Gastric Ulcer
Conditions
Keywords
Drug therapy
Brief summary
The purpose of this study is to demonstrate the non-inferior efficacy of TAK-438 versus lansoprazole in the treatment of participants with gastric ulcer.
Detailed description
The drug being tested in this study is called TAK-438. TAK-438 is being tested to treat people who have stomach ulcers and also may or may not have Helicobacter pylori (HP) infection. This study will look at stomach ulcer healing and also the elimination of HP in people who take TAK-438 versus lansoprazole. The study will enroll approximately 830 patients. Participants will be randomly assigned (by chance, like flipping a coin) to one of the two treatment groups-which will remain undisclosed to the participants and study doctor during the study (unless there is an urgent medical need): * TAK-438 20 mg * Lansoprazole 30 mg Study treatment will depend upon the Helicobacter pylori infection status of the participant, and include bismuth-containing quadruple therapy for the first 2 weeks in H pylori infected (HP+) participants. HP+ participants will be asked to take a TAK- 438 tablet or a lansoprazole capsule twice daily in conjunction with bismuth-containing quadruple therapy for 2 weeks, followed up by a TAK-438 tablet or a lansoprazole capsule once daily for up to 6 weeks. HP- participants will be asked to take a TAK-438 tablet or a lansoprazole capsule once daily for up to 8 weeks. This multi-center trial will be conducted in China, Korea, Taiwan, and Philippines. The overall time to participate in this study is up to 12 weeks. Participants will make multiple visits plus final visit at 2 weeks or 4 weeks after last dose of study drug for a follow-up assessment.
Interventions
DRUGTAK-438
TAK-438 tablets
DRUGLansoprazole
Lansoprazole capsules
DRUGTAK-438 Placebo
TAK-438 placebo-matching tablets
Lansoprazole placebo-matching capsules
1 g Amoxicillin, 500 mg clarithromycin and 600 mg bismuth potassium citrate/bismuth tripotassium dicitrate, twice daily (BID).
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\. Has endoscopic evidence of active gastric ulcer(s) (i.e. mucosal defects with white coating \[including cases associated with blood coagula as long as there is no active bleeding\]) measuring 5 mm or larger in longest diameter within 14 days prior to randomization.
Exclusion criteria
1. Has received TAK-438 in a previous clinical study or as a therapeutic agent. 2. Has a history or clinical manifestations of significant central nervous system (CNS), cardiovascular, pulmonary, hepatic, renal, metabolic, gastrointestinal, urological, endocrine or hematological disease that, in the opinion of the investigator, would confound the study results or compromise participant safety. 3. Has been treated with Helicobacter pylori eradication therapy within 30 days prior to study treatment. 4. Has any gastric ulcer of \>2 cm in any diameter or with \>3 separate gastric ulcers in total as evident by endoscopy within 14 days prior to randomization. 5. Has a diagnosis of gastric malignancy or a gastric ulcer whose morphology suggested malignancy as evident by endoscopy within 14 days prior to randomization. 6. Is suspected of having acute gastro-duodenal mucosal lesions (AGDML) as evident by endoscopy within 14 days prior to randomization. 7. Has a linear ulcer (including a linear ulcer scar) that has been confirmed by endoscopy within 14 days prior to randomization. 8. Has active postoperative (e.g. endoscopic mucosal resection/endoscopic submucosal dissection) ulcer(s) as confirmed by endoscopy within 14 days prior to randomization. 9. Has duodenal ulcer that has been confirmed by endoscopy within 14 days prior to randomization. 