Gastroesophageal Reflux
Conditions
Keywords
Drug therapy
Brief summary
The purpose of this study is to determine the effect of vonoprazan compared to esomeprazole for preventing heartburn symptoms over a 4-week treatment period in participants who have a partial response to treatment with esomeprazole.
Detailed description
The drug being tested in this study is called vonoprazan. Vonoprazan is being tested to treat people who have symptomatic gastroesophageal reflux disease (GERD) with a partial response to treatment with a high dose of esomeprazole. This study will look at improvement in heartburn symptoms in participants who take vonoprazan compared to esomeprazole. The study will enroll approximately 213 patients. All participants will receive esomeprazole or esomeprazole placebo-matching capsules (this is a capsule that looks like esomeprazole but has no active ingredient) during a 7-week run-in period. Participants will then be randomly assigned (by chance, like flipping a coin) to one of the three treatment groups-which will remain undisclosed to the patient and study doctor during the study (unless there is an urgent medical need): * Esomeprazole 40 mg * Vonoprazan 20 mg * Vonoprazan 40 mg All participants will be asked to take one capsule at the same time each day throughout the study. All participants will be asked to record heartburn symptoms in a diary every morning upon waking and every evening before going to sleep. This multi-center trial will be conducted in Europe. The overall time to participate in this study is 12 weeks. Participants will make multiple visits to the clinic, and will be contacted by telephone 1 week after the last dose of study drug for a follow-up assessment.
Interventions
DRUGVonoprazan
Vonoprazan over-encapsulated capsules
DRUGEsomeprazole
Esomeprazole over-encapsulated tablets
Esomeprazole placebo-matching capsules
Sponsors
Takeda
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. In the opinion of the investigator, the participant is capable of understanding and complying with protocol requirements. 2. The participant or, when applicable, the participant's legally acceptable representative signs and dates a written, informed consent form and any required privacy authorization prior to the initiation of any study procedures. 3. Is a man or a woman and ≥18 years of age, at the time of the Screening visit. 4. Has a documented history of symptoms of both heartburn (burning pain) and acid regurgitation prior to entry into the study. 5. The subject has a medical history of ≥ 8 weeks of persistent heartburn symptoms in the presence of regurgitation symptoms (persistent heartburn symptoms defined as heartburn symptoms on ≥ 2 days a week) that are troublesome despite appropriate and correctly performed treatment with a PPI at standard doses. 6. Is ≥85% compliant at taking their Run-in medication and completing their e-Diary. Compliance for taking the Run-in medication is defined as the medication provided (esomeprazole and placebo) taken for 85% of the 6 weeks Run-in Period (or on 36 of 42 days of the Run-in Period).Compliance for the e-Diary is defined as the percentage of scheduled assessments that are completed based on 2 assessments per day (daytime and nighttime). For randomization, 85% compliance is required and is defined as 12 of 14 assessments completed over the 7-day period (Day -21 to Day-14) prior to the single blind Placebo Run-in Period. 7. Has a partial response to a PPI defined as having heartburn on 2 to 5 days and regurgitation on at least one day of the last week (Week 4) of a 4 week PPI Run-In Period with esomeprazole 40 mg and an increase of at least 2 symptom days of heartburn in the last week of a 2 week Placebo Run-In Period (4 to 7 symptom days) and at least one symptom day with regurgitation compared with the last week of the PPI Run-In Period. 8. A female participant of childbearing potential who is sexually active with a nonsterilized male partner agrees to use routinely adequate contraception from signing of informed consent throughout the duration of the study and for 4 weeks after last dose of the study medication.
