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Efficacy of Acotiamide in PDS type Functional Dyspepsia symptoms with and without PPI and laxative co-therapy

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  • Dr Varsha's Health Solutions

Abstract and Figures

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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Original Article
The Indian Practitioner q Vol.71 No.6. June 2018
19
Efcacy of Acotiamide in PDS type Functional Dyspepsia
symptoms with and without PPI and laxative co-therapy
Varsha Narayanan1, Shailesh Pallewar2, Amit Bhargava3
DGM Medical Services1, Manager Medical Services2, VP Medical Services3, Lupin Ltd
Corresponding Author: Dr Varsha Narayanan, DGM – Medical Services, Lupin Ltd, Laxmi Towers ‘C’, BKC, Bandra (East), Mumbai - 400051
Email: varshanarayanan@lupin.com
Abstract
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 efcacy 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 lack-
ing.
Methodology: Data, evaluated from 314 patients through questionnaires to record patient’s perception of
improvement in the presenting symptoms, as well as tolerance to treatment with acotiamide 100 mg thrice
daily, across gastroenterology clinics in India, was analyzed.
Results: The responder rate for treatment with acotiamide in the groups receiving only acotiamide and in
those also receiving Proton Pump Inhibitor (PPI) and laxatives as concomitant therapy, for each of function-
al dyspepsia symptoms of post prandial fullness, upper abdominal bloating and early satiety was 72.5% and
86.5%, 68.8% and 80.2%, and, 80% and 74.1% respectively. No signicant difference was seen in the number
of patients achieving complete relief or signicant improvement from both post prandial fullness and early
satiety at nal follow up between the two groups. A signicant difference was seen in the number of patients
who ‘signicantly improved’ from epigastric bloating in the group co-prescribed a PPI or a laxative with
acotiamide versus the group which was only given acotiamide. Overall a low treatment discontinuation rate
of 1.3% was observed.
Conclusion: This real-world study suggests that use of acotiamide is associated with improvement of meal-
related (PDS) FD symptoms with good safety prole, in patients also receiving a PPI or a laxative for other
overlapping symptoms with PDS.
Key Words: Rome IV Criteria, Functional Dyspepsia, Gastric emptying, Constipation, PPI, Acotiamide,
Prokinetic, Laxative, Post prandial fullness, Abdominal Bloating, Early satiety, Epigastric pain.
Original Article
The Indian Practitioner q Vol.71 No.6. June 2018
20
Introduction
Functional Dyspepsia (FD) represents a condition
of impaired digestion and has been dened by
Rome IV as presence of one or more of the fol-
lowing symptoms: Bothersome post-prandial fullness,
early satiation, epigastric pain or epigastric burning,
and no evidence of structural disease (including at
upper endoscopy) to explain the symptoms.1 These
criteria are to be fullled for the last 3 months with
symptom onset at least 6 months before diagnosis. FD
has been classied into 2 subtypes as Post-prandial
Distress Syndrome (PDS) which includes bothersome
postprandial fullness (ie, severe enough to impact on
usual activities and/or bothersome early satiation (ie,
severe enough to prevent nishing a regular-size meal)
at least 3 times/week and Epigastric Pain Syndrome
(EPS), which includes bothersome epigastric pain (ie,
severe enough to impact on usual activities) and/or
bothersome epigastric burning (ie, severe enough to
impact on usual activities) at least 1 day/week. Rome
IV introduced some changes as compared to the previ-
ous Rome III criteria to improve the specicity of the
denition, by adding that not only postprandial full-
ness, but also epigastric pain, epigastric burning, and
early satiation should be “bothersome” symptoms.1
The prevalence of functional dyspepsia worldwide is
about 20-30%.2 Almost 60% dyspepsia patients have
functional dyspepsia with 25-40% FD patients pre-
senting with delayed gastric emptying.3 Delayed acid
clearance has also been seen in FD patients. A study
from India showed a 9% and 27% rate of EPS and PDS
type FD while 64% patients had overlapping PDS and
EPS symptoms.4 Some patients with FD symptoms
and delayed gastric emptying may also have associ-
ated constipation.5
Randomized controlled clinical trials commonly
exclude patients with overlapping symptoms. The
phase 2 studies in US with acotiamide were done af-
ter excluding patients who responded to PPI therapy.6
In both phase 3 studies in Japan and Europe, patients
with PDS-FD have been studied.7,8 However in the
real world clinical practice, the proportion of patients
presenting with overlapping symptoms of PDS (meal
related FD symptoms) with epigastric burning or con-
stipation, are considerable. Acotiamide will be com-
monly administered with proton pump inhibitors (PPI)
and laxatives in clinical practice seing and therefore
generating real world data for acotiamide in relieving
meal related (PDS) FD symptoms in a clinical seing
of other overlapping symptoms and with co-therapies
like PPIs and laxatives become pertinent and relevant.
