Gastroesophageal Reflux Disease
Conditions
Keywords
acid reflux, acid regurgitation, esophagitis, GERD, heartburn, pain, peptic
Brief summary
The purpose of this project is to compare the efficacy (how successful) 1) standard-dose proton pump inhibitor (PPI) (rabeprazole 20 mg once daily) (a medication that completely blocks the stomach from producing acid) plus low dose tricyclic antidepressant (nortriptyline 50mg) (TCA); 2) double-dose PPI (rabeprazole 20 mg twice a day); to 3) standard-dose PPI (rabeprazole 20mg once daily) and placebo (an inactive substance, like a sugar pill) to determine the relative symptom resolution and health-related quality of life in gastroesophageal reflux disease (a disease characterized by a burning sensation (heartburn) behind the breast bone caused by a backflow of stomach contents into the esophagus) (GERD) patients who fail standard-dose PPI and you will be randomly assigned (similar to flipping a coin) to one of the three groups.
Detailed description
Failure of standard dose PPI to control GERD symptoms has been increasingly encountered in clinical practice (both primary care and sub-specialties) and has become one of the most challenging therapeutic dilemmas in GERD management. It has been estimated that up to 30% of the patients receiving PPI once daily will continue to report typical GERD symptoms \[1\]. Presently, increasing the PPI dose has been the standard of care in these patients \[2\]. However, success in relieving refractory GERD symptoms with such a therapeutic approach has been extremely limited, resulting in frustration of both the patient as well as the health care provided. Furthermore, patients who fail PPI will continue to seek medical attention and may undergo a variety of invasive or non-invasive tests, and thus consume already limited health care resources. Recent advancement in the understanding of the diverse composition of the different GERD groups as well as symptom generation has led to the recognition of alteration in pain perception as an important contributing factor for PPI failure in some and the presence of non-acid related stimuli in others \[3\]. This study will clarify for the first time the role of pain modulation in patients who failed standard dose of PPI. The clinical experience with doubling the PPI dose, which is the current standard of care, has been very limited and relatively disappointing. Additionally, this study may identify the group of PPI failure patients that may benefit from doubling the dose of PPI and the group that will benefit more from adding a pain modulator. This study is timely, has never been performed and addresses a prevalent emerging clinical dilemma in GI as well as primary care clinics.
Interventions
DRUGRabeprazole 20mg, placebo dinner and bedtime
Breakfast study medication - Rabeprazole 20mg, matching placebo at dinner , Placebo for tricyclic antidepressant at bedtime
DRUGRabeprazole 20 mg two times, Placebo at bedtime
Breakfast & Dinner study medication - Rabeprazole, placebo for tricyclic antidepressant at bedtime
DRUGRabeprazole 20mg,placebo dinner ,Low dose Tricyclic Antidepressant
Rabeprazole (Breakfast) study medication, dinner placebo medication, tricyclic antidepressant at bedtime
Sponsors
US Department of Veterans Affairs
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Currently being treated with a PPI, but continue to experience GERD symptoms (such as heartburn) at least 2 times per week.
Exclusion criteria
* Known allergy or intolerance to TCA * History of serious arrhythmia or use of anti-arrhythmics * History of seizures * Subjects with significant co-morbidity, e.g., cardiovascular, respiratory, urogenital, renal, gastrointestinal, hepatic, hematological, endocrine, neurologic or psychiatric * With evidence or history of drug abuse within the past 6 months * Erosive esophagitis, esophageal ulceration, peptic stricture, Barrett's esophagus or adenocarcinoma of the esophagus on endoscopy * History of esophagogastric surgery * Gastric or duodenal lesions (ulcer, tumor, etc.) * Women who are pregnant or of childbearing age who are not on contraception * Patients who are unwilling or unable to provide informed consent * Insulin dependent diabetes
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Daytime Heartburn, Number of Days in Week Symptoms Intensity Score < 3 (Better) | Symptom control after 6 weeks of treatment | the number of days with Symptom Intensity Score \< 3 (better) for daytime heartburn during week 6 as compared to baseline |
| Nighttime Heartburn, Number of Days in Week Symptom Activity Score <3 (Better) in Week 6 Compared to Baseline | Symptom control after 6 weeks of treatment | the number of days with Symptom Intensity Score \< 3 (better) for nighttime heartburn during week 6 as compared to baseline |
| Acid Regurgitation, Number of Days in Week Symptoms Intensity Score < 3 (Better) | Symptom control after 6 weeks of treatment | the number of days with Symptom Intensity Score \< 3 (better) for acid regurgitation during week 6 as compared to baseline |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Health Related Quality of Life | end of study | SF-36 Physical Component Score (higher number better quality of life), is a measure of overall physical quality of life distinct from mental health. The range is 0 - 100. It has been adjusted to US national norms so that a score of 50 corresponds to the national mean. |
Countries
United States
Participant flow
Recruitment details
Recruitment from GI clinic in VA medical center between 4/19/2006 and 3/31/2010
Pre-assignment details
Eligibility screening occurred prior to randomization. Of 236 patients enrolled, 68 patients were not randomized due to abnormal endoscopy (14 patients), asymptomatic during run-in period (2 patients), lost to follow-up (11 patients), consent withdrawal, protocol deviation and screen failure (32 patients) and other causes (9 patients).
