TAK-438 Bismuth Drug Interaction Study

• Sponsor: Takeda (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02892409
• Collaborator: (none)
• Enrollment: 30
• Location: 1
• Arms: 2
• Actual Duration (Months): 8.1
• Patients Per Site Per Month: 3.7

Study Details

Study Description

Brief Summary

To evaluate the safety, tolerability, and pharmacokinetics (PK) of quadruple therapy with bismuth, clarithromycin, amoxicillin, and TAK-438 versus quadruple therapy with bismuth, clarithromycin, amoxicillin, and lansoprazole.

Condition or Disease	Intervention/Treatment	Phase
Helicobacter Pylori	Drug: Clarithromycin; Drug: Amoxicillin; Drug: Tripotassium bismuth dicitrate; Drug: Lansoprazole; Drug: TAK-438	Phase 1

Detailed Description

This is a phase 1, double-blind, parallel group study in participants with Helicobacter pylori (HP positive) who are, additionally, cytochrome P-450 (CYP)2C19 extensive metabolizers (EM) to evaluate the safety, tolerability and pharmacokinetics (PK) of a quadruple therapy with bismuth, clarithromycin, amoxicillin, and TAK-438 versus quadruple therapy with bismuth, clarithromycin, amoxicillin, and lansoprazole. The study will enroll 30 participants.

The treatment phase consists of quadruple therapy twice daily (BID) with tripotassium bismuth dicitrate (600 mg), clarithromycin (500 mg), amoxicillin (1000 mg), and TAK-438 (20 mg) (Group B) or quadruple therapy BID with tripotassium bismuth dicitrate (600 mg), clarithromycin (500 mg), amoxicillin (1000 mg),and lansoprazole (30 mg) (Group A) from Days 1 to 14. Participants will be discharged on Day 15 after final PK blood samples are collected and all procedures performed.

This single-center will be conducted in Korea. Participants will remain confined to the study site from check-in (Day -1) through Day 15 and will followed up through call on Day 17 and return on Day 42 for a follow-up assessment.

Study Design

• Study Type: Interventional
• Actual Enrollment: 30 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 1, Double-Blind, Parallel Group Study to Evaluate the Safety and Pharmacokinetics of Quadruple Therapy (Bismuth, Clarithromycin, and Amoxicillin) With TAK-438 Versus Quadruple Therapy With Lansoprazole
• Actual Study Start Date: Sep 5, 2016
• Actual Primary Completion Date: Apr 17, 2017
• Actual Study Completion Date: May 11, 2017

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Clarithromycin + Amoxicillin + Bismuth + Lansoprazole Clarithromycin 500 milligram (mg), tablets, orally, twice daily, along with amoxicillin 1000 mg capsules, orally, twice daily, tripotassium bismuth dicitrate 600 mg, tablets, orally, twice daily, and lansoprazole 30 mg, capsules, orally, twice daily on Days 1 to 14.	Drug: Clarithromycin; Clarithromycin tablets; Drug: Amoxicillin; Amoxicillin capsules; Drug: Tripotassium bismuth dicitrate; Tripotassium bismuth dicitrate tablets; Drug: Lansoprazole; Lansoprazole capsules
Experimental: Clarithromycin + Amoxicillin + Bismuth + TAK-438 Clarithromycin 500 mg, tablets, orally, twice daily, along with amoxicillin 1000 mg, capsules, orally, twice daily, tripotassium bismuth dicitrate 600 mg, tablets, orally, twice daily, and TAK-438 20 mg, tablets, orally, twice daily on Days 1 to 14.	Drug: Clarithromycin; Clarithromycin tablets; Drug: Amoxicillin; Amoxicillin capsules; Drug: Tripotassium bismuth dicitrate; Tripotassium bismuth dicitrate tablets; Drug: TAK-438; TAK-438 tablets

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants Who Experience at Least One Treatment Emergent Adverse Event (TEAE) [Baseline up to Day 17]

