Esophagitis, Peptic, Esophagitis, Reflux
Conditions
Keywords
Erosive Esophagitis
Brief summary
The purpose of this study is to assess the ability of once-daily (QD) treatment with dexlansoprazole modified release (MR) 30 mg and 60 mg or placebo in maintaining healing of erosive esophagitis (EE).
Detailed description
This is a Phase 3, randomized, double-blind, multicenter, placebo-controlled, 6 month maintenance study. The study is designed to compare the efficacy and safety of daily dexlansoprazole MR (30 mg and 60 mg) with that of placebo, in maintaining healing of EE.
Interventions
Dexlansoprazole MR 30 mg, capsules, orally, once daily for up to six months.
DRUGPlacebo
Dexlansoprazole placebo-matching capsules, orally, once daily for up to six months.
Sponsors
Takeda
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Subjects must have successfully completed the Phase 3 Study T-EE04-084 (NCT00251693) or T-EE04-085 (NCT00251719); and have healed esophageal erosions proven by endoscopy. Complete healing was assessed for change in LA Esophagitis Classification grades A, B, C, or D to healed (defined as anything less than the criterion for Grade A). The subject was counted as healed if endoscopy findings did not meet the Grade A criterion.
Exclusion criteria
* Use of prescription or nonprescription proton pump inhibitors (PPIs), histamine (H2) receptor antagonists, sucralfate, misoprostol, or prokinetics throughout the study. * Use of antacids (except for study supplied) throughout the study. * Use of drugs with significant anticholinergic effects such as tricyclics who cannot stay on a stable dose throughout the study. * Chronic (\>12 doses per month) use of nonsteroidal anti-inflammatory drugs (NSAIDs) or cyclo-oxygenase-2 (COX-2) inhibitors. * Need for continuous anticoagulant therapy. * Evidence of uncontrolled systemic disease. * Subjects who have participated in either maintenance study (T-EE04-086 \[NCT00255164\] or T-EE04-087 \[NCT00255151\]). * Subjects who, in the opinion of the investigator, is unable to comply with the requirements of the study or is unsuitable for any reason.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Subjects Who Maintained Complete Healing of Erosive Esophagitis as Assessed by Endoscopy - Crude Rate Analysis. | 6 months | Crude rates analyzed maintenance of healed EE from baseline of this study and considered prematurely discontinued subjects as relapsed. |
| Percentage of Subjects Who Maintained Complete Healing of Erosive Esophagitis as Assessed by Endoscopy - Life Table Method | 6 months | Percentage of subjects who maintained complete healing of erosive esophagitis as assessed by endoscopy. In the life table method, subjects without post-baseline endoscopy were included as censored; subjects who did not have a recurrence of EE and did not complete the study were also considered censored. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Days Without Daytime or Nighttime Heartburn as Assessed by Daily Diary-Median. | 6 months | The percentage was calculated as the days that were heartburn-free out of the total number of days for which either a daytime or nighttime result was reported. |
| Percentage of Days Without Daytime or Nighttime Heartburn as Assessed by Daily Diary-Mean. | 6 months | The percentage was calculated as the days that were heartburn-free out of the total number of days for which either a daytime or nighttime result was marked. |
| Percentage of Days Without Nighttime Heartburn as Assessed by Daily Diary-Median. | 6 months | The percentage was calculated as the nights that were heartburn-free out of the total number of days for which a nighttime result was marked. |
| Percentage of Days Without Nighttime Heartburn as Assessed by Daily Diary-Mean. | 6 months | The percentage was calculated as the nights that were heartburn-free out of the total number of days for which a nighttime result was marked. |
Countries
Australia, Canada, Czechia, Estonia, Latvia, Lithuania, Slovakia, United States
Participant flow
Recruitment details
Subjects were enrolled at a total of 94 sites: 75 sites in the United States and 19 sites in Australia, Canada, the Czech Republic, Estonia, India, Latvia, Lithuania, Poland, and the Slovak Republic (date of first dose: 19 May 2006; date of last procedure: 21 May 2007).
Pre-assignment details
Subjects had to have endoscopically proven healed erosive esophagitis (EE) after 4 to 8 weeks of treatment with lansoprazole 30 mg once-daily (QD), dexlansoprazole modified release (MR) 60 mg QD, or dexlansoprazole MR 90 mg QD in the EE healing studies, T-EE04-084 (NCT00251693) and T-EE04-085 (NCT00251719).
