Randomised clinical trial: the clinical efficacy and safety of an alginate-antacid (Gaviscon Double Action) versus placebo, for decreasing upper gastrointestinal symptoms in symptomatic gastroesophageal reflux disease (GERD) in China.

BACKGROUND: There is a paucity of large-scale studies evaluating the clinical benefit of the Gaviscon Double Action (DA) alginate-antacid formulation for treating gastroesophageal reflux disease (GERD) symptoms. AIM: Randomised double-blind placebo-controlled parallel-group study to evaluate efficacy and safety of Gaviscon DA in reducing heartburn, regurgitation and dyspepsia symptoms in individuals with mild-to-moderate GERD in China.
METHODS: Participants with symptomatic GERD (n = 1107) were randomised to receive Gaviscon DA or placebo (two tablets four times daily) for seven consecutive days. The primary endpoint compared the change in Reflux Disease Questionnaire (RDQ) score for the GERD (heartburn + regurgitation) dimension between Gaviscon DA and placebo. Secondary endpoints compared the change in RDQ scores for individual heartburn, regurgitation and dyspepsia dimensions, overall treatment evaluation (OTE) scores and incidence of adverse events (AEs).
RESULTS: Mean RDQ GERD scores: 2.51 for Gaviscon DA and 2.50 for placebo at baseline; 1.25 for Gaviscon DA and 1.46 for placebo post treatment. Gaviscon DA was statistically superior to placebo in reducing GERD and dyspepsia RDQ scores [least-squares mean (LSM) difference: GERD -0.21, P < 0.0001; dyspepsia -0.18, P = 0.0004], despite a substantial placebo response. The Gaviscon DA group reported more favourable overall treatment responses than the placebo group across all OTE categories (P < 0.0001). Superior relief of GERD symptoms was observed both in those with non-erosive and those with erosive reflux disease (LSM difference -0.14 [P = 0.038] and -0.29 [P < 0.0001] respectively). Incidence of AEs was similar in both groups.
CONCLUSION: Gaviscon DA tablets provide effective and safe reduction in acid reflux and dyspepsia symptoms in Chinese individuals with mild-to-moderate GERD. ClinicalTrials.gov: NCT01869491.

RCT Entities:   Population Interventions Outcomes

Introduction

Gastroesophageal reflux disease (GERD) is a chronic condition that develops when the reflux of gastric contents into the oesophagus causes troublesome symptoms with or without complications. Heartburn and regurgitation are two of the most common GERD symptoms,1 with many GERD patients also experiencing dyspepsia.2 The troublesome symptoms of GERD can have a significant impact on health‐related quality of life and work productivity.3, 4 The prevalence of GERD in East Asia is rising rapidly, although still lower than in the rest of the world.5, 6 This places an increasing burden on society and health services in the region.

Gastroesophageal reflux events and related symptoms commonly occur after meals.7, 8 The ‘acid pocket’ is a zone containing unbuffered, highly acidic gastric secretions that accumulate in the proximal stomach after meals. The acid pocket has been identified as a cause of post‐prandial acid reflux and represents an attractive target for the treatment of GERD.9 Proton pump inhibitors (PPIs), which inhibit gastric acid secretion and attenuate acid pocket development,10 are considered the gold standard treatment for patients with GERD. Despite the high efficacy of PPIs in providing symptom relief via acid suppression, up to a third of patients with GERD fail to respond adequately to PPI therapy.11 In particular, patients with non‐erosive reflux disease (NERD) are known to have a lower response rate to PPIs, compared to those with erosive reflux disease (ERD).12, 13, 14

