A Bioequivalence (BE) Study of TAK-438 Orally Disintegrating (OD) Tablet

• Sponsor: Takeda (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03808493
• Collaborator: (none)
• Enrollment: 48
• Location: 1
• Arms: 4
• Actual Duration (Months): 1.3
• Patients Per Site Per Month: 35.6

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the BE of single oral dose of TAK-438 OD 20 milligram (mg) tablet without water and TAK-438 20 mg tablet with water (Study 1), and TAK-438 OD 20 mg tablet with water and TAK-438 20 mg tablet with water (Study 2) in Japanese healthy adult male participants.

Condition or Disease	Intervention/Treatment	Phase
Japanese Healthy Adult Male	Drug: TAK-438 OD; Drug: TAK-438	Phase 1

Detailed Description

The drug being tested in this study is called TAK-438 OD tablet. TAK-438 OD tablet is being tested in Japanese healthy adult men. This study will evaluate bioequivalence of single oral dose of TAK-438 OD 20 mg tablet without water and TAK-438 20 mg tablet with water (Study 1), and TAK-438 OD 20 mg tablet with water and TAK-438 20 mg tablet with water (Study 2).

The study will enroll up to 144 participants in total (Study 1 + 2). In Study 1 and 2, participants will be randomly assigned (by chance, like flipping a coin) to one of the two treatment groups;

Study 1:

• TAK-438 OD 20 mg tablet without water (Period 1) + TAK-438 20 mg tablet with water (Period 2)

• TAK-438 20 mg tablet with water (Period 1) + TAK-438 OD 20 mg tablet without water (Period 2)

Study 2:

• TAK-438 OD 20 mg tablet with water (Period 1) + TAK-438 20 mg tablet with water (Period

• TAK-438 20 mg tablet with water (Period 1) + TAK-438 OD 20 mg tablet with water (Period

This single-center trial will be conducted in Japan. The overall time to participate in this study is approximately 11 days. Participants will make two visits to the clinic and be hospitalized for four days each in Periods 1 and 2.

Study Design

• Study Type: Interventional
• Actual Enrollment: 48 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Other
• Official Title: A Randomized, Open-Label, Single-Dose, 2×2 Crossover Phase 1 Study to Evaluate the Bioequivalence of TAK-438 OD (Orally Disintegrating) 20 mg Tablet When Administered Without Water (Study 1) or With Water (Study 2) and TAK-438 20 mg Tablet When Administered With Water in Japanese Healthy Volunteer Male Subjects
• Actual Study Start Date: Jan 30, 2019
• Actual Primary Completion Date: Mar 12, 2019
• Actual Study Completion Date: Mar 12, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Study 1, TAK-438 OD + TAK-438 One TAK-438 OD 20 mg tablet, orally without water under fasted condition, on Period 1 Day 1 in Study 1 (Day 1), followed by a wash-out period (Days 2 to 8), followed by one TAK-438 20 mg tablet, orally with water under fasted condition, on Period 2 Day 1 in Study 1 (Day 9).	Drug: TAK-438 OD; TAK-438 OD tablet; Drug: TAK-438; TAK-438 tablet
Experimental: Study 1, TAK-438 + TAK-438 OD One TAK-438 20 mg tablet, orally with water under fasted condition, on Period 1 Day 1 in Study 1 (Day 1), followed by a wash-out period (Days 2 to 8), followed by one TAK-438 OD 20 mg tablet, orally without water under fasted condition, on Period 2 Day 1 in Study 1 (Day 9).	Drug: TAK-438 OD; TAK-438 OD tablet; Drug: TAK-438; TAK-438 tablet
Experimental: Study 2, TAK-438 OD + TAK-438 One TAK-438 OD 20 mg tablet, orally with water under fasted condition, on Period 1 Day 1 in Study 2 (Day 1), followed by a wash-out period (Days 2 to 8), followed by one TAK-438 20 mg tablet, orally with water under fasted condition, on Period 2 Day 1 in Study 2 (Day 9).	Drug: TAK-438 OD; TAK-438 OD tablet; Drug: TAK-438; TAK-438 tablet
Experimental: Study 2, TAK-438 + TAK-438 OD One TAK-438 20 mg tablet, orally with water under fasted condition, on Period 1 Day 1 in Study 2 (Day 1), followed by a wash-out period (Days 2 to 8), followed by one TAK-438 OD 20 mg tablet, orally with water under fasted condition, on Period 2 Day 1 in Study 2 (Day 9).	Drug: TAK-438 OD; TAK-438 OD tablet; Drug: TAK-438; TAK-438 tablet

