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Real World Efficacy and Tolerability of Acotiamide, in Relieving Meal related Symptoms of Functional Dyspepsia

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Background: Functional Dyspepsia (FD) is a highly prevalent clinical condition that imposes negative economic burden on health-care system as well as greatly impairs quality of life. Treatment of non-specific and bothersome meal-related FD symptoms like post-prandial fullness, upper abdominal bloating and early satiety, is a therapeutic challenge for the clinicians as poorly-defined and ill-understood pathogenesis has hampered efforts to develop effective treatments. Acotiamide is first-in-class drug that exerts its gastro-kinetic effect by enhancing acetylcholine release. Though evidence of its efficacy and tolerance are available through randomized clinical trials, real world data from its regular in-clinic use is lacking.Methodology: In this study, 314 FD patients with meal-related-symptoms, visiting 63 gastroenterology clinics across India, received Acotiamide 100 mg thrice daily for 4 weeks. These patients were retrospectively evaluated with a questionnaire to record patient’s perception on improvement in the presenting symptoms, as well as tolerance to treatment.Results: It was observed that, complete relief or significant improvement from post prandial fullness, upper abdominal bloating and early satiety was achieved by 79.2%, 74.4%, and 77.1% patients respectively. (P<0.001 for all vs. no/slight improvement). Significantly more number of patients achieved complete relief when treated for >28 days or 14-28 days than when treated for less than 2 weeks (P<0.05). Adverse events were reported by 6% patients; mainly headache, nausea, vomiting, vertigo, burning sensation, palpitation, and epigastric pain, and were all mild and transient in nature. Conclusion: This real world study suggests that use of Acotiamide was associated with improvement of mealrelated FD symptoms with good safety profile.
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Real World Efficacy and Tolerability of Acotiamide, in Relieving Meal-
related Symptoms of Functional Dyspepsia
Varsha Narayanan*, Amit Bhargava and Shailesh Pallewar
1Department of Medical Services and Research, Lupin Ltd., India
*Corresponding author: Narayanan V, Department of Medical Services and Research, Lupin Ltd., Mumbai, India, Tel: +912266402222; E-mail:
varshanarayanan@lupin.com
Received date: February 09, 2018; Accepted date: February 21, 2018; Published date: February 27, 2018
Copyright: © 2018 Narayanan V, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
Background: Functional Dyspepsia (FD) is a highly prevalent clinical condition that imposes negative economic
burden on health-care system as well as greatly impairs quality of life. Treatment of non-specific and bothersome
meal-related FD symptoms like post-prandial fullness, upper abdominal bloating and early satiety, is a therapeutic
challenge for the clinicians as poorly-defined and ill-understood pathogenesis has hampered efforts to develop
effective treatments. Acotiamide is first-in-class drug that exerts its gastro-kinetic effect by enhancing acetylcholine
release. Though evidence of its efficacy and tolerance are available through randomized clinical trials, real world
data from its regular in-clinic use is lacking.
Methodology: In this study, 314 FD patients with meal-related-symptoms, visiting 63 gastroenterology clinics
across India, received Acotiamide 100 mg thrice daily for 4 weeks. These patients were retrospectively evaluated
with a questionnaire to record patient’s perception on improvement in the presenting symptoms, as well as tolerance
to treatment.
Results: It was observed that, complete relief or significant improvement from post prandial fullness, upper
abdominal bloating and early satiety was achieved by 79.2%, 74.4%, and 77.1% patients respectively. (P<0.001 for
all vs. no/slight improvement). Significantly more number of patients achieved complete relief when treated for >28
days or 14-28 days than when treated for less than 2 weeks (P<0.05). Adverse events were reported by 6%
patients; mainly headache, nausea, vomiting, vertigo, burning sensation, palpitation, and epigastric pain, and were
all mild and transient in nature.
Conclusion: This real world study suggests that use of Acotiamide was associated with improvement of meal-
related FD symptoms with good safety profile.
Keywords: Rome III criteria; Functional dyspepsia; Acotiamide;
Prokinetic; Post prandial fullness; Abdominal bloating; Early satiety;
Impaired gut motility
Introduction
Rome III consensus denes functional dyspepsia as presence of
symptoms thought to originate in the gastroduodenal region
(postprandial fullness, early satiation, epigastric pain or burning), in
the absence of any organic, systemic or metabolic disease that is likely
to explain the symptoms. ese symptoms are mostly chronic,
occurring at least weekly and over a period of at least 6 months.
According to this denition, approximately 5-11% of global population
suers from FD [1]. FD being a heterogeneous disorder signicantly
impairs health related quality of life, work productivity and incur
direct and indirect economic burden on patients and health care
system [2,3]. Overall it is dicult to estimate the magnitude of
problem of FD in India as most of the prevalence studies report the
estimates of uninvestigated dyspepsia (UD). Several studies have
reported the frequency of UD and FD between 8%-30% and 8%-23%,
respectively in Asia [4]. ere are very few population-based
prevalence studies in India and in one such population study from
Mumbai, almost one third of the population suered from dyspepsia
(30.4%) and 12% of study patients reported signicant dyspeptic
symptoms [5].