Alginate‐based formulations act primarily by a unique nonsystemic mechanism of action, different from antacids, PPIs or histamine H2‐receptor antagonists (H2 antagonists).15 Upon coming into contact with gastric acid, alginate rapidly forms a gel ‘raft’ of near‐neutral pH that creates a protective barrier above the acidic gastric contents. This alginate raft protects the oesophageal mucosa by limiting gastric reflux into the oesophagus.16, 17 Alginate‐based formulations have been shown to act more rapidly than PPIs and H2 antagonists,18 and to provide longer‐lasting relief of symptoms than conventional antacids.19 These formulations have been shown to provide effective relief of upper gastrointestinal (GI) symptoms, either as a monotherapy or in combination treatment. A recent randomised double‐blind comparative trial showed that Gaviscon suspension, an alginate‐antacid formulation containing sodium alginate and sodium bicarbonate, was non‐inferior to omeprazole in achieving a 24‐h heartburn‐free period in patients with moderate GERD.20 These findings suggest that alginate‐based formulations could be considered as an alternative or add‐on therapy in GERD patients, including those with NERD.

A number of alginate‐based formulations are currently available on the market. These contain various concentrations of alginate and sodium bicarbonate, as well as other antacid components, and exhibit varying raft strength and acid neutralisation properties.15, 21 Gaviscon Double Action [Gaviscon DA; Reckitt Benckiser Healthcare (UK) Limited, Hull, UK] is an alginate‐antacid formulation with improved raft resilience.21 It contains sodium alginate and high concentrations of two antacids, calcium carbonate and sodium bicarbonate.22 Recent studies demonstrated that Gaviscon DA rapidly localises to the post‐prandial acid pocket and displaces it away from the oesophagus.23, 24 Gaviscon DA was found to be significantly superior to antacids in decreasing both acid reflux events24 and oesophageal acid exposure25 after meals.

The clinical benefit of Gaviscon DA was recently demonstrated in a single‐centre pilot study conducted in participants with GERD in the UK. Gaviscon DA significantly reduced heartburn, regurgitation and dyspepsia symptoms in GERD patients and showed a tolerability profile similar to that of placebo.26 The present study, a large‐scale randomised placebo‐controlled trial, was subsequently conducted in China to assess the efficacy and safety of Gaviscon DA in relieving the GERD‐related symptoms of heartburn, regurgitation and dyspepsia.

Methods

Participants and study design

This was a randomised, double‐blind, two‐arm, parallel‐group, placebo‐controlled study conducted in the gastroenterology clinics of 31 hospitals across China between June 2013 and May 2014. Participants were recruited from among patients attending the clinics or individuals who visited the clinics to participate in the trial. The trial included individuals who were between 18 and 65 years old (inclusive), who had a diagnosis of uncomplicated symptomatic GERD in accordance with the Montreal definition,1 as well as a history of frequent episodes of heartburn, regurgitation or dyspepsia symptoms for at least 3 months and on at least 5 of the 7 days prior to screening. Individuals were excluded if they had (i) taken any medications which might interfere with the action of the study medications prior to the start of the study or during the study; (ii) a clinical history or symptom profile suggestive of complicated GERD, other GI diseases (including Barrett's oesophagus, acute peptic ulcer, or indication for Helicobacter pylori eradication therapy) or any severe diseases of other major body systems; (iii) any existing conditions that might compromise their safety or participation in the study. Details of the trial eligibility criteria can be found on the ClinicalTrials.gov trial registry website.27

This study was approved by independent ethics committees and all participants provided written informed consent prior to the initiation of any study‐related activities. This study was conducted in accordance with the Declaration of Helsinki, the International Conference on Harmonisation Good Clinical Practice (ICH GCP) guidelines, and applicable regulatory requirements, and is registered in the ClinicalTrials.gov trial registry (NCT01869491).

Treatment allocation and treatment schedule

Participants were randomly assigned to receive either Gaviscon DA or placebo tablets, based on a computer‐generated randomisation code list provided by Reckitt Benckiser. Each participant was allocated a unique patient number in sequential order. The study medication was packaged and labelled according to the randomisation code list and issued to the participants with the corresponding patient numbers. Each Gaviscon DA tablet contained 250 mg sodium alginate, 106.5 mg sodium bicarbonate and 187.5 mg calcium carbonate as active ingredients. The placebo tablets contained no active ingredients and were composed mainly of mannitol and xylitol. The placebo tablets matched the Gaviscon DA tablets in appearance, taste and consistency and the study medications were packaged identically. All study personnel and participants were blinded to the treatment allocated. The study was unblinded only after the database had been locked. Participants started treatment the day after their randomisation visit. They took two tablets of the assigned medication four times a day for seven consecutive days: 30 min after breakfast, 30 min after lunch, 30 min after dinner and immediately before lying down for bed.