Outcome Measures

Primary Outcome Measures

1. AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Plasma Concentration for TAK-438 Free Base (TAK-438F) [Day 1 pre-dose and at multiple time points (up to 48 hours; 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 and 48 hours) post-dose]

2. Cmax: Maximum Observed Plasma Concentration for TAK-438F [Day 1 pre-dose and at multiple time points (up to 48 hours; 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 and 48 hours) post-dose]

Secondary Outcome Measures

1. AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for TAK-438F [Day 1 pre-dose and at multiple time points (up to 48 hours; 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 and 48 hours) post-dose]

2. Tmax: Time of First Occurrence of Maximum Plasma Concentration (Cmax) for TAK-438F [Day 1 pre-dose and at multiple time points (up to 48 hours; 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 and 48 hours) post-dose]

3. MRT∞,ev: Mean Residence Time After Extravascular Administration From Time 0 to Infinity for TAK-438F [Day 1 pre-dose and at multiple time points (up to 48 hours; 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 and 48 hours) post-dose]

4. λz: Terminal Disposition Phase Rate Constant for TAK-438F [Day 1 pre-dose and at multiple time points (up to 48 hours; 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 and 48 hours) post-dose]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 20 Years to 60 Years
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

1. In the opinion of the investigator or sub-investigator, the participant is capable of understanding and complying with protocol requirements.

2. The participant signs and dates a written, informed consent form prior to the initiation of any study procedures.

3. The participant is a healthy Japanese adult male, aged 20 to 60 years, inclusive, at the time of informed consent.

4. The participant weighs at least 50 kilogram (kg) and has a body mass index (BMI) from 18.5 to 25.0 kilogram per square meter (kg/m^2), inclusive at Screening.

5. The participant must be a current nonsmoker who has not used tobacco- or nicotine-containing products (example, nicotine patch) for at least 6 months prior to the start of study drug administration in Period 1.

6. The participant must be judged to be in good health by the investigator, based on clinical evaluations including laboratory safety tests, medical history, physical examination, 12-lead electrocardiogram (ECG), and vital sign measurements performed at the Screening Visit and prior to the start of study drug administration in Period 1.

Exclusion Criteria:

1. The participant has received any investigational compound within 16 weeks (112 days) prior to the start of study drug administration in Period 1.

2. The participant has received TAK-438 in a previous clinical study or as a therapeutic agent.

3. The participant is an immediate family member of or a study site employee, or is in a dependent relationship with a study site employee who is involved in the conduct of this study (example, spouse, parent, child, sibling) or may consent under duress.

4. The participant has uncontrolled, clinically significant neurologic, cardiovascular, pulmonary, hepatic, renal, metabolic, gastrointestinal, urologic, or endocrine disease or other abnormality (other than the disease being studied), which may impact the ability of the participant to participate in the study or potentially confound its results.

5. The participant has hypersensitivity to any component of TAK-438 OD tablet or TAK-438 tablet.

6. The participant has a positive urine drug result for drugs of abuse at Screening.

7. The participant has a history of drug or alcohol abuse within 2 years prior to the Screening visit or is unwilling to agree to abstain from alcohol and drugs throughout the study.

8. The participant has taken any excluded medication, supplements, or food products during the specified time periods.

9. The participant has current or recent (within 6 months) gastrointestinal disease that would be expected to influence the absorption of drugs (ie, a history of malabsorption, esophageal reflux, peptic ulcer disease, erosive esophagitis), frequent (more than once per week) occurrence of heartburn, or any surgical intervention.

