Dyspepsia, Healthy
Conditions
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.
Interventions
DRUGHuman Secretin
Injected once over one minute
DRUGPlacebo
Injected once over one minute
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Mayo Clinic
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Masking description
Blinded
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
Patients with FD and prior documentation of normal or accelerated gastric emptying and/or reduced gastric accommodation. 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, other than functional dyspepsia, for that group * Body mass index of 18-35 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 \[i.e., tubal ligation, hysterectomy, or post-menopausal (defined as a minimum of one year since the last menstrual period)\].
Exclusion criteria
* Unable or unwilling to provide informed consent or to comply with study procedures * Diagnosis of other gastrointestinal diseases besides functional dyspepsia * Structural or metabolic diseases that affect the GI system * Unable to avoid the following over-the-counter medications 48 hours prior to the baseline period and throughout the study: * 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 * Analgesic drugs including NSAIDs and COX-2 inhibitors * 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Satiation | 60 minutes | Thirty (30) minutes after ingesting the meal of 300 mL radio-labeled Ensure drink, an additional Ensure drink was ingested at a constant rate of 30 mL/min until maximum tolerated volume was reached. |
| Fasting Gastric Volume | Baseline | Gastric fasting volume was measured prior to a meal of 300 mL standardized radio-labeled Ensure drink using an intravenous injection of Technetium Tc-99m pertechnetate and noninvasive single photon emission-computed tomography (SPECT). |
| Postprandial Volume | 15 minutes | Postprandial volume was measured 15 minutes after ingestion of 300 mL standardized radio-labeled Ensure drink using an intravenous injection of Technetium Tc-99m pertechnetate and noninvasive single photon emission-computed tomography (SPECT). |
| Change in Gastric Accommodation | Baseline, 30 minutes | The change in gastric accommodation was measured in mL using the difference between the fasting gastric volume and the postprandial volume. |
| Gastric Emptying | 30 minutes | Gastric emptying was measured via scintigraphy 30 minutes after ingestion of 300 mL of radio-labeled Ensure drink and was reported as the percentage of the radio-labeled liquid meal emptied from the stomach. |
| Change in Postprandial Symptoms | Baseline, 30 minutes | 30 minutes after ingesting a meal of 300 mL of Ensure drink postprandial symptoms of fullness, nausea, bloating and pain were measured using a horizontal visual analog scales from 0 to 100, where 0 was 'none' and 100 was 'worst ever'. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Healthy Controls Healthy controls were randomly assigned to secretin or placebo allocation before treatment. After a 1 to 4 week washout period, they received the alternate treatment from that administered on Day 1. | 10 |
| Functional Dyspepsia Functional Dyspepsia subjects were randomly assigned to secretin or placebo allocation before treatment. After a 1 to 4 week washout period, they received the alternate treatment from that administered on Day 1. | 10 |
| Total | 20 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Second Intervention (1 Day) | Adverse Event | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Healthy Controls | Total | Functional Dyspepsia |
|---|---|---|---|
| Age, Continuous | 45.0 years | 47.0 years | 50.5 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) White | 10 Participants | 18 Participants | 8 Participants |
| Region of Enrollment United States | 10 participants | 20 participants | 10 participants |
| Sex: Female, Male Female | 8 Participants | 15 Participants | 7 Participants |
| Sex: Female, Male Male | 2 Participants | 5 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 10 | 0 / 10 | 0 / 10 |
| other Total, other adverse events | 0 / 10 | 1 / 10 | 10 / 10 | 10 / 10 |
| serious Total, serious adverse events | 0 / 10 | 0 / 10 | 0 / 10 | 0 / 10 |
Outcome results
Primary
Change in Gastric Accommodation
The change in gastric accommodation was measured in mL using the difference between the fasting gastric volume and the postprandial volume.
