Dyspepsia and Other Specified Disorders of Function of Stomach
Conditions
Keywords
Bloating, Early Fullness, Nausea, Upper Abdominal Discomfort, dyspepsia, stomach pain, stomach discomfort
Brief summary
Functional dyspepsia is a common gastrointestinal disorder. Symptoms can include stomach pain or discomfort, bloating, fullness after eating meals, and nausea. These symptoms often interfere with school and work, and weight loss may occur due to dietary restrictions. The hypothesis of this study was that antidepressant therapy is more effective than placebo in relief of the symptoms of functional dyspepsia, adjusting for psychological and psychiatric co-morbidity. The study also examined if antidepressant therapy reduces disability and improves quality of life in functional dyspepsia.
Detailed description
The aims of this study were to: 1. Determine whether antidepressant therapy is more efficacious than placebo in relief of the symptoms of functional dyspepsia, adjusting for psychological and psychiatric co-morbidity. The investigators also planned to determine if antidepressant therapy reduces disability, improves quality of life and influences clinical response over 6 months after ceasing medication. 2. Determine if gastric emptying (motor dysfunction) and the nutrient drink test (a test that assesses gastric hypersensitivity and/or gastric accommodation) is altered by antidepressant therapy with a tricyclic or selective serotonin re-uptake inhibitors (SSRI), and whether subgroups with altered physiology are associated with treatment outcome.
Interventions
DRUGAmitriptyline
25 mg capsule by mouth at bedtime for two weeks, then 50 mg capsule by mouth at bedtime for 10 weeks. The drug will be provided in blister packs.
DRUGEscitalopram
10 mg tablets by mouth at bedtime for 12 weeks. The drug will be provided in blister packs.
DRUGPlacebo
Placebo escitalopram and placebo amitriptyline will be manufactured to ensure all tablets and capsules will be indistinguishable, and provided in blister packs.
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Mayo Clinic
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Normal esophagogastroduodenoscopy (EGD) (no esophagitis, Barrett's esophagus, cancer, erosions, or ulcer disease) within the past 5 years * Diagnosis of functional dyspepsia * Patients may have failed to adequately respond to antisecretory therapy in the past for functional dyspepsia to be suitable; a good response to antisecretory therapy, which remains first line therapy, suggests underlying gastroesophageal reflux disease (GERD).
Exclusion criteria
* Any documented history of endoscopic esophagitis, or predominant heartburn or acid regurgitation, or these symptoms two or more times per week in the prior year, to exclude GERD. * Those who have had an adequate response to antisecretory therapy according to the physician interview, to exclude patients with disease easy to control with first line therapy or misdiagnosed GERD. * Any documented peptic ulcer disease. * Regular use of non-steroidal anti-inflammatory drugs (except long term low dose aspirin ≤ 325 mg / day) * Subjects undergoing psychiatric treatment, having a current history of drug or alcohol abuse, or currently taking psychotropic medication for depression or psychosis, or eating disorders * A history of abdominal surgery except appendectomy, cholecystectomy or hysterectomy, tubal ligations, bladder slings, and vasectomies * Subjects with concurrent major physical illness (including cardiac or liver disease, diabetes, inflammatory bowel disease, glaucoma, urinary retention, active thyroid disease, vasculitis, lactose intolerance explaining symptoms) * Subjects whose literacy skills are insufficient to complete self report questionnaires. * Pregnancy, or refusal to apply adequate contraceptive measures during the trial * Subjects currently on antidepressant therapy will be excluded. * Patients who score 11 or greater on the 7 questions related to depression of the Hospital Anxiety Depression Scale will be excluded. These patients will be encouraged to get follow up for depression. * All eligible patients over age 50 will have an EKG before randomization. Those found to have significant arrhythmias, conduction defects or a previous myocardial infarction on EKG will be excluded. Anyone with QT prolongation will be excluded. The following concomitant medications will be prohibited during the trial: * Systemically acting cholinergics and anticholinergics (atropine, didinium bromide, propantheline) * Prokinetics (e.g., metoclopramide, tegaserod) * Macrolide antibiotics (e.g., erythromycin, azithromycin) * Aspirin (\> 325 mg/day) * Spasmolytics (e.g., dicyclomine) * Antidepressants other than study medications * Serotonin enhancing drugs: monamine oxidase inhibitors, anticonvulsants, dextromethorphan. Participants will be instructed to avoid grapefruit/grapefruit juice during the trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Self-Report of Adequate Relief of Dyspepsia (Yes/No) For at Least 50% of Weeks 3 -12 of Treatment | 3 weeks through 12 weeks | The first two weeks of treatment were excluded to allow for establishment of steady state drug levels. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Gastric Emptying Half-Time (T1/2) | 12 weeks | The time for half of the ingested solids or liquids to leave the stomach. |
| Maximum Tolerated Volume by Nutrient Drink Test | 12 weeks | The nutrient drink test for meal-induced satiety had subjects drink 120 ml of ENSURE every four minutes. Satiety scores were measured on a scale graded 0-5 (1, no symptoms; 5, maximum satiety). When a score of 5 was reached, the maximum tolerated volume intake was measured. Abnormal satiety was defined as inability to consume \> 800 ml of Ensure. |
| Dyspepsia-Specific Quality of Life | 12 Weeks | The Nepean Dyspepsia Index (NDI) assessed quality of life. NDI scores are summarized into overall quality of life and 5 subscales: Interference, Knowledge/Control, Eating/Drinking, Sleep Disturbance, Work/Study. The scale consists of 25 items, yielding 5 sub-scales. Range 0-100, higher numbers indicate a greater quality of life. |
Countries
Canada, United States
Participant flow
Recruitment details
Study enrollment was during October 27, 2006 to February 11, 2013.