10. The participant has a history of cancer, except basal cell carcinoma which has been in remission for at least 5 years prior to Day 1.

11. The participant has a positive test result for hepatitis B virus surface antigen (HBsAg), hepatitis C virus (HCV) antibody, human immunodeficiency virus (HIV) antibody/antigen, or serological reactions for syphilis at Screening.

12. The participant has poor peripheral venous access.

13. The participant has undergone whole blood collection of at least 200 milliliter (mL) within 4 weeks (28 days) or at least 400 mL within 12 weeks (84 days) prior to the start of study drug administration in Period 1.

14. The participant has undergone whole blood collection of at least 800 mL in total within 52 weeks (364 days) prior to the start of study drug administration in Period

16. The participant has undergone blood component collection within 2 weeks (14 days) prior to the start of study drug administration in Period 1.

17. The participant has a Screening or Check-in (Day -1) ECG that was abnormal (clinically significant).

18. The participant has abnormal Screening laboratory values that suggest a clinically significant underlying disease or participant with the following laboratory abnormalities: alanine aminotransferase (ALT) or aspartate aminotransferase (AST) above the upper limits of normal (ULN).

19. The participant who, in the opinion of the investigator or sub-investigator, is unlikely to comply with the protocol or is unsuitable for any other reason.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Sekino Clinical Pharmacology Clininc	Toshima-ku	Tokyo	Japan

Sponsors and Collaborators

• Takeda

Investigators

• Study Director: Study Director, Takeda

Study Documents (Full-Text)

• Study Protocol - Dec 12, 2018
• Statistical Analysis Plan - Dec 27, 2018

More Information

Publications

None provided.

• Responsible Party: Takeda
• ClinicalTrials.gov Identifier: NCT03808493
• Other Study ID Numbers: TAK-438ODT-1001; U1111-1225-5005; JapicCTI-194587
• First Posted: Jan 17, 2019
• Last Update Posted: Apr 7, 2020
• Last Verified: Mar 1, 2020

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Takeda: Drug Therapy

Study Results

Participant Flow

Recruitment Details	Participants took part in the study at 1 investigative site in Japan from 30 January 2019 to 12 March 2019.
Pre-assignment Detail	Healthy Japanese male participants were enrolled in 1 of the 2 treatment sequences to receive TAK-438 OD 20 milligram (mg) or TAK-438 20 mg with or without water in Study 1, and TAK-438 OD 20 mg or TAK-438 20 mg with water in Study 2. Study was completed with Pilot study since results from interim analysis satisfied the criteria of bioequivalence.

Arm/Group Title	Pilot BE Study 1, Sequence A: TAK-438 OD 20 mg + TAK-438 20 mg	Pilot BE Study 1, Sequence B: TAK-438 20 mg + TAK-438 OD 20 mg	Pilot BE Study 2, Sequence C: TAK-438 OD 20 mg + TAK-438 20 mg	Pilot BE Study 2, Sequence D: TAK-438 20 mg + TAK-438 OD 20 mg
Arm/Group Description	TAK-438 orally disintegrating (OD) 20 mg, tablet, orally without water under fasted condition, once on Day 1 of Period 1, followed by a washout period of at least 7 days, further followed by TAK-438 20 mg, tablet, orally with water under fasted condition, once on Day 1 of Period 2.	TAK-438 20 mg, tablet, orally with water under fasted condition, once on Day 1 of Period 1 followed by a washout period of at least 7 days, further followed TAK-438 OD 20 mg, tablet, orally without water under fasted condition, once on Day 1 of Period 2.	TAK-438 OD 20 mg, tablet, orally with water under fasted condition, once on Day 1 of Period 1, followed by a washout period of at least 7 days, further followed by TAK-438 20 mg tablet, orally with water under fasted condition, once on Day 1 of Period 2.	TAK-438 20 mg, tablet, orally with water under fasted condition, once on Day 1 of Period 1, followed by a washout period of at least 7 days, further followed by TAK-438 OD 20 mg tablet, orally with water under fasted condition, once on Day 1 of Period 2.
Period Title: Overall Study
STARTED	12	12	12	12
COMPLETED	12	12	12	12
NOT COMPLETED	0	0	0	0