Majority of FD patients complain of meal-related symptoms.
However, the pathophysiology of FD remains poorly elucidated. Many
of these patients have no exclusive cause of dyspepsia by standard
diagnostic tests. Being a heterogeneous disorder, FD involves multiple
pathogenic factors, such as excessive gastric acid secretion, gastric
motility disorders,
Helicobacter pylori
infection, psychological factors
and visceral hypersensitivity. ese factors interactively contribute to
the manifestation of FD symptoms. Currently available pharmacologic
treatments for the management of FD have only been shown to be of
limited ecacy. erefore, it is logical to direct the therapeutic
approaches towards underlying pathophysiologic factors to enhance
treatment ecacy [6,7].
e mainstay of FD treatment has been targeted to (a) reduce
gastric-acid secretion and (b) enhance the reduced gut motility. e
role of acid inhibitory drugs, such as proton pump inhibitors in the
treatment of FD is well established. Consequently, prokinetics were
developed based on the concept that improving impaired gut motility
could diminish the symptoms of FD. Apart from acid inhibitory
therapy, gastroprokinetic drugs are the mainstay of the treatment of
FD. Acotiamide is a rst-in-class gastroprokinetic agent extensively
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ISSN: 2161-069X
Journal of Gastrointestinal &
Digestive System Narayanan et al., J Gastrointest Dig Syst 2018, 8:1
DOI: 10.4172/2161-069X.1000553
Research Article Open Access
J Gastrointest Dig Syst, an open access journal
ISSN:2161-069X
Volume 8 • Issue 1 • 1000553
studied in clinical trials. It improves upper gastrointestinal motility to
relieve abdominal symptoms arising due to impaired GI motility in FD
patients. Acotiamide received its rst global regulatory approval in
Japan in 2013 and was approved in India in 2016 for the treatment of
bloating aer meals, epigastric bloating and early satiety in FD
patients. In USA and Europe, Acotiamide is undergoing phase III trials
[8,9]. Acotiamide has been listed in Rome IV as a treatment option for
FD [10]. Gastroprokinetic action of Acotiamide results from enhanced
action of acetylcholine (ACh) by (a) increasing release by antagonizing
the M1 and M2 muscarinic receptors in the enteric nervous system
and (b) prolonging the action of the ACh by inhibiting
acetylcholinesterase activity. ese actions increase the availability of
ACh at postsynaptic receptors in neuromuscular junctions in enteric
nervous system.
Apart from these prokinetic actions, few studies have also reported
that Acotiamide may also modulate gut-brain interactions via its
eects on the aerent vagus nerve, modifying sensory input from the
GI tract to the CNS. Unlike metoclopramide or domperidone, the
gastroprokinetic activity of Acotiamide does not appear to be
associated with prolongation of the QTc interval, based on preclinical
research. Aer oral administration, maximum plasma levels of
Acotiamide are achieved in 1-1.5 hours, with a plasma half-life of 7-10
hours. Approximately, 45% of Acotiamide is excreted in the feces with
no marked CYP inhibition [11].
In number of clinical trials across various countries, Acotiamide has
been reported to improve meal-related symptoms of FD and quality of
life in patients with FD. Although clinical trials are always considered
to be an acceptable standard for establishing ecacy, in general,
clinical trials utilize a standardized therapy in a select patients group.
As clinical trials are performed in controlled conditions such as strict
inclusion and exclusion criteria, drug provided free of cost, compliance
monitored, etc., they fail to assess multifaceted interactions within a
study arm and fail to ascertain continuous relationship between
treatment and study results. Due to these limitations, there is a need
for real-world (RW) study in which data regarding actual care received
by patients in clinics is recorded. Instead of having strict inclusion and
exclusion criteria as in randomized clinical trials, all the patients
including those with co-morbidities have to be treated. Such RW
studies generate long term ecacy and safety data along with
economic assessment under pragmatic conditions [12,13].
is RW study was performed to evaluate the knowledge gap
between Acotiamide clinical trials and actual clinical usage, with an
objective to understand how gastroprokinetic treatment with
Acotiamide will work when applied in clinical practice environment.
e expectation is that systematically analyzed RW data can deliver
key insights which, aer due validation, could help to deploy
Acotiamide in a manner, which in turn, could result in a safer and
more appropriate choice of FD-patients for treatment with
Acotiamide, making it a better therapeutic experience for the physician
and patient alike.
Methodology
Total 314 adult patients, who presented clinically with any of the
symptoms of post prandial fullness, upper abdominal bloating, and/or
early satiety in the Gastroenterologist’s out-patient department and
were prescribed 100 mg Acotiamide thrice daily, were evaluated with a
questionnaire to record patient’s perception of improvement in the
presenting symptoms, as well as tolerance to treatment.
e data was captured from 63 Gastroenterologists across India (20
each in north and east zone, 14 in west zone and 9 in south zone).
