Duodenal Ulcer
Conditions
Keywords
Drug therapy, Gastrointestinal Diseases, Digestive System Diseases, Lansoprazole, Anti-Ulcer Agents, Gastrointestinal Agents, Proton Pump Inhibitors, Enzyme Inhibitors, Molecular Mechanisms of Pharmacological Action
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 duodenal ulcer.
Detailed description
The drug being tested in this study is called TAK-438. TAK-438 is being tested to treat people who have duodenal ulcers and also may or may not have Helicobacter pylori (HP) infection. This study will look at duodenal ulcer healing and also the elimination of HP in people who take TAK-438 versus lansoprazole. The study will enroll approximately 530 patients. Participants were randomly assigned (by chance, like flipping a coin) to one of the two treatment groups-which remained undisclosed to the participant and study doctor during the study (unless there is an urgent medical need): * TAK-438 20 mg * Lansoprazole 30 mg HP+ participants will be asked to take a TAK- 438 tablet and a lansoprazole capsule twice daily in conjunction with bismuth-containing quadruple therapy for 2 weeks, followed up by a TAK-438 tablet and a lansoprazole capsule once daily for up to 4 weeks. HP negative (HP-) participants will be asked to take a TAK-438 tablet and a lansoprazole capsule once daily for up to 6 weeks. This multi-center trial will be conducted China, Korea and Taiwan. The overall time to participate in this study is up to 10 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
1 g Amoxicillin, 500 mg clarithromycin and 600 mg bismuth potassium citrate/bismuth tripotassium dicitrate, twice daily (BID).
DRUGTAK-438
TAK-438 tablets
DRUGLansoprazole
Lansoprazole capsules
DRUGTAK-438 Placebo
TAK-438 placebo-matching tablets.
Lansoprazole 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\. Has endoscopic evidence of active duodenal ulcer(s) (i.e., mucosal defects with white coating \[including cases associated with blood coagulation as long as there is no active bleeding\]) 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 a diagnosis of duodenal malignancy or a duodenal ulcer whose morphology suggested malignancy as evident by endoscopy within 14 days prior to randomization. 5. Is suspected of having acute gastro-duodenal mucosal lesions (AGDML) as evident by endoscopy within 14 days prior to randomization. 6. Has a linear ulcer (including a linear ulcer scar) that has been confirmed as evident by endoscopy within 14 days prior to randomization. 7. Has active postoperative (eg, endoscopic mucosal resection / endoscopic submucosal dissection) ulcer(s) as confirmed by endoscopy within 14 days prior to randomization. 8. Has gastric ulcer that has been confirmed by endoscopy within 14 days prior to randomization. 9. Has ulcers for which medical therapy alone is not indicated (eg, perforation, pyloric stenosis, duodenal stenosis, major bleeding). 10. Has undergone therapeutic upper gastrointestinal (GI) endoscopic therapy (eg, endoscopic hemostasis or excision including biopsy) within 30 days prior to visit 1. 11. Has Zollinger-Ellison syndrome or gastric acid hypersecretion or those with a history of gastric acid hypersecretion. 12. 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 (eg, abdominal surgery, vagotomy or craniotomy). 13. 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). 14. Has a known acquired immunodeficiency syndrome (AIDS) 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). 15. 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). 16. 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 Duodenal Ulcers | Week 4 or Week 6 | Endoscopic healing was defined as the disappearance of all white coats associated with duodenal ulcers as confirmed endoscopically. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Helicobacter Pylori Infected (HP+) Participants With Successful HP Eradication After 4 or 6 Weeks of Treatment | 4 weeks post treatment (Up to 10 weeks) | HP infection status was determined by \^13C Urea Breath Test (\^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. |
| Percentage of Participants With Endoscopically Confirmed Healing of Duodenal Ulcer at Week 4 | Week 4 | Endoscopic healing is defined as the disappearance of all white coats associated with duodenal ulcers as confirmed endoscopically. |
| Percentage of Participants With Posttreatment Resolution of Gastrointestinal Symptoms Associated With Duodenal Ulcer at Weeks 2 Through 6 | Week 2 up to Week 6 | The percentage of participants with resolution of various gastrointestinal symptoms are reported as categories. Gastrointestinal symptoms included epigastric pain (postprandial, fasting, nocturnal), abdominal bloating, nausea/vomiting, heartburn and lack of appetite. The severity of subjective symptoms of erosive esophagitis were recorded as: none = 0, mild = 1, moderate = 2 or severe = 3. |
Countries
China, Philippines, South Korea, Taiwan
Participant flow
Recruitment details
Participants took part in the study at 52 investigative sites in China, Korea, and Taiwan from 05 April 2017 to 19 July 2019.