Baseline Characteristics

Arm/Group Title	Pilot BE Study 1, Sequence A: TAK-438 OD 20 mg + TAK-438 20 mg	Pilot BE Study 1, Sequence B: TAK-438 20 mg + TAK-438 OD 20 mg	Pilot BE Study 2, Sequence C: TAK-438 OD 20 mg + TAK-438 20 mg	Pilot BE Study 2, Sequence D: TAK-438 20 mg + TAK-438 OD 20 mg	Total
Arm/Group Description	TAK-438 OD 20 mg, tablet, orally without water under fasted condition, once on Day 1 of Period 1, followed by a washout period of at least 7 days, further followed by TAK-438 20 mg, tablet, orally with water under fasted condition, once on Day 1 of Period 2.	TAK-438 20 mg, tablet, orally with water under fasted condition, once on Day 1 of Period 1 followed by a washout period of at least 7 days, further followed TAK-438 OD 20 mg, tablet, orally without water under fasted condition, once on Day 1 of Period 2.	TAK-438 OD 20 mg, tablet, orally with water under fasted condition, once on Day 1 of Period 1, followed by a washout period of at least 7 days, further followed by TAK-438 20 mg tablet, orally with water under fasted condition, once on Day 1 of Period 2.	TAK-438 20 mg, tablet, orally with water under fasted condition, once on Day 1 of Period 1, followed by a washout period of at least 7 days, further followed by TAK-438 OD 20 mg tablet, orally with water under fasted condition, once on Day 1 of Period 2.	Total of all reporting groups
Overall Participants	12	12	12	12	48
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	22.1 (3.87)	26.0 (6.74)	26.5 (7.19)	26.0 (6.76)	25.1 (6.34)
Sex: Female, Male (Count of Participants)
Female	0 0%	0 0%	0 0%	0 0%	0 0%
Male	12 100%	12 100%	12 100%	12 100%	48 100%
Race and Ethnicity Not Collected (Count of Participants)
Count of Participants [Participants]	0 0%
Region of Enrollment (Count of Participants)
Japan	12 100%	12 100%	12 100%	12 100%	48 100%
Height (centimeter (cm)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [centimeter (cm)]	171.8 (4.00)	170.0 (6.52)	173.9 (4.32)	172.2 (6.94)	172.0 (5.59)
Weight (kilogram (kg)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilogram (kg)]	59.83 (4.672)	60.95 (4.720)	63.29 (4.860)	65.44 (6.716)	62.38 (5.586)
Body Mass Index (BMI) (kilogram per square meter (kg/m^2)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilogram per square meter (kg/m^2)]	20.28 (1.817)	21.15 (1.829)	20.94 (1.781)	22.03 (1.043)	21.10 (1.718)
Caffeine Consumption (Count of Participants)
Had caffeine consumption	2 16.7%	1 8.3%	4 33.3%	4 33.3%	11 22.9%
Had no caffeine consumption	10 83.3%	11 91.7%	8 66.7%	8 66.7%	37 77.1%
Alcohol Consumption (Count of Participants)
Drank a few times per week	0 0%	2 16.7%	0 0%	1 8.3%	3 6.3%
Drank a few times per month	6 50%	3 25%	4 33.3%	1 8.3%	14 29.2%
Never drank	6 50%	7 58.3%	8 66.7%	10 83.3%	31 64.6%
Smoking Classification (Count of Participants)
Never smoked	11 91.7%	11 91.7%	10 83.3%	11 91.7%	43 89.6%
Former smoker	1 8.3%	1 8.3%	2 16.7%	1 8.3%	5 10.4%

Outcome Measures

1. Primary Outcome

Title	AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Plasma Concentration for TAK-438 Free Base (TAK-438F)
Time Frame	Day 1 pre-dose and at multiple time points (up to 48 hours; 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 and 48 hours) post-dose

Outcome Measure Data

Analysis Population Description

The pharmacokinetic (PK) analysis set was defined as all participants who received at least one dose of study drug, and whose PK data were evaluable.