Study assessments

Efficacy assessments were based on the Reflux Disease Questionnaire (RDQ)28 and the overall treatment evaluation (OTE).29, 30 Participants completed the RDQ before the start of treatment and completed both the RDQ and OTE at the end of treatment. The recall period used for both questionnaires was ‘the last 7 days’.

The RDQ is a 12‐item self‐administered questionnaire designed to assess symptom frequency and severity in three dimensions corresponding to heartburn, regurgitation and dyspepsia symptoms. Responses are scored on a six‐point scale, with higher scores indicating more severe or frequent symptoms.28 A validated Chinese‐language version of the RDQ was used in this study.31 The primary endpoint was the RDQ GERD dimension score, an equally weighed combination of the heartburn and regurgitation dimension scores. This was calculated as the mean of all frequency and intensity scores for the heartburn and regurgitation dimensions, weighted equally. Secondary endpoints included the heartburn, regurgitation and dyspepsia RDQ dimension scores. The change in each RDQ dimension score was calculated as the difference between the baseline and post‐treatment scores. Changes in RDQ dimension scores (from baseline to post treatment) were then compared between the DA and placebo groups.

The OTE, a measure of patient responsiveness and satisfaction with treatment, was a further secondary endpoint. The OTE is an instrument designed to assess respondents’ perceptions of the magnitude of change in their symptoms after treatment and the perceived importance of the change.29, 30 Participants were asked to rate their symptoms on a 15‐point scale: worse (−7 to −1), unchanged (0), or better (+1 to +7) (Question 1). If participants reported a change in their symptoms, they were asked to rate the importance of the change (Question 2) on a seven‐point scale, with higher scores indicating greater importance. The percentages of participants in each OTE category were then compared between the DA and placebo groups.

Safety was assessed based on vital signs and clinical laboratory results, as well as physical examinations before the start of treatment and at the end of treatment. All adverse events (AEs) occurring during the treatment period were documented.

Sample size determination

The sample size for this study was estimated based on the results of an earlier pilot study (GA1203) conducted in the UK.26 The effect sizes for the RDQ GERD dimension (combined heartburn and regurgitation dimensions) and the dyspepsia dimension were 0.627 and 0.384, respectively, in the pilot study.26 However, it was anticipated that the effect size in the present Gaviscon DA study would be smaller than in the GA1203 UK pilot study.26 This was based on observations from a pair of studies conducted in the UK and China on a different alginate‐antacid formulation, which revealed a much larger placebo effect in the Chinese study population.32, 33 The sample size calculation for this study assumed a similar inflated placebo response and therefore a smaller effect size: 0.4 for the RDQ GERD dimension and 0.2 for the dyspepsia dimension. It was estimated that a sample size of at least 1054 participants would be required to detect differences in RDQ scores between the treatment groups with at least 90% power at the 5% significance level. To allow for a 5% dropout rate, it was estimated that 1100 participants would need to be randomised to ensure evaluable data from 1054 participants.

Statistical analysis

The primary endpoint compared the change in RDQ symptom scores for the GERD dimension (from baseline to the end of treatment) between the Gaviscon DA group and the placebo group. The key secondary endpoint compared the change in RDQ symptom scores for the dyspepsia dimension between the DA and placebo groups. Other secondary endpoints included comparisons between the two groups for the following variables: (i) change in RDQ symptom score for individual heartburn and regurgitation dimensions; (ii) scores for both questions of the OTE questionnaire and (iii) incidence of AEs.

