Clinical trial NCT03617861
Conditions: Dyspepsia Healthy
Sponsor: Mayo Clinic
Start date: 2018-11-07; Completion date: 2019-08-01
Enrollment: 20 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
Insights into the pathophysiology of functional dyspepsia, with recent demonstration of inflammation with eosinophilia and mastocytosis in the duodenum (3, 6, 7), providing a possible lead toward reduced secretion of a potential mediator of post-prandial gastric accommodation, the gastrointestinal peptide hormone secretin. The dominant site of synthesis and secretion of this hormone are enteroendocrine S cells in the duodenum. Inflammation-induced damage to these cells could produce a deficiency. Since intraluminal acid is a prominent stimulant of S cell secretion, the attempts to treat functional dyspepsia with anti-secretory medications could actually exacerbate a secretin deficiency syndrome. This raises the possibility of the therapeutic use of a secretin agonist or a positive allosteric modulator of the secretin receptor for patients with functional dyspepsia.

Detailed description:
The investigators will utilize single photon emission computed tomography (SPECT) methodology and gamma scintigraphy present in the GI laboratory of the outpatient Clinical Research Unit to study fasting gastric volumes and postprandial gastric accommodation responses and gastric emptying rates of a standardized meal in patients with functional dyspepsia and healthy subjects. Both groups will be studied twice, using crossover design, once with administration of secretin and once with placebo.

Arms: arm 1: Healthy subjects first receive human Secretin 0.2 mcg/kg via IV over 1 min on Visit Day 1. After a 1 to 4 week washout period, they received the placebo treatment (normal saline, matching Secretin dose) via IV over 1 min on Visit Day 2. arm 2: Healthy subjects first receive placebo treatment (normal saline, matching Secretin dose) via IV over 1 min on Visit Day 1. After a 1 to 4 week washout period, they received the human Secretin 0.2 mcg/kg via IV over 1 min on Visit Day 2. arm 3: Functional Dyspepsia subjects first receive human Secretin 0.2 mcg/kg via IV over 1 min on Visit Day 1. After a 1 to 4 week washout period, they received the placebo treatment (normal saline, matching Secretin dose) via IV over 1 min on Visit Day 2. arm 4: Functional Dyspepsia subjects first receive placebo treatment (normal saline, matching Secretin dose) via IV over 1 min on Visit Day 1. After a 1 to 4 week washout period, they received the human Secretin 0.2 mcg/kg via IV over 1 min on Visit Day 2.
Interventions: intervention 1: Human Secretin intervention 2: Placebo
Intervention descriptions: intervention 1: Injected once over one minute intervention 2: Injected once over one minute

Protocol documents:
Prot_SAP_000.pdf: 
 
Effect Of Secretin On Gastric 
Accommodation, Emptying, 
and Post-nutrient Challenge 
Symptoms in Functional 
Dyspepsia and Healthy Subjects 
 
NCT# 03617861 
 
April 19, 2019 


Effect of secretin on gastric accommodation, emptying and post-nutrient challenge 
symptoms in functional dyspepsia and healthy subjects 
 
Version /7, date 4/19/2019  
Co-Principal Investigators:  
Michael Camilleri, MD, Mayo Clinic Rochester 
Laurence J. Miller, MD, Mayo Clinic Arizona 
Co-investigators:  Priya Vijayvargiya MD, Justin Brandler MD, Andres Acosta MD, PhD, Duane 
Burton, MHA, Irene Busciglio BS, William S Harmsen MS,  
 
Hypothesis: Secretin enhances gastric accommodation and reduces post-nutrient challenge 
symptoms without altering gastric emptying in patients with functional dyspepsia with normal 
baseline gastric emptying.  
 
Specific Aims:  
1. To compare the effects of secretin vs. saline on satiation, fasting gastric volume, gastric 
accommodation and emptying, and symptoms in patients with functional dyspepsia with 
normal gastric emptying. 
2. To compare the effects of secretin vs. saline on satiation, fasting gastric volume, gastric 
accommodation and emptying, and symptoms in healthy human volunteers. 
3. To compare effects of secretin on satiation, fasting gastric volume, gastric 
accommodation and emptying, and symptoms in patients with functional dyspepsia with 
normal gastric emptying and in healthy human volunteers  
 
Background 
 
 
Functional dyspepsia (FD) is a very common cause of substantial morbidity, estimated to 
affect ten percent of the population, and manifest as abdominal pain after eating, present at 
least three days per week. It has been estimated that 40 percent of patients with this symptom 
complex consult their physician, with impact on their workplace attendance and productivity, and 
an economic impact in excess of 18 billion dollars in 2009 (1). Current medical treatment 
includes eradication of H pylori, acid suppression, prokinetic drugs, antidepressants, and 
psychological and alternative therapy, yet, despite this, many patients remain refractory to 
treatment, experiencing continued disabling symptoms (2).  
 
Insights into the pathophysiology of this disorder provide clues suggesting possible 
dysfunction of the gastrointestinal hormone, secretin, and the possible therapeutic use of a 
secretin agonist or positive allosteric modulator (PAM) in the management of this syndrome. A 
prominent pathophysiologic feature of FD is defective gastric accommodation, with inadequate 
relaxation of the fundus of the stomach in response to eating responsible for the post-cibal pain. 
A key physiologic regulator of gastric accommodation is secretin. Additionally, the site of 
synthesis and secretion of this hormone is enteroendocrine S cells in the duodenum, a site 
recently described as being involved pathologically with inflammation and eosinophilia in FD (3). 
Secretin is believed to elicit gastric fundic relaxation through its effects on secretin receptors on 
vagal afferent neurons, which go on to release VIP and prostaglandins (4, 5). While these 
events have been well documented in animal models and healthy human subjects, there are no 
published data for the effectiveness of secretin in stimulating gastric accommodation in patients 
with FD.  
 


Secretin and its potential role in functional dyspepsia 
Insights into the pathophysiology of functional dyspepsia, with recent demonstration of 
inflammation with eosinophilia and mastocytosis in the duodenum (3, 6, 7), providing a possible 
lead toward reduced secretion of a potential mediator of post-prandial gastric accommodation, 
the gastrointestinal peptide hormone secretin. The dominant site of synthesis and secretion of 
this hormone are enteroendocrine S cells in the duodenum. Inflammation-induced damage to 
these cells could produce a deficiency. Since intraluminal acid is a prominent stimulant of S cell 
secretion, the attempts to treat functional dyspepsia with anti-secretory medications could 
actually exacerbate a secretin deficiency syndrome. This raises the possibility of the therapeutic 
use of a secretin agonist or a positive allosteric modulator of the secretin receptor for patients 
with functional dyspepsia. 
A prominent pathophysiologic feature of functional dyspepsia is defective gastric 
accommodation, with inadequate relaxation of the fundus of the stomach in response to eating 
responsible for the postcibal pain. This was observed in 47% of 151 patients with functional 
dyspepsia in a Mayo Clinic study performed in the clinical practice of the PI (8). There are 
presently no generally effective medications to restore normal gastric accommodation, and 
there is only limited support, based on single-center studies, for the use of such diverse 
medications as clonidine, sumatriptan, and buspirone, many of which have central or vascular 
side effects, or acotiamide, a cholinesterase inhibitor approved for use in Japan, but not in the 
USA. 
  A key physiologic regulator of gastric accommodation is secretin. Secretin is believed 
to elicit gastric fundic relaxation through its effects on secretin receptors on vagal afferent 
neurons, which go on to release VIP and prostaglandins (4, 5). While these events have been 
well documented in animal models and healthy human subjects, there are no published data for 
the effectiveness of secretin in stimulating gastric accommodation in patients with functional 
dyspepsia. 
We postulate that therapy that increases levels and/or effectiveness of secretin to relax 
the gastric fundus in FD patients will increase gastric accommodation and reduce post-cibal 
abdominal pain and other symptoms. This can theoretically be accomplished with a secretin 
agonist or a PAM increasing the biological response to physiologically-released secretin. 
Therefore, it is important to establish whether secretin can induce gastric accommodation in FD, 
supporting use of exogenous secretin, or, if the secretin response is blunted or absent, 
suggesting that an allosteric modulator might be important to develop for this application.  
Currently, only natural secretin peptide is approved for clinical use, and is a safe and 
effective reagent that can only be administered parenterally for diagnostic purposes. No orally 
active secretin agonist or PAM has yet been reported.  
 