Arm/Group Title	Pilot BE Study 1: TAK-438 OD 20 mg	Pilot BE Study 1: TAK-438 20 mg	Pilot BE Study 2: TAK-438 OD 20 mg	Pilot BE Study 2: TAK-438 20 mg
Arm/Group Description	TAK-438 OD 20 mg, tablet, orally without water under fasted condition, once on Day 1 of either Period 1 or 2.	TAK-438 20 mg, tablet, orally with water under fasted condition, once on Day 1 of either Period 1 or 2.	TAK-438 OD 20 mg, tablet, orally with water under fasted condition, once on Day 1 of either Period 1 or 2.	TAK-438 20 mg, tablet, orally with water under fasted condition, once on Day 1 of either Period 1 or 2.
Measure Participants	24	24	24	24
Geometric Mean (Standard Deviation) [hour*nanogram per milliliter (h*ng/mL)]	190.2 (67.984)	194.3 (67.693)	201.6 (81.799)	201.2 (75.813)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pilot BE Study 1: TAK-438 OD 20 mg, Pilot BE Study 1: TAK-438 20 mg
	Comments
	Type of Statistical Test	Equivalence
	Comments	For log-transformed (natural log) AUClast, the two-sided 90% CI of the difference in the least square means (LS-Means) between the formulations (TAK-438 OD tablet-TAK-438 tablet) was provided using the ANOVA model.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS-Means Difference
	Estimated Value	-0.0211
	Confidence Interval	(2-Sided) 90%; -0.0752 to 0.0329
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Pilot BE Study 2: TAK-438 OD 20 mg, Pilot BE Study 2: TAK-438 20 mg
	Comments
	Type of Statistical Test	Equivalence
	Comments	For log-transformed (natural log) AUClast, the two-sided 90% CI of the difference in the LS-Means between the formulations (TAK-438 OD tablet-TAK-438 tablet) was provided using the ANOVA model.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS-Means Difference
	Estimated Value	0.0019
	Confidence Interval	(2-Sided) 90%; -0.0778 to 0.0815
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Cmax: Maximum Observed Plasma Concentration for TAK-438F
Time Frame	Day 1 pre-dose and at multiple time points (up to 48 hours; 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 and 48 hours) post-dose

Outcome Measure Data

Analysis Population Description

The PK analysis set was defined as all participants who received at least one dose of study drug, and whose PK data were evaluable.

Arm/Group Title	Pilot BE Study 1: TAK-438 OD 20 mg	Pilot BE Study 1: TAK-438 20 mg	Pilot BE Study 2: TAK-438 OD 20 mg	Pilot BE Study 2: TAK-438 20 mg
Arm/Group Description	TAK-438 OD 20 mg, tablet, orally without water under fasted condition, once on Day 1 of either Period 1 or 2.	TAK-438 20 mg, tablet, orally with water under fasted condition, once on Day 1 of either Period 1 or 2.	TAK-438 OD 20 mg, tablet, orally with water under fasted condition, once on Day 1 of either Period 1 or 2.	TAK-438 20 mg, tablet, orally with water under fasted condition, once on Day 1 of either Period 1 or 2.
Measure Participants	24	24	24	24
Geometric Mean (Standard Deviation) [nanogram per milliliter (ng/mL)]	22.62 (7.8152)	24.26 (8.0676)	21.85 (7.7286)	23.70 (8.5998)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pilot BE Study 1: TAK-438 OD 20 mg, Pilot BE Study 1: TAK-438 20 mg
	Comments
	Type of Statistical Test	Equivalence
	Comments	For log-transformed (natural log) Cmax, the two-sided 90% CI of the difference in the LS-Means between the formulations (TAK-438 OD tablet-TAK-438 tablet) was provided using the ANOVA model.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS-Means Difference
	Estimated Value	-0.0698
	Confidence Interval	(2-Sided) 90%; -0.1404 to 0.0008
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Pilot BE Study 2: TAK-438 OD 20 mg, Pilot BE Study 2: TAK-438 20 mg
	Comments
	Type of Statistical Test	Equivalence
	Comments	For log-transformed (natural log) Cmax, the two-sided 90% CI of the difference in the LS-Means between the formulations (TAK-438 OD tablet-TAK-438 tablet) was provided using the ANOVA model.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS-Means Difference
	Estimated Value	-0.0811
	Confidence Interval	(2-Sided) 90%; -0.1658 to 0.0036
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for TAK-438F
Time Frame	Day 1 pre-dose and at multiple time points (up to 48 hours; 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 and 48 hours) post-dose