2. Percentage of Participants Who Discontinue Due to an Adverse Event (AE) [Baseline up to Day 17]

3. Percentage of Participants Who Meet the Markedly Abnormal Criteria for Safety Laboratory Tests at Least Once Post-dose [Baseline up Day 15]

4. Percentage of Participants Who Meet the Markedly Abnormal Criteria for Vital Sign Measurements at Least Once Post-dose [Baseline up to Day 15]

5. Percentage of Participants Who Meet the Markedly Abnormal Criteria for Safety Electrocardiogram (ECG) Parameters at Least Once Post-dose [Baseline up to Day 15]

6. Cmax: Maximum Observed Plasma Concentration for Bismuth [Day 14 pre-dose and at multiple timepoints (up to 12 hours) post-dose]

7. AUCτ: Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau Over the Dosing Interval for Bismuth [Day 14 pre-dose and at multiple timepoints (up to 12 hours) post-dose]

8. Aeτ: Amount of Drug Excreted in Urine During a Dosing Interval for Bismuth [Day 14 pre-dose and at multiple timepoints (up to 12 hours) post-dose]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 19 Years to 60 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. HP positive participants.

2. Has body mass index between greater than (>) 18 and less than equal to (<=) 30 kilogram per square meter (kg/m^2) and weighs greater than equal to (>=) 50 kilogram (kg).

3. Is willing to abstain from strenuous exercise from 72 hours before first dose (Day 1) until the Follow-up call on Day 17.

Exclusion Criteria:

1. Has a positive urine drug result for drugs of abuse at Screening or Check-in (Day -1).

2. Has a history of drug abuse (defined as any illicit drug use) or a history of alcohol abuse (defined as regular consumption of 21 units or more units per week) at any time prior to the Screening Visit or is unwilling to agree to abstain from alcohol and drugs throughout the study (up to Day 17).

3. Has history of gastroesophageal reflux disease (GERD), symptomatic GERD, erosive esophagitis, duodenal ulcer, gastric ulcer, Barrett's esophagus, or Zollinger-Ellison syndrome.

4. Has undergone therapeutic upper gastrointestinal endoscopic therapy (example, endoscopic hemostasis or excision including biopsy) within 30 days prior to Screening.

5. Has undergone major surgical procedures within the past 1 month or are scheduled to undergo surgical procedures that may affect gastric acid secretion (example, abdominal surgery, vagotomy, or craniotomy).

6. Has a history of cancer, except basal cell carcinoma or Stage 1 squamous cell carcinoma of the skin that has been in remission for at least 5 years prior to Day 1.

7. Has a positive test result for hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) antibody, human immunodeficiency virus (HIV) antibody/antigen at Screening.

8. Has used nicotine-containing products (including but not limited to cigarettes, pipes, cigars, chewing tobacco, nicotine patch or nicotine gum) within 6 weeks prior to Check-in. Cotinine test is positive at Screening or Check-in.

9. Has poor peripheral venous access. Has donated or lost 450 milliliter (mL) or more of his blood volume (including plasmapheresis), or had a transfusion of any blood product within 90 days prior to Day 1.

10. Has abnormal Screening or Check-in laboratory values that suggest a clinically significant underlying disease or subject with the following laboratory abnormalities: alanine aminotransferase (ALT), aspartate aminotransferase (AST) or total bilirubin > the upper limit of normal (ULN).

11. Has reduced renal function assessed by having an estimated glomerular filtration rate <90 milliliter per min per 1.73 square meter (mL/min/1.73 m^2) (as estimated by Chronic Kidney Disease-Epidemology Collaboration) at Screening or Check-in.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Seoul		Korea, Republic of

Sponsors and Collaborators

• Takeda

Investigators

• Study Director: Medical Director, Takeda

Study Documents (Full-Text)

• Statistical Analysis Plan - May 15, 2017
• Study Protocol - Nov 21, 2016

More Information

Publications

None provided.

