Clinical Trial Details
— Status: Not yet recruiting
Administrative data
| NCT number |
NCT03183310 |
| Other study ID # |
S60403 |
| Secondary ID |
|
| Status |
Not yet recruiting |
| Phase |
N/A
|
| First received |
May 31, 2017 |
| Last updated |
June 7, 2017 |
| Start date |
July 1, 2017 |
| Est. completion date |
October 31, 2017 |
Study information
| Verified date |
May 2017 |
| Source |
Universitaire Ziekenhuizen Leuven |
| Contact |
Jan Tack, MD, PhD |
| Phone |
003216377474 |
| Email |
jan.tack[@]kuleuven.be |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
The effect of chlorpromazine (Largactil) on esophageal sensitivity will be investigated in
this study. Overnight fasted subjects will be asked to fill out 2 questionnaires to assess
the emotional status before their onset of the stimulation tests. The multimodal stimulation
probe will be positioned through the mouth in the distal esophagus.
After the ingestion of the stimulation probe, 10mg of chlorpromazine or placebo (saline)
will be slowly administered via intravenous injection. Hereafter the multimodal stimulation
tests will be initiated.
Esophageal sensitivity will be assessed by performing thermal, mechanical, electrical and
chemical stimulation of the esophagus. The chlorpromazine condition will be compared with a
placebo condition, this will be organised on 2 separate study visits in a randomised order.
Description:
INTRODUCTION Gastro-esophageal reflux disease (GERD), defined as the presence of symptoms or
lesions that can be attributed to the reflux of gastric contents into the esophagus, is an
increasingly prevalent condition in Western societies. The most typical symptoms are
heartburn and regurgitation, however GERD can also manifest itself through a variety of
esophageal and extra-esophageal symptoms (e.g. chronic cough).
In humans, pain is a multimodal experience composted of sensory, physiological and
psychological aspects. In order to mimic the clinical situation, experimental models should
be based on multimodal testing regimens in which different receptors and central nervous
system mechanisms are activated.
Advances in esophageal sensory stimulation have established that both typical and atypical
symptoms may not only arise from acid reflux, but also from reflux events with less acidic
pH (pH 4-7). Literature review shows that in GERD patients with persisting symptoms in spite
of PPI therapy, ongoing weakly acidic reflux can be considered as an important underlying
factor. The basis for symptom generation during weakly-acidic reflux events remains to be
determined, but acid sensitivity in the pH range 4-7, mechanical distention (enhanced by air
in the refluxate), sensitivity to other chemical factors (e.g. bile salts) and esophageal
hypersensitivity to physiological levels of reflux have all been proposed.
Kahrilas et al. described psychogenic factors as an alternative explanation for
PPI-refractory symptoms: hyperalgesia, allodynia, hypervigilance, and increased anxiety.
Anxiety and depression were found to increase GERD-related symptoms in a population-based
study. Patients with a poor reflux-symptom correlation reportedly exhibit a high level of
anxiety compared with patients exhibiting good reflux-symptom correlation. In addition, it
has been shown that increased levels of anxiety were associated with more severe
retrosternal pain and retrosternal burning in GERD patients along with increased levels of
anxiety and depression.
The study of the interaction between psychological state and gastrointestinal function is
complex. It is known that anxiety is one of the factors affecting visceral sensitivity in
humans. The investigators speculate that visceral hypersensitivity plays an important role
in symptom perception in refractory GERD. This is suggested by the reflux parameters that
are usual within the physiological range during PPI therapy. The investigators previously
demonstrated that refractory GERD patients have increased visceral sensitivity for thermal,
chemical and mechanical esophageal stimulation compared to healthy subjects.
TRIAL OBJECTIVES Dopamine is an important modulator of gastrointestinal function and is
known to play a role in anxiety. Certain dopamine antagonists have gained interest in the
clinical setting because of their effect on motility of the upper gastrointestinal tract.
Dopamine inhibits lower esophageal sphincter (LES) pressure and gastroduodenal motility.
Expression of dopamine receptors in human LES has been shown by Liu et al. Certain dopamine
antagonists e.g. metoclopramide and domperidone, elicit an increase in LES pressure and
stimulate gastroduodenal motility and gastric emptying. It has been consequently proven to
be of value in certain cases of gastroparesis, and in relieving nausea and vomiting.
Dopamine antagonists also appear to be useful in the management of reflux oesophagitis.
Chlorpromazine, a dopamine receptor antagonist, has been used in the clinical practice as
one of the first anti-psychotic drugs since 1952 and is used to treat various disorders such
as schizophrenia and autism in adults and children, short term treatment of anxiety, severe
hiccups, nausea, vomiting, severe pain.
Therefore, the aim of this study is to investigate the effect of chlorpromazine
(Largactil®), on esophageal sensitivity in a group of healthy volunteers.
TRIAL DESIGN This is a randomized, double-blind, placebo-controlled study to investigate the
effect of chlorpromazine (Largactil®) on esophageal sensitivity. Due to the potent sedative
effect of chlorpromazine, the recommended administration dose is an intravenous bolus
injection of 10 mg for healthy subjects.
Chlorpromazine is rapidly absorbed and widely distributed in the body. Plasma half-life is
approximately 30 hours and the elimination of metabolites may be prolonged. It is
metabolized in the liver and excreted in the urine and bile. Whilst plasma concentration of
chlorpromazine itself rapidly declines, excretion of chlorpromazine metabolites is very
slow. Therefore, 10 mg chlorpromazine (Largactil®, Sanofi Aventis France) for i.v. infusion
will be taken from Largactil® 25 mg/5ml ampoules for i.v. infusion (Largactil®, Sanofi
Aventis France). Each ampoule of 25 mg/5ml will be used for only one volunteer.