Outcome Measure Data

Analysis Population Description

The PK analysis set was defined as all participants who received at least one dose of study drug, and whose PK data were evaluable.

Arm/Group Title	Pilot BE Study 1: TAK-438 OD 20 mg	Pilot BE Study 1: TAK-438 20 mg	Pilot BE Study 2: TAK-438 OD 20 mg	Pilot BE Study 2: TAK-438 20 mg
Arm/Group Description	TAK-438 OD 20 mg, tablet, orally without water under fasted condition, once on Day 1 of either Period 1 or 2.	TAK-438 20 mg, tablet, orally with water under fasted condition, once on Day 1 of either Period 1 or 2.	TAK-438 OD 20 mg, tablet, orally with water under fasted condition, once on Day 1 of either Period 1 or 2.	TAK-438 20 mg, tablet, orally with water under fasted condition, once on Day 1 of either Period 1 or 2.
Measure Participants	24	24	24	24
Geometric Mean (Standard Deviation) [h*ng/mL]	192.5 (68.755)	196.4 (68.436)	204.3 (83.014)	203.6 (77.630)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pilot BE Study 1: TAK-438 OD 20 mg, Pilot BE Study 1: TAK-438 20 mg
	Comments
	Type of Statistical Test	Equivalence
	Comments	For log-transformed (natural log) AUC∞, the two-sided 90% CI of the difference in the LS-Means between the formulations (TAK-438 OD tablet-TAK-438 tablet) was provided using the ANOVA model.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS-Means Difference
	Estimated Value	-0.0199
	Confidence Interval	(2-Sided) 90%; -0.0731 to 0.0333
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Pilot BE Study 2: TAK-438 OD 20 mg, Pilot BE Study 2: TAK-438 20 mg
	Comments
	Type of Statistical Test	Equivalence
	Comments	For log-transformed (natural log) AUC∞, the two-sided 90% CI of the difference in the LS-Means between the formulations (TAK-438 OD tablet-TAK-438 tablet) was provided using the ANOVA model.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS-Means Difference
	Estimated Value	0.0035
	Confidence Interval	(2-Sided) 90%; -0.0760 to 0.0830
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Tmax: Time of First Occurrence of Maximum Plasma Concentration (Cmax) for TAK-438F
Time Frame	Day 1 pre-dose and at multiple time points (up to 48 hours; 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 and 48 hours) post-dose

Outcome Measure Data

Analysis Population Description

The PK analysis set was defined as all participants who received at least one dose of study drug, and whose PK data were evaluable.