10. Has ulcers for which medical therapy alone is not indicated (e.g., perforation, pyloric stenosis, duodenal stenosis, major bleeding). 11. Has undergone therapeutic upper gastrointestinal (GI) endoscopic therapy (e.g., endoscopic hemostasis or excision including biopsy) within 30 days prior to visit 1. 12. Has Zollinger-Ellison syndrome or gastric acid hypersecretion or those with a history of gastric acid hypersecretion. 13. Has undergone major surgical procedures within 30 days prior to Visit 1 or are scheduled to undergo surgical procedures that may affect gastric acid secretion (e.g., abdominal surgery, vagotomy or craniotomy). 14. Has a history of malignancy or was treated for malignancy within 5 years before the start of the visit 1 (the participant may be included in the study if he/she has cured cutaneous basal cell carcinoma or cervical carcinoma in situ). 15. Has a known acquired immunodeficiency syndrome or hepatitis infection, including hepatitis virus carriers (hepatitis B surface-antigen \[HBsAg\] - or hepatitis C virus (HCV)-antibody-positive) (the participant may be included in the study if he/she is HCV-viral load-RNA-negative). 16. Laboratory tests performed prior to randomization revealed any of the following abnormalities in the participant: 1. Creatinine levels: \>2 mg/dL (\>177 μmol/L). 2. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST), or total bilirubin levels: \> upper limit of normal (ULN). 17. Has hypersensitivity to TAK-438, proton pump inhibitors (PPIs), bismuth, clarithromycin, or amoxicillin. Skin testing may be performed according to local standard practice (for HP+ participants only).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Endoscopically Confirmed Healing of Gastric Ulcers (GUs) at Weeks 4 or 8 | Week 4 or 8 | Endoscopic healing was defined as the disappearance of all white coats associated with GUs confirmed endoscopically. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Helicobacter Pylori Infected (HP+) Participants With Successful HP Eradication After 4 or 8 Weeks of Treatment | 4 weeks post treatment (up to approximately 12 weeks) | HP infection status was determined by 13C-UBT. The urea breath test is used to detect infection with HP, a bacteria associated with stomach ulcers, by testing individual breath samples in a central laboratory. The data is provided only for HP+ participants. The participant could take 4 or 8 weeks of treatment for GU healing, then additional 4 weeks later, to have the urea breath test (UBT) test to detect HP. |
| Percentage of Participants With Endoscopically Confirmed Healing of GU at Week 4 | Week 4 | Endoscopic healing was defined as the disappearance of all white coats associated with GUs confirmed endoscopically. |
| Percentage of Participants With Post-treatment Resolution of Gastrointestinal Symptoms Associated With GU | Week 2 up to Week 8 | The gastrointestinal symptoms included epigastric pain \[postprandial, fasting, nocturnal\], abdominal bloating, nausea/vomiting, heartburn, lack of appetite. The severity of gastrointestinal symptoms associated with GU were recorded as: none = 0, mild = 1, moderate = 2 or severe = 3. The data is reported in categories for percentage of participants with resolution of gastrointestinal symptoms associated with GU. |
Countries
China, Philippines, South Korea, Taiwan
Participant flow
Recruitment details
Participants took part in the study at 60 investigative sites in China, Korea, and Taiwan from 17 April 2017 to 26 May 2020.
Pre-assignment details
Participants with a diagnosis of gastric ulcer (GU) with or without Helicobacter pylori (H. Pylori) infection were randomized in 1:1 ratio to receive TAK-438 and lansoprazole along with placebo (to keep the blind).
