Back to resultsA Double-blind Comparative Study of the Efficacy and Safety of E3810 10mg Once and Twice Daily in Maintenance Therapy for PPI Resistant Gastroesophageal Reflux Disease Patients
Primary Purpose
Gastroesophageal Reflux Disease
Status
Completed
Phase
Phase 3
Locations
Japan
Study Type
Interventional
Intervention
Rabeprazole
Rabeprazole
Rabeprazole
Rabeprazole
Sponsored by
About this trial
This is an interventional treatment trial for Gastroesophageal Reflux Disease focused on measuring Gastroesophageal reflux disease
Eligibility Criteria
Inclusion Criteria:
Subjects fulfilling all of the below criteria shall be eligible for the study:
- Patients diagnosed with gastroesophageal reflux disease who are shown through endoscopic examination to have mucosal lesions (erosions, ulcers)
- Patients shown through endoscopy not to have recovered despite administration of PPI once daily for eight weeks.
- Patients over 20 years of age who have freely given their informed consent in writing to participation in the study.
- Patients who, having received a full explanation of the matters that must be adhered to during the study, intend to adhere to their requirements, and are capable of doing so.
Exclusion Criteria:
Subjects fulfilling any of the following criteria shall be excluded from the study:
- Patients considered candidates for surgical treatment of the upper gastrointestinal tract due to perforation, esophageal stricture, pyloric stenosis, esophageal varices, etc.
- Patients with Zollinger-Ellison syndrome.
- Patients with gastrointestinal hemorrhage.
- Patients with serious cardiovascular disease, cerebrovascular disease, hematological disorders, renal disease, liver disease, malignant tumors, etc.
- Patients with long segment Barrett's esophagus.
- Patients with open gastric or duodenal ulcers.
- Patients with drug allergies or a past history of drug allergies to PPI.
- Patients who are taking other drugs under development, or have done so within 12 weeks prior to enrollment.
- Patients who are, or may be pregnant, patients who wish to become pregnant during the study period, patients who are breastfeeding, and patients or their partners who do not wish to use reliable contraceptive measures.
- Patients with a history of dependence on or abuse of drugs or alcohol within the past two years.
- Other patients deemed unsuitable for inclusion in the study by the principal investigator or sub-investigators.
Sites / Locations
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm Type
Experimental
Experimental
Experimental
Experimental
Arm Label
Arm A
Arm B
Arm C
Arm D
Arm Description
Outcomes
Primary Outcome Measures
Rate of Non-recurrence at Week 52
The non-recurrence rate (at 52 weeks) was determined by the endoscopy central review panel who were blinded to the investigator's assessment, based on the modified Los Angeles Classification using endoscopy photos were submitted by each of the institutions. Participants showing Grade A or above based on the modified Los Angeles Classification were included as a recurrence.
Secondary Outcome Measures
Rate of Non-recurrence at Weeks 12 and 24
The non-recurrence rate (up to 52 weeks) was determined by the endoscopy central review panel who were blinded to the investigator's assessment, based on the modified Los Angeles Classification using endoscopy photos were submitted by each of the institutions. Participants showing Grade A or above based on the modified Los Angeles Classification were included as a recurrence. The 95% CI was calculated by normal approximation.
Cumulative Non-recurrence Rate at Week 52
Non-recurrence rate at Week 52 was estimated using the Kaplan-Meier method.
Percentage of Participants With Heartburn (Daytime / Nighttime) During the Maintenance Therapy Period
A comparison of the rabeprazole 10 mg once daily group and the rabeprazole 10 mg twice daily group was performed for participants who did not exhibit daytime or nighttime heartburn at Week 0 of the Maintenance Therapy Period. Heartburn is a burning sensation in the stomach or lower chest; it is worsened by bending or pressure on the abdomen. Heartburn frequency was rated from 0-day (no) to 7-day (always) and severity was graded on a 3-point scale (mild, moderate, severe). Heartburn was evaluated in the daytime (from wake-up time to time for bed) and nighttime (from time for bed to wake-up time).
Frequency of Heartburn (Daytime / Nighttime) During the Maintenance Therapy Period
A comparison of rabeprazole 10 mg once daily group and the rabeprazole 10 mg twice daily group shall be performed for participants who did not exhibit daytime or nighttime heartburn at 0 weeks of the maintenance therapy period. Daytime and nighttime heartburn, and nighttime sleep disorders shall likewise be compared. For the participants who had recurrence, values at the final evaluation were imputed using a last observation carried forward (LOCF) method.