To our knowledge this is the rst real world analysis of
acotiamide in this subset of patients.
Acotiamide is a rst gastroprokinetic agent to get
specic approval in functional dyspepsia. It relieves
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 meal re-
lated symptoms like post prandial fullness, epigastric
bloating and early satiety in FD patients. Acotiamide
has been listed in Rome IV as a treatment option for
FD.9 Gastroprokinetic action of acotiamide results
from enhanced action of acetylcholine (ACh) by an-
tagonizing pre-synaptic enteric M1 and M2 muscarinic
receptors, as well as by inhibiting acetylcholinesterase
activity thereby prolonging the availability and action
of the ACh. Acotiamide does not appear to be associ-
ated with prolongation of the QTc interval and does
not show marked CYP inhibition. Approximately, 45%
of acotiamide is excreted in the faeces with a plasma
half-life of 7–10 hours.10
This real-world study can help bridge the knowl-
edge gap between acotiamide clinical trials and actual
clinical usage, and to understand how acotiamide will
work when applied in clinical practice to patients with
varied symptoms as well as concomitant therapies.
The analyzed data can give insights for appropriate
selection of FD-patients for treatment with acotiamide
and further improving physician experience and pa-
tient benet.
Methodology
Over 60 gastroenterology clinics across the 4 zones
of India were identied and 100 patients from each
zone were evaluated for response to treatment for
their presenting meal related symptoms of functional
dyspepsia (FD) including post prandial fullness, upper
abdominal bloating, and/or early satiety. Patients were
classied into FD subtypes according to ROME III cri-
teria as Post-prandial Distress Syndrome type (PDS),
Epigastric Pain Syndrome type (EPS) or overlapping
EPS and PDS. Patients with predominantly EPS with-
out PDS symptoms were not considered for analysis.
However, patients with overlapping symptoms of con-
stipation along with PDS/or EPS were also considered.
314 patients with symptoms of PDS or overlapping
PDS with EPS or constipation, who were prescribed
Acotiamide 100mg thrice a day before the 3 principal
meals, were considered for nal analysis. Patients with
overlapping epigastric pain or burning were also pre-
scribed a PPI in standard dose while those with consti-
pation were co-prescribed a laxative.
All patients were evaluated with a questionnaire to
Original Article
The Indian Practitioner q Vol.71 No.6. June 2018
21
record patient’s perception of improvement in the pre-
senting meal related FD symptoms, as well as tolerance
to treatment. The primary parameter of evaluation
was a 4-point rating scale, comprising of (a) ‘No im-
provement’, (b) ‘Slightly improved’, (c) ‘Signicantly
improved’, and (d) ‘Complete relief’. Patients achiev-
ing signicant improvement or complete relief of
symptoms were considered ‘responders’ to treatment.
For each patient, the duration of treatment was also
recorded. Adverse events, if any, were recorded, as-
sessed and managed. All patient-data was captured
in accordance with ethical principles and with patient
consent.
Results
Out of the 314 patients evalu-
ated, 60% patients were ≥40 years,
while 13% were 60 years with an
overall male: female ratio of 3:2. 38%
had overlapping symptoms of EPS
(including epigastric pain/burning)
along with symptoms of PDS (post
prandial fullness, epigastric bloat-
ing and early satiety) who were
also prescribed a standard dose PPI
along with acotiamide. Constipation
coexisted in 26% patients who were
appropriately also prescribed a laxa-
tive.
Overall, the responder rate for
treatment with acotiamide for meal
related functional dyspepsia symp-
toms of post prandial fullness, up-
per abdominal bloating and early
satiety was 79.2%, 74.4%, and 77.1%
patients respectively. (P<0.001 for all
mentioned values versus no/ slight
improvement). The responder rate
for treatment with acotiamide in the
groups receiving only acotiamide
and in those also receiving PPI and
laxatives as concomitant therapy, for
each of functional dyspepsia symp-
toms of post prandial fullness, up-
per abdominal bloating and early
satiety was 72.5% and 86.5%, 68.8%
and 80.2%, and, 80% and 74.1% re-
spectively. Figures 1, 2 and 3 show
the treatment response for each of
the three meal related symptoms
in the groups receiving acotiamide
alone and in those who additional-
ly also received PPI and/or laxative
co-therapy. No signicant dierence was seen in the
number of patients achieving complete relief or sig-
nicant improvement from both post prandial fullness
and early satiety at nal follow up, in the group of pa-
tients who along with acotiamide were also given PPI
therapy for overlapping epigastric burning/ pain, or
laxatives for constipation versus the group of patients
who were only given acotiamide. However, there was
a signicant dierence in the number of patients who
‘signicantly improved’ from epigastric bloating in
the group co-prescribed a PPI or a laxative with aco-
tiamide versus the group which was only given aco-
tiamide (P=0.02).