Efficacy analysis was performed for all participants who were enrolled in the study and had at least a partially completed RDQ questionnaire for the study treatment period (intent‐to‐treat; ITT population). The primary endpoint (comparison of change in RDQ symptom scores for the GERD dimension between treatment groups) was analysed using a linear mixed model, with ‘treatment’ as a fixed effect, ‘centre’ as a random effect and ‘baseline RDQ score for the GERD dimension’ as a linear covariate. Similarly, linear mixed models were used to compare change from baseline values in RDQ symptom scores for each of the three dimensions (heartburn, regurgitation and dyspepsia) between treatment groups, with the baseline RDQ score for the corresponding dimension used as the covariate. Scores for both OTE questions were summarised by treatment group, and were compared between treatment groups using the Wilcoxon rank‐sum test stratified by centre. Exploratory analyses of the primary endpoint were also performed for two pre‐specified subgroups: participants with ERD [Los Angeles (LA) classification grades A or B only] and those with NERD, as confirmed by symptoms and endoscopy findings.34

Safety analysis was performed for all enrolled participants who received at least one dose of study medication. The incidence of AEs was summarised overall and by relatedness to the study medication, seriousness and severity. The incidence of AEs in the treatment groups was compared using Fisher's exact test.

All statistical analyses were conducted using two‐tailed tests at the 5% significance level. A closed testing procedure was applied to preserve the type 1 (false positive) error rate of 5% for the key secondary endpoint. A significant comparison at the 5% level for this key secondary endpoint was considered as confirmatory evidence only if the primary endpoint was also significant at the 5% level. All other secondary endpoints and any alternate analyses for the primary and key secondary endpoints were considered supportive only and no further adjustment for multiple comparisons was made. All analyses were conducted using sas, version 9.2 (SAS Institute Inc., Cary, NC, USA).

Results

Participant demographics and baseline characteristics

A total of 1107 participants were enrolled and randomised to treatment (Figure 1). Of these, 1099 participants received at least one dose of study medication and were included in the safety population. Thirty‐four participants did not answer the RDQ questionnaire at the end of the treatment; the remaining 1073 participants were included in the efficacy evaluation (ITT population): 536 in the Gaviscon DA group and 537 in the placebo group. A total of 1062 participants completed the study. The flow of participants through the trial and the reasons for withdrawal from the trial are summarised in Figure 1. Demographics and baseline characteristics, including GERD status (presence of ERD or NERD) were similar in the Gaviscon DA and placebo groups (Table 1). At baseline, the DA and placebo groups had similar scores in the GERD RDQ dimension as well as in the individual heartburn, regurgitation and dyspepsia dimensions (Table 2).

Figure 1

Study participant disposition. AE, adverse event; SAE, serious adverse event; DA, Double Action.

Table 1

Demographic and baseline characteristics of participants (ITT population)

Characteristic	Gaviscon DA (n = 536)	Placebo (n = 537)
Age (years), mean (s.d.)	45.0 (11.8)	45.0 (11.8)
Male, n (%)	261 (48.7)	284 (52.9)
BMI (kg/m2), median (range)	23.4 (16.0–34.9)	23.3 (16.6–32.7)
Current smoker, n (%)	97 (18.1)	90 (16.8)
Alcohol use, n (%)	63 (11.8)	63 (11.7)
ERDa, n (%)	259 (48.3)	251 (46.7)
LA grade A, n (%)b	203 (78.4)	197 (78.5)
LA grade B, n (%)b	56 (21.6)	54 (21.5)

BMI, body mass index; ERD, erosive reflux disease; ITT, intent‐to‐treat; LA grade, Los Angeles classification grade; GERD, gastroesophageal reflux disease; RDQ, reflux disease questionnaire.

Presence of ERD was confirmed by endoscopy. Patients with severe ERD (Los Angeles classification grades C or D) were excluded from this study.

Percentages are expressed with respect to the group of patients with ERD/abnormal endoscopy findings.