Severity of Heartburn (Daytime / Nighttime) During the Maintenance Therapy Period
A comparison of the rabeprazole (10 mg once daily group) and the rabeprazole (10 mg twice daily group) was performed for participants who did not exhibit daytime or nighttime heartburn at Week 0 of the Maintenance Therapy Period. The presence or absence of heartburn was assessed by the investigators during medical interviews. The heartburn incidence during each of the 7-day periods immediately before visiting the hospital was assessed on a scale of five stages based on the number of days with symptoms: 0 (no symptoms), 1 to 2 (occasional symptoms), 3 to 4 (sometimes had symptoms), 5 to 6 (often had symptoms), and 7 (always had symptoms). The incidence was tabulated by an analysis classifying the states into two groups: "no symptom group" (0 days with symptoms) and "with symptoms group" (1 day or more with symptoms). The severity of heartburn was as below: Mild (feel heartburn but tolerable), Moderate (feel heartburn and hard), and Severe (feel heartburn and terrible).
Percentage of Participants With Sleep Disorders During the Maintenance Therapy Period
Sleep disorders were defined as the condition of lack of dead sleep and arousal during sleep arising from heartburn or acid reflux. Sleep disorders during each of the 7-day periods immediately before visiting the hospital were assessed. Evaluation of sleep disorders arising from heartburn or acid reflux included recording if sleep-inducing drugs were being taken before enrollment; their type, method of use, and dosage. It was requested that no changes in sleep-inducing drug be made after enrollment. Sleep disorders were rated from 0-day (no) to 7-day (always). The incidence of sleep disorder was tabulated by an analysis classifying the stages into two groups: "No" (0 days with sleep disorder) and "Yes" (1 or more days with sleep disorder). Heartburn was evaluated prior to 7 days of each visit.
Frequency of Sleep Disorders During the Maintenance Therapy Period
Sleep disorders were defined as the condition of lack of dead sleep and arousal during sleep arising from heartburn or acid reflux. Evaluation of sleep disorders arising from heartburn or acid reflux included recording if sleep-inducing drugs were being taken before enrollment; their type, method of use, and dosage. It was requested that no changes in sleep-inducing drug be made after enrollment. Sleep disorders were rated from 0-day (no) to 7-day (always). Heartburn was evaluated prior to 7 days of each visit.
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
Safety was assessed by monitoring and recording all adverse events (AEs) and SAEs, regular monitoring of hematology, clinical chemistry, urine values, and regular measurement of vital signs. All AEs were graded on a 3-point scale; 1) mild was defined as discomfort that did not interfere with normal daily activities, 2) moderate was defined as discomfort that interfered with normal activities, and 3) severe was defined as discomfort that interfered with the ability to work or normal daily activities were impossible. SAEs were medical events that led to death, were life-threatening, required hospitalization or prolongation of hospitalization, caused persistent disability, or resulted in a congenital abnormality. TEAEs were AEs with an onset date on or after the first dose of study drug and up to 30 days after receiving the last dose of study drug. Treatment-related AEs were medical events that were considered by the investigator to be possibly or probably related to rabeprazole.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT02135107
Brief Title
A Double-blind Comparative Study of the Efficacy and Safety of E3810 10mg Once and Twice Daily in Maintenance Therapy for PPI Resistant Gastroesophageal Reflux Disease Patients
Official Title
A Double-blind Comparative Study of the Efficacy and Safety of E3810 10mg Once and Twice Daily in Maintenance Therapy for PPI Resistant Gastroesophageal Reflux Disease Patients
Study Type
Interventional
2. Study Status
Record Verification Date
February 2018
Overall Recruitment Status
Completed
Study Start Date
September 2013 (undefined)
Primary Completion Date
May 2016 (Actual)
Study Completion Date
June 2016 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Eisai Co., Ltd.
4. Oversight
Data Monitoring Committee
No
5. Study Description
Brief Summary
The purpose of this study is to assess the efficacy and safety of rabeprazole 10mg once and twice daily in maintenance therapy for PPI resistant gastroesophageal reflux disease patients.
