A Study to Evaluate the Bioequivalence (BE) and the Food Effect of TAK-438ASA Tablet

• Sponsor: Takeda (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03456960
• Collaborator: (none)
• Enrollment: 276
• Location: 1
• Arms: 6
• Actual Duration (Months): 7.2
• Patients Per Site Per Month: 38.5

Study Details

Study Description

Brief Summary

The purposes of this study are to evaluate BE between a single-dose of TAK-438ASA tablet versus a single-dose combination of TAK-438 tablet 10 milligram (mg) and aspirin enteric-coated tablet 100 mg in Japanese healthy adult men (Study 1), and to evaluate the effects of food on the pharmacokinetics of TAK-438ASA tablet in Japanese healthy adult men (Study 2).

Condition or Disease	Intervention/Treatment	Phase
Healthy Volunteers	Drug: TAK-438ASA; Drug: TAK-438; Drug: Aspirin	Phase 1

Detailed Description

The drug under investigation in this study is called TAK-438ASA. TAK-438ASA is being tested in Japanese healthy adult men. This study consists of two studies to evaluate bioequivalence (Study 1) and the effects of food (Study 2). Study 1 (split into a Pilot phase and a Pivotal phase) will look at bioequivalence between a single-dose of TAK-438ASA tablet versus a single-dose combination of TAK-438 tablet 10 mg and aspirin enteric-coated tablet 100 mg. Study 2 will look at the effects of food on the pharmacokinetics of TAK-438ASA tablet.

The study will enroll up to 440 participants in total (Study 1 + 2). For Study 1, 12 participants per group (24 participants in total) will be randomly assigned (by chance, like flipping a coin) to one of the two treatment groups for the pilot study to estimate the sample size of Pivotal study. After pilot study, 202 participants as a maximum per group (404 participants in total) will be randomly assigned to one of the two treatment groups:

• TAK-438ASA tablet (Period 1) + TAK-438 10 mg tablet and Aspirin 100 mg tablet (Period 2)

• TAK-438 10 mg tablet and Aspirin 100 mg tablet (Period 1) + TAK-438ASA tablet (Period 2)

For Study 2, 6 participants per group (12 participants in total) will be randomly assigned (by chance, like flipping a coin) to one of the two treatment groups:

• TAK-438ASA tablet (Fasted condition) + TAK-438ASA tablet (Fed condition)

• TAK-438ASA tablet (Fed condition) + TAK-438ASA tablet (Fasted condition) This single-center trial will be conducted in Japan. The overall time to participate in this study is approximately 18 days. Participants will make two visits to the clinic and be hospitalized for eight days in total.

