TAK-438 Bismuth Drug Interaction Study

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

Status

Completed

Phases

Phase 1

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02892409

Enrollment

Registered

2016-09-08

Start date

2016-09-05

Completion date

2017-05-11

Last updated

2019-01-03

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Helicobacter Pylori

Keywords

Drug Therapy

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.

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.

Interventions

DRUGClarithromycin

Clarithromycin tablets

DRUGAmoxicillin

Amoxicillin capsules

DRUGTripotassium bismuth dicitrate

Tripotassium bismuth dicitrate tablets

DRUGLansoprazole

Lansoprazole capsules

DRUGTAK-438

TAK-438 tablets

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

19 Years to 60 Years

Healthy volunteers

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.

Design outcomes

Primary

Measure	Time frame
Percentage of Participants Who Experience at Least One Treatment Emergent Adverse Event (TEAE)	Baseline up to Day 17
Percentage of Participants Who Discontinue Due to an Adverse Event (AE)	Baseline up to Day 17
Percentage of Participants Who Meet the Markedly Abnormal Criteria for Safety Laboratory Tests at Least Once Post-dose	Baseline up Day 15
Percentage of Participants Who Meet the Markedly Abnormal Criteria for Vital Sign Measurements at Least Once Post-dose	Baseline up to Day 15
Percentage of Participants Who Meet the Markedly Abnormal Criteria for Safety Electrocardiogram (ECG) Parameters at Least Once Post-dose	Baseline up to Day 15
Cmax: Maximum Observed Plasma Concentration for Bismuth	Day 14 pre-dose and at multiple timepoints (up to 12 hours) post-dose
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
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

Countries

South Korea

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 details

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.

Participants by arm

Arm	Count
Clarithromycin + Amoxicillin + Bismuth + TAK-438 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.	15
Clarithromycin + Amoxicillin + Bismuth + Lansoprazole 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.	15
Total	30

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Adverse Event	1	0
Overall Study	Withdrawal by Subject	2	1

Baseline characteristics

Characteristic	Clarithromycin + Amoxicillin + Bismuth + TAK-438	Total	Clarithromycin + Amoxicillin + Bismuth + Lansoprazole
Age, Continuous	32.8 years STANDARD_DEVIATION 6.87	33.1 years STANDARD_DEVIATION 7.66	33.3 years STANDARD_DEVIATION 8.61
Alcohol Consumption Drank a couple of days per month	4 Participants	10 Participants	6 Participants
Alcohol Consumption Drank a couple of days per week	2 Participants	2 Participants	0 Participants
Alcohol Consumption Never Drank	9 Participants	18 Participants	9 Participants
Body Mass Index (BMI)	24.03 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 1.795	23.58 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 2.064	23.13 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 2.271
Caffeine Consumption Had caffeine consumption	7 Participants	20 Participants	13 Participants
Caffeine Consumption Had no caffeine consumption	8 Participants	10 Participants	2 Participants
Cytochrome P450 2C19 (CYP2C19) Genotype 1/1	5 Participants	11 Participants	6 Participants
Cytochrome P450 2C19 (CYP2C19) Genotype 1/2	6 Participants	11 Participants	5 Participants
Cytochrome P450 2C19 (CYP2C19) Genotype 1/3	3 Participants	6 Participants	3 Participants
Cytochrome P450 2C19 (CYP2C19) Genotype 2/2	0 Participants	0 Participants	0 Participants
Cytochrome P450 2C19 (CYP2C19) Genotype 2/3	1 Participants	1 Participants	0 Participants
Cytochrome P450 2C19 (CYP2C19) Genotype 3/3	0 Participants	0 Participants	0 Participants
Height	173.7 centimeter (cm) STANDARD_DEVIATION 5.04	171.3 centimeter (cm) STANDARD_DEVIATION 5.56	168.9 centimeter (cm) STANDARD_DEVIATION 5.14
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	15 Participants	30 Participants	15 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
Sex: Female, Male Female	1 Participants	2 Participants	1 Participants
Sex: Female, Male Male	14 Participants	28 Participants	14 Participants
Smoking Classification Ex-smoker	1 Participants	4 Participants	3 Participants
Smoking Classification Never smoked	14 Participants	26 Participants	12 Participants
Weight	72.41 kilogram (kg) STANDARD_DEVIATION 5.028	69.23 kilogram (kg) STANDARD_DEVIATION 7.528	66.05 kilogram (kg) STANDARD_DEVIATION 8.395

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 15	0 / 15
other Total, other adverse events	8 / 15	10 / 15
serious Total, serious adverse events	0 / 15	0 / 15

Outcome results

Primary

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

Population: 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	Measure	Value (MEAN)	Dispersion
Clarithromycin + Amoxicillin + Bismuth + TAK-438	Aeτ: Amount of Drug Excreted in Urine During a Dosing Interval for Bismuth	497300 nanogram (ng)	Standard Deviation 202270
Clarithromycin + Amoxicillin + Bismuth + Lansoprazole	Aeτ: Amount of Drug Excreted in Urine During a Dosing Interval for Bismuth	537600 nanogram (ng)	Standard Deviation 188340

Primary

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

Arm	Measure	Value (MEAN)	Dispersion
Clarithromycin + Amoxicillin + Bismuth + TAK-438	AUCτ: Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau Over the Dosing Interval for Bismuth	103.0 hours nanogram per milliliter (h*ng/mL)	Standard Deviation 37.498
Clarithromycin + Amoxicillin + Bismuth + Lansoprazole	AUCτ: Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau Over the Dosing Interval for Bismuth	111.1 hours nanogram per milliliter (h*ng/mL)	Standard Deviation 45.01

95% CI: [67.137, 130.569]

Primary

Cmax: Maximum Observed Plasma Concentration for Bismuth

Time frame: Day 14 pre-dose and at multiple timepoints (up to 12 hours) post-dose

Population: 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	Measure	Value (MEAN)	Dispersion
Clarithromycin + Amoxicillin + Bismuth + TAK-438	Cmax: Maximum Observed Plasma Concentration for Bismuth	28.08 nanogram per milliliter (ng/mL)	Standard Deviation 11.691
Clarithromycin + Amoxicillin + Bismuth + Lansoprazole	Cmax: Maximum Observed Plasma Concentration for Bismuth	30.14 nanogram per milliliter (ng/mL)	Standard Deviation 24.612

95% CI: [66.051, 167.183]

Primary