Two sessions will be scheduled for every subject: one placebo and one chlorpromazine
session, with at least one week interval. During placebo sessions, 3ml NaCl 0.9% will be
administered i.v. with an identical syringe as the one used for i.v. chlorpromazine
administration. Sessions will run in a double-blind randomized-controlled way. The order of
placebo and chlorpromazine administration will be randomized by an online randomization tool
(http://www.randomization.com/). The randomization scheme will be carried out by an
experienced independent researcher or study nurse, this person will prepare and inject
chlorpromazine or placebo. In this way, the investigator performing the actual study and
data analysis will be blinded until termination of the study.
TRIAL PROCEDURES After an overnight fast subjects are expected at the endoscopy unit of the
UZ Gasthuisberg, where the study will be performed. At the beginning of each session the
volunteer will be asked to fill out 2 questionnaires (PANAS and STAI-state) to assess the
emotional status before the onset of the stimulation tests.
The multimodal stimulation probe will be positioned through the mouth in the distal
esophagus. After the probe is positioned in the esophagus (top of the balloon 10 cm above
the LES), it will be fixed to the chin and the volunteer will remain in a bed, in
semi-recumbent position for the entire study period. Fifteen minutes after the ingestion of
the multimodal esophageal stimulation probe, 10mg of chlorpromazine (Largactil®) or placebo
(saline) will be slowly administered via intravenous injection. After de administration of
chlorpromazine or placebo (saline) the multimodal stimulation tests will be initiated.
Studies will be performed using a multimodal esophageal stimulation probe which allows
thermal, mechanical, electrical and chemical stimulations of the esophagus. This technique
is performed routinely since 2010p.
During each stimulation, subjects will be instructed to record perception of stimuli using
pain scoring scale. This allows the subject to scale perception and pain on a scale from 0
to 10. First perception, pain perception threshold (PPT) and pain tolerance threshold (PTT)
will be recorded. All types of esophageal stimulations will be immediately terminated when
the pain tolerance threshold is reached. At the time when the pain tolerance threshold is
reached (PTT), the subjects will be asked to draw the referred pain area, to identify where
the pain is located.
Thermal stimulation will be performed by re-circulating a saline solution (NaCl 0.09%),
heated by a water bath, through the polyurethane balloon mounted on the probe. Stimulation
temperature will be steadily increased by increasing the flow rate from the water bath to
the balloon. Flow rate will be controlled by a computer operated pump. The volume in the
balloon will be kept constant at 5mL to avoid mechanical stimulation of the esophagus. A
temperature sensor present in the balloon will continuously monitor the stimulation
temperature, which will be displayed on a computer display throughout the study. Maximum
stimulation temperature is set at 62°C. Thermal stimulation will be terminated when the
subject reaches PTT.
Mechanical stimulation will be performed by distention of the balloon mounted on the probe.
The flow of saline (NaCl 0.09%) into the balloon, inducing the distention, is regulated by a
computer controlled pump (ramp distention). The volume in the balloon is displayed on the
computer screen throughout the stimulation. Mechanical stimulations will be performed with
water of 37°C, to avoid thermal stimulation of the esophagus.
Mechanical stimulation will be preceded by a preconditioning period during which the balloon
will be distended until the pain perception threshold (PPT) is reached. This preconditioning
period is used to precondition the esophageal tissue and to allow the subject to get used to
the feeling of mechanical distention. The stimulation will be terminated when subject
reached PTT or when the maximal inflation volume of 50mL is reached.
Electrical stimulation will be performed by 2 stimulation electrodes mounted on proximal to
the balloon. Electrical block pulses will be given using a standard electrical stimulator.
Single burst pulses will be given with duration of 1ms at 200Hz. The amplitude of the pulses
will steadily increase, with steps of 0.5mA and an interval of 15 seconds. For safety, the
maximum intensity is limited to 40 mA. ECG monitoring will be performed as a safety measure
during the electrical stimulations of the esophagus. Electrical stimulation will be
terminated when the subject reached PPT.
Chemical stimulation will be performed in distal esophagus by infusing an acidic solution
(HCl 0.1N) in the esophagus. This is an adaptation of the Bernstein test, used in routine
clinical practice since the early sixties. Infusion rate is controlled by a peristaltic
infusion pump with a flow rate of 2ml/min. The stimulation will last for a maximum of 30
minutes or will be terminated when subjects reach pain tolerance threshold (PTT).
During both session, blood pressure will be monitored and an assessment of general mood will
be performed by the Positive and Negative Affect Schedule (PAS and NAS, also PANAS) and the
State-Trait Anxiety Inventory (STAI state) questionnaires before and after the stimulation
tests. The PANAS consists of a number of words that describe different feelings and emotions
at the present moment. The STAI state is validated, and widely used questionnaire measuring
transitory anxiety states. The scale consists of 20 items, which are answered on a 4-point
scale. Scores are expressed as total sum scores.
Each subject that is willing to participate in this study will be submitted to an
electrocardiogram (ECG) since alteration of the heart rhythm (prolongation of QT interval),
is a possible side effect. Medical history will be taken and the use of medication will be
inquired. During both study visits blood pressure will be measured at baseline and after
administration of chlorpromazine or saline.
