Drug Development and Industrial Pharmacy

ISSN: 0363-9045 (Print) 1520-5762 (Online) Journal homepage: http://www.tandfonline.com/loi/iddi20

Two placebo-controlled crossover studies

in healthy subjects to evaluate gastric acid
neutralization by an alginate–antacid formulation
(Gaviscon Double Action)

Joanne Wilkinson, Khalid Abd-Elaziz, Izaak den Daas, Johan Wemer, Michiel
van Haastert, Victoria Hodgkinson, Michelle Foster & Cathal Coyle

To cite this article: Joanne Wilkinson, Khalid Abd-Elaziz, Izaak den Daas, Johan Wemer, Michiel
van Haastert, Victoria Hodgkinson, Michelle Foster & Cathal Coyle (2018): Two placebo-controlled
crossover studies in healthy subjects to evaluate gastric acid neutralization by an alginate–antacid
formulation (Gaviscon Double Action), Drug Development and Industrial Pharmacy, DOI:
10.1080/03639045.2018.1546314

To link to this article: https://doi.org/10.1080/03639045.2018.1546314

Accepted author version posted online: 23

Nov 2018.
Published online: 02 Dec 2018.

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DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY
https://doi.org/10.1080/03639045.2018.1546314

Two placebo-controlled crossover studies in healthy subjects to evaluate gastric

acid neutralization by an alginate–antacid formulation (Gaviscon Double Action)
Joanne Wilkinsona, Khalid Abd-Elazizb, Izaak den Daasb, Johan Wemerb, Michiel van Haastertc, Victoria
Hodgkinsona, Michelle Fostera and Cathal Coylea
a
RB, Slough, Berkshire, UK; bQPS Netherlands, Groningen, The Netherlands; cDepartment of Gastroenterology, Martini Hospital, Groningen, The
Netherlands

ABSTRACT ARTICLE HISTORY

Objective: To investigate the intragastric acid neutralization activity of a combined alginate-antacid Received 30 July 2018
formulation. Revised 9 October 2018
Significance: Published studies have investigated the reflux-suppressing alginate component of Gaviscon Accepted 31 October 2018
Double Action (Gaviscon DA; RB, UK) but intragastric acid neutralization activity of the antacid component
KEYWORDS
has not been evaluated in vivo. Alginate; antacid; crossover
Methods: Intragastric pH monitoring, using a custom-made 10-electrode catheter, was evaluated in a two- study; healthy volunteers;
part exploratory study in healthy subjects; Part I (n ¼ 6) tested suitability of the catheter using antacid tab- gastric acid
lets (Rennie; Bayer, Germany); Part II (n ¼ 12) evaluated gastric acid neutralization activity of Gaviscon DA
liquid (20 ml) versus placebo in fasted subjects using a randomized, open-label, crossover design. The pri-
mary endpoint was the percentage of time that intragastric pH 4 was measured during 30 min post-
treatment. A confirmatory study of identical design was subsequently conducted (n ¼ 20).
Results: Monitoring pH using the multielectrode catheter was a viable approach, directly detecting
changes in intragastric pH following a single dose of antacid tablets. In the exploratory study, the percent-
age of time that pH 4 during 30 minutes post-treatment was 46.8% with Gaviscon DA liquid versus 4.7%
with placebo (p ¼ 0.0004). These findings were supported by the confirmatory study, where pH 4 was
recorded 50.8% of the time with Gaviscon DA versus 3.5% with placebo (p ¼ 0.0051). In this study,
Gaviscon DA was safe and well tolerated.
Conclusions: These studies demonstrate the effective acid neutralizing capacity of Gaviscon DA versus
placebo in healthy, fasted subjects. This adds to the evidence base for the combination of alginates
and antacids.