ROME III diagnostic criteria were used to classify patients as
functional dyspepsia with predominantly post prandial distress
syndrome (PDS-type). To facilitate objective and unambiguous
assessment by the patients, a 4 point rating scale, comprising of (a) ‘No
improvement’, (b) ‘Slightly improved’, (c) ‘Signicantly improved’, and
(d) ‘Complete relief, was used. For each patient, the duration of
treatment was also recorded. Adverse events, if any, were recorded,
assessed and managed. All patient-data was captured in accordance
with ethical principles and with patient consent.
Results
Total 314 patients were prescribed Acotiamide for their presenting
symptoms. Male: Female ratio was 3:2, and 60% patients were 40
years while 13% were ≥ 60 years. Smoking and alcohol intake was seen
in 14% and 11% patients respectively and both these factors were
present in 6% patients.
Results outcomes were 74%, 76% and 53% patients presented with
symptoms of post prandial fullness, upper abdominal bloating and
early satiety respectively. Other symptoms included epigastric pain
(38%), epigastric burning (35%), constipation (26%) and diarrhea (3%)
(Table 1).
Gender distribution 60% male; 40% female
Age distribution
60% patients ≥ 40 years; 13% patients ≥ 60
years
Symptom distribution
Postprandial fullness-74%
Upper abdominal bloating-76%
Early satiety-53%
Epigastric pain-38%
Epigastric burning-35%
Constipation-26%
Diarrhea-3%
Table 1: Baseline demographic data.
Complete relief or signicant improvement from post prandial
fullness, upper abdominal bloating and early satiety was achieved by
79.2%, 74.4%, and 77.1% patients respectively; (P<0.001 for all
mentioned values
vs.
no/slight improvement Figure 1). No signicant
dierence in complete relief or signicant improvement rates was seen
between men and women for the symptoms of post prandial fullness
and upper abdominal bloating. However for early satiety, more women
achieved a signicant improvement as compared to men (63.26%
vs.
47.05%; P=0.03)
No signicant dierence was seen between age groups <40 and ≥ 40
years or <60 and 60 years in complete relief or signicant
improvement rates. Similarly, the pre-therapy duration of symptoms (≤
6 months or >6 months) did not signicantly aect the scorings of
complete relief or signicant symptomatic improvement. Duration of
treatment did not have an eect on symptomatic relief obtained
(Figure 2). Signicantly more patients achieved complete relief when
Citation: Narayanan V, Bhargava A, Pallewar S (2018) Real World Efficacy and Tolerability of Acotiamide, in Relieving Meal-related Symptoms of
Functional Dyspepsia . J Gastrointest Dig Syst 8: 553. doi:10.4172/2161-069X.1000553
Page 2 of 4
J Gastrointest Dig Syst, an open access journal
ISSN:2161-069X
Volume 8 • Issue 1 • 1000553
treated for >28 days or 14-28 days than when treated for <2 weeks;
(P<0.05 for all 3 symptoms; 28 days
vs.
14-18 and 7-14 days).
Adverse events were reported by 6% patients. e adverse events
that were reported were headache, nausea, vomiting, vertigo, burning
sensation, palpitation, and epigastric pain. All events were mild and
transient in nature. Treatment discontinuation occurred in 2 patients
(1.36%); (1 patient each who had palpitation, nausea, epigastric pain
and 1 due to lack of ecacy).
Figure 1: Patients’ perception of symptomatic improvement;
[*P<0.0001
vs.
slightly improved and
vs.
No improvement].
Figure 2: Eect of treatment duration on number of patients
showing complete relief; [*P=0.0068
vs.
7-14 days and 0.0053
vs.
14-28 days, **P=0.019
vs.
7-14 days and 0.04
vs.
14-28 days,
***P=0.03
vs.
7-14 days and 0.01
vs.
14-28 days].
Discussion
Despite evidence of ecacy and safety of use in clinical trials, few
real world studies in clinical settings on Acotiamide have been
reported. In this study, we report that Acotiamide signicantly
improved the symptoms of post-prandial fullness, upper abdominal
bloating and early satiety in Indian patients with FD. Findings of this
study will denitely assist several clinicians seeing several dyspeptic
patients in general and specialized practice. To our knowledge this is
the rst Indian study conducted in real world settings suggesting the
positive outcomes of Acotiamide in FD patients. Impaired gastric-
emptying and accommodation are two of the known
pathophysiological mechanisms related with FD symptoms of post-
prandial fullness, upper abdominal bloating and early satiety.
Acotiamide improves gastric emptying rate and, thereby, relieves these
FD symptoms. Findings of the present study are in line with previous
reports of ecacy from randomized controlled trials on Acotiamide.
