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

Materials and Methods

Study Subjects

Male or female patients were out-patients aged ≥20 years old who had recurrent typical GERD symptoms (heartburn and regurgitation) for ≥3 months before screening, both heartburn and regurgitation for 7 days prior to randomisation, and with mild severity for ≥2 days/week or with moderate and severe ones for ≥1 day/week.

The major exclusion criteria included complications associated with erosive reflux disease (ERD), acute upper gastrointestinal bleeding, acute gastritis, gastric or duodenal ulcer within 2 months before screening esophagogastroduodenoscopy (EGD), history of gastric or oesophageal surgery, Barrett's oesophagus or oesophageal stricture, eosinophilic oesophagitis, Zollinger-Ellison syndrome, diagnosis of depression, abnormal laboratory test values at the screening (blood urea nitrogen and serum creatinine level, >1.5 upper limit of normal [ULN]; total bilirubin levels and serum levels of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and gamma glutamyltransferase, >2 ULN) or any other conditions or diseases that an investigator considered not appropriate for this study. Pregnant and lactating female subjects were excluded from this study.

Patients were not allowed to concomitantly use any medications that could affect the efficacy evaluation, such as PPIs (within 2 weeks before endoscopy), histamine receptor 2 blockers, prokinetics or antacids (within 7 days before endoscopy), anti-depressants, anti-psychotics and anti-anxiety drugs.

Study Design and Treatments

This was a phase 3, randomised, double-blind, multicentre (17 centres, 17 investigators in South Korea), placebo-controlled, parallel-group, three-arm study, conducted from September 2015 to November 2016. In this study, the therapeutic effect of tegoprazan 50 and 100 mg, compared with that of the placebo, was analysed in patients with NERD who displayed normal mucosa at the screening EGD (endoscopic appearance of NERD defined as normal (N), according to the Los Angeles classification). The clinical protocol was approved by the Institutional Review Boards of each institute and followed the Declaration of Helsinki and the International Congress on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use—Good Clinical Practice (ICH-GCP) guidelines. The study was registered in ClinicalTrials.gov under the number NCT02556021. All patients signed the informed consent form before inclusion in the study and initiation of study procedures.

Following a screening period (2 weeks), patients were randomised 1:1:1 (block randomisation, block size = 6) to receive orally and once daily either tegoprazan (50 or 100 mg) or placebo for 4 weeks. This study was assigned by central enrolment, and Interactive Web Response System (IWRS) was used for randomisation. All study drugs were manufactured by HK inno.N Corp. Patients with intolerable pain caused by NERD symptoms were allowed to take up to one dose per day of the rescue medication (Gelfos-M Suspension, Boryung Pharmaceutical Co., Ltd.).

Patients received tegoprazan 50 mg, 100 mg, or placebo, and rescue medication on day 1 and returned for visits at weeks 2, 4, and 6 (follow-up) for the assessment of NERD symptoms (Figure 1). Unused study drug and rescue medication were collected at weeks 2 and 4, and new ones were dispensed at week 2. All study patients underwent a complete physical examination and were evaluated for treatment-emergent adverse events (TEAEs). Laboratory analyses and pregnancy tests for female patients were performed at screening, week 4, and follow-up visits.

Figure 1.

Randomisation protocol and patient disposition

Patient symptoms were assessed with the Reflux Disease Questionnaire (RDQ), in which patients were asked to report six symptoms covering three items (heartburn, regurgitation and dyspepsia) using a 12-item self-administered questionnaire, designed to assess the frequency and severity of the symptoms. The mean RDQ score was calculated at baseline and at weeks 2 and 4 and follow-up visit. Heartburn and regurgitation were defined according to the Montreal definition. Heartburn was defined as a "burning sensation in the posterior bony thorax area (back of the bone, near the breast and in the epigastric region)"; meanwhile, regurgitation was defined as a "feeling of movement from the stomach to the mouth of the hypopharynx (the part adjacent to the oesophagus, below the airway), that resulted in a bitter or sour taste in the mouth."[21]

Patients recorded once a day the occurrence of heartburn and regurgitation without distinction of onset time (day or night time) in the patient diary (paper) before going to bed. The following 5-point scale, defined by the patient, assessed the severity of heartburn and regurgitation symptoms: no symptoms, mild: symptom did not interfere with routine activities including sleep; moderate: slight discomfort and interference with routine activities including sleep; severe: recurring symptoms that frequently interfered with routine activities including sleep; and very severe: consistent symptoms that substantially interfered with routine activities including sleep.

Outcome Measures

The primary efficacy endpoint was the proportion of patients with complete resolution of major symptoms (both heartburn and regurgitation) for the last 7 days of week 4 (treatment period), according to the RDQ score.[22,23] Complete resolution was defined as no symptoms. The secondary efficacy endpoints included RDQ-based complete resolution of the major symptoms at week 2, and of heartburn at weeks 2 and 4, and the proportions of days without heartburn during the 4-week treatment period, as reported in the patient's diary.

As patients with severe heartburn may be more likely to have acid-related NERD (true NERD), subgroup analyses of the proportions of heartburn-free days during the 4-week treatment period and daily proportions of patients without heartburn were performed in patients with NERD, who experienced moderate and severe heartburn during the screening period (n = 41, n = 42 and n = 39 in tegoprazan 50 mg, 100 mg and placebo groups, respectively).

Safety was evaluated by TEAEs at weeks 2 and 4, and follow-up visits as well as physical examination, electrocardiogram, vital signs (blood pressure, heart rate and temperature) and laboratory test results (haematology, blood chemistry, blood coagulation test and urinalysis). Laboratory data were monitored for clinically significant changes from baseline. Adverse drug reactions were defined as adverse events for which a causal relationship could not be ruled out. All adverse events reported during the study, regardless of their relationship with the study drug, were recorded in detail in terms of the date of onset, duration (if applicable), seriousness, severity, the required treatment modification, the causal relationship with the study medication and the outcome. Adverse events, adverse drug reactions and serious adverse events were recorded using MedDRA 19.1 and classified by System Organ Class and Preferred Term.

Statistical Analysis

Based on previous study results,[24] assuming 19.9% difference in the outcome proportion from placebo group, number of patients with this assumption was 86 in each treatment group to observe intergroup differences in the proportion of patients with complete resolution of major symptoms (heartburn and regurgitation) at week 4 of the treatment period with a power of 80% at a significance level of 0.05. Additionally, the total sample size was 324 subjects with 108 patients per group considering 20% dropout.

Efficacy assessments were analysed primarily in the full-analysis set (FAS). Safety assessments were analysed in the safety set. For the primary endpoint, the proportion of patients with complete resolution of the major symptoms for the last 7 days of week 4 (treatment period), according to the RDQ score, was calculated in the FAS. Chi-square and Fisher's exact tests were used to compare the primary endpoints, the complete resolution rate of heartburn or regurgitation, the proportion of heartburn-free days and the daily proportion of patients without heartburn between tegoprazan and placebo administrations. Hochberg method was used to adjust the significance level for multiple comparisons.

Statistical analyses were performed using SAS version 9.3 (SAS Institute), and two-sided P-values of < 0.05 were considered statistically significant.

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