Time frame: Baseline, 30 minutes
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Healthy Controls: Secretin | Change in Gastric Accommodation | 270.44 mL |
| Healthy Controls: Placebo | Change in Gastric Accommodation | 271.01 mL |
| Functional Dyspepsia: Secretin | Change in Gastric Accommodation | 378.6 mL |
| Functional Dyspepsia: Placebo | Change in Gastric Accommodation | 370.2 mL |
Comparison: Healthy Controls Secretin vs Healthy Controls Placebop-value: 0.92Wilcoxon (Mann-Whitney)
Comparison: Functional Dyspepsia Secretin vs Functional Dyspepsia Placebop-value: 1Wilcoxon (Mann-Whitney)
Comparison: Healthy Controls vs Functional Dyspepsiap-value: 0.3891ANCOVA
Primary
Change in Postprandial Symptoms
30 minutes after ingesting a meal of 300 mL of Ensure drink postprandial symptoms of fullness, nausea, bloating and pain were measured using a horizontal visual analog scales from 0 to 100, where 0 was 'none' and 100 was 'worst ever'.
Time frame: Baseline, 30 minutes
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Healthy Controls: Secretin | Change in Postprandial Symptoms | Nausea | 1.5 score on a scale |
| Healthy Controls: Secretin | Change in Postprandial Symptoms | Fullness | 7 score on a scale |
| Healthy Controls: Secretin | Change in Postprandial Symptoms | Bloating | 1.5 score on a scale |
| Healthy Controls: Secretin | Change in Postprandial Symptoms | Abdominal pain | 1 score on a scale |
| Healthy Controls: Placebo | Change in Postprandial Symptoms | Fullness | 4.5 score on a scale |
| Healthy Controls: Placebo | Change in Postprandial Symptoms | Bloating | 1.5 score on a scale |
| Healthy Controls: Placebo | Change in Postprandial Symptoms | Abdominal pain | 2 score on a scale |
| Healthy Controls: Placebo | Change in Postprandial Symptoms | Nausea | 1.5 score on a scale |
| Functional Dyspepsia: Secretin | Change in Postprandial Symptoms | Bloating | 24 score on a scale |
| Functional Dyspepsia: Secretin | Change in Postprandial Symptoms | Fullness | 31 score on a scale |
| Functional Dyspepsia: Secretin | Change in Postprandial Symptoms | Abdominal pain | 5 score on a scale |
| Functional Dyspepsia: Secretin | Change in Postprandial Symptoms | Nausea | 10 score on a scale |
| Functional Dyspepsia: Placebo | Change in Postprandial Symptoms | Abdominal pain | 10 score on a scale |
| Functional Dyspepsia: Placebo | Change in Postprandial Symptoms | Fullness | 11 score on a scale |
| Functional Dyspepsia: Placebo | Change in Postprandial Symptoms | Nausea | 4 score on a scale |
| Functional Dyspepsia: Placebo | Change in Postprandial Symptoms | Bloating | 26 score on a scale |
Comparison: Nausea: Healthy Controls Secretin vs Healthy Controls Placebop-value: 0.5Wilcoxon (Mann-Whitney)
Comparison: Nausea: Functional Dyspepsia Secretin vs Functional Dyspepsia Placebop-value: 0.16Wilcoxon (Mann-Whitney)
Comparison: Nausea: Healthy Controls vs Functional Dyspepsiap-value: 0.0016ANCOVA
Comparison: Fullness: Healthy Controls Secretin vs Healthy Controls Placebop-value: 0.1Wilcoxon (Mann-Whitney)
Comparison: Fullness: Functional Dyspepsia Secretin vs Functional Dyspepsia Placebop-value: 0.3Wilcoxon (Mann-Whitney)
Comparison: Fullness: Healthy Controls vs Functional Dyspepsiap-value: 0.0002ANCOVA
Comparison: Bloating: Healthy Controls Secretin vs Healthy Controls Placebop-value: 0.41Wilcoxon (Mann-Whitney)
Comparison: Bloating Functional Dyspepsia Secretin vs Functional Dyspepsia Placebop-value: 0.67Wilcoxon (Mann-Whitney)
Comparison: Bloating: Healthy Controls vs Functional Dyspepsiap-value: 0.033ANCOVA
Comparison: Abdominal Pain: Healthy Controls Secretin vs Healthy Controls Placebop-value: 0.25Wilcoxon (Mann-Whitney)
Comparison: Abdominal Pain: Functional Dyspepsia Secretin vs Functional Dyspepsia Placebop-value: 0.57Wilcoxon (Mann-Whitney)
Comparison: Abdominal Pain: Healthy Controls vs Functional Dyspepsiap-value: 0.2375ANCOVA
Primary
Fasting Gastric Volume
Gastric fasting volume was measured prior to a meal of 300 mL standardized radio-labeled Ensure drink using an intravenous injection of Technetium Tc-99m pertechnetate and noninvasive single photon emission-computed tomography (SPECT).