Matsueda et al. performed a 4 week, phase III, randomized, placebo
controlled trial with 100 mg Acotiamide in 892 FD patients in Japan to
study elimination rate of all three meal-related symptoms
(postprandial fullness, upper abdominal bloating and early satiation)
[14]. During global assessment of treatment ecacy, researchers
classied 52.2% patients receiving Acotiamide and 34.8% patients
receiving placebo as respondents (P<0.001). Interestingly, at the end of
4 weeks, signicantly more number of patients from Acotiamide group
(P=0.004) showed improvement in all three meal related FD symptoms
[14].
In a long-term 48-week study carried out by Matsueda et al. to
investigate the ecacy, safety and administration pattern in 405 FD
patients, researchers observed favorable outcomes with global overall
treatment ecacy (OTE) [15]. e OTE improvement rate was 26.1%
at week 1 and increased with time reaching 60.6% (week 8), 66.7%
(week 48) and 73.2% (during the last period of treatment). Many
patients who met the cessation criterion achieved remission of FD
symptoms aer experiencing dose interruption and re-administration.
is study concluded that FD symptoms were controlled even by
intermittent administration of Acotiamide in patients with relapsing
FD [15].
Another study employed gastric ultrasound to measure the cross-
sectional area of the proximal stomach aer a liquid meal to assess
gastric accommodation in FD patients before and aer treatment with
Acotiamide 100 mg t.i.d. e study also evaluated gastric emptying
rate, motility index and duodeno-gastric reux index for assessment of
gastroduodenal motility. A signicant dierence was found in the
change of gastric accommodation between the Acotiamide group and
the placebo group (21.7
vs.
4.4%) [16]. Furthermore, Acotiamide was
found to signicantly accelerate the gastric emptying rate, which was
not seen in the placebo group. e subjective improvement rates also
tended to be better in the Acotiamide group (31.6
vs.
16.7%) [17].
None of these studies reported serious adverse eect and change in
ECG during or aer Acotiamide treatment.
Recently, Behera et al. compared the ecacy and safety of
Acotiamide with Levosulpiride in Indian FD patients [18]. 60 patients
were divided in two groups to receive either Acotiamide 100 mg t.i.d.
or Levosulpiride 25 mg t.i.d. for 8 weeks. Approximately 93% patients
reported excellent to good improvement of FD symptoms aer 4 week
administration of Acotiamide compared to 80% improvement with
Levosulpiride. e study concluded that, Acotiamide was superior to
Levosulpiride in, both, ecacy and tolerability in FD patients [18].
In a randomized, double-blind placebo-controlled study with 46
Japanese FD patients by Nakamura et al. Acotiamide signicantly
increased gastric accommodation compared to placebo (P=0.04
vs.
P=0.08), signicantly accelerated gastric emptying (50% half-emptying
time P=0.02
vs.
P=0.59) and signicantly improved the total GSRS
scores and HADS anxiety score compared to placebo (P=0.0007
vs.
P=0.14 and P=0.04
vs.
P=0.20 respectively) [19].
In a retrospective study by Shinozaki et al. in 79 patients with
functional dyspepsia whose symptoms improved with Acotiamide
therapy and who were followed up, at one year, dyspepsia symptoms
recurred in 25% of the patients [20]. Patients with severe dyspepsia
before starting Acotiamide had signicantly more recurrences than
those with mild symptoms (P=0.004). Patients who continued
Acotiamide therapy throughout the follow-up period had signicantly
fewer recurrences than those who stopped therapy (P<0.001).
Citation: Narayanan V, Bhargava A, Pallewar S (2018) Real World Efficacy and Tolerability of Acotiamide, in Relieving Meal-related Symptoms of
Functional Dyspepsia . J Gastrointest Dig Syst 8: 553. doi:10.4172/2161-069X.1000553
Page 3 of 4
J Gastrointest Dig Syst, an open access journal
ISSN:2161-069X
Volume 8 • Issue 1 • 1000553
In the European phase III open-label study [21] to evaluate the
long-term safety and ecacy of Acotiamide on PDS symptoms, adult
FD-PDS patients (dened by ROME III criteria) with active PDS
symptoms and without predominant overlapping symptoms of
epigastric pain syndrome and related disorders were enrolled to receive
100 mg Acotiamide three times daily for 1 year. 81.6% patients
maintained exposure to Acotiamide for >50 weeks, with a mean
duration of 320.3 days. No specic clinically signicant safety concerns
have been shown, with no deaths or treatment-related severe/serious
adverse events, or any clinically signicant laboratory test results.
Acotiamide showed a change in severity larger than the minimum
clinically important dierence at weeks 1 and 2 for the meal related
symptoms-postprandial fullness and early satiation with improvement
of quality of life and work productivity from week 12 up to 1 year.
Conclusion
e ecacy assessed by patients’ assessment of their symptomatic
improvement along with the safety and tolerance of Acotiamide
observed in the present real world study, corroborates with the
published clinical trials in literature. Since clinical trials do not address
all relevant clinical requirements and real-world clinical situations.