Arm/Group Title	Pilot BE Study 1: TAK-438 OD 20 mg	Pilot BE Study 1: TAK-438 20 mg	Pilot BE Study 2: TAK-438 OD 20 mg	Pilot BE Study 2: TAK-438 20 mg
Arm/Group Description	TAK-438 OD 20 mg, tablet, orally without water under fasted condition, once on Day 1 of either Period 1 or 2.	TAK-438 20 mg, tablet, orally with water under fasted condition, once on Day 1 of either Period 1 or 2.	TAK-438 OD 20 mg, tablet, orally with water under fasted condition, once on Day 1 of either Period 1 or 2.	TAK-438 20 mg, tablet, orally with water under fasted condition, once on Day 1 of either Period 1 or 2.
Measure Participants	24	24	24	24
Median (Full Range) [hour]	2.000	1.750	2.000	2.000

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pilot BE Study 1: TAK-438 OD 20 mg, Pilot BE Study 1: TAK-438 20 mg
	Comments
	Type of Statistical Test	Equivalence
	Comments	For log-transformed (natural log) Tmax, the two-sided 90% CI of the difference in the LS-Means between the formulations (TAK-438 OD tablet-TAK-438 tablet) was provided using the ANOVA model.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS-Means Difference
	Estimated Value	0.1902
	Confidence Interval	(2-Sided) 90%; 0.0199 to 0.3605
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Pilot BE Study 2: TAK-438 OD 20 mg, Pilot BE Study 2: TAK-438 20 mg
	Comments
	Type of Statistical Test	Equivalence
	Comments	For log-transformed (natural log) Tmax, the two-sided 90% CI of the difference in the LS-Means between the formulations (TAK-438 OD tablet-TAK-438 tablet) was provided using the ANOVA model.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS-Means Difference
	Estimated Value	0.2142
	Confidence Interval	(2-Sided) 90%; 0.0558 to 0.3725
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	MRT∞,ev: Mean Residence Time After Extravascular Administration From Time 0 to Infinity for TAK-438F
Time Frame	Day 1 pre-dose and at multiple time points (up to 48 hours; 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 and 48 hours) post-dose

Outcome Measure Data

Analysis Population Description

The PK analysis set was defined as all participants who received at least one dose of study drug, and whose PK data were evaluable.

Arm/Group Title	Pilot BE Study 1: TAK-438 OD 20 mg	Pilot BE Study 1: TAK-438 20 mg	Pilot BE Study 2: TAK-438 OD 20 mg	Pilot BE Study 2: TAK-438 20 mg
Arm/Group Description	TAK-438 OD 20 mg, tablet, orally without water under fasted condition, once on Day 1 of either Period 1 or 2.	TAK-438 20 mg, tablet, orally with water under fasted condition, once on Day 1 of either Period 1 or 2.	TAK-438 OD 20 mg, tablet, orally with water under fasted condition, once on Day 1 of either Period 1 or 2.	TAK-438 20 mg, tablet, orally with water under fasted condition, once on Day 1 of either Period 1 or 2.
Measure Participants	24	24	24	24
Mean (Standard Deviation) [hour]	9.576 (1.1807)	9.258 (0.91125)	9.831 (1.3506)	9.544 (1.4121)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pilot BE Study 1: TAK-438 OD 20 mg, Pilot BE Study 1: TAK-438 20 mg
	Comments
	Type of Statistical Test	Equivalence
	Comments	For log-transformed (natural log) MRT∞,ev, the two-sided 90% CI of the difference in the LS-Means between the formulations (TAK-438 OD tablet-TAK-438 tablet) was provided using the ANOVA model.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS-Means Difference
	Estimated Value	0.0311
	Confidence Interval	(2-Sided) 90%; 0.0022 to 0.0599
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Pilot BE Study 2: TAK-438 OD 20 mg, Pilot BE Study 2: TAK-438 20 mg
	Comments
	Type of Statistical Test	Equivalence
	Comments	For log-transformed (natural log) MRT∞,ev, the two-sided 90% CI of the difference in the LS-Means between the formulations (TAK-438 OD tablet-TAK-438 tablet) was provided using the ANOVA model.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS-Means Difference
	Estimated Value	0.0306
	Confidence Interval	(2-Sided) 90%; -0.0003 to 0.0616
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	λz: Terminal Disposition Phase Rate Constant for TAK-438F
Time Frame	Day 1 pre-dose and at multiple time points (up to 48 hours; 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 and 48 hours) post-dose

Outcome Measure Data

Analysis Population Description

The PK analysis set was defined as all participants who received at least one dose of study drug, and whose PK data were evaluable.