• Responsible Party: Takeda
• ClinicalTrials.gov Identifier: NCT02892409
• Other Study ID Numbers: TAK-438_115; U1111-1179-5816; 02892409
• First Posted: Sep 8, 2016
• Last Update Posted: Jan 3, 2019
• Last Verified: Jun 1, 2018

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Takeda: Drug Therapy
• Additional relevant MeSH terms: Amoxicillin; Clarithromycin; Lansoprazole; Dexlansoprazole; Bismuth

Study Results

Participant Flow

Recruitment Details	Participants took part in the study at 1 investigative site in Korea from 05 September 2016 to 11 May 2017.
Pre-assignment Detail	Participants with diagnosis of positive helicobacter pylori (HP) were enrolled in 1 of the 2 treatment groups to receive: Clarithromycin + Amoxicillin + Tripotassium Bismuth Dicitrate (Bismuth) + Lansoprazole twice daily or Clarithromycin + Amoxicillin + Bismuth + TAK-438 twice daily.

Arm/Group Title	Clarithromycin + Amoxicillin + Bismuth + TAK-438	Clarithromycin + Amoxicillin + Bismuth + Lansoprazole
Arm/Group Description	Clarithromycin 500 milligram (mg), tablets, orally, twice daily, amoxicillin 1000 mg, capsules, orally, twice daily, bismuth 600 mg, tablets, orally, twice daily, and TAK-438 20 mg, tablets, orally, twice daily on Days 1 to 14.	Clarithromycin 500 mg, tablets, orally, twice daily, amoxicillin 1000 mg capsules, orally, twice daily, bismuth 600 mg, tablets, orally, twice daily, and lansoprazole 30 mg, capsules, orally, twice daily on Days 1 to 14.
Period Title: Overall Study
STARTED	15	15
COMPLETED	12	14
NOT COMPLETED	3	1

Baseline Characteristics

Arm/Group Title	Clarithromycin + Amoxicillin + Bismuth + TAK-438	Clarithromycin + Amoxicillin + Bismuth + Lansoprazole	Total
Arm/Group Description	Clarithromycin 500 milligram (mg), tablets, orally, twice daily, amoxicillin 1000 mg, capsules, orally, twice daily, bismuth 600 mg, tablets, orally, twice daily, and TAK-438 20 mg, tablets, orally, twice daily on Days 1 to 14.	Clarithromycin 500 mg, tablets, orally, twice daily, amoxicillin 1000 mg capsules, orally, twice daily, bismuth 600 mg, tablets, orally, twice daily, and lansoprazole 30 mg, capsules, orally, twice daily on Days 1 to 14.	Total of all reporting groups
Overall Participants	15	15	30
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	32.8 (6.87)	33.3 (8.61)	33.1 (7.66)
Sex: Female, Male (Count of Participants)
Female	1 6.7%	1 6.7%	2 6.7%
Male	14 93.3%	14 93.3%	28 93.3%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	15 100%	15 100%	30 100%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	0 0%	0 0%	0 0%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Height (centimeter (cm)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [centimeter (cm)]	173.7 (5.04)	168.9 (5.14)	171.3 (5.56)
Weight (kilogram (kg)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilogram (kg)]	72.41 (5.028)	66.05 (8.395)	69.23 (7.528)
Body Mass Index (BMI) (kilogram per square meter (kg/m^2)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilogram per square meter (kg/m^2)]	24.03 (1.795)	23.13 (2.271)	23.58 (2.064)
Smoking Classification (Count of Participants)
Never smoked	14 93.3%	12 80%	26 86.7%
Ex-smoker	1 6.7%	3 20%	4 13.3%
Alcohol Consumption (Count of Participants)
Drank a couple of days per week	2 13.3%	0 0%	2 6.7%
Drank a couple of days per month	4 26.7%	6 40%	10 33.3%
Never Drank	9 60%	9 60%	18 60%
Caffeine Consumption (Count of Participants)
Had caffeine consumption	7 46.7%	13 86.7%	20 66.7%
Had no caffeine consumption	8 53.3%	2 13.3%	10 33.3%
Cytochrome P450 2C19 (CYP2C19) Genotype (Count of Participants)
*1/*1	5 33.3%	6 40%	11 36.7%
*1/*2	6 40%	5 33.3%	11 36.7%
*1/*3	3 20%	3 20%	6 20%
*2/*2	0 0%	0 0%	0 0%
*2/*3	1 6.7%	0 0%	1 3.3%
*3/*3	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants Who Experience at Least One Treatment Emergent Adverse Event (TEAE)
Time Frame	Baseline up to Day 17