Signicantly more patients achieved complete re-
Original Article
The Indian Practitioner q Vol.71 No.6. June 2018
22
lief when 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).
Discussion
Randomized Control Trials are performed in con-
trolled conditions with strict inclusion and exclusion
criteria, along with monitored patient care and com-
pliance. Understandably, these may provide limited
insights into multifaceted interactions, and continu-
ous relationships between treatment and study results.
Therefore, there is a need for real-world data genera-
tion which captures actual in-clinic usage and patient
responses in a varied population. The results of our
rst Indian study conducted in real world seings 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 present-
ing with overlapping symptoms.
Overall, our study ndings in terms of responder
rates for acotiamide are in line with previous reports
of ecacy from randomized controlled trials on aco-
tiamide. Though there was no dierence in post pran-
dial fullness and early satiety responder rates when
comparing the groups receiving and not receiving
co-therapy of PPIs and laxatives
with acotiamide, there was a sig-
nicantly beer response rate for
upper abdominal bloating in those
patients receiving acotiamide with
these co-therapies.
Randomized control studies
with acotiamide have been done
mainly with patients of PDS type
(meal related) FD symptoms. In
the phase 2b study completed with
acotiamide in the US, patient pop-
ulation was selected after a trial
run of a two-week course of stan-
dard dose PPI and excluding all re-
sponders to the same.6 Thereafter
the overall treatment evaluation
(OTE) was found to be signicant-
ly beer for acotiamide 300mg/day
as compared to placebo, at 4 and 12 weeks.
Long term Phase 3 studies for acotiamide have been
completed in Japan and Europe. In the Japanese phase
3 study, the 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)8, while in the European phase 3, OTE im-
provement increased from 13.1% at Week 1 to 41.5%
at Week 12, then increased further to 70.2% at Week
52.7 Placebo controlled studies for acotiamide showed
an OTE improvement rate of 52.2% patients receiv-
ing acotiamide & 34.8 % patients receiving placebo
(p<0.001) which was well maintained for 4 weeks post
withdrawing treatment.12
Two studies showed the eect of acotiamide on
gastric accommodation and gastric emptying. The rst
study evaluated by gastric ultrasound found signi-
cant dierence in the change of gastric accommoda-
tion between the acotiamide group and the placebo
group. (21.7 vs 4.4%) with a signicant acceleration in
the gastric emptying rate, which was not seen in the
placebo group.13 The second study evaluated by gastric
scintigraphy also showed increased gastric accommo-
dation compared to placebo (P = 0.04 vs. P = 0.08) and
signicantly accelerated gastric emptying (50% half-
emptying time- P = 0.02 vs. P = 0.59).14
Acotiamide added to a PPI (Esomeprazole) has
been evaluated in patients with residual symptoms
of functional dyspepsia after standard treatment with
Esomeprazole alone.15 78% achieved an overall im-
provement in symptoms after 2 weeks of combination
therapy. Almost all FD-related symptoms statistically
improved after the combination therapy, with an im-
Original Article
The Indian Practitioner q Vol.71 No.6. June 2018
provement in the mFSSG score relevant to the post-
prandial distress syndrome and epigastric pain syn-
drome. Symptomatic improvement was irrespective of
age, gender, and the pre-combination therapy score of
the mFSSG. These ndings suggested that the combi-
nation therapy of acotiamide and PPI may be eective
in selected FD patients with insucient improvement
with an initial PPI.
In a recent study, acotiamide 100mg tidin combina-
tion with standard dose of PPI (Rabeprazole 10mg) was
evaluated versus a double dose of PPI (Rabeprazole
20mg).16 Patients showing overlapping symptoms
between GERD and FD experiencing heartburn and
epigastric fullness symptoms after standard-dose PPI
for ≥ 8 weeks were included. In the primary endpoint,
the three upper gastrointestinal symptoms (heartburn,
epigastric pain, and epigastric fullness) were reduced
by ≥ 50% in 40.8% and 46.9% of patients in the combi-
nation (acotiamide with standard dose PPI), and PPI
double-dose groups, respectively, with no signicant
dierence between the two groups. Therefore, adding
acotiamide to a standard dose PPI can be an eective
option to doubling PPI dose in patients of FD with
heartburn.
Though our real-world study did not have patients
with heartburn, there were a number of patients who
had meal related FD symptoms with epigastric burn-
ing/pain, and these patients showed signicant re-
sponse to treatment with acotiamide in combination
with PPIs thus corroborating clinical trial ndings.
In Indian clinical practice seing, constipation can be
commonly present along with symptoms of delayed
gastric emptying. Acotiamide can be used in combina-
tion with laxatives in such patients to improve relief
from upper abdominal bloating as seen in our study.