Study Design 
 We will utilize single photon emission computed tomography (SPECT) methodology and 
gamma scintigraphy present in the GI laboratory of the outpatient Clinical Research Unit to 
study fasting gastric volumes and postprandial gastric accommodation responses and gastric 
emptying rates of a standardized meal in patients with functional dyspepsia and healthy 
subjects. Both groups will be studied twice, using crossover design, once with administration of 
secretin and once with placebo. This will provide each subject as his/her own control, as well as 
providing contrast in baseline and responsiveness to this hormone across the groups.  
Rationale for Crossover design and selection of FD patients 
The pathophysiology of functional dyspepsia includes: 


a. Delayed gastric emptying 
b. Accelerated gastric emptying (sometimes associated with impaired gastric 
accommodation) 
c. Reduced postprandial gastric accommodation  
d. Hypersensitivity to  gastric mechanical distension 
e. Hypersensitivity to duodenal nutrients 
f. Duodenal inflammation 
g. Combinations of different mechanisms 
Given the interest in secretin, we shall select patients with FD and prior documentation of 
normal or accelerated gastric emptying and/or reduced gastric accommodation. Given the 
diversity of mechanisms, the most efficient way to appraise the effects of secretin or PAM is 
through a crossover design.     
Eligibility Criteria 
Functional dyspepsia patients (n=15) and healthy subjects (n=15) aged 18-65 years will 
be recruited, and enrolled after providing written informed consent. The goal is to obtain the 
completed crossover results from 10 healthy and 10 Functional dyspepsia patients. Once that 
criterion is satisfied, enrollment will stop. The FD group will be identified from Mayo Clinic 
patients living within a 50 mile radius (Olmsted and Goodhue counties) who have symptoms 
consistent with this diagnosis and who have been studied and found to have normal or 
accelerated gastric emptying. Subjects may be involved in study activity for up to six weeks from 
screening date to completion of all studies. The actual study will be conducted on two separate 
days, each involving 3-4 hours of study. These testing visits should be scheduled one week 
apart, but within 4 weeks. 
Male and female subjects, aged 18 to 65 years at screening, who meet the following 
criteria, will be eligible for enrollment. A detailed history will be obtained with validated 
questionnaires [including Hospital Anxiety and Depression Inventory, Functional Dyspepsia 
Symptom Diary, abridged Bowel Disease questionnaire (for healthy subjects only) and the long 
Bowel Disease (for functional dyspepsia patients only) (Zigmond & Snaith 1983, Patient-
Reported Outcome Consortium’s Functional Dyspepsia Working Group 2018, Talley 1990, 
Talley 1990)].  
Inclusion criteria: 
• 
Able to provide written informed consent prior to any study procedures and be willing 
and able to comply with study procedures 
• 
No medical problems or chronic diseases that could significantly affect GI function, other 
than functional dyspepsia, for that group 
• 
Body mass index of 18-40 kg/m2 


• 
Female subjects must have negative urine pregnancy tests and must not be lactating 
prior to receiving study medication and radiation exposure. For females able to bear 
children, a hormonal (i.e., oral, implantable, or injectable) and single-barrier method, or a 
double-barrier method of birth control must be used throughout the study. Female 
subjects unable to bear children must have this documented in the medical record [i.e., 
tubal ligation, hysterectomy, or post-menopausal (defined as a minimum of one year 
since the last menstrual period)].  
• 
Rapid or normal gastric emptying (GE) measured via scintigraphy in past 5 years for FD 
subjects  
• 
Normal upper endoscopy (EGD) in past 5 years for FD subjects 
Exclusion criteria: 
• 
Significant change in symptoms since previous EGD and/or GE study for FD subjects  
 
• 
Unable or unwilling to provide informed consent or to comply with study procedures 
• 
Structural or metabolic diseases that affect the GI system 
• 
Unable to stop acid reducers such as proton pump inhibitors, H2 blockers 3 days prior to 
study days 
o May permit antacids on as needed basis but must stop 8 hours before study days 
• 
Unable to avoid the following over-the-counter medications 48 hours prior to the baseline 
period and throughout the study: 
o 
Medications that alter GI transit or motor function including laxatives, magnesium 
and aluminum containing antacids, prokinetics, erythromycin, buspirone, 
clonidine, tricyclic antidepressants, and secretin-norepinephrine reuptake 
inhibitors, 
buproprion, 
benzodiazepines 
(, 
,), 
anticholinergics 
(tricyclic 
antidepressants, trazodone, cyclobenzaprine, antihistamines), anti-emetics 
(promethazine, prochloperazine, ondansetron) 
o Analgesic drugs including NSAIDs and COX-2 inhibitors 
o NOTE:  Stable doses of thyroid replacement, estrogen replacement, low-dose 
aspirin for cardio-protection, low stable dose antidepressants of the SSRI class, 
and birth control (but with adequate backup contraception, as drug interactions 
with birth control have not been conducted) are permissible.  
• 
History of recent surgery (within 60 days of screening) 
• 
Acute or chronic illness or history of illness which in the opinion of the investigator could 
pose a threat or harm to the subject or obscure interpretation of laboratory test results or 
interpretation of study data, such as frequent angina, Class III or IV congestive heart 
failure, moderate impairment of renal or hepatic function, poorly controlled diabetes, etc. 


• 
Any clinically significant abnormalities on physical examination or laboratory 
abnormalities identified in the medical record, as determined by the investigator 
• 
Acute GI illness within 48 hours of initiation of the baseline period 
• 
Females who are pregnant or breastfeeding 
• 
History of excessive alcohol use or substance abuse 
• 
Participation in an investigational study within the 30 days prior to dosing in the present 
study 
• 
Any other reason, which in the opinion of the investigator, would confound proper 
interpretation of the study 
Preliminary Data  
We have conducted a search of Mayo Clinic database for patients with functional dyspepsia and 
identified 34 potential candidates for the study:  
Pharmacokinetics and Dosing of Secretin 
Synthetic natural human secretin 
Pharmacokinetics and Dosing of Secretin: The standard dose of secretin used in exocrine 
pancreatic function testing is 0.2 mcg/kg IV over 1 min. This is also the dose used most 
commonly for radiographic procedures. This peptide has a half-life of approximately 2-4 min, yet 
has been observed to elicit agonist responses at the exocrine pancreas for a much longer 
period of time (minutes to hours afterward).  
Dosing: We will administer the secretin at 0.2 mcg/kg IV over 1 min, immediately before 
initiating the Ensure administration. The placebo will be similar infusion of normal saline. 
Participants will receive the i.v. secretin dose on 1 occasion and the i.v. placebo on 1 occasion. 
IND: Use of the medication will be as a proof of concept with pharmacodynamics measurements 
rather than with intention of developing secretin as a therapeutic. However, the medication is 
being provided by ChiRhoClin, Inc. who has requested a new IND from the FDA: the study will 
be conducted under the new IND number 141437.   
Supply: Human Secretin for injection (16 mcg/10 ml vial) will be provided (60 vials) by 
ChiRhoClin, Inc, Burtonsville, MD and will be stored in and dispensed by Mayo Clinic Pharmacy. 
Secretin is available as a lyophilized sterile powder in 10-mL vials containing 16mcg of human 
secretin. The pharmacist will reconstitute with 8mL of saline for injection to yield a final 
concentration of 2mcg of human secretin/mL.    
 
Randomization  
The randomization schedule will be generated before the start of the study in the Mayo 
Clinic Section of Biomedical Statistics and Informatics, and will be given to the research 
pharmacist. Medications will be stored in a monitored, climate-controlled environment according 
to manufacturer’s directions. Monitoring records will be available for review to ensure quality 
control.  
 
Experimental Procedures  
Design: We propose to measure fasting gastric volumes, and postprandial gastric 
accommodation responses and gastric emptying rates of a standardized meal in functional 


dyspepsia patients and healthy subjects during two testing periods. Participants in each group 
will be randomly assigned to receive secretin or placebo at the first sitting and the opposite for 
the second sitting.  We will also measure acute food intake (meal size) in each participant, as 
the total volume ingested until they reach satiation, and postprandial symptoms. The plasma 
levels of several neuropeptides and hormones will be measured during fasting and 
postprandially to provide an initial understanding of the mechanism of action of secretin on 
gastric volume, accommodation and satiation indices.  
Gastric Accommodation Measurements; Fasting and postprandial gastric volume 
(GV) by single photon emission computed tomography (SPECT [9]) developed and validated 
(including performance characteristics) 
in our lab.  Using the ratio of 
postprandial volume over the fasting 
volume 
is 
a 
measure 
of 
the 
postprandial gastric accommodation. 
Radiation exposure listed in Appendix. 
Gastric Emptying 
To assess gastric emptying during the 
satiation test (10), the first 300 mL of 
Ensure® will be radiolabeled with 50 
μCi of 111In-DTPA and 2-minute duration anterior and posterior scans of the abdomen will be 
obtained right after the Ensure is ingested and  then 15 minutes (which will be after the end of 
SPECT imaging) at 5 minute intervals and then through 30 minutes from first 300mL of 
Ensure®. Radiation exposure listed in Appendix. 
 