Time frame: Baseline
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Healthy Controls: Secretin | Fasting Gastric Volume | 171.28 mL |
| Healthy Controls: Placebo | Fasting Gastric Volume | 152.96 mL |
| Functional Dyspepsia: Secretin | Fasting Gastric Volume | 227 mL |
| Functional Dyspepsia: Placebo | Fasting Gastric Volume | 210.2 mL |
Comparison: Healthy Controls Secretin vs Healthy Controls Placebop-value: 0.85Wilcoxon (Mann-Whitney)
Comparison: Functional Dyspepsia Secretin vs Functional Dyspepsia Placebop-value: 0.82Wilcoxon (Mann-Whitney)
Comparison: Healthy Controls vs Functional Dyspepsiap-value: 0.1451ANCOVA
Primary
Gastric Emptying
Gastric emptying was measured via scintigraphy 30 minutes after ingestion of 300 mL of radio-labeled Ensure drink and was reported as the percentage of the radio-labeled liquid meal emptied from the stomach.
Time frame: 30 minutes
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Healthy Controls: Secretin | Gastric Emptying | 7.0 percentage of gastric emptying |
| Healthy Controls: Placebo | Gastric Emptying | 19.0 percentage of gastric emptying |
| Functional Dyspepsia: Secretin | Gastric Emptying | 0 percentage of gastric emptying |
| Functional Dyspepsia: Placebo | Gastric Emptying | 8.0 percentage of gastric emptying |
Comparison: Healthy Secretin vs Healthy Placebop-value: 0.004Wilcoxon (Mann-Whitney)
Comparison: Functional Dyspepsia Secretin vs Functional Dyspepsia Placebop-value: 0.03Wilcoxon (Mann-Whitney)
Comparison: Healthy vs Functional Dyspepsiap-value: 0.0355ANCOVA
Primary
Maximum Satiation
Thirty (30) minutes after ingesting the meal of 300 mL radio-labeled Ensure drink, an additional Ensure drink was ingested at a constant rate of 30 mL/min until maximum tolerated volume was reached.
Time frame: 60 minutes
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Healthy Controls: Secretin | Maximum Satiation | 892.5 mL |
| Healthy Controls: Placebo | Maximum Satiation | 951.75 mL |
| Functional Dyspepsia: Secretin | Maximum Satiation | 655.5 mL |
| Functional Dyspepsia: Placebo | Maximum Satiation | 892.5 mL |
Comparison: Healthy Controls Secretin vs Healthy Controls Placebop-value: 0.12Wilcoxon (Mann-Whitney)
Comparison: Functional Dyspepsia Secretin vs Functional Dyspepsia Placebop-value: 0.65Wilcoxon (Mann-Whitney)
Comparison: Healthy Controls vs Functional Dyspepsiap-value: 0.0574ANCOVA
Primary
Postprandial Volume
Postprandial volume was measured 15 minutes after ingestion of 300 mL standardized radio-labeled Ensure drink using an intravenous injection of Technetium Tc-99m pertechnetate and noninvasive single photon emission-computed tomography (SPECT).
Time frame: 15 minutes
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Healthy Controls: Secretin | Postprandial Volume | 435.85 mL |
| Healthy Controls: Placebo | Postprandial Volume | 457.43 mL |
| Functional Dyspepsia: Secretin | Postprandial Volume | 593.80 mL |
| Functional Dyspepsia: Placebo | Postprandial Volume | 582.36 mL |
Comparison: Healthy Controls Secretin vs Healthy Controls Placebop-value: 0.85Wilcoxon (Mann-Whitney)
Comparison: Functional Dyspepsia Secretin vs Functional Dyspepsia Placebop-value: 1Wilcoxon (Mann-Whitney)
Comparison: Healthy Controls vs Functional Dyspepsiap-value: 0.4233ANCOVA