Introduction replace the reflux of gastric material [14,15]. Gaviscon Double

Symptoms caused by the reflux of stomach contents are experi-
enced by a large proportion of the general population [1,2]. After
meals, newly secreted acid in the stomach forms a layer on top of
ingested food rather than mixing with it, acting as a source for
acidic gastroesophageal reflux [3]. While heartburn and regurgita-
tion are the most common reflux symptoms [4], there is consider-
able overlap with symptoms of indigestion, such as epigastric
pain and burning [5,6]. Despite the overall level of gastric acid
secretion in reflux disease being typically similar to that seen in
asymptomatic individuals [7], the most widely adopted thera-
peutic strategy is the reduction of gastric acidity [8]. However,
increasing insight into gastroesophageal reflux pathophysiology
has revealed that weakly acidic gastric contents may also elicit
symptoms in some individuals and different symptoms vary in
their response to acid suppression [9–12]. As such, effective relief
from multiple, often fluctuating [13], reflux-associated symptoms
may require a strategy that targets both acidity and the reflux of
gastric contents [10].
Alginate-containing treatments have been used for the symp-
tomatic treatment of heartburn and indigestion for over 40 years.
Alginates are natural polysaccharides, derived from seaweed, that
form a viscous “raft” on exposure to acid and act to impede or
Action (Gaviscon DA; RB, Slough, UK) is an alginate formulation
that was developed to deliver the dual action of reflux suppres-
sion and acid neutralization, with the addition of two antacids,
calcium carbonate and sodium bicarbonate [16]. Clinical studies
demonstrate that Gaviscon DA is effective for the relief of reflux
and dyspeptic symptoms [17,18], likely owing to both the alginate
raft and antacid components of the formulation. The mode of
action of the alginate raft of Gaviscon DA has been well-character-
ized both in vitro and in vivo [16,19,20]. It rapidly localizes on top
of the acid pocket, a major source of postprandial reflux, physic-
ally replacing it and shifting the pH transition point away from
the esophago-gastric junction [19,20]. Furthermore, compared to
non raft-forming antacids alone, Gaviscon DA shows significant
superiority in decreasing postprandial acid reflux and esophageal
acid exposure [19,21]. The antacid action of Gaviscon DA is less
well characterized. While the acid neutralization capacity has been
assessed in vitro [22], confirmation of intragastric acid neutraliza-
tion activity in vivo is lacking. Owing to regional variations in gas-
tric acid content, determination of intragastric pH over time
requires a net measurement of acidity throughout the stomach
[23]. Here, we present the findings from studies evaluating the
intragastric acid neutralization activity of Gaviscon DA versus pla-
cebo in healthy subjects using a multielectrode catheter.

