Real World Efficacy and Tolerability of Acotiamide in Relieving Multiple and Overlapping Symptoms in Patients of Functional Dyspepsia

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Archives of Gastroenterology and Hepatology V1 . I1 . 2018 1

Fu
nctional Dyspepsia (FD) represents a conditi
on
o
f impaired digestion with the presence of bothe
r
so
me dyspeptic symptoms of Postprandial Distre
ss
Syndrome (PDS) mainly composed of early satia tion or
postprandial fullness, and Epigastric Pain Syndrome
(EPS), mainly composed of epigastric pain/discomfort
or burning, in the absence of an organic, structural
Archives of Gastroenterology and Hepatology
Volume 1, Issue 1, 2018, PP: 1-6

in Relieving Multiple and Overlapping Symptoms in
Patients of Functional Dyspepsia
Varsha Narayanan1*, Shailesh Pallewar2, Maneesha Khalse2, Amit Bhargava3
1*DGM Medical services, Lupin Ltd, Mumbai, India.
2Manager Medical Services, Lupin Ltd, Mumbai, India.
3VP Medical Services, Lupin Ltd, Mumbai, India.
varshanarayanan@lupin.com
*Corresp
onding Author: Dr. Varsha Narayanan, DGM – Medical Services, Lupin Ltd, Laxmi towers ‘C’,
BKC, Mumbai, India.

Background: 
     
    
        
            
             




Methodology: In this study, 1525 FD patients visiting 148 gastroenterology clinics across India, received


Results:


           



Conclusion: 


Keywords: 


Archives of Gastroenterology and Hepatology V1 . I1 . 2018
2
or metabolic disease to explain these symptoms.
FD is known to be a heterogeneous disorder, with
multiple pathogenic factors, such as excessive gastric
acid secretion, gastric motility disorder, Helicobacter
pylori infection, psychological factors and visceral
hypersensitivity1.
The prevalence of functional dyspepsia worldwide is
about 20-30% (representing 60% of the dyspepsia
patient pool).2About one third of FD patients present
with delayed gastric emptying.3with or without
delayed acid clearance. Around 9% and 27% of FD
patients present exclusively with EPS and PDS type FD
respectively but majority (64% patients) present with
overlapping PDS and EPS symptoms.4GERD symptoms
(mainly heartburn and belching) have also been seen
to overlap with FD symptoms in up to 25% patients
and this subset of patients often are refractory to
PPIs.5In clinical practice, patients commonly describe
in various ways an abdominal or epigastric discomfort
not amounting to typical epigastric pain or burning.
Some patients with FD symptoms and delayed gastric
emptying may also have associated constipation.6
     
extensively studied in clinical trials. It improves
upper gastrointestinal motility to relieve abdominal
symptoms arising due to impaired GI motility in
FD patients. Acotiamide receive   
regulatory approval in Japan in 2013 and was
approved in India in 2016 for the treatment of bloating
after meals, epigastric bloating and early satiety in
FD patients and is listed in Rome IV as a treatment
option for FD7. Gastroprokinetic action of Acotiamide
res
ults from enhancedaction of acetylchol
ine
(ACh) by antagonizingpre-synaptic enteric M1 and
M2 muscarinic receptors,as well as by inhibiting
acetylcholin esterase activity thereby prolonging the
availability and action of the ACh. Acotiamide does not
appear to be associated with prolongation of the QTc
interval and does not show marked CYP inhibition.
Approximately, 45% of Acotiamide is excreted in the
feces with a plasma half-life of 7–10 hours.8
Randomized controlled clinical trials for Acotiamide
have usually excluded patients with overlapping
symptoms. The phase 2 studies in US as well as long
term phase 3 studies in Japan and Europe have mainly
studied patients with PDS-FD.9,10,11We had recently
conducted and published the real world in clinic data
       
in meal related symptoms (PDS type FD).12 Given the
high rate of overlapping meal related, epigastric and
        
particularly relevant to see how Acotiamide fares
in the real world in relieving these symptoms apart
from meal related symptoms ofearly satia tion and
      
tolerance of Acotiamide is already well documented.

Acotiamide in this subset of FD patients with multiple
overlapping symptoms.