Pre-assignment details
Participants with or without diagnosis of Helicobacter pylori (H. Pylori) Infection were enrolled and randomly assigned in 1:1 ratio to receive either TAK-438 20 mg or lansoprazole 30 mg along with matching placebo (to keep the blind).
Participants by arm
| Arm | Count |
|---|---|
| TAK-438 20 mg HP - participants: TAK-438 20 mg, tablets, orally, once daily (QD) and lansoprazole placebo-matching capsules, orally, QD for up to 6 weeks. HP + participants: TAK-438 20 mg, tablets, orally, twice daily (BID) and lansoprazole placebo-matching capsules, orally, BID for first 2 weeks along with Bismuth-Containing Quadruple Therapy followed byTAK-438 20 mg, tablets, orally, QD and lansoprazole placebo-matching capsules, orally, QD for up to 4 weeks. | 265 |
| Lansoprazole 30 mg HP - participants: lansoprazole 30 mg, capsules, orally, QD and TAK-438 placebo-matching tablets, orally, QD for up to 6 weeks. HP + participants: lansoprazole 30 mg, capsules, orally, BID and TAK-438 placebo-matching tablets, orally, BID for first 2 weeks along with Bismuth-Containing Quadruple Therapy followed by lansoprazole 30 mg, capsules, orally, QD and TAK-438 placebo-matching tablets, orally, BID for up to 4 weeks. | 268 |
| Total | 533 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 2 | 1 |
| Overall Study | Pregnancy | 1 | 0 |
| Overall Study | Pretreatment Event/Adverse Event | 5 | 10 |
| Overall Study | Randomized But Not Treated | 2 | 0 |
| Overall Study | Reason Not Specified | 1 | 0 |
| Overall Study | Significant Protocol Deviation | 2 | 3 |
| Overall Study | Voluntary Withdrawal | 4 | 6 |
Baseline characteristics
| Characteristic | TAK-438 20 mg | Total | Lansoprazole 30 mg |
|---|---|---|---|
| Age, Continuous | 42.0 years STANDARD_DEVIATION 12.18 | 41.7 years STANDARD_DEVIATION 12.53 | 41.4 years STANDARD_DEVIATION 12.89 |
| Body Mass Index (BMI) | 22.87 kg/m^2 STANDARD_DEVIATION 3.365 | 22.85 kg/m^2 STANDARD_DEVIATION 3.27 | 22.83 kg/m^2 STANDARD_DEVIATION 3.181 |
| Characteristics of Current DU: Mean Number of Ulcers Found | 1.2 number of ulcers STANDARD_DEVIATION 0.48 | 1.2 number of ulcers STANDARD_DEVIATION 0.51 | 1.3 number of ulcers STANDARD_DEVIATION 0.54 |
| Characteristics of Current Duodenal Ulcers (DU): Location Descending Part | 3 Participants | 4 Participants | 1 Participants |
| Characteristics of Current Duodenal Ulcers (DU): Location Superior Part (Including Bulb) | 262 Participants | 528 Participants | 266 Participants |
| Characteristics of Current DU: Ulcer Morphology Circular | 110 Participants | 227 Participants | 117 Participants |
| Characteristics of Current DU: Ulcer Morphology Ellipsoidal | 109 Participants | 216 Participants | 107 Participants |
| Characteristics of Current DU: Ulcer Morphology Other | 46 Participants | 90 Participants | 44 Participants |
| Characteristics of Current DU: Ulcer Size Giant (>=30 mm) | 0 Participants | 1 Participants | 1 Participants |
| Characteristics of Current DU: Ulcer Size Intermediate (>=10 mm/<=20 mm) | 81 Participants | 159 Participants | 78 Participants |
| Characteristics of Current DU: Ulcer Size Large (>20 mm/<30 mm) | 1 Participants | 1 Participants | 0 Participants |
| Characteristics of Current DU: Ulcer Size Minor (>=5 mm/<10 mm) | 183 Participants | 371 Participants | 188 Participants |
| Characteristics of Current DU: Ulcer Size Minuscule (<5 mm) | 0 Participants | 1 Participants | 1 Participants |
| Consumption of Alcohol Drink a Couple of Days Per Month | 48 Participants | 106 Participants | 58 Participants |
| Consumption of Alcohol Drink a Couple of Days Per Week | 20 Participants | 41 Participants | 21 Participants |
| Consumption of Alcohol Drink Everyday | 6 Participants | 8 Participants | 2 Participants |
| Consumption of Alcohol Never Drink | 191 Participants | 378 Participants | 187 Participants |
| Consumption of Caffeine No (Never Drink or Less Than 5 Times Per Week) | 242 Participants | 494 Participants | 252 Participants |
| Consumption of Caffeine Yes (More Than 5 Times Per Week) | 23 Participants | 39 Participants | 16 Participants |