Table 2

Baseline and end of treatment RDQ scores (ITT population)

RDQ dimension score	Gaviscon DA (n = 536)	Placebo (n = 537)
GERD (combined heartburn and regurgitation)
Baseline score	2.51 (0.93)	2.50 (0.94)
Range of scores	0.0–5.0	0.0–5.0
Post‐treatment score	1.25 (0.94)	1.46 (1.00)
Range of scores	0.0–4.9	0.0–4.5
Min/max score change from baseline	−4.6–1.5	−4.0–1.4
Heartburn
Baseline score	2.37 (1.33)	2.30 (1.35)
Range of scores	0.0–5.0	0.0–5.0
Post‐treatment score	1.20 (1.15)	1.38 (1.24)
Range of scores	0.0–5.0	0.0–5.0
Min/max score change from baseline	−4.5–2.5	−4.5–2.0
Regurgitation
Baseline score	2.65 (1.26)	2.70 (1.25)
Range of scores	0.0–5.0	0.0–5.0
Post‐treatment score	1.30 (1.13)	1.54 (1.21)
Range of scores	0.0–5.0	0.0–5.0
Min/max score change from baseline	−5.0, 1.0	−4.5–2.5
Dyspepsia
Baseline score	2.02 (1.39)	2.02 (1.36)
Range of scores	0.0–5.0	0.0–5.0
Post‐treatment score	1.04 (1.10)	1.22 (1.14)
Range of scores	0.0–5.0	0.0–5.0
Min/max score change from baseline	−5.0–2.8	−5.0–2.3

RDQ, reflux disease questionnaire; ITT, intent‐to‐treat; DA, Double Action; GERD, gastroesophageal reflux disease.

Efficacy

At baseline, the mean (s.d.) RDQ score for the GERD dimension was 2.51 (0.93) in the DA group and 2.50 (0.94) in the placebo group (Table 2). The range of baseline GERD RDQ scores was the same in both groups (0–5). At the end of the 7‐day treatment period, GERD RDQ scores were lower in both groups: 1.25 (0.94) for the DA group and 1.46 (1.00) for placebo [mean (s.d.)]. These correspond to mean score changes of −1.26 (DA) and −1.06 (placebo). The magnitude of the GERD RDQ score change (post‐treatment score minus baseline score) ranged from −4.6 to 1.5 in the DA group, compared with −4.0 to 1.4 in the placebo group (Table 2). For the dyspepsia endpoint, mean RDQ scores decreased from 2.02 at baseline to 1.04 post treatment in the DA group, and from 2.02 to 1.22 in the placebo group (Table 2). In both the GERD and dyspepsia RDQ dimensions, the placebo response was considerably larger than that seen in the pilot study.

Adjusted changes in RDQ score for the GERD dimension and the individual RDQ dimensions at the end of treatment are summarised in Table 3. At the end of the treatment period, there was a decrease in GERD RDQ score in both treatment groups, with a least‐squares mean (LSM) change of −1.27 for Gaviscon DA and −1.06 for placebo. The decrease in RDQ score was significantly greater for Gaviscon DA than placebo, with a LSM difference of −0.21 (P < 0.0001). Decreases were also observed in scores for the individual RDQ dimensions (heartburn, regurgitation and dyspepsia) at the end of treatment, with significantly greater reductions in the Gaviscon DA group than the placebo group (Table 3).

Table 3

Adjusted change in RDQ score for the GERD dimension and the individual RDQ dimensions from baseline to the end of treatment (ITT population)

RDQ dimension	LSM change (95% CI)		LSM differencea
	Gaviscon DA (n = 536)	Placebo (n = 537)	(95% CI); P‐valueb
GERD (heartburn + regurgitation)	−1.27 (−1.37 to −1.16)	−1.06 (−1.17 to −0.95)	−0.21 (−0.31 to −0.11); P < 0.0001
Heartburn	−1.16 (−1.28 to −1.04)	−0.95 (−1.07 to −0.83)	−0.21 (−0.32 to −0.10); P = 0.0001
Regurgitation	−1.37 (−1.48 to −1.26)	−1.16 (−1.27 to −1.05)	−0.21 (−0.32 to −0.09); P = 0.0004
Dyspepsia	−0.98 (−1.10 to −0.86)	−0.80 (−0.91 to −0.68)	−0.18 (−0.29 to −0.08); P = 0.0004

CI, confidence interval; GERD, gastroesophageal reflux disease; LSM, least‐squares mean; RDQ, reflux disease questionnaire; DA, Double Action; ITT, intent‐to‐treat.

