Gastroesophageal Reflux
Conditions
Keywords
Acid reflux disease, Gastroesophageal Reflux Disease
Brief summary
The study investigates the efficacy of long-term treatment of esomeprazole compared to anti-reflux surgery in the control of gastroesophageal reflux disease by assessing time to treatment failure.
Interventions
DRUGesomeprazole
40 mg oral tablet administered daily
PROCEDURELaparoscopic fundoplication (surgery)
Surgery
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Subjects considered suitable for surgical treatment and long-term management of esomeprazole. * History of chronic reflux esophagitis or symptomatic GERD
Exclusion criteria
* History of esophageal, gastric, or duodenal surgery predicted to influence negatively on subsequent treatment within the study. * Contraindication to the study drug. * Pregnancy, lactating or of child-bearing potential.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment Failure at 5 Years | During 5 years | Treatment failure in the surgical arm defined when need for medical treatment for control of symptoms from reflux disease. Treatment failure in the medical arm defined when need for treatment other than esomeprazole for control of symptoms of reflux disease. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Investigator-assessed Heartburn Severity at 5 Year Visit, Participants With no Heartburn | At 5 year visit | Presence of heartburn assessed retrospectively by the investigator. Classified by severity (none, mild, moderate, severe) Participants with no heartburn |
| Total Score for Microscopic Reflux-related Changes in the Distal Esophagus 2 cm Above the Z-line, at 5 Year Visit | At 5 year visit | The total score expressed as a mean of all the scores/number of lesions assessed; scored 2 when erosion/necrosis is found. The score could range from 0 to 2 (maximum severity). Only participants with biopsy at 5 years visit included |
| Percentage Time With pH<4 During 24-hour pH Metry at 5 Year Visit | At 5 year visit | Intra-gastric acid exposures assessed by 24-h pH-metry. Only participants with pH-emtry performed at 5 year visit included |
| Los Angeles (LA) Grade 'A' at 5 Year Visit | At 5 year visit | Endoscopic findings classified according to the Los Angeles classification: Grade Normal - endoscopy reveals no mucosal break Grade A- one or more mucosal breaks \<5 mm in maximal length Grade B - one or more mucosal breaks \>5 mm, but without continuity across mucosal folds Grade C - Mucosal breaks continuous between \>2 mucosal folds, but involving less than 75% of the esophageal circumference Grade D - Mucosal breaks involving more than 75% of the esophageal circumference |
| Los Angeles (LA) Grade 'Normal' at 5 Year Visit | At 5 year visit | Endoscopic findings classified according to the Los Angeles classification: Grade Normal - endoscopy reveals no mucosal break Grade A- one or more mucosal breaks \<5 mm in maximal length Grade B - one or more mucosal breaks \>5 mm, but without continuity across mucosal folds Grade C - Mucosal breaks continuous between \>2 mucosal folds, but involving less than 75% of the esophageal circumference Grade D - Mucosal breaks involving more than 75% of the esophageal circumference |
| Los Angeles (LA) Grade C at 5 Year Visit | At 5 year visit | Endoscopic findings classified according to the Los Angeles classification: Grade Normal - endoscopy reveals no mucosal break Grade A- one or more mucosal breaks \<5 mm in maximal length Grade B - one or more mucosal breaks \>5 mm, but without continuity across mucosal folds Grade C - Mucosal breaks continuous between \>2 mucosal folds, but involving less than 75% of the esophageal circumference Grade D - Mucosal breaks involving more than 75% of the esophageal circumference |
| Investigator-assessed Heartburn Severity at 5 Year Visit, Participants With Mild Heartburn | At 5 year visit | Presence of heartburn assessed retrospectively by the investigator. Classified by severity (none, mild, moderate, severe). Participants with mild heartburn |
| Investigator-assessed Heartburn Severity at 5 Year Visit, Participants With Moderate Heartburn | At 5 year visit | Presence of heartburn assessed retrospectively by the investigator. Classified by severity (none, mild, moderate, severe). Participants with moderate heartburn |
| Investigator-assessed Heartburn Severity at 5 Year Visit, Participants With Severe Heartburn | At 5 year visit | Presence of heartburn assessed retrospectively by the investigator. Classified by severity (none, mild, moderate, severe). Participants with severe heartburn |
| Los Angeles (LA) Grade 'B' at 5 Year Visit | At 5 year visit | Endoscopic findings classified according to the Los Angeles classification: Grade Normal - endoscopy reveals no mucosal break Grade A- one or more mucosal breaks \<5 mm in maximal length Grade B - one or more mucosal breaks \>5 mm, but without continuity across mucosal folds Grade C - Mucosal breaks continuous between \>2 mucosal folds, but involving less than 75% of the esophageal circumference Grade D - Mucosal breaks involving more than 75% of the esophageal circumference |
Countries
Austria, Belgium, Denmark, Finland, France, Germany, Iceland, Italy, Netherlands, Norway, Sweden, United Kingdom
Participant flow
Recruitment details
The first patient was enrolled on 16 October 2001. Last patient completed the last visit on 07 April 2009.