Participants by arm
| Arm | Count |
|---|---|
| Amitriptyline Amitriptyline capsule (50 mg) plus a placebo escitalopram tablet will be taken at night half an hour before bedtime. To maximize patient tolerability, in the first 2 weeks the dose of amitriptyline will be 25 mg and then the dose will be increased to 50 mg, but the 25 mg and 50 mg capsules will be indistinguishable to maintain blinding. | 97 |
| Escitalopram Escitalopram tablet (10 mg) plus a placebo amitriptyline capsule will be taken by mouth at night half an hour before bedtime for 12 weeks. | 98 |
| Placebo Placebo escitalopram tablets and placebo amitriptyline capsules will be taken by mouth half an hour before bedtime for 12 weeks. | 97 |
| Total | 292 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Withdrawal by Subject | 28 | 40 | 32 |
Baseline characteristics
| Characteristic | Amitriptyline | Escitalopram | Placebo | Total |
|---|---|---|---|---|
| Age, Continuous | 43 years STANDARD_DEVIATION 15 | 45 years STANDARD_DEVIATION 15 | 45 years STANDARD_DEVIATION 16 | 44 years STANDARD_DEVIATION 15 |
| Region of Enrollment Canada | 3 participants | 4 participants | 1 participants | 8 participants |
| Region of Enrollment United States | 94 participants | 94 participants | 96 participants | 284 participants |
| Sex: Female, Male Female | 74 Participants | 72 Participants | 73 Participants | 219 Participants |
| Sex: Female, Male Male | 23 Participants | 26 Participants | 24 Participants | 73 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 29 / 97 | 28 / 98 | 20 / 97 |
| serious Total, serious adverse events | 0 / 97 | 0 / 98 | 0 / 97 |
Outcome results
Primary
Self-Report of Adequate Relief of Dyspepsia (Yes/No) For at Least 50% of Weeks 3 -12 of Treatment
The first two weeks of treatment were excluded to allow for establishment of steady state drug levels.
Time frame: 3 weeks through 12 weeks
Population: The intent-to-treat analysis included all randomized subjects.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Amitriptyline | Self-Report of Adequate Relief of Dyspepsia (Yes/No) For at Least 50% of Weeks 3 -12 of Treatment | 53 percentage of participants |
| Escitalopram | Self-Report of Adequate Relief of Dyspepsia (Yes/No) For at Least 50% of Weeks 3 -12 of Treatment | 38 percentage of participants |
| Placebo | Self-Report of Adequate Relief of Dyspepsia (Yes/No) For at Least 50% of Weeks 3 -12 of Treatment | 40 percentage of participants |
Comparison: Overall treatment effect from logistic regression model incorporating balancing factors. A p-value of \<0.05 was considered statistically significant.p-value: 0.05ANCOVA
Secondary
Dyspepsia-Specific Quality of Life
The Nepean Dyspepsia Index (NDI) assessed quality of life. NDI scores are summarized into overall quality of life and 5 subscales: Interference, Knowledge/Control, Eating/Drinking, Sleep Disturbance, Work/Study. The scale consists of 25 items, yielding 5 sub-scales. Range 0-100, higher numbers indicate a greater quality of life.