More real world studies are required which have a larger population
size, longer follow up periods, capturing many more clinically relevant
parameters to further supplement the earlier clinical studies.
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Citation: Narayanan V, Bhargava A, Pallewar S (2018) Real World Efficacy and Tolerability of Acotiamide, in Relieving Meal-related Symptoms of
Functional Dyspepsia . J Gastrointest Dig Syst 8: 553. doi:10.4172/2161-069X.1000553
Page 4 of 4
J Gastrointest Dig Syst, an open access journal
ISSN:2161-069X
Volume 8 • Issue 1 • 1000553
... Acotiamide showed improvement in the symptoms in a larger number of patients. Clinically important minimum differences started to appear from week 1 to week 2 for the postprandial fullness and early satiety [7]. ...
Article
Functional dyspepsia (FD) is mainly treated by drugs like H2 receptors antagonists, Proton pump inhibitors, prokinetics. A novel prokinetic drug to treat FD with 2 subtypes: Epigastric pain syndrome (EPS) & postprandial distress syndrome (PDS), has been introduced recently by the approval of Acotiamide, the first in class, muscarinic receptor antagonist & cholinesterase inhibitor. It has shown improvement in gastric motility in rodents & dogs and reduced PDS symptoms in patients in Double- blinded multicentric study.
... Behera and Sethi [15] reported approximately 93% of patients' improvement of FD symptoms after four-week administration of acotiamide. Narayanan et al. [16] reported that complete relief or significant improvement from PPF, upper abdominal bloating, and early satiety was achieved by 79.2%, 74.4%, and 77.1% of patients, respectively (P<0.001 for all vs. no/slight improvement) when treated for >28 days or 14-28 days with acotiamide. Matsueda et al. [17] reported the responder rate based on the OTE was 52.2% receiving acotiamide 100 mg TID and 34.8% of patients receiving placebo (p<0.001); at the end of four weeks acotiamide group (P=0.004) ...
Article
Background: Acotiamide, is the world's first-in-class, prokinetic drug and world's first approved treatment for postprandial distress syndrome (PDS) symptoms of functional dyspepsia (FD). An extended-release (ER) formulation of this drug product, developed first-time in the world has been evaluated in phase 3, a comparative trial to explore the efficacy and safety in patients with FD-PDS. Methods: In this study, 219 patients with FD-PDS aged 18-65 years were randomized (1:1) to receive either acotiamide ER 300 mg once daily or acotiamide 100 mg three times daily for four weeks. The primary efficacy endpoint was responder rates for the overall treatment effect (OTE) at end of week 4. Secondary efficacy endpoints included OTE at each week, elimination rate of postprandial fullness, upper abdominal bloating and early satiation, improvement of individual symptom scores, and quality of life (QoL). The safety endpoints included assessments of treatment-emergent adverse events (TEAEs). Results: The responder rate for OTE at the end of the four week period, in acotiamide ER 300 mg OD versus acotiamide 100 mg TID group was 92.66% and 94.39% (97.5% CI -8.3,4.8), respectively, in per-protocol (PP) population and 92.66% and 92.73% (97.5% CI -7.0,6.8), respectively, in intent to treat (ITT) population. All other secondary efficacy endpoints, including QoL, were significantly improved with acotiamide ER 300 mg. Both the formulations of acotiamide significantly improved symptom severity and eliminated meal-related symptoms in patients with FD. Adverse events were reported by 7.9% of patients in acotiamide ER 300 mg and 9.2% in acotiamide 100 mg patients; the most common adverse event reported was a headache. Conclusions: The efficacy and safety of acotiamide ER 300 mg once daily were observed to be comparable to acotiamide immediate release 100 mg thrice daily. A significant improvement in QoL over a four-week treatment period in FD-PDS patients was observed.
... The results of our first Indian study conducted in real world settings was recently published showing positive outcomes with acotiamide in FD patients for obtaining relief from meal related symptoms. 11 However a very important aspect to be kept in mind while managing functional dyspepsia in the real world, especially in a country like India, is the frequent overlapping symptoms of PDS type FD with epigastric pain/burning or constipation. Therefore, an analysis of responses in such groups of patients receiving co-therapies like PPI and laxatives with acotiamide, can be valuable for physicians for making multiple therapy choices in patients presenting with overlapping symptoms. ...
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Background: Functional Dyspepsia (FD) is a common condition presenting at the clinic of a gastroenterolo-gist. Though the Post-prandial Distress Syndrome (PDS) type is more commonly seen in clinical practice, often the symptoms overlap with Epigastric pain or burning and sometimes even with other gastro-intestinal symptoms like constipation. Acotiamide, approved specially for meal related FD symptoms, exerts its gas-tro-kinetic effect by enhancing the action of acetylcholine. Evidence of its efficacy and safety are available from various randomized clinical trials. However, real-world data from its regular in-clinic use especially in patients presenting with overlapping symptoms and being prescribed other concomitant therapies, is lacking .