1525 adult patients who presented clinically with
mu
ltiple FD symptoms of post prandial fullne
ss,
early satiety along with other overlapping symptoms
in
cluding upper abdominal (epigastric) pain/
bu
rning, Upper abdominal (epigastric) discomfo
rt,
Upper abdominal bloating, Excessive belching and
Heartburn in the Gastroenterologist’s out-patient
department and were prescribed 100mg Acotiamide
thrice daily, were assessed by the treating physician
with a questionnaire to capture patient’s perception
of improvement in the presenting symptoms, as well
as tolerance to treatment.
The data was capturedfrom 148 Gastroenterologists
across India (71 in north, 34 in east zone, 24 in west
zone and 19 in south zone). To facilitate objective and
unambiguous assessment by the patients, a 4-point
rating scale, comprising of (a) ‘No improvement’, (b)
     
(d) ‘Complete relief’, was used. For each patient, the
duration of treatment and co-prescribed therapies 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.

1
525 patients were prescribed Acotiamide for
their FD symptoms. 66.6% were male patients, and
       
        
with symptoms of early satiety and postprandial
fullness. The percentage of patients presenting with
other overlapping symptoms was as follows: Upper
a
bdominal (epigastric) pain (1036) 68%, Uppe
r

Patients of Functional Dyspepsia

Archives of Gastroenterology and Hepatology V1 . I1 . 2018 3
abd
ominal (epigastric) discomfort (1077) 7
0.6%,
Upper abdominal bloating (1118) 73.3%, Excessive
belching (870) 57%, and Heartburn (858) 56.2%.
Comp
 
rom
Upper abdominal (epigastric) pain, Upper abdominal
(epigastric) discomfort, Upper abdominal bloating,
Excessive belching and Heartburn was seen in 65.5%,
75.5%, 77.4%, 68.7% and 64% patients respectively.
(P<0.001 for all mentioned values versus no/slight
improvement – Figure 1).
     
or



      

o
     
ptomatic
improvement seen for upper abdominal discomfort
and bloating. However, for upper abdominal pain,

the group with symptom duration less than 6 months,

The symptomatic relief with Acotiamide was seen to
be obtained as early as 1-2 weeks of therapy with 50%,
58.9%, 52.2%, 45.2% and 49.4% patients obtaining
     
pain, Upper abdominal (epigastric) discomfort, Upper
abdominal bloating, Excessive belching and Heartburn
respectively after 7-14 days of Acotiamide therapy.
A sub-analysis was also performed comparing the
symptomatic improvement rates in patients who
were given a PPI as co-therapy along with Acotiamide
and those that were not. Being real world data, co-
prescriptions of PPI in patients with overlapping
sym
ptoms is expected
higher number of patients achieved complete
relief from upper abdominal bloating, when given
Acotiamide alone as compared to those patients
prescribed both Acotiamide and PPI (P=
0.007)

symptoms. The number of patients who showed no
improvement/no relief from upper abdominal pain,
      
the Acotiamide group not prescribed PPI as compared
to those patients given PPI as co-therapy (P=0.018,

was seen for these symptoms for patients achieving

and without co-therapy.
Adverse events were reported by 1.3% patients, which
were mainly nausea, vomiting, abdominal cramps,
diarrhoea and constipation, all of which were mild and
transient in nature and most did not require cessation
of Acotiamide. Treatment discontinuation occurred in
23 patients (16 due to cost, 5 due to perceived lack of
adequate symptomatic relief, 1 each due to diarrhoea
and development of another comorbid condition).
Figure 1. 
symptomatic improvement

Ac
otiamideacts by improving gastric emptying an
d
accommodation, thereby, relieves meal related F
D
symptoms. Studies have also demonstrated the mechanism
of action of Acotiamide on gastric accommodation and
gastric emptying by gastric ultrasound and scintigraphy
which found

of gastric accommodation between the Acotiamideand

accelerated gastric emptying (50 % half-emptying
time- P = 0.02 vs. 0.59 for placebo).13,14
Randomized control studies with Acotiamide have
been done in patients with mainly PDS type (meal
related) FD symptoms: post prandial fullness and
early satiety. The US phase 2b study of Acotiamide
included patients who did not show response to
PPI, post a trial run in two-week period.6 The overall
     