| Height | 166.1 centimeter (cm) STANDARD_DEVIATION 8.21 | 166.6 centimeter (cm) STANDARD_DEVIATION 8.16 | 167.1 centimeter (cm) STANDARD_DEVIATION 8.09 |
| History of DU: Time Since Onset of Current Ulcers | 1.0 days | 1.0 days | 1.0 days |
| History of DU: Type of Ulcers Primary | 230 Participants | 457 Participants | 227 Participants |
| History of DU: Type of Ulcers Recurrent | 35 Participants | 76 Participants | 41 Participants |
| History of H.pylori Eradication Therapy No (Never Receive Any Therapy) | 249 Participants | 512 Participants | 263 Participants |
| History of H.pylori Eradication Therapy Yes (Therapy Received Ever) | 16 Participants | 21 Participants | 5 Participants |
| H. pylori Infection Status Negative | 37 Participants | 75 Participants | 38 Participants |
| H. pylori Infection Status Positive | 226 Participants | 455 Participants | 229 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 265 Participants | 533 Participants | 268 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 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 | 252 Participants | 507 Participants | 255 Participants |
| Region of Enrollment Korea, Republic Of | 10 Participants | 18 Participants | 8 Participants |
| Region of Enrollment Taiwan, Province Of China | 3 Participants | 8 Participants | 5 Participants |
| Sex: Female, Male Female | 99 Participants | 191 Participants | 92 Participants |
| Sex: Female, Male Male | 166 Participants | 342 Participants | 176 Participants |
| Smoking Classification The Participant Has Never Smoked | 164 Participants | 329 Participants | 165 Participants |
| Smoking Classification The Participant Is a Current Smoker | 86 Participants | 170 Participants | 84 Participants |
| Smoking Classification The Participant Is an Ex-smoker | 15 Participants | 34 Participants | 19 Participants |
| Time Since Onset of Recurrent Ulcers | 1149.3 days STANDARD_DEVIATION 910.72 | 1068.7 days STANDARD_DEVIATION 859.12 | 999.7 days STANDARD_DEVIATION 828.57 |
| Use of NSAIDs or Low-dose Aspirin at the Time of Ulcer Onset No | 264 Participants | 530 Participants | 266 Participants |
| Use of NSAIDs or Low-dose Aspirin at the Time of Ulcer Onset Yes | 1 Participants | 3 Participants | 2 Participants |
| Weight | 63.45 kilograms (kg) STANDARD_DEVIATION 12.342 | 63.72 kilograms (kg) STANDARD_DEVIATION 11.86 | 64.00 kilograms (kg) STANDARD_DEVIATION 11.383 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 263 | 0 / 268 |
| other Total, other adverse events | 162 / 263 | 113 / 268 |
| serious Total, serious adverse events | 1 / 263 | 3 / 268 |
Outcome results
Primary
Percentage of Participants With Endoscopically Confirmed Healing of Duodenal Ulcers
Endoscopic healing was defined as the disappearance of all white coats associated with duodenal ulcers as confirmed endoscopically.
Time frame: Week 4 or Week 6
Population: Full Analysis Set (FAS) included all participants who were randomized and 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 Duodenal Ulcers | 96.9 percentage of participants |
| Lansoprazole 30 mg | Percentage of Participants With Endoscopically Confirmed Healing of Duodenal Ulcers | 96.5 percentage of participants |
95% CI: [-2.998, 3.791]
Secondary
Percentage of Helicobacter Pylori Infected (HP+) Participants With Successful HP Eradication After 4 or 6 Weeks of Treatment
HP infection status was determined by \^13C Urea Breath Test (\^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.
Time frame: 4 weeks post treatment (Up to 10 weeks)
Population: Participants from FAS, included all participants who were randomized and received at least 1 dose of the study drug with H pylori positive status at Baseline 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 6 Weeks of Treatment | 91.5 percentage of participants |
| Lansoprazole 30 mg | Percentage of Helicobacter Pylori Infected (HP+) Participants With Successful HP Eradication After 4 or 6 Weeks of Treatment | 86.8 percentage of participants |
95% CI: [-1.281, 10.69]
Secondary
Percentage of Participants With Endoscopically Confirmed Healing of Duodenal Ulcer at Week 4
Endoscopic healing is defined as the disappearance of all white coats associated with duodenal ulcers as confirmed endoscopically.
