Content uploaded by Peter Lipták
Author content
All content in this area was uploaded by Peter Lipták on May 10, 2018
Content may be subject to copyright.
AGA Abstracts
SE: Standard Error; IQR: Inter Quartile Range
Su1628
LONG-TERM SAFETY AND EFFICACY OF ACOTIAMIDE IN PATIENTS
WITH FUNCTIONAL DYSPEPSIA (POSTPRANDIAL DISTRESS
SYNDROME) — RESULTS FROM THE EUROPEAN PHASE 3 TRIAL
Jan F. Tack, Juris Pokrotnieks, Gediminas Urbonas, Christian Banciu, Vladimir
Yakusevich, Ivan Bunganic, Hans Törnblom, Yaroslav Kleban, Patrick Eavis, Masaru
Tsuchikawa, Tomoharu Miyagawa
Background Acotiamide is a novel compound with fundus-relaxing and gastroprokinetic
properties based on an antagonism of the inhibitory muscarinic type 1 and type 2 autorecep-
tors on cholinergic nerve endings and acetylcholinesterase inhibition for treatment of post-
prandial distress syndrome (PDS) symptoms of functional dyspepsia (FD). It showed signifi-
cant efficacy with a good safety profile in patients with FD-PDS in past clinical trials, which
led to the marketing approval of acotiamide in Japan. Since there has been no trial conducted
in the western population that assesses the long-term safety of acotiamide, this trial was
aimed primarily to evaluate the safety of acotiamide for 1 year, with secondary objectives
to explore the effect of 1-year acotiamide treatment on FD symptoms, QoL and work
productivity. Methods FD-PDS patients (defined by ROME III criteria) aged $18 years with
active symptoms of PDS and without predominant overlapping symptoms of epigastric pain
syndrome and related disorders were enrolled in the trial to receive 100 mg acotiamide
three times daily for 1 year. Patients' safety profile was monitored throughout the trial.
Efficacy of acotiamide was measured using multiple scales; the validated Leuven Postprandial
Distress Scale (LPDS) for individual FD symptoms, OTE for overall efficacy, SF-NDI and
SF-36 for Quality of Life, and WPAI for work productivity. Results Between March 2014
and September 2015, 354 patients were screened, 207 patients were enrolled, and 168
patients completed 52 weeks of treatment. The majority of the enrolled patients (81.6%)
maintained exposure to acotiamide for > 50 weeks. In the treated population, no specific
clinically significant safety concerns have been shown, without any deaths or treatment-
related severe/serious adverse events, nor any clinically significant test results including
haematology, biochemistry, urine, and ECG. Though being an open label trial, acotiamide
quickly improved meal-related symptoms of FD, reaching a level larger than the minimum
clinically important difference of -0.5 for the mean score of postprandial fullness (2.13
[baseline] vs 1.58 [week 1]) and early satiation (1.77 [baseline] vs 1.13 [week 2]). Moreover,
each measured PDS symptom showed a continuous decrease in score throughout the 52
week treatment period, for example from 2.13 to 0.33 for postprandial fullness and from
1.77 to 0.32 for early satiation. Additionally, sustained improvement of quality of life and
work productivity was suggested from the first measurement (at week 12) up to 1 year.
Conclusion Long-term safety of acotiamide treatment was confirmed, and PDS symptoms,
QoL, and work productivity improved during the observation period. This data supports
conducting further clinical trials with acotiamide, to obtain marketing authorisation in
Europe for treating meal-related symptoms of FD, an unmet need.