Participants by arm
| Arm | Count |
|---|---|
| Placebo QD Placebo capsules, orally, once daily for up to 6 months. | 147 |
| Dexlansoprazole MR 30 mg QD Dexlansoprazole MR 30 mg, capsules, orally, once daily for up to 6 months. | 140 |
| Dexlansoprazole MR 60 mg QD Dexlansoprazole MR 60 mg, capsules, orally, once daily for up to 6 months. | 158 |
| Total | 445 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 11 | 3 | 6 |
| Overall Study | Lost to Follow-up | 5 | 5 | 6 |
| Overall Study | Noncompliance | 2 | 0 | 0 |
| Overall Study | Possible Barrett's Esophagus | 2 | 1 | 1 |
| Overall Study | Pregnancy | 0 | 2 | 0 |
| Overall Study | Protocol Violation | 0 | 0 | 1 |
| Overall Study | Relapse of Erosive Esophagitis | 76 | 25 | 19 |
| Overall Study | Subject Request/ Subject Unavailable | 0 | 0 | 2 |
| Overall Study | Therapeutic Failure | 6 | 0 | 2 |
| Overall Study | Unmet Inclusion/Exclusion Criteria | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 19 | 12 | 17 |
Baseline characteristics
| Characteristic | Placebo QD | Dexlansoprazole MR 30 mg QD | Dexlansoprazole MR 60 mg QD | Total |
|---|---|---|---|---|
| Age Continuous | 49.5 years STANDARD_DEVIATION 12.94 | 47.1 years STANDARD_DEVIATION 13.15 | 47.9 years STANDARD_DEVIATION 11.72 | 48.2 years STANDARD_DEVIATION 12.6 |
| Age, Customized 45 - <65 years | 83 participants | 75 participants | 89 participants | 247 participants |
| Age, Customized <45 years | 50 participants | 54 participants | 58 participants | 162 participants |
| Age, Customized ≥65 years | 14 participants | 11 participants | 11 participants | 36 participants |
| Baseline Los Angeles (LA) Classification Grade for Erosive Esophagitis (EE) A: ≥1 mucosal break <5 mm | 51 participants | 53 participants | 56 participants | 160 participants |
| Baseline Los Angeles (LA) Classification Grade for Erosive Esophagitis (EE) B: ≥1 mucosal break ≥5 mm | 57 participants | 46 participants | 57 participants | 160 participants |
| Baseline Los Angeles (LA) Classification Grade for Erosive Esophagitis (EE) C: ≥1 mucosal break <75% of circumference | 34 participants | 31 participants | 39 participants | 104 participants |
| Baseline Los Angeles (LA) Classification Grade for Erosive Esophagitis (EE) D: ≥1 mucosal break ≥75% of circumference | 5 participants | 10 participants | 6 participants | 21 participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 20 Participants | 21 Participants | 19 Participants | 60 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 127 Participants | 119 Participants | 139 Participants | 385 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 4 Participants | 4 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 3 Participants | 5 Participants | 11 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 6 Participants | 11 Participants | 21 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 4 Participants | 2 Participants | 7 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 138 Participants | 127 Participants | 135 Participants | 400 Participants |
| Sex: Female, Male Female | 75 Participants | 71 Participants | 84 Participants | 230 Participants |
| Sex: Female, Male Male | 72 Participants | 69 Participants | 74 Participants | 215 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 | 11 / — | 26 / — | 35 / — |
| serious Total, serious adverse events | 1 / — | 2 / — | 6 / — |
Outcome results
Primary
Percentage of Subjects Who Maintained Complete Healing of Erosive Esophagitis as Assessed by Endoscopy - Crude Rate Analysis.
Crude rates analyzed maintenance of healed EE from baseline of this study and considered prematurely discontinued subjects as relapsed.
Time frame: 6 months
Population: The crude rate analysis was performed on intent-to-treat (ITT) subjects (subjects from Studies T-EE04-084 or T-EE04-085 with endoscopically proven healed EE who received at least 1 dose of study drug in this study and did not have a gap of \>7 days between the EE healing studies and this study) with at least one endoscopy in this maintenance study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo QD | Percentage of Subjects Who Maintained Complete Healing of Erosive Esophagitis as Assessed by Endoscopy - Crude Rate Analysis. | 14.3 Percentage of Subjects |
| Dexlansoprazole MR 30 mg QD | Percentage of Subjects Who Maintained Complete Healing of Erosive Esophagitis as Assessed by Endoscopy - Crude Rate Analysis. | 66.4 Percentage of Subjects |
| Dexlansoprazole MR 60 mg QD | Percentage of Subjects Who Maintained Complete Healing of Erosive Esophagitis as Assessed by Endoscopy - Crude Rate Analysis. | 66.4 Percentage of Subjects |
p-value: <0.00001Fisher Exact
p-value: <0.00001Fisher Exact
p-value: >0.99999Fisher Exact
Primary
Percentage of Subjects Who Maintained Complete Healing of Erosive Esophagitis as Assessed by Endoscopy - Life Table Method
Percentage of subjects who maintained complete healing of erosive esophagitis as assessed by endoscopy. In the life table method, subjects without post-baseline endoscopy were included as censored; subjects who did not have a recurrence of EE and did not complete the study were also considered censored.