Outcome Measure Data

Analysis Population Description

The safety analysis set included all participants who received at least one dose of study drug.

Arm/Group Title	Clarithromycin + Amoxicillin + Bismuth + TAK-438	Clarithromycin + Amoxicillin + Bismuth + Lansoprazole
Arm/Group Description	Clarithromycin 500 milligram (mg), tablets, orally, twice daily, amoxicillin 1000 mg, capsules, orally, twice daily, bismuth 600 mg, tablets, orally, twice daily, and TAK-438 20 mg, tablets, orally, twice daily on Days 1 to 14.	Clarithromycin 500 mg, tablets, orally, twice daily, amoxicillin 1000 mg capsules, orally, twice daily, bismuth 600 mg, tablets, orally, twice daily, and lansoprazole 30 mg, capsules, orally, twice daily on Days 1 to 14.
Measure Participants	15	15
Number [percentage of participants]	53.3 355.3%	66.7 444.7%

2. Primary Outcome

Title	Percentage of Participants Who Discontinue Due to an Adverse Event (AE)
Time Frame	Baseline up to Day 17

Outcome Measure Data

Analysis Population Description

The safety analysis set included all participants who received at least one dose of study drug.

Arm/Group Title	Clarithromycin + Amoxicillin + Bismuth + TAK-438	Clarithromycin + Amoxicillin + Bismuth + Lansoprazole
Arm/Group Description	Clarithromycin 500 milligram (mg), tablets, orally, twice daily, amoxicillin 1000 mg, capsules, orally, twice daily, bismuth 600 mg, tablets, orally, twice daily, and TAK-438 20 mg, tablets, orally, twice daily on Days 1 to 14.	Clarithromycin 500 mg, tablets, orally, twice daily, amoxicillin 1000 mg capsules, orally, twice daily, bismuth 600 mg, tablets, orally, twice daily, and lansoprazole 30 mg, capsules, orally, twice daily on Days 1 to 14.
Measure Participants	15	15
Number [percentage of participants]	6.7 44.7%	0.0 0%

3. Primary Outcome

Title	Percentage of Participants Who Meet the Markedly Abnormal Criteria for Safety Laboratory Tests at Least Once Post-dose
Time Frame	Baseline up Day 15

Outcome Measure Data

Analysis Population Description

The safety analysis set included all participants who received at least one dose of study drug.

Arm/Group Title	Clarithromycin + Amoxicillin + Bismuth + TAK-438	Clarithromycin + Amoxicillin + Bismuth + Lansoprazole
Arm/Group Description	Clarithromycin 500 milligram (mg), tablets, orally, twice daily, amoxicillin 1000 mg, capsules, orally, twice daily, bismuth 600 mg, tablets, orally, twice daily, and TAK-438 20 mg, tablets, orally, twice daily on Days 1 to 14.	Clarithromycin 500 mg, tablets, orally, twice daily, amoxicillin 1000 mg capsules, orally, twice daily, bismuth 600 mg, tablets, orally, twice daily, and lansoprazole 30 mg, capsules, orally, twice daily on Days 1 to 14.
Measure Participants	15	15
Amylase (greater than [>] 2*upper limit of normal)	0.0 0%	6.7 44.7%
Potassium (>6.0 millimole per liter [mmol/L])	0.0 0%	6.7 44.7%

4. Primary Outcome

Title	Percentage of Participants Who Meet the Markedly Abnormal Criteria for Vital Sign Measurements at Least Once Post-dose
Time Frame	Baseline up to Day 15

Outcome Measure Data

Analysis Population Description

The safety analysis set included all participants who received at least one dose of study drug.