Plasma Measurements Blood draws (18 cc each) will be taken during fasting (in two 
occasions) and postprandially (at 15, 45 and 90 minutes after starting ingestion of Ensure) 
during the gastric function measurements. We will measure plasma levels of GIP, pancreatic 
polypeptide, and glucagon-like peptide-1 (GLP-1). A blood sample for possible future DNA 
testing will be collected also. 
GLP-1 will be measured as the biologically active GLP-1 (active and total) using a 2-site, non-
competitive immunoassay based on enzyme-labeled quantification of GLP-1 detected by a 
fluorogenic substrate. Total GIP will be measured using a two-site sandwich immunoassay 
using a total GIP ELISA kit (Millipore Corp, Billerica, MA, USA); the antibody used specifically 
recognizes human GIP (1-42) and GIP (3-42), but not other forms of oxyntomodulin, GLP-1, or 
GLP-2.  Pancreatic polypeptide will be measured (at Mayo ICL) on the same plasma samples 
using radioimmunoassay technique. 
 
Satiation (11) by Ensure® nutrient drink test with ingestion (1kcal/mL, 11% fat, 73% 
carbohydrate, and 16% protein) at a constant rate of 30ml/min to measure volume to fullness 
(VTF), and MTV. This will start 30 minutes after the initial 300 mL of Ensure was ingested. 
Briefly, participants record their time from their first intake to when they reach 5 levels of 
fullness. These levels of fullness are from 1) first sensation; 2) mild satiety; 3) moderate satiety; 
4) severe satiety and 5) maximum satiety.  Nutrient intake is stopped when subjects reach the 
maximum satiety. Time and total volume consumed to maximum satiety is calculated and the 
time and total volume is also calculated to moderate satiety Postprandial symptoms of fullness, 
nausea, bloating, and pain are measured 30 minutes after the meal using 100mm horizontal 
visual analog scales, with the words “none” and “worst ever” anchored at each end.  Before 
starting any gastric testing, we will assess the volunteer’s current symptoms using the 
Functional Dyspepsia Symptom Diary and then again along with the postprandial symptoms 
questionnaire 30 minutes after the meal. Questionnaires used are in Appendix. 


Study Schedule 
 
Measurement/Outcomes 
Participants will undergo the following tests on two separate occasions, each lasting 3-4 hours: 
• Single photon emission computed tomography (SPECT) to calculate fasting 
gastric volume and postprandial gastric accommodation  
• Gastric emptying (by scintigraphy) of Ensure after 30 minutes 
• Measurement of volume to fullness (mL), maximum tolerated volume (MTV), 
postprandial symptoms on satiation (nutrient drink) test  
Pharmacodynamic Endpoints 
Comparison of the effects of secretin vs. placebo (saline) on the following 
gastrointestinal functions in FD patients and healthy subjects:  
• Difference in fasting gastric volume 
• Difference in gastric volume after the 300 mL Ensure meal for secretin vs. 
placebo 
• Difference in gastric emptying of radiolabeled Ensure after 30 minutes 
• Volume to fullness (sensation of usual postprandial fullness) and maximum 
tolerated volume (MTV). 
• Difference in postprandial symptoms 30 minutes after ingesting maximum 
tolerated volume of Ensure 
Sample Size Determination 
 Sample size assessment for primary aim to examine the within dyspepsia patient 
response when receiving Secretin versus Placebo.  Sample size is based on the results of 
primary endpoints in the Mayo Clinic lab [data show mean ± SD). Within 10 dyspepsia patients, 
assuming a two-sided paired T test (80% power, α=0.05) in this crossover trial demonstrable 
differences for secretin compared to placebo is 21% in fasting gastric volume, 13.0% in 


postprandial gastric volume and 16.6% in amount of gastric retention of Ensure at 30 
minutes based on the coefficients of variation observed from the Mayo Clinic laboratory of Dr. 
M. Camilleri in prior studies as shown in the table below.   
Response 
Mean 
SD 
Effect 
size 
detectable 
(absolute [% of mean],  n=10 
Based on cross-over design  
Fasting gastric volume, mL 
Post prandial gastric volume, mL 
273 
848 
57 
111 
56.8mL (20.8%) 
110.6mL (13.0%) 
Gastric 
emptying 
expressed 
as 
retention of Ensure at 30 mins, (%)  
72 
12 
11.95 (16.6%) 
Volume to fullness, mL 
755 
330 
328.5mL (43.5%) 
Maximum tolerated volume, mL 
1283 
400 
398.5mL (31.1%) 
Peak postprandial GLP-1, pmol/L 
18.8 
14 
13.94pmol/L (74.1%) 
Therefore the study is powered to detect clinically relevant effects of the study medication.  
A similar analysis will be conducted in the healthy human volunteers based on the cross-over 
design, and the anticipated effect sizes that would be demonstrable in this second group is 
similar to that summarized above for patients with functional dyspepsia. 
A subsidiary (secondary) analysis will compare the response using secretin in FD and healthy 
volunteers.  This will be a 2 sample, unpaired analysis of the observations on secretin 
treatment, with ten patients in each cohort. 
The table below shows the effects sizes demonstrable for the comparison between FD and 
health, using a 2-group analysis (unpaired analysis), again a two-sided test at α=0.05, with 80% 
power. 
Response 
Mean 
SD 
Effect 
size 
detectable 
(absolute [% of mean],  n=10 
Based on 2-group comparison  
Fasting gastric volume, mL 
Post prandial gastric volume, mL 
273 
848 
57 
111 
75.5mL (27.7%) 
147.0mL (17.3%) 
Gastric 
emptying 
expressed 
as 
retention of Ensure at 30 mins, (%)  
72 
12 
15.9 (22.1%) 
Volume to fullness, mL 
755 
330 
437mL (57.9%) 
Maximum tolerated volume, mL 
1283 
400 
530mL (41.3%) 


Peak postprandial GLP-1, pmol/L 
18.8 
14 
18.55pmol/L (98.8%) 
 
Statistical Methods  
It is anticipated that all primary and secondary endpoints will be normally distributed. We 
will use parametric tests to assess study parameters.    If the data are not normally distributed 
we will use non-parametric tests.    
For the primary aim, comparison of responses in the 10 completed dyspepsia patients 
for secretin versus placebo, as well as the subsidiary, analogous study conducted in healthy 
volunteers, the analysis will be a paired test, either a paired t test or signed rank test.   
For the secondary aim, comparison of 10-15 dyspepsia patients with 10-15 healthy 
controls for responses after receiving secretin, the analysis will be either a two-sample t test or a 
rank sum test.  
Covariate analysis may be conducted using a regression model, including gender and 
BMI as covariates, since these may significantly affect gastric functions such as satiation 
maximum tolerated volume, and smoking and gender since this may significantly affect drug 
levels of secretin.  It is unclear if these covariate analyses will be required given the small 
sample sizes (n=10 in each group)   
Safety Considerations 
Informed consent 
A complete description of the study will be presented to each potential study participant and 
signed and dated informed consent will be obtained before any study specific procedures are 
performed. 
Demographics and medical history 
A medical history and review of body systems along with demographic data will be obtained for 
all patients during the screening period (Days -30 to -1). Data that will be recorded in the source 
document/CRF include gender, race, date of birth, cigarette smoking history, alcohol use, drug 
abuse history and concomitant medication use. 
Physical examination 
A physical examination will be performed during the screening period to confirm eligibility. 
Concomitant medication review 
A review of concomitant medications will be conducted during the screening period and at every 
study visit. Any medications taken by study patients or changes in dose regimens will be 
recorded on a Concomitant Medication CRF. 
Vital signs and weight 


Vital signs will be obtained in the sitting position. Body temperature (°C), respiration rate 
(breaths/minute) and weight will be recorded at each time point when vital signs are measured. 
Height (cm) will be measured at the screening visit. 
Pregnancy testing 
Urine pregnancy testing will be done for women of childbearing potential at screening. Urine 
pregnancy testing will be done on day 1 prior to randomization to study drug and placebo and at 
the final study visit or earlier if the patient is discontinued. 
A woman of childbearing potential is defined as any female who has experienced menarche and 
who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation or 
bilateral oophorectomy) or is not postmenopausal [defined as amenorrhea >12 consecutive 
months; or women with documented plasma follicle-stimulating hormone level >35lU/mL].  
Women who are using oral, implanted or injectable contraceptive hormones, an intrauterine 
device, barrier methods (diaphragm, condoms, spermicidal) to prevent pregnancy, practicing 
abstinence or where partner is sterile (e.g., vasectomy) will be considered to be of childbearing 
potential. 
Adverse Events: 
Adverse Event Grading will be in accordance with the severity grading scheme of the National 
Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), Version 5.  
Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated.  
Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age appropriate 
instrumental ADL.  
Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self care ADL.  
Grade 4 Life-threatening consequences; urgent intervention indicated.  
Grade 5 Death related to AE. 
 