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Efficacy and Safety of Acotiamide Versus Mosapride in Patients With Functional Dyspepsia Associated With Meal-Induced Postprandial Distress Syndrome: A Phase III Randomized Clinical Trial
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Background: Acotiamide is a novel prokinetic drug that acts by enhancing the release of acetylcholine and is used in the treatment of functional dyspepsia-postprandial distress syndrome (FD-PDS). Mosapride is indicated to FD-PDS as per the Rome III treatment guidelines. Mosapride 5 mg three times daily (TID) is approved by the Drugs Controller General of India (DCGI) for the treatment of FD-PDS. The objective of this study was to determine the efficacy and safety of Acotiamide in comparison with Mosapride on FD-PDS. Methods: The 220 patients of either gender (aged 18-64 years) with active PDS included in the study were centrally randomized 1:1 to receive either 100 mg Acotiamide (test product) or 5 mg Mosapride (reference product) TID for four weeks. Responder rates for the overall treatment effect (OTE) at the end of four weeks were the primary efficacy endpoint. Secondary efficacy endpoints included the elimination rate of postprandial fullness, upper abdominal bloating, and early satiation. The study also evaluated the OTE at each week, individual symptom scores, and quality of life (QoL) assessed by the Short Form-Nepean Dyspepsia Index questionnaire (SF-NDI). The safety endpoints included assessments of treatment-emergent adverse events (TEAEs). Results: At the end of four weeks, the responders in the Acotiamide versus Mosapride group for OTE was 98% versus 93.27% in the per-protocol (PP) population. Among the intent to treat (ITT) population, the comparison of Acotiamide versus Mosapride stood at 95.15% versus 89.81%. Secondary efficacy endpoints were significantly improved with 100 mg TID Acotiamide, which was evident from the improvement in postprandial fullness (14.56%), upper abdominal bloating (15.53%), early satiation (10.68%), and QoL (13.7 ± 4.67). Conclusions: Our study results demonstrated that Acotiamide is effective, safe, and well-tolerated and had significantly improved the QoL over a four-week treatment period in FD-PDS patients. The efficacy and safety profiles of Acotiamide were similar to Mosapride.
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Introduction: Gastroesophageal reflux disease (GERD) is a digestive disorder that affects the lower esophageal sphincter (LES). Functional dyspepsia (FD) is characterized by troublesome early satiety, epigastralgia or heart burn. It is often overlooked as the symptoms overlap with GERD. This study aims to compare the effectiveness of Acotiamide+Rabeprazole vs. a double dose of Rabeprazole in Indian population. Method: In this study 60 patients diagnosed with PPI refractory GERD (taking PPI>8weeks) and FD with no gastric or duodenal organic abnormalities were randomly allocated in two groups. Group 1 received a combination of Acotiamide (200mg/day) +Rabeprazole (20mg/day) and group 2 received a double dose of Rabeprazole (40mg/day). Follow ups were done every month for 3 consecutive months. The frequency and severity of symptoms were assessed using standard Izumo scale and FSSG scale. Results: The total score and GERD score from the baseline were significantly reduced in group 1 however the reduction in FD score from baseline did not differ significantly in the two treatment groups according to F-scale. The proportion of patients with ≥ 50% reduction in the total score for three upper gastrointestinal symptoms (heart burn, epigastralgia, and epigastric fullness) in the izumo scale was 96.7% in group 1 and 33.3% in group 2. Significant difference were noticed between the two groups. No serious adverse events were observed. Conclusion: The combination group of Acotiamide+Rabeprazole was found to be more effective than double dose of Rabeprazole in reducing the overlapping symptoms of PPI refractory GERD and FD.
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Backgrounds: Acotiamide is a novel acetylcholinesterase inhibitor for treatment of postprandial distress syndrome (PDS) symptoms of functional dyspepsia (FD). This European phase 3 open-label safety trial has been conducted to evaluate the long-term safety of acotiamide and explore the efficacy of acotiamide on PDS symptoms using the validated LPDS, quality of life using SF-36 and SF-NDI, and work productivity using WPAI. Methods: FD-PDS patients (defined by ROME III criteria) aged ≥18 years with active PDS symptoms and without predominant overlapping symptoms of epigastric pain syndrome and related disorders were enrolled to receive 100 mg acotiamide three times daily for 1 year. Patients' safety profile and efficacy of acotiamide were monitored. Key results: The majority of patients (81.6%) maintained exposure to acotiamide for >50 weeks, with a mean duration of 320.3 days. No specific clinically significant safety concerns have been shown, with no deaths, treatment-related severe/serious adverse events, or any clinically significant laboratory test results. Although being an open-label trial, acotiamide showed a change in severity larger than the minimum clinically important difference at weeks 1 and 2 for postprandial fullness and early satiation (meal-related symptoms), and showed improvement of quality of life and work productivity from the first measurement (at week 12) up to 1 year. Conclusions & inferences: The long-term safety of acotiamide treatment was confirmed. A clinically important change for PDS symptoms, QoL, and work productivity was suggested; however a controlled trial is required to confirm this hypothetic efficacy of acotiamide. (NCT01973790).