Exclusion criteria
1. Has received any investigational compound within 30 days prior to the Screening Visit. 2. Has received vonoprazan in a previous clinical study. 3. Is an immediate family member, study site employee, is in a dependent relationship with a study site employee who is involved in conduct of this study (eg, spouse, parent, child, sibling), or may have consented under duress. 4. Has, in the judgment of the investigator, clinically significant abnormal hematological parameters of hemoglobin, hematocrit, or erythrocytes at Screening. 5. Has a history of erosive esophagitis of Los Angeles (LA) Classification Grade B severity or worse prior to screening or at Screening endoscopy. 6. Has a history of or any coexisting diseases affecting the esophagus (eg, Barrett's esophagus, eosinophilic esophagitis, esophageal varices, scleroderma, viral or fungal infection, or esophageal stricture), history of radiation therapy or cryotherapy to the esophagus, caustic trauma, or physiochemical trauma such as sclerotherapy to the esophagus. 7. Has alarm features in symptomatology, including odynophagia, severe dysphagia, bleeding, weight loss, anemia, and blood in stool, pointing to a possible malignant disease of the gastrointestinal (GI) tract. Participants displaying alarm symptoms in addition to the typical gastroesophageal reflux disease (GERD) symptoms may be included based on endoscopic exclusion of malignancy. 8. Has current or historical chest pain due to cardiac diseases (eg, within one year). 9. Has had surgical treatment for GERD (eg, cardiaplasty), dilation of an esophageal stricture (other than Schatzki ring) or gastric or duodenal surgery, except simple oversew of an ulcer or endoscopic polypectomy of benign polyps. 10. Has active gastric or duodenal ulcers which have been confirmed by endoscopy within 30 days prior to Screening. Gastric or duodenal erosions are not exclusionary, unless considered severe and symptomatic by the investigator. 11. Has had an acute upper gastrointestinal hemorrhage within 30 days prior to Screening. 12. Has current or historical evidence of Zollinger-Ellison syndrome or other hypersecretory condition. 13. Has current or historical evidence of eosinophilic esophagitis (evidence may be based on the following: missing response to acid suppressive therapy, the presence of eosinophilia in histological probes of the esophageal mucosa, a normal pH profile of the distal esophagus, symptoms of dysphagia and food impaction). The exclusion of participants based on a predominance of the typical eosinophilic esophagitis symptoms only (as above) is considered acceptable. However, in participants with a predominance of typical symptoms and co-existing significant dysphagia and food impaction, the syndrome should be excluded by endoscopy with biopsy. 14. Has a documented history (within 6 months prior to screening) of functional dyspepsia (suggested by the presence of one or more of the following symptoms: epigastric pain, postprandial fullness or early satiety), or irritable bowel syndrome or other gastrointestinal diseases which are not acid-related, and therefore, are nonresponsive to gastric acid-blocking treatment. 15. Has a documented history of familial adenomatous polyposis. 16. Has known intolerance, hypersensitivity or allergies to any PPI or their components (including lansoprazole, dexlansoprazole, omeprazole, rabeprazole, pantoprazole, or esomeprazole), any component of vonoprazan, or antacid(s) selected as rescue medication for this study. 17. Has a history of alcohol abuse, illegal drug use, or drug addiction within the 12 months prior to Screening, or regularly consumes \>21 units of alcohol (1 unit = 12 oz/300 mL beer, 1.5 oz/25 mL hard liquor/spirits, or 5 oz/100 mL wine) per week. Participants must have a negative drug screen at Screening. 18. Has evidence of a serious uncontrolled concomitant disease including: clinically significant neurologic, cardiovascular, pulmonary, hepatic, renal, metabolic, gastrointestinal, systemic, or endocrine disease or other abnormality (other than the disease being studied), which may impact the ability of the participant to participate or potentially confound the study results. 19. Has planned, or is likely to require, in-patient surgery during the course of the study. 20. Has a history of cancer (except basal cell carcinoma of the skin) within 3 years prior to Screening. 21. Is known to have acquired immunodeficiency syndrome or chronic hepatitis due to any etiology. 22. Has abnormal laboratory values at Screening that suggest a clinically significant underlying disease or condition that may prevent the participant from completing the study. 23. Has an alanine aminotransferase (ALT), aspartate aminotransferase (AST) or T-bilirubin level which exceeds upper limit of normal (ULN) set by the testing laboratory at the Screening. 24. If female, the participant is pregnant or lactating or intending to become pregnant before, during, or within 1 month after participating in this study; or intending to donate ova during such time period. 25. Is required to take excluded medications or it is anticipated that the participant will require treatment with at least 1 of the disallowed concomitant medications during the study. 26. 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 Heartburn-Free 24-Hour Periods (Day and Night) During 4 Weeks of Treatment | 4 Weeks | Participants used the Reflux Symptom Questionnaire Electronic Diary (RESQ-eD) every morning upon waking and every evening before going to sleep to document the presence of daytime and nighttime heartburn and regurgitation. The percentage of heartburn-free (HBF) 24-hour periods was calculated for each participant using the following formula: (total 24-hour periods that are heartburn free / total 24-hour periods for which both a daytime and nighttime result is marked) x 100%. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With ≥1 Sustained Resolution of Heartburn During the 4-Week Treatment Period | 4 Weeks | ≥1 sustained resolution of heartburn is defined as ≥7 consecutive days without both daytime and nighttime heartburn anytime during the 4-week treatment period. Daytime and nighttime heartburn were documented by all participants using the Reflux Symptom Questionnaire Electronic Diary (RESQ-eD). |
Countries
Belgium, Bulgaria, Czechia, Estonia, Poland, United Kingdom
Participant flow
Recruitment details
Participants took part in the study at 33 investigative sites in Belgium, Bulgaria, Czech Republic, Estonia, Poland and United Kingdom from 14 July 2016 to 12 October 2018.