Study Stopping Rules: 
Individual: 
1. Acute hypersensitivity reactions (CTCAE Grade 3, 4, or 5) 
2. Severe abdominal pain, hypotension, diarrhea or vomiting requiring hospitalization 
(CTCAE Grade 3, 4, or 5) 
 
General: 
1. Development in 3 or more participants of severe abdominal pain requiring hospitalization 
(CTCAE Grade 3, 4, or 5) 
2. Development in 3 or more participants of hypotension requiring i.v. hydration or 
hospitalization (CTCAE Grade 3, 4, or 5) 
3. Development in 3 or more participants of diarrhea requiring i.v. hydration or 
hospitalization (CTCAE Grade 3, 4, or 5) 


4. Development in 3 or more participants of vomiting requiring i.v. hydration or 
hospitalization (CTCAE Grade 3, 4, or 5) 
 
Safety Monitoring Duration 
As the half-life of i.v. secretin is approximately 2-4 minutes, the drug should be eliminated from 
the bloodstream within 16-20 minutes.  Thus planned study duration of 3 to 4 hours past 
secretin infusion is an adequate timeframe for adverse event monitoring prior to discharge 
home.  They will remain monitored in the Clinical Research Trials Unit (CRTU) for the entirety of 
their two individual study visit days.   
References 
1. Lacy BE, Weiser KT, Kennedy AT, Crowell MD, Talley NJ.  Functional dyspepsia: the 
economic impact to patients. Aliment Pharmacol Ther 2013;38:170-7 
2. Talley NJ and Ford AC, Functional Dyspepsia New Eng J Med 2015;373:1853-63 
3. Walker MM, Aggarwal KR, Shim LS, Bassan M, Kalantar JS, Weltman MD, Jones M, 
Powell N, Talley NJ. Duodenal eosinophilia and early satiety in functional dyspepsia: 
confirmation of a positive association in an Australian cohort. J Gastroenterol Hepatol 
2014;29:474-9 
4. Lu Y and Owyang C, Duodenal acid-induced gastric relaxation is mediated by multiple 
pathways. Am J Physiol 1999;39:G1501-6;  
5. Lu Y and Owyang C, Secretin-induced gastric relaxation is mediated by vasoactive 
intestinal 
polypeptide 
and 
prostaglandin 
pathways. 
Neurogastroenterol 
Motil 
2009;21:754-60 
6. Talley NJ, Walker MM, Aro P, Ronkainen J, Storskrubb T, Hindley LA, Harmsen WS, 
Zinsmeister AR, Agréus L. Non-ulcer dyspepsia and duodenal eosinophilia: an adult 
endoscopic population-based case-control study. Clin Gastroenterol Hepatol 
2007;5:1175-83  
7. Walker MM, Talley NJ, Prabhakar M, Pennaneac'h CJ, Aro P, Ronkainen J, Storskrubb 
T, Harmsen WS, Zinsmeister AR, Agreus L. Duodenal mastocytosis, eosinophilia and 
intraepithelial lymphocytosis as possible disease markers in the irritable bowel syndrome 
and functional dyspepsia. Aliment Pharmacol Ther. 2009;29:765-73 
8. Bredenoord AJ, Chial HJ, Camilleri M, et al. Gastric accommodation and emptying in 
evaluation of patients with upper gastrointestinal symptoms. Clin Gastroenterol Hepatol 
2003;1:264-272 
9. Breen M, Camilleri M, Burton D, Zinsmeister AR.  Performance characteristics of the 
measurement of gastric volume using single photon emission computed tomography.  
Neurogastroenterol Motil 23:308-315, 2011]), 
10. Delgado-Aros S, Camilleri M, Castillo EJ, Cremonini F, Stephens D, Ferber I, Baxter K, 
Burton D, Zinsmeister AR:  Effect of gastric volume or emptying on meal-related 
symptoms after liquid nutrients in obesity: a pharmacological study.  Clin Gastroenterol 
Hepatol 3:997-1006, 2005 
11. Chial HJ, Camilleri C, Delgado-Aros S, Burton D, Thomforde G, Ferber I, Camilleri M:  A 
nutrient drink test to assess maximum tolerated volume and postprandial symptoms:  


effects of gender, body mass index and age in health.  Neurogastroenterol Mot 14:249-
253, 2002 
 
Appendix 


Satiation test: Levels of Fullness Questionnaire
   
Satiation test: VAS Symptom Scales   


 
Gastric Accommodation and Gastric Emptying tests: Radiation Exposure 
 


SPECT (upper table) and Gastric Emptying (lower table) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
Questionnaire: Hospital anxiety and depression questionnaire (Zigmond & Snaith 
1983) 
Subject Initials: _______ 
Screen Number: _______ 


Please read each item and circle the reply which best describes how you have been feeling 
during the past week.  Don’t devote too much time to your responses; your immediate reaction 
will probably be more accurate than a long thought out response. 
1. I feel tense or ‘wound up’ : 
 
Most of the time 
A lot of the time 
Occasionally 
Not at all 
 
2. I still enjoy the things I used to enjoy : 
 
Definitely as much 
Not quite so much 
Only a little  
Hardly at all 
 
3. I get a frightened feeling, as if something awful is about to happen : 
 
Very definitely and quite badly 
Yes, but not too badly 
A little, but it doesn’t worry me 
Not at all 
 
4. I can laugh and see the funny side of things : 
 
As much as I always could 
Not quite so much now 
Definitely not so much now 
Not at all 
 
5. Worrying thoughts go through my mind : 
 
A great deal of the time 
A lot of the time 
From time to time 
Only occasionally 
 
6. I feel cheerful : 
 
Not at all 
Not often 
Sometimes 
Most of the time 
 
7. I can sit at ease and feel relaxed : 
 
Definitely 
Usually 
Not often 
Not at all 
8. I feel as if I am slowed down : 
 
Nearly all the time 
Very often 


Sometimes 
Not at all 
 
9. I get a frightened feeling, like ‘butterflies in the stomach’ : 
 
Not at all  
Occasionally 
Quite often 
Very often 
 
10.  I have lost interest in my appearance : 
 
Definitely 
I don’t take as much care as I should 
I may not take quite as much care 
I take just as much care as ever 
 
11. I feel restless as if I have to be on the move : 
 
Very much indeed 
Quite a lot 
Not very much 
Not at all 
 
12. I look forward with enjoyment to things : 
 
As much as I ever did 
Rather less than I used to 
Definitely less than I used to 
Hardly at all 
 
13. I get sudden feelings of panic : 
 
Very often indeed 
Quite often 
Not very often 
Not at all 
 
14. I can enjoy a good book or TV program : 
 
Often 
Sometimes 
Not often 
Very seldom 
 
 
 
Sign___________________________________ Date _______________ 
 
Questionnaire: Functional Dyspepsia Symptom Diary (Patient-Reported Outcome 
Consortium’s Functional Dyspepsia Working Group 2018) 


 
 
 
 
Functional Dyspepsia Symptom Diary (Am J Gastroenterol. 2018; 113: 39–48) 
FDSD Item 
0=No; 10=Worst imaginable  
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
1. Stomach pain. 
 
 
 
 
 
 
 
 
 
 
 
2. Burning in the stomach. 
 
 
 
 
 
 
 
 
 
 
 
3. Nausea 
 
 
 
 
 
 
 
 
 
 
 
4. Bloating 
 
 
 
 
 
 
 
 
 
 
 
5. Stomach fullness 
 
 
 
 
 
 
 
 
 
 
 
6. Early satiety 
 
 
 
 
 
 
 
 
 
 
 
7. Burping/belching rating 
 
 
 
 
 
 
 
 
 
 
 
8. Burping/belching bother 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Questionnaire: Abridged bowel disease questionnaire (Talley, 1990) (healthy 
subjects only): 
Subject Initials: _______ 
Screen Number: _______ 


Subjects Initials _____  
Screen Number _____ 
In the past 12 months, have you experienced the following? 
 