Participants by arm
| Arm | Count |
|---|---|
| AciPhex 20 mg BID and Once Daily Placebo AciPhex 20 mg BID and once daily placebo
Rabeprazole 20mg, placebo dinner and bedtime: Breakfast study medication - Rabeprazole 20mg, matching placebo at dinner , Placebo for tricyclic antidepressant at bedtime | 59 |
| AcipHex 20 mg Once Daily and BID Placebo AcipHex 20 mg once daily and BID placebo
Rabeprazole 20 mg two times, Placebo at bedtime: Breakfast & Dinner study medication - Rabeprazole, placebo for tricyclic antidepressant at bedtime | 55 |
| AcipHex 20 mg Once, Placebo Once, Nortriptyline AcipHex 20 mg once daily, placebo once daily and nortriptyline once daily
Rabeprazole 20mg,placebo dinner ,Low dose Tricyclic Antidepressant: Rabeprazole (Breakfast) study medication, dinner placebo medication, tricyclic antidepressant at bedtime | 54 |
| Total | 168 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 3 | 1 | 10 |
| Overall Study | Lost to Follow-up | 2 | 3 | 1 |
| Overall Study | Protocol Violation | 1 | 1 | 4 |
| Overall Study | Withdrawal by Subject | 0 | 2 | 0 |
Baseline characteristics
| Characteristic | AciPhex 20 mg BID and Once Daily Placebo | AcipHex 20 mg Once Daily and BID Placebo | AcipHex 20 mg Once, Placebo Once, Nortriptyline | Total |
|---|---|---|---|---|
| Age, Continuous | 56 years STANDARD_DEVIATION 13.8 | 54.8 years STANDARD_DEVIATION 13.4 | 56 years STANDARD_DEVIATION 11.5 | 55.6 years STANDARD_DEVIATION 13 |
| Body Mass Index | 29.4 kg/meter-squared STANDARD_DEVIATION 6.1 | 29.3 kg/meter-squared STANDARD_DEVIATION 6.5 | 29.8 kg/meter-squared STANDARD_DEVIATION 4.6 | 29.5 kg/meter-squared STANDARD_DEVIATION 5.9 |
| Region of Enrollment United States | 59 participants | 55 participants | 54 participants | 168 participants |
| Sex: Female, Male Female | 16 Participants | 19 Participants | 13 Participants | 48 Participants |
| Sex: Female, Male Male | 43 Participants | 36 Participants | 41 Participants | 120 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 | 3 / 59 | 1 / 55 | 10 / 54 |
| serious Total, serious adverse events | 0 / 59 | 0 / 55 | 0 / 54 |
Outcome results
Primary
Acid Regurgitation, Number of Days in Week Symptoms Intensity Score < 3 (Better)
the number of days with Symptom Intensity Score \< 3 (better) for acid regurgitation during week 6 as compared to baseline
Time frame: Symptom control after 6 weeks of treatment
Population: ITT
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1 | Acid Regurgitation, Number of Days in Week Symptoms Intensity Score < 3 (Better) | 6.7 days | Standard Deviation 0.8 |
| Arm 2 | Acid Regurgitation, Number of Days in Week Symptoms Intensity Score < 3 (Better) | 5.9 days | Standard Deviation 2.1 |
| Arm 3 | Acid Regurgitation, Number of Days in Week Symptoms Intensity Score < 3 (Better) | 6.3 days | Standard Deviation 1.4 |
p-value: 0.04Regression, Linear
p-value: 0.2Regression, Linear
Primary
Daytime Heartburn, Number of Days in Week Symptoms Intensity Score < 3 (Better)
the number of days with Symptom Intensity Score \< 3 (better) for daytime heartburn during week 6 as compared to baseline
Time frame: Symptom control after 6 weeks of treatment
Population: intention to treat (ITT)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1 | Daytime Heartburn, Number of Days in Week Symptoms Intensity Score < 3 (Better) | 6.6 days | Standard Deviation 0.9 |
| Arm 2 | Daytime Heartburn, Number of Days in Week Symptoms Intensity Score < 3 (Better) | 5.9 days | Standard Deviation 2.2 |
| Arm 3 | Daytime Heartburn, Number of Days in Week Symptoms Intensity Score < 3 (Better) | 6.1 days | Standard Deviation 1.8 |
p-value: 0.04Regression, Linear
p-value: 0.5Regression, Linear
Primary
Nighttime Heartburn, Number of Days in Week Symptom Activity Score <3 (Better) in Week 6 Compared to Baseline
the number of days with Symptom Intensity Score \< 3 (better) for nighttime heartburn during week 6 as compared to baseline
Time frame: Symptom control after 6 weeks of treatment
Population: ITT
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1 | Nighttime Heartburn, Number of Days in Week Symptom Activity Score <3 (Better) in Week 6 Compared to Baseline | 6.6 days | Standard Deviation 0.9 |
| Arm 2 | Nighttime Heartburn, Number of Days in Week Symptom Activity Score <3 (Better) in Week 6 Compared to Baseline | 5.8 days | Standard Deviation 2 |
| Arm 3 | Nighttime Heartburn, Number of Days in Week Symptom Activity Score <3 (Better) in Week 6 Compared to Baseline | 6.0 days | Standard Deviation 1.6 |
p-value: 0.04Regression, Linear
p-value: 0.5Regression, Linear
Secondary
Health Related Quality of Life
SF-36 Physical Component Score (higher number better quality of life), is a measure of overall physical quality of life distinct from mental health. The range is 0 - 100. It has been adjusted to US national norms so that a score of 50 corresponds to the national mean.
Time frame: end of study
Population: ITT
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1 | Health Related Quality of Life | 42.0 units on a scale | Standard Deviation 10.3 |
| Arm 2 | Health Related Quality of Life | 37.7 units on a scale | Standard Deviation 11 |
| Arm 3 | Health Related Quality of Life | 37.7 units on a scale | Standard Deviation 11 |
p-value: 0.19ANCOVA