Time frame: Week 4
Population: FAS included all participants who were randomized and 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 Duodenal Ulcer at Week 4 | 89.2 percentage of participants |
| Lansoprazole 30 mg | Percentage of Participants With Endoscopically Confirmed Healing of Duodenal Ulcer at Week 4 | 88.4 percentage of participants |
95% CI: [-4.901, 6.319]
Secondary
Percentage of Participants With Posttreatment Resolution of Gastrointestinal Symptoms Associated With Duodenal Ulcer at Weeks 2 Through 6
The percentage of participants with resolution of various gastrointestinal symptoms are reported as categories. Gastrointestinal symptoms included epigastric pain (postprandial, fasting, nocturnal), abdominal bloating, nausea/vomiting, heartburn and lack of appetite. The severity of subjective symptoms of erosive esophagitis were recorded as: none = 0, mild = 1, moderate = 2 or severe = 3.
Time frame: Week 2 up to Week 6
Population: FAS included all participants who were randomized and received at least 1 dose of the study drug. Number analyzed is number of participants analyzed for the particular category (symptom).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| TAK-438 20 mg | Percentage of Participants With Posttreatment Resolution of Gastrointestinal Symptoms Associated With Duodenal Ulcer at Weeks 2 Through 6 | Nausea/Vomiting | 85.2 percentage of participants |
| TAK-438 20 mg | Percentage of Participants With Posttreatment Resolution of Gastrointestinal Symptoms Associated With Duodenal Ulcer at Weeks 2 Through 6 | Abdominal Bloating | 83.3 percentage of participants |
| TAK-438 20 mg | Percentage of Participants With Posttreatment Resolution of Gastrointestinal Symptoms Associated With Duodenal Ulcer at Weeks 2 Through 6 | Heartburn | 100.0 percentage of participants |
| TAK-438 20 mg | Percentage of Participants With Posttreatment Resolution of Gastrointestinal Symptoms Associated With Duodenal Ulcer at Weeks 2 Through 6 | Epigastric Pain (Fasting/Nocturnal) | 91.7 percentage of participants |
| TAK-438 20 mg | Percentage of Participants With Posttreatment Resolution of Gastrointestinal Symptoms Associated With Duodenal Ulcer at Weeks 2 Through 6 | Lack of Appetite | 90.9 percentage of participants |
| TAK-438 20 mg | Percentage of Participants With Posttreatment Resolution of Gastrointestinal Symptoms Associated With Duodenal Ulcer at Weeks 2 Through 6 | Epigastric Pain (Postprandial) | 87.7 percentage of participants |
| Lansoprazole 30 mg | Percentage of Participants With Posttreatment Resolution of Gastrointestinal Symptoms Associated With Duodenal Ulcer at Weeks 2 Through 6 | Lack of Appetite | 100.0 percentage of participants |
| Lansoprazole 30 mg | Percentage of Participants With Posttreatment Resolution of Gastrointestinal Symptoms Associated With Duodenal Ulcer at Weeks 2 Through 6 | Epigastric Pain (Postprandial) | 91.8 percentage of participants |
| Lansoprazole 30 mg | Percentage of Participants With Posttreatment Resolution of Gastrointestinal Symptoms Associated With Duodenal Ulcer at Weeks 2 Through 6 | Abdominal Bloating | 87.3 percentage of participants |
| Lansoprazole 30 mg | Percentage of Participants With Posttreatment Resolution of Gastrointestinal Symptoms Associated With Duodenal Ulcer at Weeks 2 Through 6 | Nausea/Vomiting | 94.4 percentage of participants |
| Lansoprazole 30 mg | Percentage of Participants With Posttreatment Resolution of Gastrointestinal Symptoms Associated With Duodenal Ulcer at Weeks 2 Through 6 | Heartburn | 95.5 percentage of participants |
| Lansoprazole 30 mg | Percentage of Participants With Posttreatment Resolution of Gastrointestinal Symptoms Associated With Duodenal Ulcer at Weeks 2 Through 6 | Epigastric Pain (Fasting/Nocturnal) | 90.1 percentage of participants |
Comparison: Epigastric Pain (Postprandial)95% CI: [-15.579, 7.344]
Comparison: Epigastric Pain (Fasting/Nocturnal)95% CI: [-5.23, 8.422]
Comparison: Abdominal Bloating95% CI: [-17.338, 9.401]
Comparison: Nausea/Vomiting95% CI: [-26.334, 7.815]
Comparison: Heartburn95% CI: [-4.159, 13.25]
Comparison: Lack of Appetite95% CI: [-21.104, 2.922]