Refractory Reflux Esophagitis
Conditions
Keywords
Refractory Reflux Esophagitis,, Japanese,, Nexium,, twice daily,, oral administration
Brief summary
This is a phase 3 multicentre, randomised, double-blind, parallel-group, comparative study to evaluate the efficacy of esomeprazole (D961H) 20 mg twice daily and esomeprazole (D961H) 20 mg once daily in patients (in the form of esomeprazole magnesium salt) with refractory reflux esophagitis after 8 weeks of standard Proton-pump inhibitor (PPI) therapy by assessment of presence/absence of inflammation (esophagitis) at Week 8 according to the Los Angeles (LA) classification
Detailed description
A multicentre, randomised, double-blind, parallel-group, comparative study to compare the efficacy and safety of D961H 20 mg twice daily oral administration and D961H 20 mg once daily oral administration in patients with refractory reflux esophagitis
Interventions
DRUGEsomeprazole (D961H) twice daily
One capsule of esomeprazole 20 mg (in the form of esomeprazole magnesium salt) will be administered in the morning and in the evening
DRUGEsomeprazole (D961H) once daily
One capsule of esomeprazole 20 mg (in the form of esomeprazole magnesium salt) will be administered in the morning and one corresponding placebo capsule in the evening
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Provision of informed consent prior to any study specific procedures. 2. Patients with RE classified into LA classification Grade A, B, C or D by Endoscopy despite of at least 8-week treatment using standard doses of PPIs. 3. Patients must fulfill at least one of the following criteria such as (i) RE with LA grade C/D at Endoscopy on visit 1 and/or history of RE with LA grade C/D, (ii) RE was diagnosed more than 1 year before visit 1. 4. Patients who are able to complete the Patient Diary
Exclusion criteria
1. Male or female aged less than 20 years at the time of informed consent. 2. Patients with current evidence of the gastrointestinal diseases/conditions such as esophageal stricture to interfere with the evaluation of the study etc 3. Gastric or duodenal ulcer verified by Endoscopy within 12 weeks before randomisation. 4. Previous esophageal, gastric or duodenal surgery except simple closure of perforated ulcer, simple endoscopic treatment with simple operation etc 5. Current or historical evidence (within 12 weeks prior to randomisation) of the diseases/conditions as judged to interfere with the evaluation of the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Healing of RE Who Were Graded O at Week 8 Out of Participants Who Were Graded A to D at Baseline According to Los Angeles Classification | 8 Weeks | Percentage of participants with healing of reflux esophagitis (RE) who were graded O (No RE) at Week 8 out of participants who were graded A (least severe) to D (most severe) at baseline according to Los Angeles classification |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cumulative Percentage of Participants Who Had Sustained Resolution of GERD Symptom -Heartburn at Week 4 | 4 Weeks | Cumulative percentage of participants who had sustained resolution (defined as at least 7-day consecutive symptom free) of gastroesophageal reflux disease (GERD) symptom -heartburn at Week 4 (on Day 29) based on the Kaplan-Meier method. |
| Cumulative Percentage of Participants Who Had Sustained Resolution of GERD Symptom -Acid Regurgitation at Week 4 | 4 Weeks | Cumulative percentage of participants who had sustained resolution (defined as at least 7-day consecutive symptom free) of gastroesophageal reflux disease (GERD) symptom -acid regurgitation at Week 4 (on Day 29) based on the Kaplan-Meier method. |
| Percentage of Participants With Healing of RE Who Were Graded O at Week 4 Out of Participants Who Were Graded A to D at Baseline According to Los Angeles Classification | 4 Weeks | Percentage of participants with healing of reflux esophagitis (RE) who were graded O (No RE) at Week 4 out of participants who were graded A (least severe) to D (most severe) at baseline according to Los Angeles classification |
| Cumulative Percentage of Participants Who Had Sustained Resolution of GERD Symptom -Difficulty of Swallowing at Week 4 | 4 Weeks | Cumulative percentage of participants who had sustained resolution (defined as at least 7-day consecutive symptom free) of gastroesophageal reflux disease (GERD) symptom -difficulty of swallowing at Week 4 (on Day 29) based on the Kaplan-Meier method. |
| Cumulative Percentage of Participants Who Had Sustained Resolution of GERD Symptom -Sleep Disturbance at Week 4 | 4 Weeks | Cumulative percentage of participants who had sustained resolution (defined as at least 7-day consecutive symptom free) of gastroesophageal reflux disease (GERD) symptom -sleep disturbance at Week 4 (on Day 29) based on the Kaplan-Meier method. |
| Cumulative Percentage of Participants Who Had Sustained Resolution of GERD Symptom -Abdominal Pain at Week 4 | 4 Weeks | Cumulative percentage of participants who had sustained resolution (defined as at least 7-day consecutive symptom free) of gastroesophageal reflux disease (GERD) symptom -abdominal pain at Week 4 (on Day 29) based on the Kaplan-Meier method. |
Countries
Japan
Participant flow
Recruitment details
First subject enrolled on 25 August 2012. Last subject completed on 30 May 2014.