CONTACT Cathal Coyle cathal.coyle@rb.com RB, 103 - 105 Bath Road, Slough, Berkshire, SL1 3UH, UK
ß 2018 Informa UK Limited, trading as Taylor & Francis Group
2 J. WILKINSON ET AL.
Methods
An exploratory study and a subsequent confirmatory study were
performed. The exploratory study had two parts with two broad
aims: Part I assessed the suitability of pH monitoring methodology
using a custom-made, 10-electrode pH catheter in subjects treated
with antacid tablets. Part II used this methodology for the initial
evaluation of the acid neutralization activity of Gaviscon DA
liquid in a randomized, placebo-controlled, crossover study. This
exploratory study was used to inform the sample size and
methodology of a second confirmatory study of Gaviscon DA
liquid versus placebo, which was conducted according to an iden-
tical study design.
Both studies were conducted at QPS-Netherlands B.V.,
Groningen, the Netherlands (NL), in cooperation with Martini
Hospital Groningen, NL. They were conducted in accordance with
the International Conference on Harmonization (ICH) guidance on
Good Clinical Practice (GCP) and the ethical principles contained
within the Declaration of Helsinki, as referenced in the EU
Directive 2001/20/EC. Both studies were approved by the local
Institutional Review Board in Assen, NL. Informed, written consent
was obtained from all participants prior to any study assessments
and the studies were registered on Eudra CT (2014–003158-15
and 2016–000539-42).
Study participants
Study subjects were recruited by the contract research organiza-
tion QPS-Netherlands B.V. (Groningen, NL) using the company’s
website, online recruitment via Facebook and LinkedIn, and a vol-
unteer database. Each study recruited healthy male and female
subjects aged from 18 to 50 years, with a body mass index (BMI)
ranging from 18.5 to 24.9 kg/m2. Healthy subjects were recruited
to reduce variability in data caused by disease. In addition, the
presence of reflux symptoms or signs was not required for the
purpose of the study, which was designed to assess mode of
action as opposed to symptomatic efficacy. Subjects were
excluded from the trial if they had a history of gastroesophageal
reflux disease or active gastrointestinal disease within the preced-
ing year, any clinically significant disease, or had been hospitalized
for major surgery or illness during the previous 3 months. Subjects
were also excluded if they had taken medication for relief of gas-
tric acid reflux within 2 weeks of enrollment, proton pump inhibi-
tors (PPIs) within 4 weeks of enrollment, or any prescription or
non-prescription medication within 7 days of screening that was
Figure 1. Crossover study design used for the assessment of Gaviscon DA liquid versus matched placebo liquid (exploratory study Part II and confirmatory study).
deemed by the Principal Investigator as having the potential to
interfere with the study objectives.
Study design
Exploratory study part I
As this part of the exploratory study was not controlled and had
no crossover element, participants attended the clinic for just
three visits: screening, treatment (single dose of calcium carbon-
ate/magnesium carbonate chewable tablets), and follow-up
(3–7 days after treatment visit).
Exploratory study part II and confirmatory study
These studies were placebo-controlled with a crossover design, so
that each participant served as their own control (Figure 1).
Subjects attended the clinic for four visits in total: a screening visit
(V1), two treatment visits (V2, V3), and a follow-up visit (V4). The
screening visit took place up to 21 days before the first treatment
visit. At the treatment visits, eligible subjects were fasted over-
night, to remove the variability caused by postprandial buffering
of stomach contents, before receiving study medication and moni-
toring of their gastric pH. Each participant received Gaviscon DA
or matched placebo liquid in a randomized order. There was a
washout period, of a minimum of 5 days and maximum of 14 days,
between the two dosing visits. The follow-up visit took place
3–7 days after the second dosing visit.
Randomization and treatment
In the randomized studies (exploratory Part II and confirmatory
study), patients were randomly assigned to either Gaviscon DA
liquid or matched placebo liquid in a 1:1 ratio according to a
computer-generated randomization list. The computer-generated
randomization schedule was produced by RB Healthcare (UK) Ltd.
using the statistical software package SAS, version 9.2 (SAS
Institute Inc., Cary, NC). RB Healthcare held the master code for
the randomization schedule and provided the randomization
schedule to QPS to dispense as an open list.
In this open-label study, medications were administered after
catheter placement and baseline pH recordings had been con-
firmed. Subjects participating in the exploratory study (Part I)
were required to chew a single dose of two tablets containing
680 mg calcium carbonate and 80 mg magnesium carbonate per
tablet (Rennie; Bayer, Leverkusen, Germany). Subjects in the