Participants by arm
| Arm | Count |
|---|---|
| TAK-438 20 mg Helicobacter Pylori positive (HP+) participants: TAK-438 20 mg tablet, twice daily (BID) along with lansoprazole placebo-matching, capsule BID in addition to bismuth-containing quadruple antibiotic therapy for the first 2 weeks. Following 2 weeks of eradication therapy participants received TAK-438 20 mg QD along with lansoprazole matching placebo 30 mg, capsule QD for up to 6 weeks. HP- participants: TAK-438 20 mg tablet, (QD) along with lansoprazole matching placebo, 30 mg capsule QD for up to 8 weeks. | 115 |
| Lansoprazole 30 mg HP+ participants: Lansoprazole 30 mg, capsule, orally, BID and TAK-438 placebo-matching tablet, orally, BID along with bismuth-containing quadruple antibiotic therapy for first 2 weeks. Following 2 weeks participants received Lansoprazole 30 mg, capsule, orally, QD along with TAK-438 placebo-matching tablet, orally, QD for up to 6 weeks. HP- participants: Lansoprazole 30 mg, capsule, orally, QD along with TAK-438 placebo-matching tablet, orally, QD for up to 8 weeks. | 119 |
| Total | 234 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 4 | 2 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Reason not Specified | 1 | 1 |
| Overall Study | Significant Protocol Deviation | 0 | 1 |
| Overall Study | Voluntary Withdrawal | 3 | 4 |
Baseline characteristics
| Characteristic | TAK-438 20 mg | Lansoprazole 30 mg | Total |
|---|---|---|---|
| Age, Continuous | 54.0 years STANDARD_DEVIATION 13.68 | 53.5 years STANDARD_DEVIATION 13.37 | 53.7 years STANDARD_DEVIATION 13.5 |
| Body Mass Index | 23.25 kg/m^2 STANDARD_DEVIATION 3.224 | 23.85 kg/m^2 STANDARD_DEVIATION 3.255 | 23.56 kg/m^2 STANDARD_DEVIATION 3.247 |
| Caffeine Consumption No (Never or <5 Times a Week) | 93 Participants | 90 Participants | 183 Participants |
| Caffeine Consumption Yes (>5 Times per Week) | 22 Participants | 29 Participants | 51 Participants |
| Characteristics of GUs: Location I Cardiac Fundus | 2 Participants | 2 Participants | 4 Participants |
| Characteristics of GUs: Location I Gastric Angle | 37 Participants | 42 Participants | 79 Participants |
| Characteristics of GUs: Location I Lower Gastric Corpus | 10 Participants | 13 Participants | 23 Participants |
| Characteristics of GUs: Location I Middle Gastric Corpus | 11 Participants | 7 Participants | 18 Participants |
| Characteristics of GUs: Location I Pyloric Antral Zone | 50 Participants | 51 Participants | 101 Participants |
| Characteristics of GUs: Location I Upper Gastric Corpus | 5 Participants | 4 Participants | 9 Participants |
| Characteristics of GUs: Location II Anterior Wall | 26 Participants | 20 Participants | 46 Participants |
| Characteristics of GUs: Location II Greater Curvature | 13 Participants | 15 Participants | 28 Participants |
| Characteristics of GUs: Location II Lesser Curvature | 50 Participants | 63 Participants | 113 Participants |
| Characteristics of GUs: Location II Posterior Wall | 19 Participants | 15 Participants | 34 Participants |
| Characteristics of GUs: Number of ulcers | 1.3 number of ulcers STANDARD_DEVIATION 0.56 | 1.2 number of ulcers STANDARD_DEVIATION 0.45 | 1.2 number of ulcers STANDARD_DEVIATION 0.51 |
| Characteristics of GUs: Ulcer morphology Circular | 53 Participants | 56 Participants | 109 Participants |
| Characteristics of GUs: Ulcer morphology Ellipsoid | 47 Participants | 52 Participants | 99 Participants |
| Characteristics of GUs: Ulcer morphology Other | 15 Participants | 11 Participants | 26 Participants |
| Characteristics of GUs: Ulcer size Intermediate (≥10 mm and ≤20 mm) | 33 Participants | 42 Participants | 75 Participants |
| Characteristics of GUs: Ulcer size Miniscule (<5 mm) | 0 Participants | 1 Participants | 1 Participants |
| Characteristics of GUs: Ulcer size Minor (≥5 mm and <10 mm) | 82 Participants | 76 Participants | 158 Participants |
| Consumption of Alcohol Drinks Every Day | 9 Participants | 6 Participants | 15 Participants |
| Consumption of Alcohol Drinks Two Days a Month | 17 Participants | 25 Participants | 42 Participants |
| Consumption of Alcohol Drinks Two Days a Week | 20 Participants | 25 Participants | 45 Participants |
| Consumption of Alcohol Never Drinks | 69 Participants | 62 Participants | 131 Participants |
| Height | 165.4 cm STANDARD_DEVIATION 7.49 | 167.1 cm STANDARD_DEVIATION 7.96 | 166.2 cm STANDARD_DEVIATION 7.76 |