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Background and aims: Long-term outcomes in patients with functional dyspepsia remain elusive. Acotiamide, a prokinetic drug, has been available in Japan since 2013. The aim of this study was to assess long-term outcomes in patients with functional dyspepsia treated with acotiamide. Methods: We retrospectively reviewed 79 consecutive patients with functional dyspepsia whose symptoms improved with acotiamide therapy and who were followed for more than one year. All patients underwent esophagogastroduodenoscopy prior to acotiamide therapy. The mean follow-up was 1.9 (range, 1.0-3.3) years. We assessed the patients' symptom severity using the Izumo scale, which reflects changes in various abdominal symptoms. Results: At one year, dyspepsia symptoms recurred in 25% (20/79) of the patients. In multivariate analysis, severe dyspepsia was significantly associated with increased recurrence (odds ratio [OR] 15.04, 95% confidence interval [CI] 1.73-130.47, p=0.013). Continued use of acotiamide for one year diminished the recurrence of dyspepsia symptoms significantly (OR 0.16, 95%CI 0.04-0.61, p=0.006). The influence of these significant predictors on long-term outcomes was analyzed using the Kaplan-Meier method. Patients with severe dyspepsia before starting acotiamide had significantly more recurrences than those with mild symptoms (p=0.004, log-rank test). Patients who continued acotiamide therapy throughout the follow-up period had significantly fewer recurrences than those who stopped therapy (p<0.001). Conclusions: Over the long-term, patients with functional dyspepsia have a considerable rate of recurrence of dyspepsia. Severe dyspepsia before treatment increases the recurrence rates, while adherence to an acotiamide therapeutic regimen decreases recurrence rate.
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The Rome criteria were amended as Rome IV. For functional esophageal disorders, the exclusion criteria have been more specifically revised based on further understanding of other esophageal disorders, including eosinophilic esophagitis and spastic and hypercontractile motor disorders. Another revised point is the more restrictive definition of gastroesophageal reflux disease, indicating that sensitivity to a physiological reflux burden may be placed more firmly within the functional group. For functional dyspepsia (FD), only minor changes were introduced, mainly to improve specificity. Among the major symptoms of FD, not only postprandial fullness, but also epigastric pain, epigastric burning, and early satiation should be “bothersome.” Investigation on the effect of meal ingestion on symptom generation has indicated that not only postprandial fullness and early satiety, but also epigastric pain, epigastric burning sensation and nausea (not vomiting) may increase after meals. Helicobacter pylori infection is considered a possible cause of dyspepsia if successful eradication leads to sustained resolution of symptoms for more than 6 months, and such status can be termed as “H. pylori–associated dyspepsia.” Prompt esophagogastroduodenoscopy and H. pylori testing and treatment would be more beneficial, especially in Asia, which has a high prevalence of gastric cancer. Acotiamide, tandospirone, and rikkunshito are the newly listed as treatment options for FD. For further therapeutic development, clinical studies based on the strict Rome IV criteria should be performed.
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Background Controversies persist regarding the effect of prokinetics for the treatment of functional dyspepsia (FD). This study aimed to assess the comparative efficacy of prokinetic agents for the treatment of FD. Methods Randomized controlled trials (RCTs) of prokinetics for the treatment of FD were identified from core databases. Symptom response rates were extracted and analyzed using odds ratios (ORs). A Bayesian network meta-analysis was performed using the Markov chain Monte Carlo method in WinBUGS and NetMetaXL. Results In total, 25 RCTs, which included 4473 patients with FD who were treated with 6 different prokinetics or placebo, were identified and analyzed. Metoclopramide showed the best surface under the cumulative ranking curve (SUCRA) probability (92.5%), followed by trimebutine (74.5%) and mosapride (63.3%). However, the therapeutic efficacy of metoclopramide was not significantly different from that of trimebutine (OR:1.32, 95% credible interval: 0.27–6.06), mosapride (OR: 1.99, 95% credible interval: 0.87–4.72), or domperidone (OR: 2.04, 95% credible interval: 0.92–4.60). Metoclopramide showed better efficacy than itopride (OR: 2.79, 95% credible interval: 1.29–6.21) and acotiamide (OR: 3.07, 95% credible interval: 1.43–6.75). Domperidone (SUCRA probability 62.9%) showed better efficacy than itopride (OR: 1.37, 95% credible interval: 1.07–1.77) and acotiamide (OR: 1.51, 95% credible interval: 1.04–2.18). Conclusions Metoclopramide, trimebutine, mosapride, and domperidone showed better efficacy for the treatment of FD than itopride or acotiamide. Considering the adverse events related to metoclopramide or domperidone, the short-term use of these agents or the alternative use of trimebutine or mosapride could be recommended for the symptomatic relief of FD. Electronic supplementary material The online version of this article (doi:10.1186/s12876-017-0639-0) contains supplementary material, which is available to authorized users.