X : 18982$CH1B
04-12-18 21:20:27 Page 554
PDFd : 18982B : e
S-554AGA Abstracts
Trial scheme. FD = functional dyspepsia; F-up = follow-up; LPDS = Leuven Postprandial
Distress Scale; OTE = Overall Treatment Evaluation; QoL = quality of life; SF-36 = Short
Form-36 survey; SF-NDI = Short Form-Nepean Dyspepsia Index; V = study visit; WPAI =
Work Productivity and Activity Impairment
PDS symptom score change from baseline (Full Analysis Set)
Su1629
IMPAIRED AUTONOMIC RESPONSE TO MENTAL AND PHYSICAL
STRESSORS IN FUNCTIONAL DYSPEPSIA
Peter Liptak, Ingrid Tonhajzerova, Michal Mestanik, Peter Banovcin, Rudolf Hyrdel
Background: Functional dyspepsia (FD) is a common functional gastrointestinal disorder
(FGID). The pathophysiological mechanisms of FGID are complex. Accumulating evidence
indicates that autonomic dysregulation contributes to FGID. The symptoms of FGID are
often triggered by stress, however, the mechanisms of autonomic dysregulation in FGID,
especially in response to stress are incompletely understood. Aim: The aim of this study
was to assess potential changes of vagal and sympathetic regulation in patients suffering
from FD in response to distinct types of stressors (active mental stress vs. passive physical
stress). Methods: Studied population included 10 patients diagnosed with FD and 11 age-
and sex-matched healthy controls. All patients were diagnosed according to ROME IV criteria
for functional gastrointestinal disorders. Blood pressure (BP) and heart rate were continuously
recorded using Finometer MIDI (FMS, Netherlands) at rest and during two distinct stressors
- mental arithmetic test and cold pressor test (cooling of forearm in 1-3
o
C water bath for
5 min). Evaluated parameters: 1) baroreflex sensitivity (BRS, calculated from spontaneous
heart rate variability and BP variability) reflecting vagally-mediated heart rate regulation in
response to changes of BP, 2) spectral power in low-frequency band of systolic BP variability
(LF-SBP) reflecting sympathetic alpha-adrenergic stimulation of vascular smooth muscles,
3) systolic and diastolic BP, and 4) mean heart rate. Results (figure 1): BRS (reflecting
vagal function) in patients with FD was substantially (by 50%) reduced compared to controls
at rest and in response to both mental arithmetic test and to cold pressor test (p<0.01 for
all comparisons). In contrast, LF-SBP (reflecting sympathetic function) was normal at baseline,
but significantly increased in FD compared to controls during both mental arithmetic test
and cold pressor test (p<0.05, p<0.01, respectively). No differences were found in systolic
and diastolic BP and heart rate. Conclusion: Our data show impaired dynamic sympatho-
vagal balance in patients with functional dyspepsia at rest and in response to different types
of stressors. The vagal function is reduced at baseline and not influenced by stress, while
the sympathetic response is exaggerated by stress. These findings support the hypothesis of
altered autonomic regulation during stress as a potential mechanism worsening the symptoms
of FD. We suggest that comprehensive evaluation of stress response using noninvasive
analysis of distinct autonomic effectors could help to better understand the role of autonomic
dysregulation in functional gastrointestinal disorders. Support: Slovak Scientific Grant Agency
[VEGA 1/0044/18]; project Biomedical Center Martin [ITMS 26220220187] co-financed
from EU sources.
Su1630
EXPRESSION AND SIGNIFICANCE OF ENTERIC GLIAL AND NERVE
GROWTH FACTOR IN FUNCTIONAL DYSPEPSIA
Shanshan Zhu, Haitao Shi, Bin Qin, Juan Yang, Guolong Lu, Fei Dai
Background: Functional dyspepsia (FD) is a common functional gastrointestinal disorder
which pathogenesis is not completely understood. Enteric glial cell (EGC), the main compo-
nent of enteric nervous system, can maintain the integrity of mucosa and regulate gastrointesti-
nal motility. Glial fibrillary acidic protein (GFAP) is the marker of EGC activation. Nerve
growth factor (NGF) and its high-affinity receptor TrkA play a pivotal role in visceral pain
and hyperalgesia. However, the role of EGC and NGF/TrkA in FD is unclear. Aims: This
study was to investigate the EGC activation and expression of NGF/TrkA in gastric mucosa
of FD patients and the relationship between GFAP, NGF and the symptoms of FD. Methods:
34 patients with FD and 16 healthy controls were enrolled. The patients were divided into
three subtype groups according to the Rome IV standard: the epigastric pain syndrome
(EPS) group (n=11), the postprandial distress syndrome (PDS) (n=10) group and the EPS
overlapping PDS group (n=13). The distribution and expression of NGF, TrkA and GFAP
in gastric mucosa were detected by immune histochemical staining, immunofluorescence
double labeling and western blotting.A correlation analysis was performed to examine the
relationship between NGF, GFAP expression in gastric mucosa and the dyspeptic symptom
scores. Results: (1) The expression of GFAP, NGF and TrkA in gastric mucosa of patients
with FD was significantly higher than that in the control group. The expression of GFAP,
NGF and TrkA in gastric mucosa was significantly higher in the EPS group, the PDS group
and the EPS overlapping PDS group than that in the control group. There was no significant
difference among the subtype groups of FD. (2) GFAP colocalized with TrkA, and the
expression of TrkA in EGC was significantly higher in FD group than that in the control
group. (3) The expression of GFAP and NGF was positively correlated with epigastric pain,
postprandial fullness and early satiation, and had no significant relationship with epigastric
burning. Conclusions: EGC and NGF/TrkA may interact and participate in the pathogenesis
of FD.