Time frame: 12 Weeks
Population: The intent-to-treat analysis included all randomized subjects.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Amitriptyline | Dyspepsia-Specific Quality of Life | Overall Quality of Life | 80.6 units on a scale |
| Amitriptyline | Dyspepsia-Specific Quality of Life | Interference Subscale | 83.2 units on a scale |
| Amitriptyline | Dyspepsia-Specific Quality of Life | Knowledge/Control Subscale | 78.2 units on a scale |
| Amitriptyline | Dyspepsia-Specific Quality of Life | Eat/Drink Subscale | 72.4 units on a scale |
| Amitriptyline | Dyspepsia-Specific Quality of Life | Sleep Disturbance Subscale | 86.3 units on a scale |
| Amitriptyline | Dyspepsia-Specific Quality of Life | Work/Study Subscale | 86.9 units on a scale |
| Escitalopram | Dyspepsia-Specific Quality of Life | Work/Study Subscale | 87.2 units on a scale |
| Escitalopram | Dyspepsia-Specific Quality of Life | Overall Quality of Life | 82.8 units on a scale |
| Escitalopram | Dyspepsia-Specific Quality of Life | Eat/Drink Subscale | 70.6 units on a scale |
| Escitalopram | Dyspepsia-Specific Quality of Life | Sleep Disturbance Subscale | 80.8 units on a scale |
| Escitalopram | Dyspepsia-Specific Quality of Life | Interference Subscale | 82.8 units on a scale |
| Escitalopram | Dyspepsia-Specific Quality of Life | Knowledge/Control Subscale | 76.2 units on a scale |
| Placebo | Dyspepsia-Specific Quality of Life | Interference Subscale | 76.2 units on a scale |
| Placebo | Dyspepsia-Specific Quality of Life | Knowledge/Control Subscale | 72.9 units on a scale |
| Placebo | Dyspepsia-Specific Quality of Life | Work/Study Subscale | 79.7 units on a scale |
| Placebo | Dyspepsia-Specific Quality of Life | Eat/Drink Subscale | 64.8 units on a scale |
| Placebo | Dyspepsia-Specific Quality of Life | Overall Quality of Life | 73.5 units on a scale |
| Placebo | Dyspepsia-Specific Quality of Life | Sleep Disturbance Subscale | 76.4 units on a scale |
Comparison: Comparison between antidepressant arms and placebo for overall quality of life. A p-value of \<0.05 was considered statistically significant.p-value: 0.02ANCOVA
Comparison: Comparison between antidepressant arms and placebo for Eat/Drink subscale. A p-value of \<0.05 was considered statistically significant.p-value: 0.06ANCOVA
Comparison: Comparison between antidepressant arms and placebo for Interference subscale. A p-value of \<0.05 was considered statistically significant.p-value: 0.06ANCOVA
Comparison: Comparison between antidepressant arms and placebo for Sleep Disturbance subscale. A p-value of \<0.05 was considered statistically significant.p-value: 0.01ANCOVA
Comparison: Comparison between antidepressant arms and placebo for Work/Study subscale. A p-value of \<0.05 was considered statistically significant.p-value: 0.04ANCOVA
Secondary
Gastric Emptying Half-Time (T1/2)
The time for half of the ingested solids or liquids to leave the stomach.
Time frame: 12 weeks
Population: The intent-to-treat analysis included all randomized subjects.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Amitriptyline | Gastric Emptying Half-Time (T1/2) | 117 minutes | Standard Deviation 43 |
| Escitalopram | Gastric Emptying Half-Time (T1/2) | 108 minutes | Standard Deviation 36 |
| Placebo | Gastric Emptying Half-Time (T1/2) | 115 minutes | Standard Deviation 40 |
Secondary
Maximum Tolerated Volume by Nutrient Drink Test
The nutrient drink test for meal-induced satiety had subjects drink 120 ml of ENSURE every four minutes. Satiety scores were measured on a scale graded 0-5 (1, no symptoms; 5, maximum satiety). When a score of 5 was reached, the maximum tolerated volume intake was measured. Abnormal satiety was defined as inability to consume \> 800 ml of Ensure.
Time frame: 12 weeks
Population: The intent-to-treat analysis included all randomized subjects.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Amitriptyline | Maximum Tolerated Volume by Nutrient Drink Test | 764 ml | Standard Deviation 319 |
| Escitalopram | Maximum Tolerated Volume by Nutrient Drink Test | 823 ml | Standard Deviation 391 |
| Placebo | Maximum Tolerated Volume by Nutrient Drink Test | 839 ml | Standard Deviation 442 |