placebo-controlled, crossover studies (exploratory Part II and con-
firmatory studies) received a single dose of 20 ml Gaviscon DA
(sodium alginate 500 mg, sodium bicarbonate 213 mg and calcium
carbonate 325 mg) and a single dose of matched placebo liquid
(20 ml) at two different clinic visits. Subjects were dosed straight
to mouth via a dosing syringe for liquids and a dosing cup for
tablets. After treatment administration clinic staff conducted a
mouth inspection to confirm that the full dose had
been swallowed.
Multi-electrode pH catheter and pH measurement protocol
A custom-designed multi-electrode catheter (Figure 2), which is a
CE marked class III medical device, produced by Synectics Medical
(Barcarena, Portugal) and approved by SGS United Kingdom Ltd
(Notified Body 0120), was used to enable pH monitoring through-
out the stomach without the need to re-position the catheter
or to use a pull-through technique. The catheter and protocol
were informed to a degree by a previous study performed by
Clarke et al. [24].
The catheter was equipped with 10 electrodes for pH measure-
ments from 5 cm above to 16 cm below the squamocolumnar
junction (SCJ). Prior to catheter placement, the SCJ was located
visually using nasal endoscopy, then a guide wire was used to aid
correct placement of the catheter. Electrodes 1 and 2 were placed
above the SCJ and a marker between electrodes 2 and 3 was
aligned with the upper border of the SCJ. Electrodes 3 and 4 were
situated 2 and 4 cm below the SCJ, respectively. After placement
of the catheter, the pH readings confirmed correct positioning. To
ensure stable and consistent results, and to alleviate any potential
problems with movement during breathing, only data from elec-
trodes 5 to 10 (6 and 16 cm from the SCJ, respectively) were ana-
lyzed. By combining data from electrodes 5 to 10, changes in pH
could be observed across the entire stomach.
The catheter was inserted nasogastrically by an experienced
board-certified gastroenterologist. Local anesthetic spray was used
for the endoscopy procedure. Once the correct position was
reached, the catheter was taped to the face. To allow dissipation
of any gas in the stomach resulting from catheter insertion, each
participant rested in a semi-recumbent position (at an angle of
approximately 60 ) for at least 60 min following catheter insertion
until readings had been stable for at least 15 min. If necessary, the
subject could continue to rest for a further 30 min prior to record-
ing of baseline pH readings. Baseline intragastric pH readings
were recorded continuously every 4 s for at least 30 (and up to
45) minutes. The consultant gastroenterologist was required to
confirm that the readings across electrodes 5–10 were sufficiently
stable and, on average, below pH 3 across the baseline recording
period. After treatment was administered, the pH was measured
continuously for 65 (± 5) minutes. Subjects remained in a semi-
recumbent position throughout the entire pH-monitor-
ing procedure.
Primary and secondary endpoints
Our analysis was adapted from that described previously by
Clarke et al. [24]. Changes to the intragastric luminal acidity in
response to treatment were examined by subdividing the post-
dose monitoring period into consecutive 10 min intervals and
determining the percentage of time that a pH threshold
was achieved.
DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY 3
Figure 2. Schematic of the custom-made 10-electrode catheter. The total length
of the catheter was 222 ± 5 cm, with a tubing diameter of 0.5 ± 0.1 mm. A marker
between electrodes 2 and 3 was positioned at the squamocolumnar junction
(SCJ) to aid placement.
The primary endpoint was the percentage of time that pH
measured 4 over 0 to 30 min post-dose across electrodes 5–10.
Secondary endpoints included the following:
 The percentage of time that pH measured 4 over the interval
30 to 60 minutes post-dose across electrodes 5–10
 The percentage of time that pH measured 3 over the inter-
vals 0 to 30 minutes and 30 to 60 minutes post-dose across
electrodes 5–10
 The percentage of time that pH measured 3 or 4 over the
10 minute intervals post-dose across electrodes 5–10
 The percentage of time that pH measured 3 or 4 over the
10 minute and 30 minute intervals at each electrode
In the crossover studies, these endpoints were compared
between Gaviscon DA liquid and placebo. For the exploratory
study (Part I) they were assessed non-comparatively.
Statistical analysis
In both crossover studies, all statistical tests performed were two-
tailed with significance determined by reference to the 5% signifi-
cance level. Data are presented descriptively using mean values
where data were normally distributed, and statistical significance
was assessed using the ANCOVA model. Data are presented
descriptively using median values where data were not normally
distributed, and statistical significance was assessed using the
Wilcoxon Rank Sum Test on the paired difference for each subject.
The null hypothesis was at all times the equality of the treatments
being compared. All comparisons between the treatments are
reported with 95% confidence intervals.
Sample size calculation
No statistical justification for the sample size was performed for
the exploratory study, as this was intended to provide estimates
of effect size and variance for use in the subsequent study.
Sample size estimates for the confirmatory study were calculated
from the exploratory study (Part II) data for the percentage of
4 J. WILKINSON ET AL.