 
 
 
 
 
QUESTION 
YES 
NO 
1. 2 or less than 2 bowel movements/week 
 
 
2. Excessive straining or sensation of incomplete evacuation of stool on 
more than 25% of occasions 
 
 
3. Lumpy stools on more than 25% of occasions 
 
 
At least 3 months of continuous or recurrent symptoms of: 
 
4. Abdominal pain or discomfort relieved by defecation 
 
5. Abdominal pain or discomfort associated with a change in stool frequency 
 
6. Abdominal pain or discomfort associated with a change in stool consistency 
 
 
 
 
 
 
7. More than 3 bowel movements per day 
 
 
8. Loose watery stools 
 
 
9. Bloating 
 
 
10. Swallowing difficulties 
 
 
11. Upper abdominal pain after meals more than once a month 
 
 
12. Abdominal bloating after meals 
 
 
13. Nausea regularly more than once a month 
 
 
14. Vomiting regularly more than once a month 
 
 
15. Heartburn regularly more than once a week 
 
 
16. Acid reflux regularly more than once a week 
 
 
 
 
 
Sign____________________________________ Date _________________ 
 


Questionnaire: Long bowel disease questionnaire (Talley 1990) (functional dyspepsia 
patients only) 
 
 
 
 
 
 
 
 
 
A QUESTIONNAIRE OF  
GASTROINTESTINAL SYMPTOMS 
 
 
 
Please answer ALL questions.  If you are uncertain, please write down your best 
guess.  It is easy to miss questions, so please check that you haven't left any out 
as you go.  If you wish to comment on any questions or qualify your answers, use 
the space in the margins; these comments will be read and taken into account. 
 
 
 
All information provided will be kept confidential. 
 
 
Thank you for your help. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subject Initials: _______ 
Screen Number: _______ 


 
First we w o ul d li ke t o as k y o u s o me q uesti o ns a b o ut T R O U B L E S W A L L O WI N G           
( a feeli n g t h at f o o d stic ks i n y o ur t hr o at or c hest) i n t he l ast ye ar. 
 
    1.  
   H a ve y o u h a d diffic ult y s w all o wi n g i n t he l ast ye ar?   ( C hec k o ne) 
1  N o  →   
Ple ase g o t o q uesti o n 9 o n P A G E 2.  
 
2  Yes → 
Ple ase a ns wer t he f oll o wi n g q uesti o ns.  
  
   
  
  
 
↓ 
2.  
W he n i n y o ur life  di d t his tr o u ble s w all o wi n g FI R S T be gi n, as cl ose as y o u c a n rec all ?   
( C hec k o ne) 
 
1  I n t he last 6 m o nt hs  
 
2  7 m o nt hs t o 1 year a g o  
 
3  M ore t ha n 1 year t o 2 years a g o  
 
4  M ore t ha n 2 years t o 5 years a g o  
 
5  M ore t ha n 5 years t o 1 0 years a g o  
 
6  M ore t ha n 1 0 years t o 2 0 years a g o  
 
7  M ore t ha n 2 0 years a g o  
 
3.  
H o w m a n y ti mes  h a ve y o u h a d t his tr o u ble s w all o wi n g i n t he l ast ye ar ?  ( C hec k o ne) 
 
1  Less t ha n o nce a m o nt h  
 
2  A b o ut o nce a m o nt h  
 
3  A b o ut o nce a wee k  
 
4  Se veral ti mes a wee k  
 
5  Dail y  
 
4.  
H o w b a d  is y o ur tr o u ble s w all o wi n g us u all y ?  ( C hec k o ne) 
 
 
1  MI L D - ca n be i g n ore d if I d o n't t hi n k a b o ut it  
 
2  M O D E R A T E - ca n n ot  be i g n ore d, b ut d oes n ot  affect m y life-st yle 
 
3  S E V E R E - affects m y life-st yle 
 
4  V E R Y S E V E R E - mar ke dl y  affects m y life-st yle 
 
5.  
D oes it h urt (is it p ai nf ul) w he n y o u s w all o w ?  ( C hec k o ne) 
 
 
1  N o  
 
2  Yes  
 
 
 
 
 
 
Ple ase c hec k t h at all q uesti o ns t h at a p pl y t o y o u h a ve bee n a ns were d.  


 
6. 
What do you have trouble swallowing?  (Check one) 
 
1  Both solid foods and liquids 
 
2  Solid foods only 
 
3  Liquids only 
 
7. 
Has your trouble swallowing gotten progressively worse in the last year?  (Check one) 
 
1  Yes, rapidly worse 
 
2  Yes, slowly worse 
 
3  No, has not gotten worse 
 
8. 
Does your trouble swallowing come and go so that there are times when you have no trouble 
no matter what you eat?  (Check one) 
 
1  No 
 
2  Yes 
 
Next, we would like to ask you some questions about heartburn in the last year. 
 
9. 
Have you had a burning pain or discomfort behind the breast bone in your chest in the last 
year?  (Please do NOT count pain in your stomach or pain from heart trouble.)  (Check one) 
1  No  →   
Please go to question 16 on PAGE 3. 
 
2  Yes → 
Please answer the following questions. 
  
  
 
 
 
↓ 
In this survey the term "heartburn" will be used to mean a burning pain or discomfort behind 
the breast bone in your chest.  When answering these questions, please do not count any other 
sensations as "heartburn". 
 
10. 
When in your life did this heartburn FIRST begin, as close as you can recall?  (Check one) 
         1  In the last 6 months 
 
2  7 months to 1 year ago 
 
3  More than 1 year to 2 years ago 
 
4  More than 2 years to 5 years ago 
 
5  More than 5 years to 10 years ago 
 
6  More than 10 years to 20 years ago 
 
7  More than 20 years ago 
 
 
 
 
 
 
Please check that all questions that apply to you have been answered. 
 


 
11. How many times have you had heartburn in the last year?  (Check one) 
 
1  Less than once a month 
 
2  About once a month 
 
3  About once a week 
 
4  Several times a week 
 
5  Daily 
 
12. 
How bad is your heartburn usually?  (Check one) 
 
1  MILD - can be ignored if I don't think about it 
 
2  MODERATE - cannot be ignored, but does not affect my life-style 
 
3  SEVERE - affects my life-style 
 
4  VERY SEVERE - markedly affects my life-style 
 
13. 
Has your heartburn awakened you at night in the last year?  (Check one) 
 
1  No  
 
2  Yes   
 
NOTE:  When we say "often" we mean more than 25% of the time in the last year. 
 
14. 
Does your heartburn often travel up toward your neck?  (Check one) 
 
1  No 
 
2  Yes 
 
15. 
Is your heartburn often made better (eased) by taking antacids (like Amphojel, 
AlternaGEL, Gaviscon, Maalox, Mylanta, Riopan, Rolaids or Tums)?  (Check one) 
 
1  No 
 
2  Yes   
 
3  I have not taken antacids for heartburn 
 
We would now like to ask you about other complaints you have had in the last year. 
 
 
16. 
  How many times have you had a feeling of WANTING TO THROW UP (nausea) in the last 
year? (Check one) 
 
 
          1  None 
 
          2  Less than once a month  
 
          3  About once a month 
 
          4  About once a week   
 
          5  Several times a week 
                  6  Daily 
 
 
 
Please check that all questions that apply to you have been answered. 
 
 


17.  How many times have you ACTUALLY THROWN UP (vomited) in the last year?  (Check one) 
 
1  None 
 
2  Less than once a month 
 
3  About once a month 
 
4  About once a week 
 
5  Several times a week 
 
6  Daily  
 
18. Have you thrown up (vomited) bright red blood in the last year?  (Check one) 
 
1  No 
 
2  Yes 
 
19. Has your food come back up into your mouth or throat in the last year?  (Please do not include 
vomiting) (Check one) 
 
1  No 
 
2  Yes 
 
NOTE:  When we say "often" we mean more than 25% of the time in the last year. 
 
20. Have you often been troubled by burping (belching) up gas through the mouth in the last year?  
(Check one) 
 
1  No  
 
2  Yes 
 
21. Have you often been troubled by hiccups in the last year?  (Check one) 
 
1  No 
 
2  Yes 
 
22. Have you lost weight in the last year without deliberately dieting?  (Check one)  
 
1  No 
 
2  Less than 7 lbs.  
 
3  7 lbs. or more 
 
 
23. Is your appetite in the last year compared with before:  (Check one) 
 
1  Decreased?  
 
2  About the same? 
 
3  Increased?  
 
 
 
 
 
 
Please check that all questions that apply to you have been answered. 
 
 


24.  Have you often lost your appetite and felt full soon after starting to eat so that you could not finish a 
normal meal in the last year?  (Check one) 
 
     1  No 
 
     2  Yes 
 
Next, we would like to ask you some questions about stomach, belly or tummy pain in the last 
year. 
 
25. Have you had an ache or pain in your stomach or belly (gut) in the last year?  (Please do NOT count 
cramps or pain with menstrual periods, heartburn, or chest pain.) (Check one) 
1  No  →   
Please go to question 45 on PAGE 8. 
 