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Efficacy of acotiamide for improving symptoms in patients with functional dyspepsia was shown by several clinical trials. In a randomized, double-blind, placebo-controlled, parallel-group comparative Phase III trial conducted in Japan, 100 mg of acotiamide three times a day for 4 weeks was more effective than a placebo for improving symptoms, and quality of life. Acotiamide was well-tolerated treatment, with no significant adverse events. The aim of this review was to summarize the current evidence of the efficacy of acotiamide in the treatment of patients with functional dyspepsia.
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Background Acotiamide is widely used to improve symptoms in patients with functional dyspepsia (FD) in multiple large-scale clinical studies, but there are few reports about the drug’s mechanism of action. The aim of this study was to assess the effects of acotiamide on gastric accommodation and gastric emptying, gastrointestinal symptoms, and health-related quality of life (HR-QOL) in a placebo-controlled study. Methods We conducted a randomized, double-blind placebo-controlled study. Fifty Japanese FD patients were randomly assigned to either placebo (n = 25) or acotiamide 100 mg × 3/day for 2 weeks (n = 25). At baseline and at 2 weeks of treatment, we evaluated the patients’ gastric motility using scintigraphy to determine the accommodation and emptying values, gastrointestinal symptom rating scale (GSRS), HR-QOL (SF-8), and anxiety and depression scale (HADS). ResultsFour patients failed to complete the medication regimen and were omitted from analysis; data from 24 placebo patients and 22 acotiamide patients were analyzed. Acotiamide significantly increased gastric accommodation compared to the placebo (p = 0.04 vs. p = 0.08; respectively). Acotiamide significantly accelerated gastric emptying (50 % half-emptying time) (p = 0.02 vs. p = 0.59). Acotiamide significantly improved the total GSRS scores compared to placebo (p = 0.0007 vs. p = 0.14). HR-QOL did not differ significantly between the two groups, but acotiamide significantly improved the HADS anxiety score compared to placebo (p = 0.04 vs. p = 0.20). Conclusions Our placebo-controlled study demonstrated that acotiamide significantly increased both gastric accommodation and gastric emptying in Japanese FD patients. Acotiamide also improved the patients’ dyspeptic symptoms and anxiety score.Clinical Trials Registry no: UMIN000013544.
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Dyspepsia is a constellation of symptoms referable to the gastroduodenal region of the upper gastrointestinal tract. Functional dyspepsia, a relapsing and remitting disorder, is the most common cause of these symptoms. The current standard for the diagnosis of functional dyspepsia is the Rome III criteria, developed by the Rome III Committees, a multinational group of experts in the field, first convened in 1990, that meets regularly to review and revise the diagnostic criteria for all functional gastrointestinal disorders. The Rome III criteria for functional dyspepsia consist of a sensation of pain or burning in the epigastrium, early satiety (inability to finish a normal-sized meal), fullness during or after a meal, or a combination of these symptoms (Table S1 in the Supplementary Appendix, available with the full text of this article at NEJM.org). Symptoms must be chronic, occurring at least weekly and over a period of at least 6 months, in the absence of an organic explanation. 1 The global prevalence of functional dyspepsia in the community according to this definition is between 5% and 11%.(2) Up to 40% of persons who have functional dyspepsia consult a physician,(3) and the condition negatively affects attendance and productivity in the workplace.(4) Functional dyspepsia has substantial financial implications for patients, health care organizations, and society as a whole; costs associated with the condition in the United States in 2009 were in excess of $18 billion.(5) It is therefore important that physicians be able to recognize functional dyspepsia, use investigations and diagnostic tests judiciously, and recommend effective treatments, in order to minimize the potential adverse social and economic effects of the condition.
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Functional dyspepsia is a highly prevalent symptom complex and a heterogenous disorder. Recent studies showed potential associations between specific pathophysiologic disturbances and dyspeptic symptoms. Delayed gastric emptying reported in about 30% of patients with functional dyspepsia is associated with the symptoms of postprandial fullness, nausea, and vomiting. Impaired gastric accommodation present in 40% of functional dyspepsia patients is found to be associated with early satiety. Hypersensitivity to gastric distension is observed in 37% of functional dyspepsia patients and associated with the symptoms of postprandial pain, belching, and weight loss. Psychosocial factors and altered response to duodenal lipids or acid have also been identified as pathophysiologic mechanisms. Therapeutic options are still limited but targeted therapy directed at the underlying pathophysiology seems desirable. Thus, efforts to further elucidate underlying pathophysiologic mechanisms and identify the appropriate patient population using some type of pathophysiologic testing will be required.