Su1631
PROXIMAL GASTRIC EMPTYING ANALYSIS IN PATIENTS WITH
SUSPECTED UPPER GI MOTILITY DISORDER: ADDED VALUE TO
ROUTINE GASTRIC EMPTYING SCINTIGRAPHY
Marvin I. Friedman, Jesus R. Diaz, Karen Vaz, Anna Leykekhman, Kenneth Dominguez,
Hugo Sandoval, Carola Mullins, Irene Sarosiek, Richard W. McCallum
Impaired fundic function affects the intragastric distribution of a meal, and can result in
symptoms. Our aims were to study fundic accommodation, as assessed by analyzing proximal
gastric emptying (PGE) during a scintigraphic gastric emptying (GE) test in patients with a
suspected upper GI motility disorder (UGID), and to simultaneously monitor the symptoms
induced by the test meal. Methods 20 adult patients with suspected UGID, mean age 52.2
years (range 21-80), 65% female, 8 with diabetes mellitus, and none with surgical resection
of the stomach were included. Values for PGE were established from a study in normal
subjects (Gastroenterology 2017; 152(5) S-932). Delayed GE was defined as >10% retention
at 4 hours; rapid GE was defined as < 35% retention at 1 hour. Throughout this 4 hour
study, patients were questioned every 30 minutes about nausea, bloating, fullness, and
abdominal pain, which were graded as absent, minimal, mild, moderate, or severe (0-4)
respectively. Upright anterior/posterior GE scintigraphic data was acquired immediately after
ingestion of a standardized Tc-99m labeled meal (time 0), and at 15, 30, 45, 60, 75, 90,
105, 120, 180, and 240 minutes. PGE was evaluated from computer-generated rectangular
regions of interest applied to anterior images (Fig 1). Proximal time-activity curves were
decay corrected, normalized to their maximum value, and fit to a power exponential function.
Lag times were estimated by linearly interpolating the proximal emptying curve to find times
at which the proximal remaining food decreased to 95 and 90% of maximum value. Mean
residence time was calculated and compared to data in normals. An elliptical region of
interest was placed on the antrum to assess initial radioactivity count. Initial intragastric
distribution of food could be assessed in the proximal region, the antrum and, by subtraction,
the body of the stomach. Results: PGE and overall GE were concordant in 18 of the patients;
specifically, 6 with delayed GE had slow PGE, 3 with rapid GE had accelerated PGE, and
9 had both normal GE and PGE rates (Table 1). In addition 2 patients with normal GE had
discordant patterns for PGE; 1 with rapid PGE and one slow. (Table1) Symptoms in the
rapid PGE patient differed from the other normal GE patients, in having severe bloating,
X : 18982$CH1B
04-12-18 21:20:27 Page 555
PDFd : 18982B : o
S-555 AGA Abstracts
fullness, and abdominal pain. Conclusions: 1) Most patients have consistency between PGE
and overall GE patterns, suggesting integration and concordance of emptying by the proximal
and distal stomach, as evidenced by the observation that proximal and total GE patterns
were observed to change at the same time points; 2) 18 % of normal GE patients had
disparity between PGE and total GE with implications for interpreting their symptoms of
suspected UGID. Identifying PGE patterns in standard GE scintigraphic methodology is
important, and will guide treatment strategies.
Figure 1. Computer generated rectangular proximal regions of interest superimposed on an
anterior image set at successive 15-minute time points. The lowest boundary of each total
stomach region of interest was consistently positioned at the most inferior aspect of the
antrum. After rotating the image set so that the axis of the stomach body is vertical, the
most superior aspect of the rectangular region of interest at each time point was positioned
a fixed distance, measured along the body axis, from the most inferior aspect of the total
stomach region of interest. The height of all of the rectangular proximal regions of interest
was 50% of the longest total stomach region of interest.