LSM difference is the difference in RDQ score changes between treatment groups (LSM change for Gaviscon DA group minus LSM change for placebo group).

P‐value for comparison between treatment groups.

Within the ERD and NERD subgroups, mean baseline GERD RDQ scores were similar in the DA and placebo groups (Table 4). Changes in RDQ score for the GERD dimension for the ERD and NERD subgroups are summarised in Table 4. In both subgroups, decreases in GERD RDQ score were observed at the end of treatment. Furthermore, reductions in GERD RDQ score were significantly greater among participants receiving Gaviscon DA than among those receiving placebo in both the ERD and NERD subgroups. The LSM difference between Gaviscon DA and placebo was −0.29 (P < 0.0001) in the ERD subgroup and −0.14 (P = 0.038) in the NERD subgroup.

Table 4

Adjusted change in RDQ score for the GERD dimension (combined heartburn and regurgitation dimensions) for NERD and ERD subgroups (ITT population)

Subgroup	LSM change (95% CI)		LSM differencea (95%CI); P‐valueb
	Gaviscon DA	Placebo	Gaviscon DA − Placebo
ERD	n = 259	n = 251
Baseline score	2.62	2.52
Post‐treatment score	1.31	1.55
LSM change (95% CI)	−1.33 (−1.47 to −1.18)	−1.04 (−1.18 to −0.89)	−0.29 (−0.43 to −0.14); P < 0.0001
NERD	n = 277	n = 286
Baseline score	2.41	2.49
Post‐treatment score	1.20	1.38
LSM change (95% CI)	−1.22 (−1.36 to −1.09)	−1.09 (−1.22 to −0.96)	−0.14 (−0.27 to −0.01); P = 0.038

CI, confidence interval; ERD, erosive reflux disease; GERD, gastroesophageal reflux disease; LSM, least‐squares mean; ITT, intent‐to‐treat; NERD, non‐erosive reflux disease; DA, Double Action; RDQ, reflux disease questionnaire.

LSM difference is the difference in RDQ score changes between treatment groups (LSM change for Gaviscon DA group minus LSM change for placebo group).

P‐value for comparison between treatment groups.

Based on the OTE assessments, the majority of participants in both the DA (90.3%) and placebo (84.2%) groups experienced an improvement in their symptoms following treatment (OTE responses from ‘+1 – Hardly any better’ to ‘+7 – A very great deal better’; Question 1) (Table S1). Moreover, over half (52.2%) of participants in the DA group rated their symptoms as at least ‘Moderately better’ (OTEs from +4 to +7), compared to 39.2% of the placebo group. Across all OTE response categories, participants in the Gaviscon DA group reported a more favourable overall treatment response (Question 1) than those in the placebo group (P < 0.0001; Wilcoxon rank‐sum test stratified by centre). This improvement in symptoms was perceived as important (Question 2) by the majority of participants in both groups (Gaviscon DA 96.3%, placebo 95.1%).

Figure 2 shows the observed relationship between the mean reduction in RDQ dimension scores for GERD and dyspepsia and participants’ overall rating of their response to treatment (OTE response category). This allows numerical changes in RDQ score to be interpreted in terms of the degree of improvement reported by participants. In the GERD RDQ dimension, the mean score change of −1.27 in the DA group corresponded to an OTE of between ‘4 – Moderately better’ and ‘3 – Somewhat better’. The smaller GERD RDQ score reduction in the placebo group (−1.06) corresponded to a less favourable OTE of between ‘3 – Somewhat better’ and ‘2 – A little better’ (Figure 2). Similarly, the mean score reduction in the dyspepsia RDQ dimension for the DA group (0.98) corresponded to a more favourable OTE than the mean score reduction for the placebo group (0.80).