Arm/Group Title	Clarithromycin + Amoxicillin + Bismuth + TAK-438	Clarithromycin + Amoxicillin + Bismuth + Lansoprazole
Arm/Group Description	Clarithromycin 500 milligram (mg), tablets, orally, twice daily, amoxicillin 1000 mg, capsules, orally, twice daily, bismuth 600 mg, tablets, orally, twice daily, and TAK-438 20 mg, tablets, orally, twice daily on Days 1 to 14.	Clarithromycin 500 mg, tablets, orally, twice daily, amoxicillin 1000 mg capsules, orally, twice daily, bismuth 600 mg, tablets, orally, twice daily, and lansoprazole 30 mg, capsules, orally, twice daily on Days 1 to 14.
Measure Participants	15	15
Body temperature (less than [<] 35.6 celsius [C])	0.0 0%	6.7 44.7%
Body temperature (>37.7 C)	6.7 44.7%	6.7 44.7%
Systolic blood pressure(<85 millimeter of mercury)	6.7 44.7%	6.7 44.7%
Diastolic blood pressure(<50millimeter of mercury)	6.7 44.7%	6.7 44.7%

5. Primary Outcome

Title	Percentage of Participants Who Meet the Markedly Abnormal Criteria for Safety Electrocardiogram (ECG) Parameters at Least Once Post-dose
Time Frame	Baseline up to Day 15

Outcome Measure Data

Analysis Population Description

The safety analysis set included all participants who received at least one dose of study drug.

Arm/Group Title	Clarithromycin + Amoxicillin + Bismuth + TAK-438	Clarithromycin + Amoxicillin + Bismuth + Lansoprazole
Arm/Group Description	Clarithromycin 500 milligram (mg), tablets, orally, twice daily, amoxicillin 1000 mg, capsules, orally, twice daily, bismuth 600 mg, tablets, orally, twice daily, and TAK-438 20 mg, tablets, orally, twice daily on Days 1 to 14.	Clarithromycin 500 mg, tablets, orally, twice daily, amoxicillin 1000 mg capsules, orally, twice daily, bismuth 600 mg, tablets, orally, twice daily, and lansoprazole 30 mg, capsules, orally, twice daily on Days 1 to 14.
Measure Participants	15	15
Number [percentage of participants]	0.0 0%	6.7 44.7%

6. Primary Outcome

Title	Cmax: Maximum Observed Plasma Concentration for Bismuth
Time Frame	Day 14 pre-dose and at multiple timepoints (up to 12 hours) post-dose

Outcome Measure Data

Analysis Population Description

The pharmacokinetic (PK) analysis set included all participants who received study drug, had sufficient plasma/urine concentration data to calculate at least one PK parameter, and had no significant protocol deviations.