2  Yes → 
Please answer the following questions. 
  
  
 
 
 
↓ 
 
Stomach or belly pain can be difficult to describe and sometimes more than one type of pain 
can occur.  Please think about the usual or primary type of pain you have.  We would like to 
ask you some questions only about the USUAL or PRIMARY pain in your stomach or belly. 
 
26. 
Have you had this same ache or pain more than SIX times in the last year?  (Check one)  
 
1  No 
 
2  Yes 
 
27. 
How bad is the ache or pain usually?   (Check one) 
 
1  MILD - can be ignored if I don't think about it 
 
2  MODERATE - cannot be ignored, but does not affect my life-style 
 
3  SEVERE - affects my life-style 
 
4  VERY SEVERE - markedly affects my life-style 
 
28. 
Does the usual ache or pain EVER WAKE YOU FROM SLEEP AT NIGHT? (Check 
one) 
 
1  No 
 
2  Yes 
 
29. 
Does this pain come and go periodically?  (Periodically here means periods of at least a 
month with no pain, with periods in between of weeks to months when there is pain.) (Check 
one) 
 
1  No 
 
2  Yes 
 
 
 
Please check that all questions that apply to you have been answered. 


30.   How many times did you get this pain in the last year? (Check one) 
          1  Less than once a month 
 
2  About once a month 
 
3  About once a week 
 
4  Several times a week 
 
5  Daily 
 
31. 
When this pain occurs, how long does it usually last? (Check one) 
 
1  Less than 30 minutes 
 
2  30 minutes to 2 hours  
 
3  More than 2 hours to 6 hours 
 
4  More than 6 hours 
 
32. 
When in your life did this ache or pain FIRST begin as close as you can recall? (Check 
one)  
 
1  In the last 6 months 
 
2  7 months to 1 year ago 
 
3  More than 1 year to 2 years ago 
 
4  More than 2 years to 5 years ago 
 
5  More than 5 years to 10 years ago 
 
6  More than 10 years to 20 years ago 
 
7  More than 20 years ago 
 
33. 
Does this ache or pain often occur BEFORE meals or when hungry?  (Check one) 
 
1  No 
 
   2  Yes 
 
NOTE:  When we say "often" we mean more than 25% of the time in the last year. 
 
34. 
Does this ache or pain often occur IMMEDIATELY AFTER (less than 30 minutes) 
meals? (Check one) 
 
1  No 
 
2  Yes 
 
35. 
Does this ache or pain often occur 30 minutes to 2 hours AFTER meals?  (Check one) 
 
1  No 
 
2  Yes 
 
36. 
Is this pain often made BETTER (relieved) by burping (bringing up air through the 
mouth)?  (Check one) 
 
1  No 
 
2  Yes 
 
 
Please check that all questions that apply to you have been answered. 


            37.Is this pain often made BETTER by having a bowel movement?  (Check one) 
 
1  No 
 
2  Yes 
 
38. 
Is this pain often made BETTER by eating? (Check one) 
 
1  No 
 
2  Yes 
 
39. 
Is this pain often made BETTER by taking antacids (like Tums, Riopan, Mylanta, 
Maalox, Gaviscon or Rolaids)?  (Check one) 
 
1  No 
 
2  Yes 
 
3  I don't take antacids 
 
40. 
Is this pain often made WORSE by food or milk?  (Check one) 
 
1  No 
 
2  Yes 
 
41. 
Do you often have MORE bowel movements when this pain begins?  (Check one) 
 
1  No 
 
2  Yes 
 
42. 
Do you often have LOOSER bowel movements (stools) when this pain begins?  (Check 
one) 
 
1  No 
 
2  Yes 
  
43. 
Do you often feel bloated and actually see your belly swell up?  (Check one) 
 
1  No 
 
2  Yes 
 
44. 
Have you seen MUCUS in your stools in the last year (that is, white or green slimy 
material)? (Check one) 
 
1  No 
 
2  Yes 
 
 
 
 
 
 
 
 
 
Please check that all questions that apply to you have been answered. 
 


An important purpose of this study is to learn about bowel habits in the community 
in the last year. 
 
45. In the last year, how regular were your bowel movements?  (Check one) 
 
 
1  Often had constipation (more than 25% of the time) 
 
2  Sometimes had constipation (less than 25% of the time) 
 
3  Alternating diarrhea and constipation 
 
4  Sometimes diarrhea (less than 25% of the time) 
 
5  Often had diarrhea (more than 25% of the time) 
 
6  Usually normal 
 
46. What is the longest number of days you have ever gone without having a bowel movement in the 
last year?  (Check one) 
 
 
1  2 days or less 
 
2  More than 2 to 4 days 
 
3  More than 4 days to 1 week 
 
4  More than 1 to 2 weeks 
 
5  More than 2 weeks 
 
47. How many bowel movements do you usually have in a WEEK? (Check one) 
 
 
1  1 or less 
 
2  2 
 
3  3-4 
 
4  5-8 
 
5  9-12 
 
6  13-16 
 
7  17-21 
 
8  22-26 
 
9  More than 26 
 
48. In the last year, did you need to take anything to help you have a bowel movement (such as 
laxative, enema, or suppository, but not including fiber products)?  (Check one) 
 
 
1  No 
 
2  Yes, sometimes (less than 25% of the time) 
 
3  Yes, often (more than 25% of the time) 
 
4  Yes, usually (more than 75% of the time) 
 
 
If yes, what did you take?  _______________________________________________________ 
 
 
Please check that all questions that apply to you have been answered. 


 
49.    In the last year, have you needed to strain a lot (for more than 1 to 2 minutes) to have a bowel 
movement?  (Check one) 
 
1  No 
 
2  Yes, sometimes (less than 25% of the time) 
 
3  Yes, often (more than 25% of the time) 
 
4  Yes, usually (more than 75% of the time) 
 
50. How severe was your straining with bowel movements in the last year?  (Check one) 
 
1  I never strain with bowel movements 
 
2  Very mild 
 
3  Mild 
 
4  Moderate 
 
5  Severe 
 
6  Very severe 
 
51. In the last year, have your stools been loose or watery?  (Check one) 
 
1  Never 
 
2  Sometimes (less than 25% of the time) 
 
3  Often (more than 25% of the time) 
 
4  Usually (more than 75% of the time) 
 
52. In the last year, have your stools been hard?  (Check one) 
 
1  Never 
 
2  Sometimes (less than 25% of the time) 
 
3  Often (more than 25% of the time) 
 
4  Usually (more than 75% of the time) 
 
53. In the last year, after finishing a bowel movement, have you felt there was still stool that needs to 
be passed?  (Check one) 
 
1  No 
 
2  Yes 
 
54. In the last year, have you experienced an urgent need to open your bowels that made you rush to 
the toilet?  (Check one) 
 
1  Never 
 
2  Sometimes (less than 25% of the time) 
 
3  Often (more than 25% of the time) 
 
4  Usually (more than 75% of the time) 
 
55. Have you noticed ANY BLOOD in your stools or in the toilet bowl in the last year? (Check one) 
 
1  No 
 
2  Yes 
 
Please check that all questions that apply to you have been answered. 
 


 
56.    In the last year, did you ever press your finger in or around the anus (back passage) to help a 
bowel movement come out?  (Check one) 
 
1  No  
2  Yes 
 
  
57. How much time did you usually need to spend each time on the toilet to move your bowels during 
the last year?  (Check one) 
 
 
1  Less than 5 minutes 
 
2  5 to 10 minutes 
 
3  More than 10 minutes up to 30 minutes 
 
4  More than 30 minutes up to 1 hour 
 
5  More than 1 hour 
 
58. In the last year, did you have to position yourself other than in the sitting position to help a bowel 
movement come out?  (Check one) 
 
 
1  Never 
 
2  Sometimes (less than 25% of the time) 
 
3  Often (more than 25% of the time) 
 
4  Usually (more than 75% of the time) 
 
 
If yes, which position usually? ________________________________________________ 
 
59. In the last year, did you feel there was a blockage in your rectum or anus (back passage) which 
made it difficult for you to pass the stool?  (Check one) 
 
 
1  Never 
 
2  Sometimes (less than 25% of the time) 
 
3  Often (more than 25% of the time) 
 
4  Usually (more than 75% of the time) 
 
 
 
 
 
 
 
 
 
 
 
Please check that all questions that apply to you have been answered. 
 


 
60.   Have you had problems with leakage of stool (accidents or soiling because of the inability 
to   control the passage of stool until you reached a toilet)?  (Check one)  
 
 No  →   
Please go to question 70 on PAGE 13. 
 
 Yes → 
Please answer the following questions. 
  