Figure 2

Relationship between reduction in RDQ dimension scores and participants’ overall rating of their response to treatment (OTE Question 1). Results shown are for participants who reported improvement in symptoms (OTE Question 1). ‘G’ and ‘P’ denote the mean RDQ score change from baseline for the Gaviscon DA and Placebo groups, respectively. GERD, gastroesophageal reflux disease; OTE, overall treatment evaluation; DA, Double Action.

Safety

Adverse events reported during treatment are summarised in Table 5. The incidence of AEs was similar in the Gaviscon DA and placebo groups. Seventy‐four participants (13.5%) in the Gaviscon DA group and 63 participants (11.5%) in the placebo group experienced AEs during treatment. Twenty‐nine participants (5.3%) in the Gaviscon DA group and 19 participants (3.5%) in the placebo group had AEs that were at least possibly related to the study medication. Most of these AEs were GI disorders such as constipation, abdominal distension, flatulence and nausea (Table S2). One participant (0.2%) in the Gaviscon DA group reported a serious AE. Two participants [one in each group (0.2%)] had severe AEs. Treatment discontinuation due to AEs was reported for two participants (0.4%) in the Gaviscon DA group and four participants (0.7%) in the placebo group. No deaths or significant laboratory findings were reported during the study. No significant changes in vital signs were observed in either group.

Table 5

Incidence of AEs in Gaviscon DA and placebo groups (safety population)

Adverse events	Gaviscon DA (n = 549) n (%)	Placebo (n = 550) n (%)	P‐valuea
Any AE	74 (13.5)	63 (11.5)	0.317
Any related AE	29 (5.3)	19 (3.5)	0.143
Any SAE	1 (0.2)	0 (0.0)	−
Any severe AE	1 (0.2)	1 (0.2)	1.000
Any AE leading to discontinuation of study medication	2 (0.4)	4 (0.7)	−

AE, adverse event; SAE, serious adverse event; DA, Double Action.

P‐value for comparison between treatment groups.

Discussion

This study is the first large‐scale randomised, double‐blind, placebo‐controlled clinical trial to evaluate treatment with Gaviscon DA tablets for relief of heartburn, regurgitation and dyspepsia symptoms in individuals with GERD. Treatment with Gaviscon DA significantly decreased GERD and dyspepsia symptoms, as assessed by the change in RDQ dimension scores. Reductions in GERD and dyspepsia scores were also observed in the placebo group following treatment; this placebo response was considerably larger than that seen in the earlier UK pilot study.26 In spite of this enhanced placebo response, Gaviscon DA was statistically superior to placebo for all primary and secondary endpoints. There was no evidence to suggest any inconsistency in treatment effects across the 31 study centres in China.

Participants who received Gaviscon DA reported significantly greater overall improvement in their symptoms (higher OTE ratings) after the 7‐day treatment than those who received placebo. The mean reductions in GERD and dyspepsia RDQ scores in the DA group also corresponded to more favourable OTE ratings than the reductions seen in the placebo group. Overall, the number of serious or severe AEs was low and incidence of AEs was similar in the Gaviscon DA and placebo groups. These AEs were not deemed to be related to the study medication. The incidence of discontinuation due to AEs was very low (<1%) and was similar in the two groups.

Study participants were recruited from among attendees of 31 gastroenterology clinics across China, and are likely to be representative of the local population of patients with mild‐to‐moderate symptomatic GERD. Patients with severe ERD (LA classification grade C or D) were excluded from this study, and therefore the findings may not be generalisable to patients with more severe disease. Due to the short study duration, the findings are primarily applicable to situations involving short–term treatment of GERD symptoms, whereas individuals with severe or chronic disease might be more likely to receive long‐term treatment with multiple types of medication. This study did not include follow‐up or extension of treatment after the end of the study period. The maximum dose of Gaviscon DA is four tablets four times daily.22 Although the minimum dose (two tablets four times daily) was used in this study to maximise compliance, a statistically significantly greater improvement was still observed in the active treatment group.