Arm/Group Title	Pilot BE Study 1: TAK-438 OD 20 mg	Pilot BE Study 1: TAK-438 20 mg	Pilot BE Study 2: TAK-438 OD 20 mg	Pilot BE Study 2: TAK-438 20 mg
Arm/Group Description	TAK-438 OD 20 mg, tablet, orally without water under fasted condition, once on Day 1 of either Period 1 or 2.	TAK-438 20 mg, tablet, orally with water under fasted condition, once on Day 1 of either Period 1 or 2.	TAK-438 OD 20 mg, tablet, orally with water under fasted condition, once on Day 1 of either Period 1 or 2.	TAK-438 20 mg, tablet, orally with water under fasted condition, once on Day 1 of either Period 1 or 2.
Measure Participants	24	24	24	24
Mean (Standard Deviation) [per hour (1/hour)]	0.1014 (0.014441)	0.09903 (0.011269)	0.09807 (0.013021)	0.09989 (0.016690)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pilot BE Study 1: TAK-438 OD 20 mg, Pilot BE Study 1: TAK-438 20 mg
	Comments
	Type of Statistical Test	Equivalence
	Comments	For log-transformed (natural log) λz, the two-sided 90% CI of the difference in the LS-Means between the formulations (TAK-438 OD tablet-TAK-438 tablet) was provided using the ANOVA model.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS-Means Difference
	Estimated Value	0.0209
	Confidence Interval	(2-Sided) 90%; -0.0112 to 0.0530
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Pilot BE Study 2: TAK-438 OD 20 mg, Pilot BE Study 2: TAK-438 20 mg
	Comments
	Type of Statistical Test	Equivalence
	Comments	For log-transformed (natural log) λz, the two-sided 90% CI of the difference in the LS-Means between the formulations (TAK-438 OD tablet-TAK-438 tablet) was provided using the ANOVA model.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS-Means Difference
	Estimated Value	-0.0135
	Confidence Interval	(2-Sided) 90%; -0.0508 to 0.0238
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Treatment-emergent adverse events (TEAEs) are adverse events (AE) that started after the first dose of study drug until Day 3 in Period 2 (up to Day 13)
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	Pilot BE Study 1: TAK-438 OD 20 mg		Pilot BE Study 1: TAK-438 20 mg		Pilot BE Study 2: TAK-438 OD 20 mg		Pilot BE Study 2: TAK-438 20 mg
Arm/Group Description	TAK-438 OD 20 mg, tablet, orally without water under fasted condition, once on Day 1 of either Period 1 or 2.		TAK-438 20 mg, tablet, orally with water under fasted condition, once on Day 1 of either Period 1 or 2.		TAK-438 OD 20 mg, tablet, orally with water under fasted condition, once on Day 1 of either Period 1 or 2.		TAK-438 20 mg, tablet, orally with water under fasted condition, once on Day 1 of either Period 1 or 2.
All Cause Mortality
	Pilot BE Study 1: TAK-438 OD 20 mg		Pilot BE Study 1: TAK-438 20 mg		Pilot BE Study 2: TAK-438 OD 20 mg		Pilot BE Study 2: TAK-438 20 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/24 (0%)		0/24 (0%)		0/24 (0%)		0/24 (0%)
Serious Adverse Events
	Pilot BE Study 1: TAK-438 OD 20 mg		Pilot BE Study 1: TAK-438 20 mg		Pilot BE Study 2: TAK-438 OD 20 mg		Pilot BE Study 2: TAK-438 20 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/24 (0%)		0/24 (0%)		0/24 (0%)		0/24 (0%)
Other (Not Including Serious) Adverse Events
	Pilot BE Study 1: TAK-438 OD 20 mg		Pilot BE Study 1: TAK-438 20 mg		Pilot BE Study 2: TAK-438 OD 20 mg		Pilot BE Study 2: TAK-438 20 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/24 (0%)		0/24 (0%)		0/24 (0%)		0/24 (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.