Time frame: 6 months
Population: Life table method for the maintenance rate of healed EE was performed on ITT subjects and included subjects without post-baseline endoscopy as censored.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo QD | Percentage of Subjects Who Maintained Complete Healing of Erosive Esophagitis as Assessed by Endoscopy - Life Table Method | 27.2 Percentage of Subjects |
| Dexlansoprazole MR 30 mg QD | Percentage of Subjects Who Maintained Complete Healing of Erosive Esophagitis as Assessed by Endoscopy - Life Table Method | 74.9 Percentage of Subjects |
| Dexlansoprazole MR 60 mg QD | Percentage of Subjects Who Maintained Complete Healing of Erosive Esophagitis as Assessed by Endoscopy - Life Table Method | 82.5 Percentage of Subjects |
p-value: <0.00001Log Rank
p-value: <0.00001Log Rank
p-value: 0.13932Log Rank
Secondary
Percentage of Days Without Daytime or Nighttime Heartburn as Assessed by Daily Diary-Mean.
The percentage was calculated as the days that were heartburn-free out of the total number of days for which either a daytime or nighttime result was marked.
Time frame: 6 months
Population: The analysis of 24-hour heartburn-free days was performed on ITT subjects with at least one daytime or nighttime heartburn Yes/No question answered during treatment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo QD | Percentage of Days Without Daytime or Nighttime Heartburn as Assessed by Daily Diary-Mean. | 36.0 Percentage of Days | Standard Deviation 32 |
| Dexlansoprazole MR 30 mg QD | Percentage of Days Without Daytime or Nighttime Heartburn as Assessed by Daily Diary-Mean. | 83.3 Percentage of Days | Standard Deviation 26.5 |
| Dexlansoprazole MR 60 mg QD | Percentage of Days Without Daytime or Nighttime Heartburn as Assessed by Daily Diary-Mean. | 78.4 Percentage of Days | Standard Deviation 28.3 |
Secondary
Percentage of Days Without Daytime or Nighttime Heartburn as Assessed by Daily Diary-Median.
The percentage was calculated as the days that were heartburn-free out of the total number of days for which either a daytime or nighttime result was reported.
Time frame: 6 months
Population: The analysis of 24-hour heartburn-free days was performed on ITT subjects with at least one daytime or nighttime heartburn Yes/No question answered during treatment.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Placebo QD | Percentage of Days Without Daytime or Nighttime Heartburn as Assessed by Daily Diary-Median. | 28.6 Percentage of Days | Inter-Quartile Range 32 |
| Dexlansoprazole MR 30 mg QD | Percentage of Days Without Daytime or Nighttime Heartburn as Assessed by Daily Diary-Median. | 96.1 Percentage of Days | Inter-Quartile Range 26.5 |
| Dexlansoprazole MR 60 mg QD | Percentage of Days Without Daytime or Nighttime Heartburn as Assessed by Daily Diary-Median. | 90.9 Percentage of Days | Inter-Quartile Range 28.3 |
p-value: <0.00001Wilcoxon (Mann-Whitney)
p-value: <0.00001Wilcoxon (Mann-Whitney)
p-value: 0.0673Wilcoxon (Mann-Whitney)
Secondary
Percentage of Days Without Nighttime Heartburn as Assessed by Daily Diary-Mean.
The percentage was calculated as the nights that were heartburn-free out of the total number of days for which a nighttime result was marked.
Time frame: 6 months
Population: The analysis was performed on ITT subjects with at least one nighttime heartburn Yes/No question answered during treatment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo QD | Percentage of Days Without Nighttime Heartburn as Assessed by Daily Diary-Mean. | 57.7 Percentage of Days | Standard Deviation 36.6 |
| Dexlansoprazole MR 30 mg QD | Percentage of Days Without Nighttime Heartburn as Assessed by Daily Diary-Mean. | 89.3 Percentage of Days | Standard Deviation 22.3 |
| Dexlansoprazole MR 60 mg QD | Percentage of Days Without Nighttime Heartburn as Assessed by Daily Diary-Mean. | 86.0 Percentage of Days | Standard Deviation 23.1 |
Secondary
Percentage of Days Without Nighttime Heartburn as Assessed by Daily Diary-Median.
The percentage was calculated as the nights that were heartburn-free out of the total number of days for which a nighttime result was marked.
Time frame: 6 months
Population: The analysis was performed on ITT subjects with at least one nighttime heartburn Yes/No question answered during treatment.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Placebo QD | Percentage of Days Without Nighttime Heartburn as Assessed by Daily Diary-Median. | 71.7 Percentage of Days | Inter-Quartile Range 36.6 |
| Dexlansoprazole MR 30 mg QD | Percentage of Days Without Nighttime Heartburn as Assessed by Daily Diary-Median. | 98.9 Percentage of Days | Inter-Quartile Range 22.3 |
| Dexlansoprazole MR 60 mg QD | Percentage of Days Without Nighttime Heartburn as Assessed by Daily Diary-Median. | 96.2 Percentage of Days | Inter-Quartile Range 23.1 |
p-value: <0.00001Wilcoxon (Mann-Whitney)
p-value: <0.00001Wilcoxon (Mann-Whitney)
p-value: 0.11257Wilcoxon (Mann-Whitney)