Table 1. Percent of proximal gastric emptying (PGE) and total gastric emptying (GE) of
radiolabeled food as a function of time in 20 patients. Note concordance of PGE with total
GE in 18 patients and also note discordance of PGE and total GE in highlighted patients.
Su1632
SPINAL CORD STIMULATION IMPROVES GLUCAGON-INDUCED
IMPAIRMENT IN GASTRIC MOTILITY AND SLOW WAVES VIA VAGAL
MECHANISMS IN DOGS
Bo Zhang, Lei Tu, Feng Ji, YI Yang, Jieyun Yin, Jiande Chen
Abstract: Background: Spinal cord stimulation (SCS) is widely used to treat chronic pain,
but has never been used to treat gastric dysmotility. The current study was designed: 1) to
evaluate the effects of SCS on gastric motility disorders and gastric dysrhythmia induced
by glucagon; 2) to investigate the mechanisms involving autonomic function in dogs. Meth-
ods: Seven male dogs with electrodes chronically placed on the dorsal column of the spinal
cord between T10 and T12 segments were studied in 3 randomized sessions (saline, glucagon,
glucagon + SCS). SCS using a set of optimized stimulation parameters at T10 was performed
for 15min immediately after glucagon injection. Antral contractions were measured by
placing a manometric catheter into the distal stomach via a chronically placed gastric
cannula. Gastric slow wave (GSW) were recorded from a pair of chronically implanted
serosal electrodes in the corpus. Autonomic function was assessed using spectral analysis
of heart rate variability from the ECG that was recorded during the study. Results: 1)
Glucagon (0.1mg/kg) suppressed antral motility index from 6230±436 at baseline to
3132±516 (P<0.001), reduced the percentage of normal GSW from 91±5% at baseline to
39±2% (P<0.01), and vagal activity from 0.70±0.04 at baseline to 0.40±0.07 (P<0.01). 2)
The vagal activity was positively correlated with antral motility index (r=0.558; P<0.01) and
percentage of normal gastric slow wave (r=0.616; P<0.01). 3) SCS substantially improved
glucagon-induced antral hypomotility (motility index: 5309±861 vs 3132±516, P<0.05) and
GSW abnormalities (% of normal waves: 78%±7 vs 39±2%, P<0.01) and vagal activity
(0.67±0.07 vs 0.40±0.07, P<0.05). Conclus ion: SCS dramatically improves glucago n-
induced impairment in gastric motility and slow waves by increasing vagal activity. This
work was supported by NIH Grant 1U18TR001920-01.
Su1633
PATTERNS OF CANNABIS USE AND EFFECTS ON SYMPTOMS IN
PATIENTS WITH CYCLIC VOMITING SYNDROME
Thangam Venkatesan, Lisa Rein, Anjishnu Banerjee, Cecilia Hillard, Krista M. Lisdahl
Background: Cannabis use has increased dramatically with ongoing legalization in the US.
Cannabis has antiemetic properties but chronic cannabis use is associated with Cannabinoid
Hyperemesis Syndrome (CHS). CHS is similar to cyclic vomiting syndrome (CVS) except
for a history of chronic, heavy cannabis use. There is a paucity of data on precise patterns
of cannabis use and effects on symptoms in patients with CVS. Aims and Methods: We
determined patterns of cannabis use in patients diagnosed with CVS using the Cannabis
Use Disorder Identification Test (CUDIT), a validated tool to screen for patients who use
cannabis in harmful ways. Detailed questionnaires to determine effects of cannabis use on
symptoms were also administered. Patients were categorized into two subgroups: non-regular
users (includes non-users and those using cannabis #1 time/month) and heavy users (those
who used cannabis $2 times/month), who could be diagnosed with CHS. The two cannabis
use groups were compared using Fisher's exact tests for categorical variables and Wilcoxon
rank-sum tests for continuous and Likert scale responses. Results: Of the 140 patients with
CVS, 72% were female and 85% were Caucasian. Mean age was 37±13 years and median
duration of disease was 10(3-39) years. Sixty-three percent suffered from anxiety and 48%
from depression. Significant differences between cannabis non-regular users and those with
AGA Abstracts