(A) (B)
Enrolled Enrolled
N=20 N=20

Randomised to Part I Randomised to Part II Randomised

N=6
Received Ca carbonate/
Mg carbonate n=6
N=14 N=20
Withdrew consent after Withdrawn prematurely
placebo, no Gaviscon DA prior to treatment
received (n=2) period (n=5)
ITT n=15
Recieved Gaviscon DA (n=12); Received Gaviscon DA (n=13);
received placebo (n=14) received placebo (n=14)

Withdrawn prematurely
Completed Completed after receiving one
n=6 n=12 treatment (n=3)

Completed
n=12

Figure 3. Patient disposition: exploratory study (A) and confirmatory study (B).

Table 1. Baseline demographics at screening (ITT). placebo was met. Of those who did not complete the study, one
Exploratory study (N ¼ 20) Confirmatory study (N ¼ 15) subject withdrew consent and discontinued prematurely; two sub-
Gender n (%) jects were withdrawn having met the withdrawal criteria (not
Male 12 (60.0) 6 (40.0) related to an AE); two subjects were withdrawn because their
Female 8 (40.0) 9 (60.0) nose was too small for endoscopy; two subjects had a baseline
Age Mean (SD) 25.4 (5.6) 22.9 (3.4) pH > 3 across electrodes 5 to 10, and one subject discontinued
Race n (%)
Caucasian 19 (95.0) 15 (100.0) prematurely due to incorrect catheter placement. Baseline demo-
Asian 1 (5.0) – graphics are presented in Table 1.
Height (cm) mean (SD) 178.01 (9.36) 175.19 (8.57)
Weight (kg) mean (SD) 69.87 (9.79) 66.49 (7.38)
BMI (kg/m2) mean (SD) 21.9 (1.4) 21.63 (1.40) Primary and secondary endpoint evaluation
ITT: intention to treat; BMI: body mass index.
Exploratory study: The mean pH per electrode and mean pH/time
profile across electrodes 5 to 10 are shown in Figures 4(A) and
time that pH  4 was recorded over the 0 to 30 min post-dose 5(A), respectively. Electrodes 5–10 were able to directly detect pH
interval. The sample size calculation was performed using Nquery
changes in the stomach at the moment that treatment was
Advisor 7.0 software (Cork, Ireland). Assuming the difference
administered (both with Gaviscon DA liquid and calcium carbon-
between Gaviscon DA and placebo in mean percentage of time
ate/magnesium carbonate chewable tablets). In Part II of the
that pH  4 is no less than 30% and the root mean squared error
exploratory study, an increase in intragastric pH (electrodes 5–10)
is the same as that observed in the exploratory study, it was cal-
was recorded after subjects received Gaviscon DA liquid but not
culated that a population size of 12 would provide 97% power to
placebo liquid (Figure 5A). The mean percentage of time that pH
show statistical superiority for Gaviscon DA versus placebo at the
measured 4 over the 0 to 30 min post-dose interval (primary
5% significance level using a two-sided test.
endpoint) was 46.8% with Gaviscon DA versus 4.7% with placebo
liquid (P ¼ 0.0004; Figure 6). Overall, the neutralization effect was
Safety analysis the highest in the first 10 min after treatment and gradually
decreased during the next 50 min (Figure 6).
Any subject who received at least one dose of study medication Confirmatory study: The mean pH per electrode (Figure 4(B))
was included in the safety population. The incidence of adverse and mean pH/time profile across electrodes 5 to 10 (Figure 5(B))
events (AEs) and treatment emergent AEs were recorded accord- for Gaviscon DA and placebo were broadly similar to those meas-
ing to treatment received, by investigator attribution of relation- ured in the exploratory study. The primary endpoint, percentage
ship with the study and by severity. of time that pH measured 4 over 0 to 30 min post-dose across
electrodes 5–10, was significantly greater after Gaviscon DA Liquid
Results treatment than after placebo (mean 50.8% versus 3.5%; Figure 7).
The median percentage within-patient difference was 54.1%
Patient disposition and baseline demographics (P ¼ 0.0051). The acid neutralization effect of Gaviscon DA
Exploratory study: Twenty subjects were enrolled into the explora- occurred almost directly after administration (within 0 to 10 min).
tory study and 18 subjects completed the study (Figure 3). Six Overall, it was most pronounced in the first 20 min after treatment
subjects were randomized to Part I, received calcium carbonate/ administration and gradually decreased over the course of the
magnesium carbonate chewable tablets and completed the study subsequent 40 min.
as per protocol. Fourteen subjects were randomized to Part II; 12
subjects completed the study per protocol, two subjects withdrew
Safety and tolerability
consent and discontinued prematurely after receiving placebo at
V2, and hence did not receive Gaviscon DA. None of the 13 subjects receiving Gaviscon DA in the confirma-
Confirmatory study: Of the 20 randomized subjects in the con- tory study experienced a treatment-emergent adverse event
firmatory study, 12 subjects received both treatments and com- (TEAE), while 3 out of 14 subjects experienced a TEAE after pla-
pleted the study (Figure 3); thus, the pre-defined sample size cebo; one subject with unrelated cystitis, one with unrelated dys-
required to show statistical superiority for Gaviscon DA versus menorrhea and one with possibly-related rhinitis. In the
 DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY 5