Detailed Description
This is randomized, multicenter, parallel-group, double-blind trial that investigates the efficacy and safety of rabeprazole 10mg twice daily over a period of 52 weeks. The 8-week Treatment Period (unblinded) was followed by a 52-week Maintenance Period (blinded). Participants with cure (modified Los Angeles Classification Grade N or Grade M) at the final endoscopy of the Treatment Period were entered into the Maintenance Period. Participants without cure were discontinued from the study. The participants in the Treatment Period were randomized to take Arm C or Arm D at a ratio of 1:1. The non-recurrence rate as endoscopically confirmed at 52 weeks shall be the primary end point, and this shall be examined through a randomized, multicenter, parallel-group, double-blind trial that investigates the efficacy and safety of rabeprazole 10mg twice daily over a period of 52 weeks.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Gastroesophageal Reflux Disease
Keywords
Gastroesophageal reflux disease
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
Double
Allocation
Randomized
Enrollment
517 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Arm A
Arm Type
Experimental
Arm Title
Arm B
Arm Type
Experimental
Arm Title
Arm C
Arm Type
Experimental
Arm Title
Arm D
Arm Type
Experimental
Intervention Type
Drug
Intervention Name(s)
Rabeprazole
Other Intervention Name(s)
E3810
Intervention Description
Rabeprazole 10 mg was administered orally twice daily during the treatment period for 8 weeks (unblinded).
Intervention Type
Drug
Intervention Name(s)
Rabeprazole
Other Intervention Name(s)
E3810
Intervention Description
Rabeprazole 20 mg was administered orally twice daily during the treatment period for 8 weeks (unblinded).
Intervention Type
Drug
Intervention Name(s)
Rabeprazole
Other Intervention Name(s)
E3810
Intervention Description
Rabeprazole 10 mg or 20 mg were administered orally twice daily during the treatment period (unblinded), and 10 mg was administered once daily during the maintenance period (double-blind).
Intervention Type
Drug
Intervention Name(s)
Rabeprazole
Other Intervention Name(s)
E3810
Intervention Description
Rabeprazole 10 or 20 mg were administered orally twice daily during the treatment period (unblinded), and 10 mg was administered twice daily during the maintenance period (double-blind).
Primary Outcome Measure Information:
Title
Rate of Non-recurrence at Week 52
Description
The non-recurrence rate (at 52 weeks) was determined by the endoscopy central review panel who were blinded to the investigator's assessment, based on the modified Los Angeles Classification using endoscopy photos were submitted by each of the institutions. Participants showing Grade A or above based on the modified Los Angeles Classification were included as a recurrence.
Time Frame
Week 52
Secondary Outcome Measure Information:
Title
Rate of Non-recurrence at Weeks 12 and 24
Description
The non-recurrence rate (up to 52 weeks) was determined by the endoscopy central review panel who were blinded to the investigator's assessment, based on the modified Los Angeles Classification using endoscopy photos were submitted by each of the institutions. Participants showing Grade A or above based on the modified Los Angeles Classification were included as a recurrence. The 95% CI was calculated by normal approximation.
Time Frame
Weeks 12 and 24
Title
Cumulative Non-recurrence Rate at Week 52
Description
Non-recurrence rate at Week 52 was estimated using the Kaplan-Meier method.
Time Frame
Week 52
Title
Percentage of Participants With Heartburn (Daytime / Nighttime) During the Maintenance Therapy Period
Description
A comparison of the rabeprazole 10 mg once daily group and the rabeprazole 10 mg twice daily group was performed for participants who did not exhibit daytime or nighttime heartburn at Week 0 of the Maintenance Therapy Period. Heartburn is a burning sensation in the stomach or lower chest; it is worsened by bending or pressure on the abdomen. Heartburn frequency was rated from 0-day (no) to 7-day (always) and severity was graded on a 3-point scale (mild, moderate, severe). Heartburn was evaluated in the daytime (from wake-up time to time for bed) and nighttime (from time for bed to wake-up time).
Time Frame
From Week 4 up to Week 52
Title
Frequency of Heartburn (Daytime / Nighttime) During the Maintenance Therapy Period
Description
A comparison of rabeprazole 10 mg once daily group and the rabeprazole 10 mg twice daily group shall be performed for participants who did not exhibit daytime or nighttime heartburn at 0 weeks of the maintenance therapy period. Daytime and nighttime heartburn, and nighttime sleep disorders shall likewise be compared. For the participants who had recurrence, values at the final evaluation were imputed using a last observation carried forward (LOCF) method.
Time Frame
From Week 4 up to Week 52
Title
Severity of Heartburn (Daytime / Nighttime) During the Maintenance Therapy Period
Description
A comparison of the rabeprazole (10 mg once daily group) and the rabeprazole (10 mg twice daily group) was performed for participants who did not exhibit daytime or nighttime heartburn at Week 0 of the Maintenance Therapy Period. The presence or absence of heartburn was assessed by the investigators during medical interviews. The heartburn incidence during each of the 7-day periods immediately before visiting the hospital was assessed on a scale of five stages based on the number of days with symptoms: 0 (no symptoms), 1 to 2 (occasional symptoms), 3 to 4 (sometimes had symptoms), 5 to 6 (often had symptoms), and 7 (always had symptoms). The incidence was tabulated by an analysis classifying the states into two groups: "no symptom group" (0 days with symptoms) and "with symptoms group" (1 day or more with symptoms). The severity of heartburn was as below: Mild (feel heartburn but tolerable), Moderate (feel heartburn and hard), and Severe (feel heartburn and terrible).