| H pylori infection status (13C-UBT) Negative | 29 Participants | 30 Participants | 59 Participants |
| H pylori infection status (13C-UBT) Positive | 85 Participants | 89 Participants | 174 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 114 Participants | 119 Participants | 233 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment China | 65 Participants | 71 Participants | 136 Participants |
| Region of Enrollment Korea, Republic Of | 44 Participants | 42 Participants | 86 Participants |
| Region of Enrollment Taiwan, Province Of China | 6 Participants | 6 Participants | 12 Participants |
| Sex: Female, Male Female | 29 Participants | 27 Participants | 56 Participants |
| Sex: Female, Male Male | 86 Participants | 92 Participants | 178 Participants |
| Smoking classification The Participant has Never Smoked | 49 Participants | 52 Participants | 101 Participants |
| Smoking classification The Participant is a Current Smoker | 50 Participants | 51 Participants | 101 Participants |
| Smoking classification The Participant is an Ex-smoker | 16 Participants | 16 Participants | 32 Participants |
| Time since onset of current ulcers | 4.0 days | 4.0 days | 4.0 days |
| Time since onset of recurrent ulcers | 393.0 days | 408.5 days | 393.0 days |
| Type of ulcers Primary | 96 Participants | 103 Participants | 199 Participants |
| Type of ulcers Recurrent | 19 Participants | 16 Participants | 35 Participants |
| Use of NSAID or LDA (except topical use) at time of onset of ulcer No | 104 Participants | 111 Participants | 215 Participants |
| Use of NSAID or LDA (except topical use) at time of onset of ulcer Yes | 11 Participants | 8 Participants | 19 Participants |
| Weight | 63.76 kg STANDARD_DEVIATION 10.743 | 66.83 kg STANDARD_DEVIATION 11.37 | 65.32 kg STANDARD_DEVIATION 11.149 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 115 | 0 / 119 |
| other Total, other adverse events | 43 / 115 | 15 / 119 |
| serious Total, serious adverse events | 3 / 115 | 2 / 119 |
Outcome results
Primary
Percentage of Participants With Endoscopically Confirmed Healing of Gastric Ulcers (GUs) at Weeks 4 or 8
Endoscopic healing was defined as the disappearance of all white coats associated with GUs confirmed endoscopically.
Time frame: Week 4 or 8
Population: Full Analysis Set (FAS) population included all randomized participants who received at least 1 dose of the study drug. Overall number of participants analyzed were participants with data available for analyses.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TAK-438 20 mg | Percentage of Participants With Endoscopically Confirmed Healing of Gastric Ulcers (GUs) at Weeks 4 or 8 | 91.1 percentage of participants |
| Lansoprazole 30 mg | Percentage of Participants With Endoscopically Confirmed Healing of Gastric Ulcers (GUs) at Weeks 4 or 8 | 94.7 percentage of participants |
95% CI: [-10.966, 3.339]
Secondary
Percentage of Helicobacter Pylori Infected (HP+) Participants With Successful HP Eradication After 4 or 8 Weeks of Treatment
HP infection status was determined by 13C-UBT. The urea breath test is used to detect infection with HP, a bacteria associated with stomach ulcers, by testing individual breath samples in a central laboratory. The data is provided only for HP+ participants. The participant could take 4 or 8 weeks of treatment for GU healing, then additional 4 weeks later, to have the urea breath test (UBT) test to detect HP.
Time frame: 4 weeks post treatment (up to approximately 12 weeks)
Population: FAS population included all randomized participants who received at least 1 dose of the study drug. Overall number of participants analyzed were participants with data available for analyses.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TAK-438 20 mg | Percentage of Helicobacter Pylori Infected (HP+) Participants With Successful HP Eradication After 4 or 8 Weeks of Treatment | 88.0 percentage of participants |
| Lansoprazole 30 mg | Percentage of Helicobacter Pylori Infected (HP+) Participants With Successful HP Eradication After 4 or 8 Weeks of Treatment | 80.8 percentage of participants |
95% CI: [-4.469, 18.825]
Secondary
Percentage of Participants With Endoscopically Confirmed Healing of GU at Week 4
Endoscopic healing was defined as the disappearance of all white coats associated with GUs confirmed endoscopically.