Therefore, acotiamide can be used with PPIs and laxa-
tives to enhance gastric emptying and symptomatic
relief in patients who present with multiple symptoms
like meal related FD symptoms with epigastric pain/
burning and/or constipation in gastroenterology clin-
ics. More real-world studies in larger population, with
longer follow up periods and associated co-morbidi-
ties can further add value to clinical practice.
Conict of interest declaration: The authors are employed
by Lupin ltd.
Funding: Real world data collected from practicing doc-
tors. Funding from Lupin Ltd for statistical analysis.
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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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Improvement in subjective symptoms has been reported in functional dyspepsia (FD) patients administered with acotiamide. Improvement was confirmed in meal-related symptoms, such as postprandial fullness, upper abdominal bloating, and early satiety. We examined the mechanism underlying the effects of acotiamide on gastric accommodation reflex (GAR) and gastroduodenal motility in FD patients. Thirty-four FD patients (mean age, 40.4 years) were examined ultrasonographically before and after 14-18 days of acotiamide (100 mg t.i.d.) or placebo administration. To assess GAR, expansion rate in cross-sectional area of the proximal stomach was measured after every 100-mL ingestion, using a straw, of up to 400 mL of a liquid meal (consommé soup, 13.1 kcal; 400 mL) in a supine position. Next, we measured gastric emptying rate (GER), motility index (MI, antral contractions), and reflux index (RI, duodenogastric reflux) to assess gastroduodenal motility. Patients also completed a survey based on the seven-point Likert scale both before and after drug administration. Of the 37 cases, 19 and 18 were administered with acotiamide and placebo A respectively, significant difference was observed in GAR between the acotiamide and placebo groups (21.7%vs 4.4%) after 400 mL ingestion. GER significantly accelerated after treatment in the acotiamide group (P = 0.012), no significant differences were observed in MI and RI between the two groups. Improvement rates were 35.3 and 11.8% for the acotiamide and placebo groups. Acotiamide significantly enhances GAR and GER in FD patients. Acotiamide may have therapeutic potential for FD patients.
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To determine the efficacy of acotiamide, an acetylcholinesterase inhibitor, in patients with functional dyspepsia (FD) in a 4-week trial. A multicentre, randomised, placebo-controlled, parallel-group, phase III trial was carried out, in which patients with FD received 100 mg of acotiamide or placebo three times a day for 4 weeks, with 4 weeks post-treatment follow-up. The primary efficacy end points were global assessment of overall treatment efficacy (OTE) and elimination rate of all three meal-related symptoms (postprandial fullness, upper abdominal bloating and early satiation), as derived from daily diaries. Secondary efficacy end points were individual symptom scores and quality of life. Adverse events were monitored. 52.2% of those receiving acotiamide and 34.8% in the placebo group (p<0.001) were classified as responders according to a global assessment of OTE. Over 4 weeks, the elimination rate for all three meal-related symptoms was 15.3% among patients receiving acotiamide compared with 9.0% in the placebo group (p=0.004). The significant benefit of acotiamide over placebo in OTE and elimination rate was maintained during the 4 week post-treatment follow-up. All other secondary efficacy end points, including quality of life, were significantly improved with 100 mg of acotiamide as compared with placebo. The number needed to treat was 6 for OTE and 16 for symptom elimination rate. The incidence of adverse events was similar between the acotiamide group and placebo group and no significant cardiovascular effects due to treatment were seen. Over 4 weeks, acotiamide significantly improved symptom severity and eliminated meal-related symptoms in patients with FD. http://ClinicalTrials.gov number, NCT00761358.
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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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Although highly prevalent, little is known about the economic impact of functional dyspepsia (FD). To quantify FD patients' health care utilisation patterns and to estimate direct and indirect costs of FD to patients. ICD-9 codes identified adult patients with dyspepsia. A validated questionnaire was mailed to patients who met Rome III criteria for FD. Three hundred and fifty-five patients met all inclusion criteria. The response rate was 63%. The respondents' mean age was 50 (14) years; 75% were women; 52% of respondents rated their FD as moderate. Patients reported 3 visits (mean) to their PCP over 12 months; 75% reported having blood work, 92% an EGD, 59% an ultrasound and 40% a CT scan. The direct cost of testing using Medicare reimbursement rates per patient was $582. To treat FD symptoms, 89% tried dietary changes, 89% over-the-counter medications, 87% prescription medications and 25% alternative therapies. Mean patient expenditure over the last year was $246 for OTC medications (range $0–12,000), $290 for co-payments (range $0–9,000) and $110 for alternative treatments (range $0–3,741). Total mean direct cost yearly to patients was $699. In the 7 days prior to completing the questionnaire, respondents reported a mean of 1.4 h absence from work. Extrapolating the results to the US population, we conservatively calculate the costs of FD were $18.4 billion in 2009. Functional dyspepsia patients incur significant direct and indirect costs and work productivity is impaired by dyspeptic symptoms.