Pre-assignment details
Out of 1398 enrolled subjects, 287 subjects were randomised and 1111 subjects were not randomised. The reasons of no randomisation were 'Eligibilty criteria not met' (1067 subjects), 'Subject decision' (37 subjects), 'Adverse event' (2 subjects) and other reasons (5 subjects).
Participants by arm
| Arm | Count |
|---|---|
| D961H 20 mg BID D961H 20 mg twice Daily | 145 |
| D961H 20 mg QD + Placebo D961H 20 mg once daily along with placebo | 140 |
| Total | 285 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 6 |
| Overall Study | Eligibility Criteria Not Fulfilled | 0 | 2 |
| Overall Study | Investigator decision | 0 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 2 |
Baseline characteristics
| Characteristic | D961H 20 mg BID | D961H 20 mg QD + Placebo | Total |
|---|---|---|---|
| Age, Continuous | 64.7 Years STANDARD_DEVIATION 13.87 | 61.7 Years STANDARD_DEVIATION 14.72 | 63.2 Years STANDARD_DEVIATION 14.35 |
| Age, Customized <65 | 68 Participants | 69 Participants | 137 Participants |
| Age, Customized >=65 | 77 Participants | 71 Participants | 148 Participants |
| Race/Ethnicity, Customized Asian | 145 Participants | 140 Participants | 285 Participants |
| Sex: Female, Male Female | 69 Participants | 70 Participants | 139 Participants |
| Sex: Female, Male Male | 76 Participants | 70 Participants | 146 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 8 / 145 | 9 / 142 |
| serious Total, serious adverse events | 1 / 145 | 3 / 142 |
Outcome results
Primary
Percentage of Participants With Healing of RE Who Were Graded O at Week 8 Out of Participants Who Were Graded A to D at Baseline According to Los Angeles Classification
Percentage of participants with healing of reflux esophagitis (RE) who were graded O (No RE) at Week 8 out of participants who were graded A (least severe) to D (most severe) at baseline according to Los Angeles classification
Time frame: 8 Weeks
Population: Included all of the randomised participants who were definitely diagnosed to have refractory RE before the randomisation and who had at least one dose of investigational product
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| D961H 20mg Bid | Percentage of Participants With Healing of RE Who Were Graded O at Week 8 Out of Participants Who Were Graded A to D at Baseline According to Los Angeles Classification | 92.4 Percentage of participants |
| D961H 20mg QD + Placebo | Percentage of Participants With Healing of RE Who Were Graded O at Week 8 Out of Participants Who Were Graded A to D at Baseline According to Los Angeles Classification | 68.6 Percentage of participants |
Comparison: To evaluate the efficacy of D20 bid on healing of refractory RE in comparison with D20 qdp-value: <0.000195% CI: [14.9, 32.6]Chi-squared
Secondary
Cumulative Percentage of Participants Who Had Sustained Resolution of GERD Symptom -Abdominal Pain at Week 4
Cumulative percentage of participants who had sustained resolution (defined as at least 7-day consecutive symptom free) of gastroesophageal reflux disease (GERD) symptom -abdominal pain at Week 4 (on Day 29) based on the Kaplan-Meier method.
Time frame: 4 Weeks
Population: Included all of the randomised participants who were definitely diagnosed to have refractory RE before the randomisation and who took at least one dose of investigational product. However, out of these participants, only participants who had the GERD symptom -abdominal pain at baseline were included.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| D961H 20mg Bid | Cumulative Percentage of Participants Who Had Sustained Resolution of GERD Symptom -Abdominal Pain at Week 4 | 68.1 Percentage of participants |
| D961H 20mg QD + Placebo | Cumulative Percentage of Participants Who Had Sustained Resolution of GERD Symptom -Abdominal Pain at Week 4 | 59.1 Percentage of participants |
Comparison: To evaluate the efficacy of D20 bid on gastroesophageal reflux disease (GERD) symptoms in comparison with D20 qdp-value: 0.267895% CI: [0.8, 2.26]Log Rank
Secondary
Cumulative Percentage of Participants Who Had Sustained Resolution of GERD Symptom -Acid Regurgitation at Week 4
Cumulative percentage of participants who had sustained resolution (defined as at least 7-day consecutive symptom free) of gastroesophageal reflux disease (GERD) symptom -acid regurgitation at Week 4 (on Day 29) based on the Kaplan-Meier method.