Time frame: Week 4
Population: FAS population included all randomized participants who received at least 1 dose of the study drug. Overall number of participants analyzed were participants with data available for analyses.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TAK-438 20 mg | Percentage of Participants With Endoscopically Confirmed Healing of GU at Week 4 | 76.1 percentage of participants |
| Lansoprazole 30 mg | Percentage of Participants With Endoscopically Confirmed Healing of GU at Week 4 | 82.1 percentage of participants |
95% CI: [-16.644, 4.741]
Secondary
Percentage of Participants With Post-treatment Resolution of Gastrointestinal Symptoms Associated With GU
The gastrointestinal symptoms included epigastric pain \[postprandial, fasting, nocturnal\], abdominal bloating, nausea/vomiting, heartburn, lack of appetite. The severity of gastrointestinal symptoms associated with GU were recorded as: none = 0, mild = 1, moderate = 2 or severe = 3. The data is reported in categories for percentage of participants with resolution of gastrointestinal symptoms associated with GU.
Time frame: Week 2 up to Week 8
Population: FAS population included all randomized participants who received at least 1 dose of the study drug. Number analyzed is the number of participants with data available for analysis for the specific category.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| TAK-438 20 mg | Percentage of Participants With Post-treatment Resolution of Gastrointestinal Symptoms Associated With GU | Epigastric Pain (Postprandial) | 78.9 percentage of participants |
| TAK-438 20 mg | Percentage of Participants With Post-treatment Resolution of Gastrointestinal Symptoms Associated With GU | Epigastric Pain (Fasting/Nocturnal) | 85.0 percentage of participants |
| TAK-438 20 mg | Percentage of Participants With Post-treatment Resolution of Gastrointestinal Symptoms Associated With GU | Abdominal Bloating | 81.3 percentage of participants |
| TAK-438 20 mg | Percentage of Participants With Post-treatment Resolution of Gastrointestinal Symptoms Associated With GU | Nausea/Vomiting | 100.0 percentage of participants |
| TAK-438 20 mg | Percentage of Participants With Post-treatment Resolution of Gastrointestinal Symptoms Associated With GU | Heartburn | 95.8 percentage of participants |
| TAK-438 20 mg | Percentage of Participants With Post-treatment Resolution of Gastrointestinal Symptoms Associated With GU | Lack of Appetite | 77.8 percentage of participants |
| Lansoprazole 30 mg | Percentage of Participants With Post-treatment Resolution of Gastrointestinal Symptoms Associated With GU | Heartburn | 85.7 percentage of participants |
| Lansoprazole 30 mg | Percentage of Participants With Post-treatment Resolution of Gastrointestinal Symptoms Associated With GU | Epigastric Pain (Postprandial) | 80.0 percentage of participants |
| Lansoprazole 30 mg | Percentage of Participants With Post-treatment Resolution of Gastrointestinal Symptoms Associated With GU | Nausea/Vomiting | 100.0 percentage of participants |
| Lansoprazole 30 mg | Percentage of Participants With Post-treatment Resolution of Gastrointestinal Symptoms Associated With GU | Epigastric Pain (Fasting/Nocturnal) | 80.5 percentage of participants |
| Lansoprazole 30 mg | Percentage of Participants With Post-treatment Resolution of Gastrointestinal Symptoms Associated With GU | Lack of Appetite | 90.0 percentage of participants |
| Lansoprazole 30 mg | Percentage of Participants With Post-treatment Resolution of Gastrointestinal Symptoms Associated With GU | Abdominal Bloating | 65.2 percentage of participants |
Comparison: Epigastric Pain (Postprandial)95% CI: [-25.175, 23.07]
Comparison: Epigastric Pain (Fasting/Nocturnal)95% CI: [-11.907, 20.931]
Comparison: Abdominal Bloating95% CI: [-11.255, 43.321]
Comparison: Heartburn95% CI: [-5.109, 25.348]
Comparison: Lack of Appetite95% CI: [-45.138, 20.694]