Arm/Group Title	Clarithromycin + Amoxicillin + Bismuth + TAK-438	Clarithromycin + Amoxicillin + Bismuth + Lansoprazole
Arm/Group Description	Clarithromycin 500 milligram (mg), tablets, orally, twice daily, amoxicillin 1000 mg, capsules, orally, twice daily, bismuth 600 mg, tablets, orally, twice daily, and TAK-438 20 mg, tablets, orally, twice daily on Days 1 to 14.	Clarithromycin 500 mg, tablets, orally, twice daily, amoxicillin 1000 mg capsules, orally, twice daily, bismuth 600 mg, tablets, orally, twice daily, and lansoprazole 30 mg, capsules, orally, twice daily on Days 1 to 14.
Measure Participants	12	14
Mean (Standard Deviation) [nanogram per milliliter (ng/mL)]	28.08 (11.691)	30.14 (24.612)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Clarithromycin + Amoxicillin + Bismuth + TAK-438, Clarithromycin + Amoxicillin + Bismuth + Lansoprazole
	Comments
	Type of Statistical Test	Equivalence
	Comments	LS Mean Ratio (TAK-438/Lansoprazole), 95 percent (%) confidence interval (CI) of the ratio were obtained by taking the anti-log of the difference or confidence limits of difference between the LS means of test and reference on the natural logarithmic scale.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Square (LS) Mean Ratio
	Estimated Value	105.1
	Confidence Interval	(2-Sided) 95%; 66.051 to 167.183
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Primary Outcome

Title	AUCτ: Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau Over the Dosing Interval for Bismuth
Time Frame	Day 14 pre-dose and at multiple timepoints (up to 12 hours) post-dose

Outcome Measure Data

Analysis Population Description

The PK analysis set included all participants who received study drug, had sufficient plasma/urine concentration data to calculate at least one PK parameter, and had no significant protocol deviations.

Arm/Group Title	Clarithromycin + Amoxicillin + Bismuth + TAK-438	Clarithromycin + Amoxicillin + Bismuth + Lansoprazole
Arm/Group Description	Clarithromycin 500 milligram (mg), tablets, orally, twice daily, amoxicillin 1000 mg, capsules, orally, twice daily, bismuth 600 mg, tablets, orally, twice daily, and TAK-438 20 mg, tablets, orally, twice daily on Days 1 to 14.	Clarithromycin 500 mg, tablets, orally, twice daily, amoxicillin 1000 mg capsules, orally, twice daily, bismuth 600 mg, tablets, orally, twice daily, and lansoprazole 30 mg, capsules, orally, twice daily on Days 1 to 14.
Measure Participants	12	14
Mean (Standard Deviation) [hours nanogram per milliliter (h*ng/mL)]	103.0 (37.498)	111.1 (45.010)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Clarithromycin + Amoxicillin + Bismuth + TAK-438, Clarithromycin + Amoxicillin + Bismuth + Lansoprazole
	Comments
	Type of Statistical Test	Equivalence
	Comments	LS Mean Ratio (TAK-438/Lansoprazole), 95% CI of the ratio were obtained by taking the anti-log of the difference or confidence limits of difference between the LS means of test and reference on the natural logarithmic scale.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS Mean Ratio
	Estimated Value	93.6
	Confidence Interval	(2-Sided) 95%; 67.137 to 130.569
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Primary Outcome

Title	Aeτ: Amount of Drug Excreted in Urine During a Dosing Interval for Bismuth
Time Frame	Day 14 pre-dose and at multiple timepoints (up to 12 hours) post-dose

Outcome Measure Data

Analysis Population Description

The PK analysis set included all participants who received study drug, had sufficient plasma/urine concentration data to calculate at least one PK parameter, and had no significant protocol deviations. The PK analysis set where data was available at specified timepoints.

Arm/Group Title	Clarithromycin + Amoxicillin + Bismuth + TAK-438	Clarithromycin + Amoxicillin + Bismuth + Lansoprazole
Arm/Group Description	Clarithromycin 500 milligram (mg), tablets, orally, twice daily, amoxicillin 1000 mg, capsules, orally, twice daily, bismuth 600 mg, tablets, orally, twice daily, and TAK-438 20 mg, tablets, orally, twice daily on Days 1 to 14.	Clarithromycin 500 mg, tablets, orally, twice daily, amoxicillin 1000 mg capsules, orally, twice daily, bismuth 600 mg, tablets, orally, twice daily, and lansoprazole 30 mg, capsules, orally, twice daily on Days 1 to 14.
Measure Participants	12	13
Mean (Standard Deviation) [nanogram (ng)]	497300 (202270)	537600 (188340)