Time frame: 4 Weeks
Population: Included all of the randomised participants who were definitely diagnosed to have refractory RE before the randomisation and who took at least one dose of investigational product. However, out of these participants, only participants who had the GERD symptom -acid regurgitation at baseline were included.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| D961H 20mg Bid | Cumulative Percentage of Participants Who Had Sustained Resolution of GERD Symptom -Acid Regurgitation at Week 4 | 73.1 Percentage of participants |
| D961H 20mg QD + Placebo | Cumulative Percentage of Participants Who Had Sustained Resolution of GERD Symptom -Acid Regurgitation at Week 4 | 61.2 Percentage of participants |
Comparison: To evaluate the efficacy of D20 bid on gastroesophageal reflux disease (GERD) symptoms in comparison with D20 qdp-value: 0.083795% CI: [0.97, 2.18]Log Rank
Secondary
Cumulative Percentage of Participants Who Had Sustained Resolution of GERD Symptom -Difficulty of Swallowing at Week 4
Cumulative percentage of participants who had sustained resolution (defined as at least 7-day consecutive symptom free) of gastroesophageal reflux disease (GERD) symptom -difficulty of swallowing at Week 4 (on Day 29) based on the Kaplan-Meier method.
Time frame: 4 Weeks
Population: Included all of the randomised participants who were definitely diagnosed to have refractory RE before the randomisation and who took at least one dose of investigational product. However, out of these participants, only participants who had the GERD symptom -difficulty of swallowing at baseline were included.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| D961H 20mg Bid | Cumulative Percentage of Participants Who Had Sustained Resolution of GERD Symptom -Difficulty of Swallowing at Week 4 | 78.6 Percentage of participants |
| D961H 20mg QD + Placebo | Cumulative Percentage of Participants Who Had Sustained Resolution of GERD Symptom -Difficulty of Swallowing at Week 4 | 74.1 Percentage of participants |
Comparison: To evaluate the efficacy of D20 bid on gastroesophageal reflux disease (GERD) symptoms in comparison with D20 qdp-value: 0.638995% CI: [0.62, 2.12]Log Rank
Secondary
Cumulative Percentage of Participants Who Had Sustained Resolution of GERD Symptom -Heartburn at Week 4
Cumulative percentage of participants who had sustained resolution (defined as at least 7-day consecutive symptom free) of gastroesophageal reflux disease (GERD) symptom -heartburn at Week 4 (on Day 29) based on the Kaplan-Meier method.
Time frame: 4 Weeks
Population: Included all of the randomised participants who were definitely diagnosed to have refractory RE before the randomisation and who took at least one dose of investigational product. However, out of these participants, only participants who had the GERD symptom -heartburn at baseline were included.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| D961H 20mg Bid | Cumulative Percentage of Participants Who Had Sustained Resolution of GERD Symptom -Heartburn at Week 4 | 81.1 Percentage of participants |
| D961H 20mg QD + Placebo | Cumulative Percentage of Participants Who Had Sustained Resolution of GERD Symptom -Heartburn at Week 4 | 72.8 Percentage of participants |
Comparison: To evaluate the efficacy of D20 bid on gastroesophageal reflux disease (GERD) symptoms in comparison with D20 qdp-value: 0.145295% CI: [0.91, 1.83]Log Rank
Secondary
Cumulative Percentage of Participants Who Had Sustained Resolution of GERD Symptom -Sleep Disturbance at Week 4
Cumulative percentage of participants who had sustained resolution (defined as at least 7-day consecutive symptom free) of gastroesophageal reflux disease (GERD) symptom -sleep disturbance at Week 4 (on Day 29) based on the Kaplan-Meier method.
Time frame: 4 Weeks
Population: Included all of the randomised participants who were definitely diagnosed to have refractory RE before the randomisation and who took at least one dose of investigational product. However, out of these participants, only participants who had the GERD symptom -sleep disturbance at baseline were included.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| D961H 20mg Bid | Cumulative Percentage of Participants Who Had Sustained Resolution of GERD Symptom -Sleep Disturbance at Week 4 | 91.2 Percentage of participants |
| D961H 20mg QD + Placebo | Cumulative Percentage of Participants Who Had Sustained Resolution of GERD Symptom -Sleep Disturbance at Week 4 | 89.3 Percentage of participants |
Comparison: To evaluate the efficacy of D20 bid on gastroesophageal reflux disease (GERD) symptoms in comparison with D20 qdp-value: 0.448595% CI: [0.8, 2.38]Log Rank
Secondary
Percentage of Participants With Healing of RE Who Were Graded O at Week 4 Out of Participants Who Were Graded A to D at Baseline According to Los Angeles Classification
Percentage of participants with healing of reflux esophagitis (RE) who were graded O (No RE) at Week 4 out of participants who were graded A (least severe) to D (most severe) at baseline according to Los Angeles classification
Time frame: 4 Weeks
Population: Included all of the randomised participants who were definitely diagnosed to have refractory RE before the randomisation and who had at least one dose of investigational product
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| D961H 20mg Bid | Percentage of Participants With Healing of RE Who Were Graded O at Week 4 Out of Participants Who Were Graded A to D at Baseline According to Los Angeles Classification | 81.4 Percentage of participants |
| D961H 20mg QD + Placebo | Percentage of Participants With Healing of RE Who Were Graded O at Week 4 Out of Participants Who Were Graded A to D at Baseline According to Los Angeles Classification | 48.6 Percentage of participants |
Comparison: To evaluate the efficacy of D20 bid on healing of refractory RE in comparison with D20 qdp-value: <0.000195% CI: [21.9, 42.6]Chi-squared