for Acotiamide 300mg/day as compared to placebo,

Patients of Functional Dyspepsia

Archives of Gastroenterology and Hepatology V1 . I1 . 2018
4
as seen at 4 and 12 weeks.9 In the long term European
phase 3 study, OTE improvement for meal related
FD symptoms increased from 13.1% at Week 1 to
41.5% at Week 12, then increased further to 70.2%
at Week 52. 81.6% of patients, maintained exposure
to Acotiamide for >50 weeks, with a mean duration of
320.3 days.10
Similarly the Japanese phase 3 study showed an OTE
improvement rate of 26.1% at week 1 which increased
with time reaching 60.6% at week 8, and improving
consistently to 66.7% at week 48 and 73.2% (during
th
e last period of treatment)11 Placebo controlled
study for Acotiamide showed an OTE improvement
rate of 52.2 % patients receiving Acotiamide and
34.8 % patients receiving placebo (p<0.001) which
was well maintained for 4 weeks post withdrawing
treatment.15Acotiamide was well tolerated in all these
studies.
Recently a real-world study in 314 patients presenting
with meal related FD symptoms evaluated th
e
improvement perception by patients on a 4-point
scale across 63 gastroenterology clinics acros
s
India.12    
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 versus

patients achieved complete relief when treated for >28
days or 14-28 days than when treated for less than 2
weeks (P<0.05). Acotiamide was well tolerated in this
study with only 2 patients discontinuing treatment.
Acotiamide100mg tidhas also been compared with
Levosulpiride 25mg tid in 60 Indian FD patients16
Approximately 93% patients reported excellent to
good improvement of FD symptoms after a 4-week
admini
stration of Acotiamide compared to 80
%
improvement with Levosulpiride. The study concluded
that, Acotiamide was superior to Levosulpiride in,
16.
Acotiamidehas also been evaluated in combination
with PPIs.In one study, 78% of FD patients with
residual symptoms post standard treatment with
Esomeprazole, achieved an overall improvement in
symptoms after 2 weeks of combination therapy of
Esomeprazole and Acotiamide.17 Almost all FD-related
symptoms statistically improved after the combination
therapy, with an improvement in the mFSSG score
r
elevant to the postprandial distress syndrom
e
and epigastric pain syndrome. In another study,
patients showing overlapping symptoms between
GERD and FD experiencing heartburn and epigastric
fullness symptoms after standard-dose Rabeprazole
        
ofAcotiamide 100mg tidplus Rabeprazole 10mg od
versus double dose Rabeprazole 20mg alone.5 The
three upper gastrointestinal symptoms (heartburn,
epigastric pain, and epigastric fullness) were reduced
          
combination (Acotiamide with standard dose PPI),
a
nd PPI double-dose groups, respectively,
with
      
Therefore, these studies show that adding Acotiamide
to a standard d      
doubling PPI dose in patients of FD with heartburn,
and that combination therapy of Acotiamide and
        

Our current real-world study has shown that
       
FD patients who present in a physician’s OPD with
        
       
Acotiamide has also been studied in symptoms other
than the typical PDS symptoms for which it has been
studied in global randomized controlled studies.
  
use in relieving meal related symptoms of early satiety
and post-prandial fullness has been consistently
demonstrated in many clinical trials and accordingly
regulatory approval globally has been received for the
same.18Though Acotiamide does not have evidence in
GERD management, our study showed improvement
in epigastric pain, heartburn and belching symptoms
with Acotiamide possibly due to enhanced acid
clearance and gastric emptying, however adding a PPI
     
reduce the number of non-responders. Acotiamide
alone relieved abdominal bloating better than when
a PPI was added. There is evidence to suggest that
PPI can decrease gastric emptying especially that of
solids, which could explain this particular result.19,20In
all other symptoms assessed including epigastric pain
and discomfort, Acotiamide fared as well alone as with

Patients of Functional Dyspepsia

Archives of Gastroenterology and Hepatology V1 . I1 . 2018 5
an added PPI. In relief of meal related symptoms, both
RCT and real-world data have shown better responses
with longer duration of treatment. In our study there

     
relief at 7-14 days as compared to 14-28 days or more
suggesting an early response of these overlapping
symptoms to Acotiamide. This real-world study further

with various published studies, and both the rate of
adverse events and treatment discontinuations were
minimal.
Findings of this study will assist clinicians commonly
seeing dyspeptic patients in general and specialized
practice, with multiple overlapping symptomatology

More real-world studies are thus welcome in even
larger population size and diverse ethnicities with,
l
onger follow up periods to continuously gui
de
      
theirpatients.
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Archives of Gastroenterology and Hepatology V1 . I1 . 2018
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Patients of Functional Dyspepsia
Citation: Varsha Narayanan, Shailesh Pallewar, Maneesha Khalse, Amit Bhargava. 
             
Dyspepsia.
Copyright: © 2018 Varsha Narayanan, Shailesh Pallewar, Maneesha Khalse, Amit Bhargava
open access article distributed under the Creative Commons Attribution License, which permits unrestricted