Adverse Events

Time Frame	Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and up to Day 17
Adverse Event Reporting Description	At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Arm/Group Title	Clarithromycin + Amoxicillin + Bismuth + TAK-438		Clarithromycin + Amoxicillin + Bismuth + Lansoprazole
Arm/Group Description	Clarithromycin 500 milligram (mg), tablets, orally, twice daily, amoxicillin 1000 mg, capsules, orally, twice daily, bismuth 600 mg, tablets, orally, twice daily, and TAK-438 20 mg, tablets, orally, twice daily on Days 1 to 14.		Clarithromycin 500 mg, tablets, orally, twice daily, amoxicillin 1000 mg capsules, orally, twice daily, bismuth 600 mg, tablets, orally, twice daily, and lansoprazole 30 mg, capsules, orally, twice daily on Days 1 to 14.
All Cause Mortality
	Clarithromycin + Amoxicillin + Bismuth + TAK-438		Clarithromycin + Amoxicillin + Bismuth + Lansoprazole
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/15 (0%)		0/15 (0%)
Serious Adverse Events
	Clarithromycin + Amoxicillin + Bismuth + TAK-438		Clarithromycin + Amoxicillin + Bismuth + Lansoprazole
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/15 (0%)		0/15 (0%)
Other (Not Including Serious) Adverse Events
	Clarithromycin + Amoxicillin + Bismuth + TAK-438		Clarithromycin + Amoxicillin + Bismuth + Lansoprazole
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/15 (53.3%)		10/15 (66.7%)
Cardiac disorders
Palpitations	1/15 (6.7%)		0/15 (0%)
Endocrine disorders
Hyperthyroidism	1/15 (6.7%)		0/15 (0%)
Eye disorders
Eye pruritus	0/15 (0%)		1/15 (6.7%)
Gastrointestinal disorders
Faeces discoloured	1/15 (6.7%)		2/15 (13.3%)
Diarrhoea	1/15 (6.7%)		1/15 (6.7%)
Dyspepsia	1/15 (6.7%)		0/15 (0%)
Gastrooesophageal reflux disease	0/15 (0%)		1/15 (6.7%)
Infrequent bowel movements	1/15 (6.7%)		0/15 (0%)
General disorders
Feeling hot	2/15 (13.3%)		1/15 (6.7%)
Catheter site erythema	0/15 (0%)		1/15 (6.7%)
Chest discomfort	1/15 (6.7%)		0/15 (0%)
Infections and infestations
Nasopharyngitis	0/15 (0%)		1/15 (6.7%)
Upper respiratory tract infection	0/15 (0%)		1/15 (6.7%)
Injury, poisoning and procedural complications
Laceration	1/15 (6.7%)		0/15 (0%)
Investigations
Neutrophil count decreased	0/15 (0%)		1/15 (6.7%)
Nervous system disorders
Dysgeusia	0/15 (0%)		3/15 (20%)
Dizziness	1/15 (6.7%)		0/15 (0%)
Headache	1/15 (6.7%)		0/15 (0%)
Reproductive system and breast disorders
Menstruation irregular	1/15 (6.7%)		0/15 (0%)
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain	1/15 (6.7%)		3/15 (20%)
Rhinorrhoea	1/15 (6.7%)		0/15 (0%)
Skin and subcutaneous tissue disorders
Hyperhidrosis	3/15 (20%)		1/15 (6.7%)
Rash	1/15 (6.7%)		0/15 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Research Organization shall not publish any articles or papers nor make any presentations, nor assist any other person in publishing any articles or papers or in making any presentations relating or referring to the Study or any results, data or insights from or any data, information or materials obtained or generated in the performance of its obligations without the prior written consent of Takeda, which consent may be granted or withheld in Takeda's sole discretion.