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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Rabeprazole morning/evening placebo bedtime | Placebo Comparator | AciPhex 20 mg BID and once daily placebo |
|
| Rabeprazole breakfast, placebo dinner and bedtime | Placebo Comparator | AcipHex 20 mg once daily and BID placebo |
|
| Rabeprazole breakfast, placebo dinner, nortriptyline bedtime | Active Comparator | AcipHex 20 mg once daily, placebo once daily and nortriptyline once daily |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Rabeprazole 20mg, placebo dinner and bedtime | Drug | Breakfast study medication - Rabeprazole 20mg, matching placebo at dinner , Placebo for tricyclic antidepressant at bedtime |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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 | Symptom control after 6 weeks of treatment |
| 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 | Symptom control after 6 weeks of treatment |
| 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 | Symptom control after 6 weeks of treatment |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | end of study |
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Inclusion Criteria:
Exclusion Criteria:
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Southern Arizona VA Health Care System, Tucson | Tucson | Arizona | 85723 | United States |
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).
Recruitment from GI clinic in VA medical center between 4/19/2006 and 3/31/2010
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| ID | Title | Description |
|---|---|---|
| FG000 | Arm 1 | 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 |
| FG001 | Arm 2 |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| Rabeprazole 20 mg two times, Placebo at bedtime | Drug | Breakfast & Dinner study medication - Rabeprazole, placebo for tricyclic antidepressant at bedtime |
|
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| Rabeprazole 20mg,placebo dinner ,Low dose Tricyclic Antidepressant | Drug | Rabeprazole (Breakfast) study medication, dinner placebo medication, tricyclic antidepressant at bedtime |
|
|
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
| FG002 | Arm 3 | 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 |
| COMPLETED |
|
| NOT COMPLETED |
|
|
Number of randomized subjects
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| ID | Title | Description |
|---|---|---|
| BG000 | 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 |
| BG001 | 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 |
| BG002 | 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 |
| BG003 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean | Standard Deviation | years |
| |||||||||||||||
| Sex: Female, Male | Count of Participants | Participants |
| ||||||||||||||||
| Region of Enrollment | Number | participants |
| ||||||||||||||||
| Body Mass Index | Mean | Standard Deviation | kg/meter-squared |
|
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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 | intention to treat (ITT) | Posted | Mean | Standard Deviation | days | Symptom control after 6 weeks of treatment |
|
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| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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. | ITT | Posted | Mean | Standard Deviation | units on a scale | end of study |
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 | ITT | Posted | Mean | Standard Deviation | days | Symptom control after 6 weeks of treatment |
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 | ITT | Posted | Mean | Standard Deviation | days | Symptom control after 6 weeks of treatment |
|
6 weeks
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Arm 1 | 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 | 0 | 59 | 3 | 59 | ||
| EG001 | Arm 2 | 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 | 0 | 55 | 1 | 55 | ||
| EG002 | Arm 3 | 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 | 0 | 54 | 10 | 54 |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Flu like symptoms | General disorders | MedDRA 10.0 | Systematic Assessment |
| |
| skin ulceration | Gastrointestinal disorders | CTCAE (4.0) | Systematic Assessment | ulcer on tongue |
|
| Other, Skin and subcutaneous tissue disorders | Skin and subcutaneous tissue disorders | CTCAE (4.0) | Systematic Assessment | Rash (type unspecified) on face |
|
| Dry mouth | Gastrointestinal disorders | CTCAE (4.0) | Systematic Assessment |
| |
| Constipation | Gastrointestinal disorders | CTCAE (4.0) | Systematic Assessment |
| |
| Gastrointestinal pain | Gastrointestinal disorders | CTCAE (4.0) | Systematic Assessment | "Stomach cramps" |
|
| Somnolence | Nervous system disorders | CTCAE (4.0) | Systematic Assessment | "Drowsiness" |
|
| Other, Renal and urinary disorders | Renal and urinary disorders | CTCAE (4.0) | Systematic Assessment | "urinary difficulty" (type unspecified) |
|
| Flushing | Vascular disorders | CTCAE (4.0) | Systematic Assessment |
| |
| Dyspepsia | Gastrointestinal disorders | CTCAE (4.0) | Systematic Assessment |
| |
| Headache | Nervous system disorders | CTCAE (4.0) | Systematic Assessment |
| |
| Blurred vision | Eye disorders | CTCAE (4.0) | Systematic Assessment |
| |
| Lethargy | Nervous system disorders | CTCAE (4.0) | Systematic Assessment |
| |
| Fatigue | General disorders | CTCAE (4.0) | Systematic Assessment |
|
Recruitment challenges, including difficulty finding patients who "fail" PPI but had not already been prescribed doubled dose. Necessitated a no-cost extension to complete recruitment
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Christopher Wendel, MS | Southern Arizona VA Health Care System | 520 792 1450 | 1824 | christopher.wendel@va.gov |
| ID | Term |
|---|---|
| D005764 | Gastroesophageal Reflux |
| D004941 | Esophagitis |
| D006356 | Heartburn |
| D010146 | Pain |
| ID | Term |
|---|---|
| D015154 | Esophageal Motility Disorders |
| D003680 | Deglutition Disorders |
| D004935 | Esophageal Diseases |
| D005767 | Gastrointestinal Diseases |
| D004066 | Digestive System Diseases |
| D005759 | Gastroenteritis |
| D012817 | Signs and Symptoms, Digestive |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D009461 | Neurologic Manifestations |
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| ID | Term |
|---|---|
| D064750 | Rabeprazole |
| D009661 | Nortriptyline |
| ID | Term |
|---|---|
| D053799 | 2-Pyridinylmethylsulfinylbenzimidazoles |
| D013454 | Sulfoxides |
| D013457 | Sulfur Compounds |
| D009930 | Organic Chemicals |
| D011725 | Pyridines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D001562 | Benzimidazoles |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D003986 | Dibenzocycloheptenes |
| D001567 | Benzocycloheptenes |
| D011084 | Polycyclic Aromatic Hydrocarbons |
| D006841 | Hydrocarbons, Aromatic |
| D006844 | Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
| D011083 | Polycyclic Compounds |
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| Male |
|
adjusted for age, sex, BMI and ethnicity |
| 0.50 |
P<0.05 considered statistically significant, No adjustment for multiple comparisons |
| No |
| Superiority or Other |
| Units | Counts |
|---|---|
| Participants |
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| Units | Counts |
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| Participants |
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| Units | Counts |
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| Participants |
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