Pre-assignment details
Participants with a symptomatic gastro-esophageal reflux disease who have a partial response following treatment with a high dose of proton pump inhibitor were enrolled in a 1:1:1 ratio to receive esomeprazole 40 mg, vonoprazan 20 mg, or vonoprazan 40 mg.
Participants by arm
| Arm | Count |
|---|---|
| Esomeprazole 40 mg Esomeprazole 40 mg over-encapsulated tablets, orally, once daily for 4 weeks then esomeprazole placebo-matching capsules, orally, once daily for 2 weeks during the run-in period, followed by esomeprazole 40 mg, over-encapsulated tablets, orally, once daily for 4 weeks during the active treatment period. | 86 |
| Vonoprazan 20 mg Esomeprazole 40 mg over-encapsulated tablets, orally, once daily for 4 weeks then esomeprazole placebo-matching capsules, orally, once daily for 2 weeks during the run-in period, followed by vonoprazan 20 mg, over-encapsulated capsules, orally, once daily for 4 weeks during the treatment period. | 85 |
| Vonoprazan 40 mg Esomeprazole 40 mg over-encapsulated tablets, orally, once daily for 4 weeks then esomeprazole placebo-matching capsules, orally, once daily for 2 weeks during the run-in period, followed by vonoprazan 40 mg, over-encapsulated capsules, orally, once daily for 4 weeks during the active treatment period. | 85 |
| Total | 256 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 2 |
| Overall Study | Significant Protocol Deviation | 2 | 0 | 1 |
| Overall Study | Voluntary Withdrawal | 2 | 1 | 0 |
Baseline characteristics
| Characteristic | Total | Esomeprazole 40 mg | Vonoprazan 20 mg | Vonoprazan 40 mg |
|---|---|---|---|---|
| Age, Continuous | 52.6 years STANDARD_DEVIATION 14.21 | 53.9 years STANDARD_DEVIATION 13.94 | 52.0 years STANDARD_DEVIATION 14.67 | 51.8 years STANDARD_DEVIATION 14.09 |
| Alcohol Classification Participant has never drunk | 160 Participants | 57 Participants | 49 Participants | 54 Participants |
| Alcohol Classification Participant is a current drinker | 90 Participants | 27 Participants | 33 Participants | 30 Participants |
| Alcohol Classification Participant is an ex-drinker | 6 Participants | 2 Participants | 3 Participants | 1 Participants |
| Alcohol Use Less than 21 units of alcohol per week | 90 Participants | 27 Participants | 33 Participants | 30 Participants |
| Alcohol Use Missing | 166 Participants | 59 Participants | 52 Participants | 55 Participants |
| Body Mass Index (BMI) | 27.03 kg per square meter (kg/m^2) STANDARD_DEVIATION 4.835 | 27.13 kg per square meter (kg/m^2) STANDARD_DEVIATION 4.611 | 27.21 kg per square meter (kg/m^2) STANDARD_DEVIATION 4.854 | 26.76 kg per square meter (kg/m^2) STANDARD_DEVIATION 5.076 |
| Caffeine Consumption No | 61 Participants | 26 Participants | 18 Participants | 17 Participants |
| Caffeine Consumption Yes | 195 Participants | 60 Participants | 67 Participants | 68 Participants |
| Depression Total | 6.0 score on scale STANDARD_DEVIATION 3.7 | 5.9 score on scale STANDARD_DEVIATION 3.62 | 6.0 score on scale STANDARD_DEVIATION 3.5 | 6.2 score on scale STANDARD_DEVIATION 3.99 |
| Did the Endoscopist Visualize Findings Suggestive of Eosinophilic Esophagitis? No | 256 Participants | 86 Participants | 85 Participants | 85 Participants |
| Height | 168.9 centimeters (cm) STANDARD_DEVIATION 8.71 | 169.9 centimeters (cm) STANDARD_DEVIATION 9.17 | 168.5 centimeters (cm) STANDARD_DEVIATION 9.07 | 168.1 centimeters (cm) STANDARD_DEVIATION 7.81 |
| Hospital Anxiety and Depression Scale (HADS) Anxiety Total | 6.6 score on scale STANDARD_DEVIATION 3.67 | 6.5 score on scale STANDARD_DEVIATION 3.81 | 6.2 score on scale STANDARD_DEVIATION 3.38 | 7.0 score on scale STANDARD_DEVIATION 3.78 |
| H Pylori Status Negative | 226 Participants | 78 Participants | 72 Participants | 76 Participants |
| H Pylori Status Positive | 29 Participants | 8 Participants | 13 Participants | 8 Participants |
| If Yes, Grade of Erosive Esophagitis Grade 0 | 2 Participants | 0 Participants | 1 Participants | 1 Participants |
| If Yes, Grade of Erosive Esophagitis Grade A | 73 Participants | 30 Participants | 27 Participants | 16 Participants |
| Is Erosive Esophagitis Present? No | 181 Participants | 56 Participants | 57 Participants | 68 Participants |
| Is Erosive Esophagitis Present? Yes | 75 Participants | 30 Participants | 28 Participants | 17 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 253 Participants | 86 Participants | 84 Participants | 83 Participants |