Time Frame
From Week 4 up to Week 52
Title
Percentage of Participants With Sleep Disorders During the Maintenance Therapy Period
Description
Sleep disorders were defined as the condition of lack of dead sleep and arousal during sleep arising from heartburn or acid reflux. Sleep disorders during each of the 7-day periods immediately before visiting the hospital were assessed. Evaluation of sleep disorders arising from heartburn or acid reflux included recording if sleep-inducing drugs were being taken before enrollment; their type, method of use, and dosage. It was requested that no changes in sleep-inducing drug be made after enrollment. Sleep disorders were rated from 0-day (no) to 7-day (always). The incidence of sleep disorder was tabulated by an analysis classifying the stages into two groups: "No" (0 days with sleep disorder) and "Yes" (1 or more days with sleep disorder). Heartburn was evaluated prior to 7 days of each visit.
Time Frame
From Week 4 up to Week 52
Title
Frequency of Sleep Disorders During the Maintenance Therapy Period
Description
Sleep disorders were defined as the condition of lack of dead sleep and arousal during sleep arising from heartburn or acid reflux. Evaluation of sleep disorders arising from heartburn or acid reflux included recording if sleep-inducing drugs were being taken before enrollment; their type, method of use, and dosage. It was requested that no changes in sleep-inducing drug be made after enrollment. Sleep disorders were rated from 0-day (no) to 7-day (always). Heartburn was evaluated prior to 7 days of each visit.
Time Frame
From Week 4 up to Week 52
Title
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
Description
Safety was assessed by monitoring and recording all adverse events (AEs) and SAEs, regular monitoring of hematology, clinical chemistry, urine values, and regular measurement of vital signs. All AEs were graded on a 3-point scale; 1) mild was defined as discomfort that did not interfere with normal daily activities, 2) moderate was defined as discomfort that interfered with normal activities, and 3) severe was defined as discomfort that interfered with the ability to work or normal daily activities were impossible. SAEs were medical events that led to death, were life-threatening, required hospitalization or prolongation of hospitalization, caused persistent disability, or resulted in a congenital abnormality. TEAEs were AEs with an onset date on or after the first dose of study drug and up to 30 days after receiving the last dose of study drug. Treatment-related AEs were medical events that were considered by the investigator to be possibly or probably related to rabeprazole.
Time Frame
From date of first dose up to 30 days after the last dose of study drug, up to approximately 1 year 3 months (Treatment Period; 8 weeks, Maintenance Therapy Period; 52 weeks, and Follow-up Period; 30 days)
10. Eligibility
Sex
All
Minimum Age & Unit of Time
20 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Subjects fulfilling all of the below criteria shall be eligible for the study:
Patients diagnosed with gastroesophageal reflux disease who are shown through endoscopic examination to have mucosal lesions (erosions, ulcers)
Patients shown through endoscopy not to have recovered despite administration of PPI once daily for eight weeks.
Patients over 20 years of age who have freely given their informed consent in writing to participation in the study.
Patients who, having received a full explanation of the matters that must be adhered to during the study, intend to adhere to their requirements, and are capable of doing so.
Exclusion Criteria:
Subjects fulfilling any of the following criteria shall be excluded from the study:
Patients considered candidates for surgical treatment of the upper gastrointestinal tract due to perforation, esophageal stricture, pyloric stenosis, esophageal varices, etc.
Patients with Zollinger-Ellison syndrome.
Patients with gastrointestinal hemorrhage.
Patients with serious cardiovascular disease, cerebrovascular disease, hematological disorders, renal disease, liver disease, malignant tumors, etc.
Patients with long segment Barrett's esophagus.
Patients with open gastric or duodenal ulcers.
Patients with drug allergies or a past history of drug allergies to PPI.
Patients who are taking other drugs under development, or have done so within 12 weeks prior to enrollment.
Patients who are, or may be pregnant, patients who wish to become pregnant during the study period, patients who are breastfeeding, and patients or their partners who do not wish to use reliable contraceptive measures.
Patients with a history of dependence on or abuse of drugs or alcohol within the past two years.