Figure 4. Mean pH measurements at each of the 10 electrodes in the exploratory study (A), Part I, patients received antacid (calcium carbonate/magnesium carbonate
chewable tablets) and Part II, patients received Gaviscon DA and placebo liquid and confirmatory study (B), patients received Gaviscon DA and placebo liquid
(ITT population).

exploratory study, 2 out of 12 subjects experienced a TEAE after Discussion

Gaviscon DA treatment; abdominal pain that was considered pos-
sibly related to treatment and headache considered unlikely to be
related. After placebo treatment, 4 out of 14 subjects experienced
a TEAE; one subject with possibly-related nausea, one subject with
a headache that was unlikely to be related and two subjects with
nasopharyngitis considered unrelated to treatment. No subjects
experienced a TEAE after calcium carbonate/magnesium carbonate
tablets.
There is a paucity of published data on the acid neutralization
capacity of alginate-antacid formulations in the stomach. The
multi-electrode pH catheter developed for our studies proved to
be a robust and viable approach for this assessment, with the pH
measurements across six electrodes (6–16 cm from the SCJ) pro-
viding stable recordings. The results confirm the intragastric acid
neutralization capacity of Gaviscon DA in vivo.
6 J. WILKINSON ET AL.

Figure 5. Mean pH time profiles across electrodes 5 to 10 for subjects in the exploratory study (A) and the confirmatory study (B). Graph A displays profiles for the
patients treated with antacid (calcium carbonate/magnesium carbonate) chewable tablets in Part I of the study and with Gaviscon DA liquid and placebo liquid in Part
II of the exploratory study (ITT population).

Figure 6. Exploratory study: The mean percentage of time that pH measured 3 or 4 over 10 or 30 min intervals post-dose for Gaviscon DA and placebo
(ITT population).

The two placebo-controlled studies of Gaviscon DA liquid were
conducted to an almost identical protocol and results were
broadly comparable, lending additional weight to the data. As
expected, intragastric pH in the fasted study subjects was low
prior to Gaviscon dosing. The pH increased rapidly immediately
after Gaviscon DA administration, peaking within 10 to 20 min and
gradually decreasing to pre-dose levels over the subsequent 50 to
60 min. There was a significantly higher percentage of time in
which pH measured 4 within the 0 to 30 min post-dose interval
with Gaviscon DA versus placebo in both the exploratory (46.8%
versus 4.7%, respectively, P ¼ 0.0004) and confirmatory (mean
50.8% and 3.5%, respectively, P ¼ 0.0051) studies. Beyond 30 min,
there was a trend for the mean percentage of time that pH meas-
ured 4 to be higher in the Gaviscon DA group but the difference
from placebo was no longer statistically significant. The reduced
activity after 30 min is consistent with previously reported antacid