The small differential benefit (DA vs. placebo) in this study can be attributed to the large placebo response observed in this Chinese GERD patient population. This is apparent when the results are compared with those of the UK pilot study (GA1203)26 that employed similar endpoints. In this study, the primary endpoint was the reduction in the RDQ GERD score following a 7‐day treatment, with LS mean reductions of 1.27 for Gaviscon DA and 1.06 for placebo. In contrast, the corresponding LS mean reductions for this endpoint in the UK pilot study26 were 1.35 for Gaviscon DA and 0.82 for placebo.

In a Chinese study (GA0917)33 involving a different Gaviscon formulation, 77% of participants taking the active treatment reported improvement in symptoms following 1 week of treatment, compared to 67% in the blinded placebo group. This was a considerably higher placebo response rate than that seen in an open‐label UK study (0100901)32 with similar endpoints, in which 74% of those taking the active treatment reported some improvement in symptoms following 2 weeks of treatment, compared to only 44% of the nonblinded placebo group.

It should be noted that, in both pairs of studies, the benefit in the active treatment group was reasonably similar across the UK and China study populations, despite the differences in study settings and patient populations. This suggests that the differential benefit (active treatment minus placebo) was smaller in the China studies due to the inflated placebo response. These observations in Chinese patient populations add to the well‐known placebo effects already documented in GERD studies.35 Further research will be needed to understand the factors contributing to the large placebo response among Chinese study participants.

To permit the detection of a smaller treatment effect against the background of the anticipated large placebo response, the present study was deliberately over‐powered in the sample size calculations, which assumed a smaller effect size than in the pilot study. It is possible that additional measures, such as including participants with more severe or frequent GERD symptoms, including more participants with erosive GERD, and/or using the maximum dose of Gaviscon DA (four tablets four times daily), might have made it possible to demonstrate a larger relative benefit for the active treatment.

Pre‐specified subgroup analyses indicated that, although a greater response was observed in participants with ERD, Gaviscon DA could provide significant symptomatic relief for GERD and dyspepsia in both ERD and NERD. This may be of clinical interest, as the effectiveness of PPI treatment is known to be more limited in patients with NERD.12 The findings of this study are consistent with those from smaller randomised controlled studies of other alginate‐based formulations in Chinese and Japanese NERD patients, which suggested that alginate‐based formulations may be effective for relieving GERD symptoms in NERD patients, either as a monotherapy or in combination treatment.13, 14

Taken together, the results of this study and those of the earlier UK pilot study26 demonstrate that Gaviscon DA is safe and effective for short‐term treatment of GERD and dyspepsia symptoms. Improvements in GERD symptoms following 7‐day treatment with Gaviscon DA were statistically significant superior to placebo, despite a substantial placebo response. Subgroup analysis provided evidence for modest but significantly greater symptomatic improvement with Gaviscon DA compared to placebo in both NERD and ERD subgroups. No safety issues were observed with Gaviscon DA treatment, which showed placebo‐like tolerability. These findings suggest that Gaviscon DA tablets may be a reasonable alternative or add‐on treatment option for patients with mild‐to‐moderate symptomatic GERD.

Authorship

Guarantor of the article: Prof. Yaozong Yuan.Author contributions: J Sun, Y Yuan, C Yang, H Zhao and P Zheng were responsible for data acquisition and revision of the article for important intellectual content. J Wilkinson was responsible for conception and design of the trial, data interpretation and revision of the article for important intellectual content. B Ng was responsible for data interpretation and revision of the article for important intellectual content. All authors approved the final version of the manuscript.

Table S1. Overall treatment evaluation (OTE) in DA and placebo groups.

Table S2. Number of patients experiencing at least one study product‐related adverse event.

Click here for additional data file.