| Region of Enrollment Belgium | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Region of Enrollment Bulgaria | 177 Participants | 61 Participants | 55 Participants | 61 Participants |
| Region of Enrollment Czech Republic | 40 Participants | 14 Participants | 16 Participants | 10 Participants |
| Region of Enrollment Estonia | 11 Participants | 2 Participants | 5 Participants | 4 Participants |
| Region of Enrollment Poland | 22 Participants | 8 Participants | 7 Participants | 7 Participants |
| Region of Enrollment United Kingdom | 5 Participants | 1 Participants | 1 Participants | 3 Participants |
| Sex: Female, Male Female | 152 Participants | 48 Participants | 53 Participants | 51 Participants |
| Sex: Female, Male Male | 104 Participants | 38 Participants | 32 Participants | 34 Participants |
| Smoking Status Participant has never smoked | 156 Participants | 50 Participants | 53 Participants | 53 Participants |
| Smoking Status Participant is a current smoker | 66 Participants | 21 Participants | 23 Participants | 22 Participants |
| Smoking Status Participant is an ex-smoker | 34 Participants | 15 Participants | 9 Participants | 10 Participants |
| Weight | 77.36 kilograms (kg) STANDARD_DEVIATION 16.481 | 78.78 kilograms (kg) STANDARD_DEVIATION 17.003 | 77.46 kilograms (kg) STANDARD_DEVIATION 16.353 | 75.81 kilograms (kg) STANDARD_DEVIATION 16.126 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 86 | 0 / 85 | 0 / 85 |
| other Total, other adverse events | 1 / 86 | 0 / 85 | 6 / 85 |
| serious Total, serious adverse events | 1 / 86 | 0 / 85 | 0 / 85 |
Outcome results
Primary
Percentage of Heartburn-Free 24-Hour Periods (Day and Night) During 4 Weeks of Treatment
Participants used the Reflux Symptom Questionnaire Electronic Diary (RESQ-eD) every morning upon waking and every evening before going to sleep to document the presence of daytime and nighttime heartburn and regurgitation. The percentage of heartburn-free (HBF) 24-hour periods was calculated for each participant using the following formula: (total 24-hour periods that are heartburn free / total 24-hour periods for which both a daytime and nighttime result is marked) x 100%.
Time frame: 4 Weeks
Population: The full analysis set (FAS) included all participants randomized to a double-blind study medication. Data are reported for evaluable participants.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Esomeprazole 40 mg | Percentage of Heartburn-Free 24-Hour Periods (Day and Night) During 4 Weeks of Treatment | 36.54 percentage of HBF 24-hour periods | Standard Deviation 35.57 |
| Vonoprazan 20 mg | Percentage of Heartburn-Free 24-Hour Periods (Day and Night) During 4 Weeks of Treatment | 36.69 percentage of HBF 24-hour periods | Standard Deviation 33.42 |
| Vonoprazan 40 mg | Percentage of Heartburn-Free 24-Hour Periods (Day and Night) During 4 Weeks of Treatment | 38.43 percentage of HBF 24-hour periods | Standard Deviation 34.793 |
p-value: 0.74897.5% CI: [0.71, 1.5778]Wilcoxon rank-sum test
p-value: 0.598597.5% CI: [0.7368, 1.6349]Wilcoxon rank-sum test
Secondary
Percentage of Participants With ≥1 Sustained Resolution of Heartburn During the 4-Week Treatment Period
≥1 sustained resolution of heartburn is defined as ≥7 consecutive days without both daytime and nighttime heartburn anytime during the 4-week treatment period. Daytime and nighttime heartburn were documented by all participants using the Reflux Symptom Questionnaire Electronic Diary (RESQ-eD).
Time frame: 4 Weeks
Population: The full analysis set (FAS) included all participants randomized to a double-blind study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Esomeprazole 40 mg | Percentage of Participants With ≥1 Sustained Resolution of Heartburn During the 4-Week Treatment Period | 32.6 percentage of participants |
| Vonoprazan 20 mg | Percentage of Participants With ≥1 Sustained Resolution of Heartburn During the 4-Week Treatment Period | 30.6 percentage of participants |
| Vonoprazan 40 mg | Percentage of Participants With ≥1 Sustained Resolution of Heartburn During the 4-Week Treatment Period | 31.8 percentage of participants |
p-value: 0.78297.5% CI: [0.44, 1.91]Pearson chi-square
p-value: 0.91297.5% CI: [0.46, 2.01]Pearson chi-square