Other patients deemed unsuitable for inclusion in the study by the principal investigator or sub-investigators.
Facility Information:
City
Nagoya
State/Province
Aichi
Country
Japan
City
Inzai
State/Province
Chiba
Country
Japan
City
Kamagaya
State/Province
Chiba
Country
Japan
City
Matsuyama
State/Province
Ehime
Country
Japan
City
Kitakyushu
State/Province
Fukuoka
Country
Japan
City
Onga
State/Province
Fukuoka
Country
Japan
City
Koriyama
State/Province
Fukushima
Country
Japan
City
Annaka
State/Province
Gunma
Country
Japan
City
Fukuyama
State/Province
Hiroshima
Country
Japan
City
Asahikawa
State/Province
Hokkaido
Country
Japan
City
Ishikari
State/Province
Hokkaido
Country
Japan
City
Sapporo
State/Province
Hokkaido
Country
Japan
City
Amagasaki
State/Province
Hyogo
Country
Japan
City
Kobe
State/Province
Hyogo
Country
Japan
City
Nishinomiya
State/Province
Hyogo
Country
Japan
City
Furukawa
State/Province
Ibaraki
Country
Japan
City
Tsuchiura
State/Province
Ibaraki
Country
Japan
City
Takamatsu
State/Province
Kagawa
Country
Japan
City
Ichikikushikino-shi
State/Province
Kagoshima
Country
Japan
City
Kamakura
State/Province
Kanagawa
Country
Japan
City
Kawasaki
State/Province
Kanagawa
Country
Japan
City
Yokohama
State/Province
Kanagawa
Country
Japan
City
Sendai
State/Province
Miyagi
Country
Japan
City
Suwa
State/Province
Nagano
Country
Japan
City
Beppu
State/Province
Oita
Country
Japan
City
Fujiidera
State/Province
Osaka
Country
Japan
City
Hirakata
State/Province
Osaka
Country
Japan
City
Kishiwada
State/Province
Osaka
Country
Japan
City
Takatsuki
State/Province
Osaka
Country
Japan
City
Karatsu
State/Province
Saga
Country
Japan
City
Ureshino
State/Province
Saga
Country
Japan
City
Ageo
State/Province
Saitama
Country
Japan
City
Hiki
State/Province
Saitama
Country
Japan
City
Toda
State/Province
Saitama
Country
Japan
City
Wako
State/Province
Saitama
Country
Japan
City
Izumo
State/Province
Shimane
Country
Japan
City
Fujieda
State/Province
Shizuoka
Country
Japan
City
Hamamatsu
State/Province
Shizuoka
Country
Japan
City
Ōtawara
State/Province
Tochigi
Country
Japan
City
Adachi
State/Province
Tokyo
Country
Japan
City
Bunkyo
State/Province
Tokyo
Country
Japan
City
Chuo
State/Province
Tokyo
Country
Japan
City
Koto
State/Province
Tokyo
Country
Japan
City
Minato
State/Province
Tokyo
Country
Japan
City
Nerima
State/Province
Tokyo
Country
Japan
City
Ota
State/Province
Tokyo
Country
Japan
City
Setagaya
State/Province
Tokyo
Country
Japan
City
Shibuya
State/Province
Tokyo
Country
Japan
City
Shinagawa
State/Province
Tokyo
Country
Japan
City
Toshima
State/Province
Tokyo
Country
Japan
City
Akita
Country
Japan
City
Fukuoka
Country
Japan
City
Hiroshima
Country
Japan
City
Kochi
Country
Japan
City
Kyoto
Country
Japan
City
Nagasaki
Country
Japan
City
Oita
Country
Japan
City
Osaka
Country
Japan
City
Saga
Country
Japan
City
Saitama
Country
Japan
City
Yamagata
Country
Japan
12. IPD Sharing Statement
Citations:
PubMed Identifier
29188387
Citation
Kinoshita Y, Kato M, Fujishiro M, Masuyama H, Nakata R, Abe H, Kumagai S, Fukushima Y, Okubo Y, Hojo S, Kusano M. Efficacy and safety of twice-daily rabeprazole maintenance therapy for patients with reflux esophagitis refractory to standard once-daily proton pump inhibitor: the Japan-based EXTEND study. J Gastroenterol. 2018 Jul;53(7):834-844. doi: 10.1007/s00535-017-1417-z. Epub 2017 Nov 29.
Results Reference
derived
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A Double-blind Comparative Study of the Efficacy and Safety of E3810 10mg Once and Twice Daily in Maintenance Therapy for PPI Resistant Gastroesophageal Reflux Disease Patients
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