in patients with NERD. Although patients who participated in this study had milder heartburn symptoms than those in the vonoprazan studies, subgroup analyses of the proportions of heartburn-free days and the daily proportions of patients without heartburn revealed that tegoprazan provided rapid and sustained heartburn relief to patients with NERD, who experienced heartburn symptom with moderate and higher severity in the screening period, from day 1 and throughout the treatment period (Figures 2 and 3). This rapid and sustained symptom relief supports that tegoprazan may provide on-demand therapeutic option to patients with NERD.

According to the safety analysis, no significant differences in the incidence of TEAEs between tegoprazan and placebo groups were noted (19.4%, 22.2% and 20.6% for tegoprazan 50 mg, 100 mg and placebo, respectively). Moreover, no significant drug-related TEAEs were reported throughout the study, confirming a favourable safety profile for the oral administration of tegoprazan.

This study has several limitations. First, it is difficult to generalise the study results for non-Korean populations. The design of this study was not active-controlled. The beneficial features of tegoprazan, such as fast onset, no food effect, nocturnal acid breakthrough control and less inter-individual variation due to different PPIs metabolism pathways, were not reflected in the design of this study. There was no information on disposition of patients infected with H. pylori infection in this randomised study although it is still controversy if status of H. pylori infection affects symptom outcomes of PPIs in patients with NERD. In addition, due to the multifactorial pathophysiology of NERD and no intra-oesophageal pH monitoring before enrolment, the patient population recruited in this study may have included patients with true NERD, oesophageal hypersensitivity, functional heartburn and functional dyspepsia, which could affect the outcome responses.

In conclusion, oral administration of 50 and 100 mg of the novel P-CAB tegoprazan, once daily for 4 weeks, resulted in a statistically superior efficacy over the placebo in terms of complete resolution of RDQ-based major symptoms in patients with NERD. Tegoprazan also significantly increased the complete heartburn relief rates at both weeks 2 and 4 and the percentage of heartburn-free days, compared with those observed in the placebo group. Tegoprazan provided effective and sustained symptom relief to NERD patients, constituting an effective therapeutic option for the treatment of NERD.

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