Pre-assignment details
The study started with a 12-week run-in period. Patients had either been treated or untreated with a proton pump inhibitor (PPI) prior to entering this phase of the study.
Participants by arm
| Arm | Count |
|---|---|
| Esomeprazole Surgical Arm Esomeprazole 40 mg once daily during a 12-week run-in period, followed by laparoscopic anti-reflux fundoplication anti-reflux surgery. | 288 |
| Esomeprazole Medical Arm Esomeprazole 40 mg once daily during a 12-week run-in period, followed by esomeprazole treatment (start dose 20 mg once daily, if needed adjusted to 40 mg once daily) | 266 |
| Total | 554 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 3 | 15 |
| Overall Study | Lack of Efficacy | 22 | 16 |
| Overall Study | Lost to Follow-up | 22 | 8 |
| Overall Study | Pregnancy | 2 | 0 |
| Overall Study | Protocol Violation | 1 | 2 |
| Overall Study | Study procedure non-compliance | 5 | 6 |
| Overall Study | Study-specific discont. achieved | 13 | 2 |
| Overall Study | Withdrawal by Subject | 40 | 25 |
Baseline characteristics
| Characteristic | Esomeprazole Surgical Arm | Esomeprazole Medical Arm | Total |
|---|---|---|---|
| Age Continuous | 44.8 Years STANDARD_DEVIATION 10.9 | 45.3 Years STANDARD_DEVIATION 11.5 | 45.05 Years STANDARD_DEVIATION 11.2 |
| Sex: Female, Male Female | 89 Participants | 67 Participants | 156 Participants |
| Sex: Female, Male Male | 199 Participants | 199 Participants | 398 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 | 0 / 248 | 0 / 266 | 0 / 40 |
| serious Total, serious adverse events | 103 / 248 | 101 / 266 | 3 / 40 |
Outcome results
Primary
Number of Participants With Treatment Failure at 5 Years
Treatment failure in the surgical arm defined when need for medical treatment for control of symptoms from reflux disease. Treatment failure in the medical arm defined when need for treatment other than esomeprazole for control of symptoms of reflux disease.
Time frame: During 5 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Esomeprazole Surgical Arm | Number of Participants With Treatment Failure at 5 Years | 33 participants |
| Esomeprazole Medical Arm | Number of Participants With Treatment Failure at 5 Years | 19 participants |
Secondary
Investigator-assessed Heartburn Severity at 5 Year Visit, Participants With Mild Heartburn
Presence of heartburn assessed retrospectively by the investigator. Classified by severity (none, mild, moderate, severe). Participants with mild heartburn
Time frame: At 5 year visit
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Esomeprazole Surgical Arm | Investigator-assessed Heartburn Severity at 5 Year Visit, Participants With Mild Heartburn | 11 participants |
| Esomeprazole Medical Arm | Investigator-assessed Heartburn Severity at 5 Year Visit, Participants With Mild Heartburn | 25 participants |
Secondary
Investigator-assessed Heartburn Severity at 5 Year Visit, Participants With Moderate Heartburn
Presence of heartburn assessed retrospectively by the investigator. Classified by severity (none, mild, moderate, severe). Participants with moderate heartburn
Time frame: At 5 year visit
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Esomeprazole Surgical Arm | Investigator-assessed Heartburn Severity at 5 Year Visit, Participants With Moderate Heartburn | 3 participants |
| Esomeprazole Medical Arm | Investigator-assessed Heartburn Severity at 5 Year Visit, Participants With Moderate Heartburn | 3 participants |
Secondary
Investigator-assessed Heartburn Severity at 5 Year Visit, Participants With no Heartburn
Presence of heartburn assessed retrospectively by the investigator. Classified by severity (none, mild, moderate, severe) Participants with no heartburn
Time frame: At 5 year visit
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Esomeprazole Surgical Arm | Investigator-assessed Heartburn Severity at 5 Year Visit, Participants With no Heartburn | 163 participants |
| Esomeprazole Medical Arm | Investigator-assessed Heartburn Severity at 5 Year Visit, Participants With no Heartburn | 161 participants |
Secondary
Investigator-assessed Heartburn Severity at 5 Year Visit, Participants With Severe Heartburn
Presence of heartburn assessed retrospectively by the investigator. Classified by severity (none, mild, moderate, severe). Participants with severe heartburn
Time frame: At 5 year visit
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Esomeprazole Surgical Arm | Investigator-assessed Heartburn Severity at 5 Year Visit, Participants With Severe Heartburn | 0 participants |
| Esomeprazole Medical Arm | Investigator-assessed Heartburn Severity at 5 Year Visit, Participants With Severe Heartburn | 2 participants |