  
 
 
 
↓ 
 
 
61. 
In the last year, did you have to take medication (like antidiarrheals, Lomotil, Imodium 
AD, etc.) to prevent leakage of stool?  (Check one) 
 
1  No 
 
2  Yes, sometimes (less than 25% of the time) 
 
3  Yes, often (more than 25% of the time) 
 
4  Yes, usually (more than 75% of the time) 
 
 
If yes, what did you take?________________________________________________ 
 
62. 
When in your life did this problem with leakage of stool first begin, as close as you can 
recall?  (Check one) 
 
1  In the last 6 months 
 
2  7 months to 1 year ago 
 
3  More than 1 year to 2 years ago 
 
4  More than 2 years to 5 years ago 
 
5  More than 5 years to 10 years ago 
 
6  More than 10 years to 20 years ago 
 
7  More than 20 years ago 
 
63. 
In the last year, did you ever wear a pad to protect your underclothes from soilage or 
leakage of stool?  (Check one) 
 
1  Never 
 
2  Sometimes (less than 25% of the time) 
 
3  Often (more than 25% of the time) 
 
4  Usually (more than 75% of the time) 
 
64. 
In the last year, when was the leakage of stool most frequent?  (Check one) 
 
 
1  While awake 
 
2  While asleep 
 
3  There was no difference in leakage while asleep or awake 
 
 
Please check that all questions that apply to you have been answered. 


 
65.    When leakage of stool has occurred in the last year, did you have problems with leakage 
of  liquid or runny stool?  (Check one) 
 
 
1  Never 
 
2  Sometimes (less than 25% of the time that leakage occurred) 
 
3  Often (more than 25% of the time that leakage occurred) 
 
4  Usually (more than 75% of the time that leakage occurred) 
 
66. 
When leakage of stool has occurred in the last year, did you have problems with leakage 
of solid, or formed stool?  (Check one) 
 
 
1  Never 
 
2  Sometimes (less than 25% of the time that leakage occurred) 
 
3  Often (more than 25% of the time that leakage occurred) 
 
4  Usually (more than 75% of the time that leakage occurred) 
 
67. 
When these "accidents" with leakage of stool occurred in the last year, how much stool 
typically leaked out?  (Check one) 
 
 
1  A small amount, with a stain about the size of a quarter 
 
2  Moderate amounts (often requiring a change of pad or underwear) 
 
3  Large bowel movements of liquid stool (often requiring a complete change of clothes) 
 
4  Solid or formed stool 
 
68. 
In the last year, have you been able to tell when this leakage of stool was about to occur?  
(Check one) 
 
 
1  Never 
 
2  Sometimes (less than 25% of the time) 
 
3  Often (more than 25% of the time) 
 
4  Usually (more than 75% of the time) 
 
69. 
In the last year, have you had difficulty telling the difference between the need to pass 
gas and the need to pass stool?  (Check one) 
 
 
1  Never 
 
2  Sometimes (less than 25% of the time) 
 
3  Often (more than 25% of the time) 
 
4  Usually (more than 75% of the time) 
 
 
 
 
Please check that all questions that apply to you have been answered. 


Questions 70 - 74 are for women, if you are a man, please go to Question 75 on page 14. 
 
70. In the last year, did you ever press your finger in or around the vagina (front passage) to help a 
bowel movement come out?  (Check one) 
 
 
1  No 
 
2  Yes 
 
71. Have you ever given birth to a child?  (Check one) 
 
 
1  No 
 
2  Yes 
 
 
If YES, how many children? __________________________________ 
 
 
 
number by vaginal delivery?  ___________________________ 
 
 
 
number by Cesarean section?   __________________________ 
 
 
 
number for which forceps were used?  ___________________ 
 
72. Have you had any injuries to your anus (back passage) during childbirth which required surgical 
repair?  (Check one) 
 
 
1  No 
 
2  Yes 
 
3  I have never given birth 
 
 
If YES, what repair was done?  _______________________________________ 
 
73. Have you ever had a protrusion of the rectum through the opening of the vagina (called a 
rectocele)?  (Check one) 
  
 
1  No 
 
2  Yes 
 
 
If YES, when? ___________________________________________________ 
 
74. Have you ever had a protrusion of the rectum through the anus (called a rectal prolapse)?  
(Check one) 
  
 
1  No 
 
2  Yes 
 
 
If YES, when? ___________________________________________________ 
 
 
 
Please check that all questions that apply to you have been answered. 


75.   In the last year, have you had slow leakage, or dribbling, or urine throughout the day?  (Check 
one) 
 
 
1  Never 
 
2  Sometimes (less than 25% of the time) 
 
3  Often (more than 25% of the time) 
 
4  Usually (more than 75% of the time) 
 
76. In the last year, have you worn a pad to protect your underclothes from leakage of urine?  (Check 
one) 
 
 
1  Never 
 
2  Sometimes (less than 25% of the time) 
 
3  Often (more than 25% of the time) 
 
4  Usually (more than 75% of the time) 
 
77. In the last year, have you had leakage of urine when you coughed or sneezed?  (Check one) 
 
 
1  Never 
 
2  Sometimes (less than 25% of the time) 
 
3  Often (more than 25% of the time) 
 
4  Usually (more than 75% of the time) 
 
 
78. In the last year, when leakage of urine has occurred, were you aware of the need to urinate before 
the leakage occurred?  (Check one) 
 
 
1  I have no leakage of urine throughout the day 
 
2  Never 
 
3  Sometimes (less than 25% of the time) 
 
4  Often (more than 25% of the time) 
 
5  Usually (more than 75% of the time) 
 
Please answer the following questions regarding other urinary symptoms. 
 
79. During the last month or so, how often have you had a sensation of not emptying your bladder 
completely after you finished urinating?  (Check one) 
 
 
1  Not at all 
 
2  Less than 1 time in 5 
 
3  Less than half the time 
 
4  About half the time 
 
5  More than half the time 
 
6  Almost always 
 
Please check that all questions that apply to you have been answered. 


80.   During the last month or so, how often have you had to push or strain to begin urination?  
(Check one) 
 
 
1  Not at all 
 
2  Less than 1 time in 5 
 
3  Less than half the time 
 
4  About half the time 
 
5  More than half the time 
 
6  Almost always 
 
81. During the last month, how many times did you most typically get up to urinate from the time 
you went to bed at night until the time you got up in the morning?  (Check one) 
 
 
1  Not at all 
 
2  Less than 1 time in 5 
 
3  Less than half the time 
 
4  About half the time 
 
5  More than half the time 
 
6  Almost always 
 
To help interpret the results of this survey, we would like to ask some questions about your 
activities, habits and work.  Please be assured that all information will be kept strictly 
confidential. 
 
82. Please indicate the IMPORTANCE of each of these ACTIVITIES to you by writing down a 
number from 1 to 5.  
1) Not at all important 
2) Minimally important 
3) Moderately important 
4) Very important 
5) Extremely important 
 
Sports/Recreation  
_______ 
Work around the house  
_______ 
Social/Entertainment 
_______ 
Family relationships 
_______ 
Travel 
 
 
_______ 
Sexual life  
 
_______ 
Work (occupational) 
_______ 
Are you retired? 
____ Yes ____ No 
 
 
 
Please check that all questions that apply to you have been answered. 


83.   Next, please indicate whether ANY problems with your BOWEL FUNCTION have affected each 
of these same activities in the LAST YEAR.  (Do NOT include problems related to TEMPORARY 
illnesses, flu, etc.)  (Write down a number from 1 to 5 on each line.) 
1) I have had no problem with bowel function 
2) I have bowel problems, but am not affected 
3) Mildly affected 
4) Moderately affected 
5) Severely affected 
 
Sports/Recreation  
_______ 
Work around the house  
_______ 
Social/Entertainment 
_______ 
Family relationships 
_______ 
Travel 
 
 
_______ 
Sexual life  
 
_______ 
Work (occupational) 
_______ 
 
 
 
84. Next, please indicate whether problems with LEAKAGE OF STOOL have affected each of these 
same activities in the LAST YEAR.  (Write down a number from 1 to 5 on each line.) 
1) I have had no problem with leakage of stool 
2) Not affected 
3) Mildly affected 
4) Moderately affected 
5) Severely affected 
 
Sports/Recreation  
_______ 
Work around the house  
_______ 
Social/Entertainment 
_______ 
Family relationships 
_______ 
Travel 
 
 
_______ 
Sexual life  
 
_______ 
Work (occupational) 
_______ 
 
 
 
 
 
 
 
 
 
 
Please check that all questions that apply to you have been answered. 
 


 
85.         Did you ever smoke cigarettes regularly (at least 1 cigarette per day for at least 30 days)?  
(Check one) 
 
1  No 
 
2  Yes 
 
       ↓ 
At what age did you start?  __________________years 
When smoking the heaviest, how many packs did you  
Smoke per day?  _________________ 
How many packs per day do you currently smoke?  _______________ 
If you stopped smoking, at what age did you stop?  ________________ 
 
Next, there is a question about drinks that contain alcohol (that is, beer, wine, or other 
liquors like whiskey, vodka, gin, or brandy).  One drink is equal to a can of beer, a glass of 
wine, or shot of spirits. 
 