Figure 7. Confirmatory study: The mean percentage of time that pH measured 3 or  4 over 10 or 30 min intervals post-dose for Gaviscon DA and placebo
(ITT population).
activity in fasted individuals [23,25] and is likely the result of stom-
ach emptying [23]. When taken postprandially, antacids sink rap-
idly to the distal stomach [26] but the action of the alginate raft
allows Gaviscon DA to float on top of stomach contents where it
is retained in the stomach for up to 4 h, until the meal empties
[16]. In recent studies, Gaviscon has been shown to have optimum
raft porosity maximizing contact between acid passing through
the raft and entrapped antacid, ultimately resulting in a longer
duration of neutralization compared to other raft-forming antacids
[22]. However, in the fasted state Gaviscon would be expected to
empty far more rapidly from the stomach, diminishing the role of
the alginate raft. This explains the similarity between the pH-time
profiles of Gaviscon DA and the non-raft forming antacid in the
exploratory studies (Figure 4), although further evaluation would
be required to confirm the relationship between neutralizing
activity and gastric emptying. Extensive clinical experience with
the active ingredients of Gaviscon DA has demonstrated its favor-
able risk–benefit profile [27]. Consistent with this, and as may be
expected for a non-systemic medication in healthy individuals, no
safety signals of concern were observed during the study.
The symptomatic efficacy of Gaviscon DA is already well estab-
lished [17,18] and this formulation is approved for the treatment
of reflux symptoms including acid regurgitation, heartburn, and
indigestion, and for symptoms of hyperacidity. In a recent multi-
centre study of patients with frequent reflux symptoms of moder-
ate intensity, a significant treatment effect was observed for
Gaviscon DA versus placebo in the reduction of heartburn, regur-
gitation and associated dyspepsia symptoms [18].
DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY 7
Furthermore, alginate-antacids can be administered with PPIs
without interfering with the pharmacokinetic profile [28]. Addition
of non-systemic Gaviscon formulations have been shown to com-
plement the action of PPIs, suppressing reflux symptoms over and
above the benefits of PPI alone in patients with breakthrough
symptoms [29,30].
It is proposed that the dual approach of acid neutralization and
reflux suppression contributes to the efficacy of Gaviscon DA for
multiple symptoms [18] but the intragastric acid neutralization cap-
acity of this formulation had not previously been confirmed in vivo.
While our study in healthy subjects clearly confirms intragastric
acid neutralization by Gaviscon DA, it was not designed to directly
investigate the link between acid neutralization and symptomatic
relief. Furthermore, the study objectives focus on pH so do not
account for other gastric factors that contribute to the clinical
expression of reflux disease, such as gas, bile and pepsin.
Nevertheless, these observations confirm that the acid neutraliza-
tion capacity of Gaviscon DA observed in vitro translates to neu-
tralization of stomach acid in vivo. This contributes to the existing
evidence base for the combination of two well-established treat-
ments, alginate and antacids, in a single, well-tolerated formula-
tion for the effective treatment of symptomatic reflux.
Acknowledgments
We would like to thank Chris Blythe (Synmed) and Ken McColl for
their expertise around catheter design and Lisa O’Rourke for writ-
ing assistance.
8 J. WILKINSON ET AL.
Data availability
The data that support the findings of this study are openly avail-
able within the EU Clinical Trials Register at www.clinicaltrialsregis-
ter.eu, reference numbers [2014–003158-15 and 2016–000539-42].
Disclosure of interest
JW, VH, MF, and CC are employees of RB Healthcare Ltd. KA-E, JW,
and IDD are employees of QPS-Netherlands, a CRO that performs
phase I/II studies for several pharmaceutical companies and aca-
demic centers. MvH is a consultant for QPS Netherlands. The cur-
rent study was commissioned and funded by RB Healthcare Ltd.
Writing support was provided by Cello Health Cypher and funded
by RB Healthcare Ltd.
ORCID
Cathal Coyle http://orcid.org/0000-0003-3190-8460
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