Secondary
Los Angeles (LA) Grade 'A' at 5 Year Visit
Endoscopic findings classified according to the Los Angeles classification: Grade Normal - endoscopy reveals no mucosal break Grade A- one or more mucosal breaks \<5 mm in maximal length Grade B - one or more mucosal breaks \>5 mm, but without continuity across mucosal folds Grade C - Mucosal breaks continuous between \>2 mucosal folds, but involving less than 75% of the esophageal circumference Grade D - Mucosal breaks involving more than 75% of the esophageal circumference
Time frame: At 5 year visit
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Esomeprazole Surgical Arm | Los Angeles (LA) Grade 'A' at 5 Year Visit | 12 participants |
| Esomeprazole Medical Arm | Los Angeles (LA) Grade 'A' at 5 Year Visit | 16 participants |
Secondary
Los Angeles (LA) Grade 'B' at 5 Year Visit
Endoscopic findings classified according to the Los Angeles classification: Grade Normal - endoscopy reveals no mucosal break Grade A- one or more mucosal breaks \<5 mm in maximal length Grade B - one or more mucosal breaks \>5 mm, but without continuity across mucosal folds Grade C - Mucosal breaks continuous between \>2 mucosal folds, but involving less than 75% of the esophageal circumference Grade D - Mucosal breaks involving more than 75% of the esophageal circumference
Time frame: At 5 year visit
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Esomeprazole Surgical Arm | Los Angeles (LA) Grade 'B' at 5 Year Visit | 5 participants |
| Esomeprazole Medical Arm | Los Angeles (LA) Grade 'B' at 5 Year Visit | 7 participants |
Secondary
Los Angeles (LA) Grade C at 5 Year Visit
Endoscopic findings classified according to the Los Angeles classification: Grade Normal - endoscopy reveals no mucosal break Grade A- one or more mucosal breaks \<5 mm in maximal length Grade B - one or more mucosal breaks \>5 mm, but without continuity across mucosal folds Grade C - Mucosal breaks continuous between \>2 mucosal folds, but involving less than 75% of the esophageal circumference Grade D - Mucosal breaks involving more than 75% of the esophageal circumference
Time frame: At 5 year visit
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Esomeprazole Surgical Arm | Los Angeles (LA) Grade C at 5 Year Visit | 1 participants |
| Esomeprazole Medical Arm | Los Angeles (LA) Grade C at 5 Year Visit | 2 participants |
Secondary
Los Angeles (LA) Grade 'Normal' at 5 Year Visit
Endoscopic findings classified according to the Los Angeles classification: Grade Normal - endoscopy reveals no mucosal break Grade A- one or more mucosal breaks \<5 mm in maximal length Grade B - one or more mucosal breaks \>5 mm, but without continuity across mucosal folds Grade C - Mucosal breaks continuous between \>2 mucosal folds, but involving less than 75% of the esophageal circumference Grade D - Mucosal breaks involving more than 75% of the esophageal circumference
Time frame: At 5 year visit
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Esomeprazole Surgical Arm | Los Angeles (LA) Grade 'Normal' at 5 Year Visit | 144 participants |
| Esomeprazole Medical Arm | Los Angeles (LA) Grade 'Normal' at 5 Year Visit | 158 participants |
Secondary
Percentage Time With pH<4 During 24-hour pH Metry at 5 Year Visit
Intra-gastric acid exposures assessed by 24-h pH-metry. Only participants with pH-emtry performed at 5 year visit included
Time frame: At 5 year visit
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Esomeprazole Surgical Arm | Percentage Time With pH<4 During 24-hour pH Metry at 5 Year Visit | 2.9 percentage of time recorded | Standard Deviation 7 |
| Esomeprazole Medical Arm | Percentage Time With pH<4 During 24-hour pH Metry at 5 Year Visit | 4.7 percentage of time recorded | Standard Deviation 7 |
Secondary
Total Score for Microscopic Reflux-related Changes in the Distal Esophagus 2 cm Above the Z-line, at 5 Year Visit
The total score expressed as a mean of all the scores/number of lesions assessed; scored 2 when erosion/necrosis is found. The score could range from 0 to 2 (maximum severity). Only participants with biopsy at 5 years visit included
Time frame: At 5 year visit
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Esomeprazole Surgical Arm | Total Score for Microscopic Reflux-related Changes in the Distal Esophagus 2 cm Above the Z-line, at 5 Year Visit | 0.23 units on a scale | Standard Error 0.1 |
| Esomeprazole Medical Arm | Total Score for Microscopic Reflux-related Changes in the Distal Esophagus 2 cm Above the Z-line, at 5 Year Visit | 0.25 units on a scale | Standard Error 0.03 |