86. 
How many drinks a WEEK have you had on average in the last year?  (Check one) 
 
1  None 
 
2  1 to 2 drinks a week 
 
3  3 to 6 drinks a week 
 
4  7 to 10 drinks a week 
 
5   More than 10 drinks a week 
 
87. 
Do you drink coffee?  (Check one) 
 
1  No 
 
2  Yes 
 
       ↓ 
Decaffeinated or regular usually? ________________ 
How many cups per day usually?  ________________ 
Does drinking coffee bring on or worsen your heartburn? 
1  No    2  Yes 
 
 
 
 
 
 
 
 
 
 
 
 
Please check that all questions that apply to you have been answered. 


 
 
88. 
Current marital status:  (Check one) 
 
1  Married 
 
2  Single 
 
3  Widowed 
 
4  Divorced 
 
5  Separated 
 
6  Other 
 
89. 
Are you presently:  (Check one) 
 
 
1  Employed 
 
2  Unemployed 
 
3  Retired 
 
4  Full-time homemaker 
 
5  Full-time student 
 
6  Disabled 
 
90.         Please indicate your educational training. (Check one) 
 
1  Professional training beyond college 
 
2  College graduate (4 years) 
 
3  Some college 
 
4  High school graduate 
 
5  10-11 years of school, include some high school 
 
6  7-9 years of school, grade school graduate 
 
7  Under 7 years of grade school 
 
91.       Indicate your  racial background (optional): 
 
1  Caucasian 
 
2  Hispanic 
 
3  African American 
 
4  Native American 
 
5  Asian/Pacific Islander 
 
6  Other _______________________________________ 
 
7  Unknown 
 
 
 
 
 
 
 
 
 
Please check that all questions that apply to you have been answered. 


 
Next, we would like to ask you questions about your general health. 
 
92. 
Do the muscles in your arms or legs feel as though their strength has decreased?  
(Check one) 
 
1  No 
 
2  Yes 
93. 
Do you get muscle craps or "Charley horse" in your arms or legs, particularly during 
exercise?  (Check one) 
 
1  No 
 
2  Yes 
94. 
Do you have any numbness, heat sensation, or prickly feeling in any part of your 
body?  (Check one) 
 
1  No 
 
2  Yes 
95. 
Do you faint on changing your position?  (Check one) 
 
1  No 
 
2  Yes 
 
96. 
Do you have blurring of vision with prolonged reading?  (Check one) 
 
1  No 
 
2  Yes 
 
97. 
Do you have episodes of overheating because you sweat insufficiently?  (Check one) 
 
1  No 
 
2  Yes 
 
98. 
Do you sweat on your face after eating cheese or red wine?  (Check one) 
 
1  No 
 
2  Yes 
 
99.      Do you feel your heart racing or pounding with force?  (Check one) 
 
1  No 
 
2  Yes 
 
100. 
Do you have chest pain that is brought on during exercise?  (Check one) 
 
1  No 
 
2  Yes 
 
101. 
Do your legs swell and does your finger leave an imprint if you press on your ankle or 
foot?  (Check one) 
 
1  No 
 
2  Yes 
 
Please check that all questions that apply to you have been answered. 


102.  Do you have cloudy or blood-stained urine?  (Check one) 
 
1  No 
 
2  Yes 
 
103. 
Have you needed laser treatment of your eyes?  (Check one) 
 
1  No 
 
2  Yes 
 
104. 
Have you needed treatment for cataract?  (Check one) 
 
1  No 
 
2  Yes 
 
 
It is important for us to know about the medications that you are taking. 
 
105. 
Are you taking any of the following medications? (Please check those you are taking) 
 
 1  Aspirin, Ibuprofen, Advil, Motrin, Voltaren, Naprosyn 
 
 2  Antacids 
 
 3  Zantac, Axid, Pepcid, Tagamet 
 
 4  Prilosec, Prevacid 
 
 5  Propulsid 
 
 6  Laxatives 
 
 7  Imodium 
 
 8  Lomotil 
 
 9  Cardizem, Isoptin, Verapamil, Adalat, Procardia 
 
10  Clonidine, Catapres 
 
11  Insulin 
 
106.       Please list below any other medication that you are taking: 
 
 
 1. ______________________________________________________________ 
 
 2. ______________________________________________________________  
 
 3. ______________________________________________________________ 
 
 4. ______________________________________________________________ 
 
 5. ______________________________________________________________ 
 
 6. ______________________________________________________________ 
 
 7. ______________________________________________________________ 
 
 8. ______________________________________________________________ 
 
 9. ______________________________________________________________ 
 
10. ______________________________________________________________ 
 
 
 
 
 
Please check that all questions that apply to you have been answered. 


Another important purpose of this study is to learn about your previous health and visits 
to the doctor. 
 
107. 
How many times have you visited a doctor or a physician for any reason in the last 
year?  (Check one) 
 
1  None 
 
2  1 to 2 times in the last year 
 
3  3 to 5 times in the last year 
 
4  6 to 10 times in the last year 
 
5  More than 10 times in the last year 
 
 
If you have visited a doctor, why did you go?___________________________________ 
 
108. 
How many times have you been hospitalized for any reason in the last year?  (Check 
one) 
 
1  None 
 
2  1 to 2 times in the last year 
 
3  3 to 5 times in the last year 
 
4  6 to 10 times in the last year 
 
5  More than 10 times in the last year 
 
If you were hospitalized, what were the reasons?___________________________________ 
 
109. 
How many times in the last year have you visited your doctor or physician for 
problems with your bowels?  (Check one) 
 
 
1  None 
 
2  1 to 2 times 
 
3  3 to 5 times 
 
4  6 to 10 times 
 
5  More than 10 times 
 
110.      How many times in the last year have you visited your doctor or physician for 
problems with leakage of stool?  (Check one) 
 
1  None 
 
2  1 to 2 times 
 
3  3 to 5 times 
 
4  6 to 10 times 
 
5  More than 10 times 
 
 
 
 
 
Please check that all questions that apply to you have been answered. 


Is there anything else you would like to tell us about your health problems?  If so, please use 
this space for that purpose. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Also, any comments that may help us understand these problems better will be appreciated, 
either here or in a separate letter. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Finally, please complete the following symptoms checklist. 
 
IMPORTANT: 
For each of the complaints or problems below, please indicate how 
often it occurred and how bothersome it was in the last year. 
 
 
 
Write down a number from 0 to 4 for all 16 questions below in both columns. 
 
 
 
HOW OFTEN? 
 
 
HOW BOTHERSOME? 
 
 
0  Not a problem 
 
 
0  Not a problem 
 
 
1  Occurs about once a month  
1  Slightly bothersome when occurs 
 
 
2  Occurs about once a week  
2  Moderately bothersome when occurs 
 
 
3  Occurs several times a week 
3  Severely bothersome when occurs 
 
 
4  Occurs daily 
 
4  Extremely bothersome when occurs 
 
 
 
 
 
 
 
HOW OFTEN? 
HOW BOTHERSOME? 
 
 
 
 
 
 
  (0-4):  
     (0-4): 
  
 1. 
Headaches 
 
 
 
__________ 
 
   __________ 
 2. 
Backaches 
 
 
 
__________ 
 
   __________ 
 3. 
Asthma (wheezing) 
 
 
__________ 
 
   __________ 
 4.  
Trouble breathing 
 
 
__________ 
 
   __________ 
 5. 
Insomnia (difficult sleeping)  
__________ 
 
   __________ 
 6. 
Fatigue (tiredness) 
 
 
__________ 
 
   __________ 
 7. 
Depression (feeling sad or blue) 
__________ 
 
   __________  
 8. 
General stiffness 
 
 
__________ 
 
   __________ 
 9. 
Heart palpitations (pounding or 
__________ 
 
   __________ 
 
racing) 
10. 
Joint pains 
 
 
 
__________ 
 
   __________ 
11. 
Eye pain associated with reading 
__________ 
 
   __________ 
12. 
Dizziness 
 
 
 
__________ 
 
   __________ 
13.  
Weakness 
 
 
 
__________ 
 
   __________ 
14.   
Nervousness or shakiness 
 
__________ 
 
   __________ 
15.  
Hot or cold spells 
 
 
__________ 
 
   __________ 
16.  
High blood pressure 
 
 
__________ 
  
   __________ 
 
Please check that you have answered all 16 questions--every question should have a number 
from 0 to 4 in the "How Often?" and in the "How Bothersome?" columns.