Study Design

• Study Type: Interventional
• Actual Enrollment: 276 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Other
• Official Title: A Phase 1, Randomized, Open-Label, Crossover Study to Evaluate the Bioequivalence of Single Oral Dose of TAK-438ASA Tablet and Single Oral Dose of TAK-438 Tablet Plus Aspirin Enteric-Coated Tablet (Study 1) and the Food Effect of Single Oral Dose of TAK-438ASA Tablet (Study 2) in Healthy Adult Male Subjects
• Actual Study Start Date: Mar 8, 2018
• Actual Primary Completion Date: Oct 10, 2018
• Actual Study Completion Date: Oct 12, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Pilot phase of Study 1,TAK-438ASA + TAK-438 and Aspirin One TAK-438ASA tablet, orally without breakfast, on Day 1 of Period 1 in the Pilot phase of Study 1 (Day 1), followed by a washout period (Days 2 to 15), followed by one TAK-438 10 mg tablet and one aspirin 100 mg tablet, orally without breakfast, on Day 1 of Period 2 in the Pilot phase of Study 1 (Day 16).	Drug: TAK-438ASA; TAK-438ASA tablet.; Drug: TAK-438; TAK-438 tablet.; Drug: Aspirin; Aspirin enteric-coated tablet.
Experimental: Pilot phase of Study 1,TAK-438 and Aspirin + TAK-438ASA One TAK-438 10 mg tablet and one aspirin 100 mg tablet, orally without breakfast, on Day 1 of Period 1 in the Pilot phase of Study 1 (Day 1), followed by a washout period (Days 2 to 15), followed by, one TAK-438ASA tablet, orally without breakfast, on Day 1 of Period 2 in the Pilot phase of Study 1 (Day 16).	Drug: TAK-438ASA; TAK-438ASA tablet.; Drug: TAK-438; TAK-438 tablet.; Drug: Aspirin; Aspirin enteric-coated tablet.
Experimental: Pivotal phase of Study 1, TAK-438ASA + TAK-438 and Aspirin One TAK-438ASA tablet, orally without breakfast, on Day 1 of Period 1 in the Pivotal phase of Study 1 (Day 1), followed by a washout period (Days 2 to 15), followed by one TAK-438 10 mg tablet and one aspirin 100 mg tablet, orally without breakfast, on Day 1 of Period 2 in the Pivotal phase of Study 1 (Day 16).	Drug: TAK-438ASA; TAK-438ASA tablet.; Drug: TAK-438; TAK-438 tablet.; Drug: Aspirin; Aspirin enteric-coated tablet.
Experimental: Pivotal phase of Study 1, TAK-438 and Aspirin + TAK-438ASA One TAK-438 10 mg tablet and one aspirin 100 mg tablet, orally without breakfast, on Day 1 of Period 1 in the Pivotal phase of Study 1 (Day 1), followed by a washout period (Days 2 to 15), followed by one TAK-438ASA tablet, orally without breakfast, on Day 1 of Period 2 in the Pivotal phase of Study 1 (Day 16).	Drug: TAK-438ASA; TAK-438ASA tablet.; Drug: TAK-438; TAK-438 tablet.; Drug: Aspirin; Aspirin enteric-coated tablet.
Experimental: Study 2,TAK-438ASA (Fasted + Fed condition) One TAK-438ASA tablet, orally without breakfast, on Day 1 of Period 1 in Study 2 (Day 1), followed by a washout period (Days 2 to 15), followed by one TAK-438ASA tablet, orally 30 minutes after breakfast, on Day 1 of Period 2 in Study 2 (Day 16).	Drug: TAK-438ASA; TAK-438ASA tablet.
Experimental: Study 2,TAK-438ASA (Fed + Fasted condition) One TAK-438ASA tablet, orally 30 minutes after breakfast, on Day 1 of Period 1 in Study 2 (Day 1), followed by a washout period (Days 2 to 15), followed by one TAK-438ASA tablet, orally without breakfast, on Day 1 of Period 2 in Study 2 (Day 16).	Drug: TAK-438ASA; TAK-438ASA tablet.

Outcome Measures

Primary Outcome Measures

1. Study 1, AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Free Base of TAK-438 (TAK-438F) [Day 1 pre-dose and at multiple time points (up to 48 hours) post-dose]

2. Study 1, Cmax: Maximum Observed Plasma Concentration for TAK-438F [Day 1 pre-dose and at multiple time points (up to 48 hours) post-dose]

3. Study 1, AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Unchanged Aspirin [Day 1 pre-dose and at multiple time points (up to 12 hours) post-dose]

4. Study 1, Cmax: Maximum Observed Plasma Concentration for Unchanged Aspirin [Day 1 pre-dose and at multiple time points (up to 12 hours) post-dose]

Secondary Outcome Measures

1. Study 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) post-dose]

2. Study 1, Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-438F [Day 1 pre-dose and at multiple time points (up to 48 hours) post-dose]

3. Study 1, MRT (Infinity,ev): Mean Residence Time From Time 0 to Infinity for TAK-438F [Day 1 pre-dose and at multiple time points (up to 48 hours) post-dose]

4. Study 1, Lambda (z): Terminal Disposition Phase Rate Constant for TAK-438F [Day 1 pre-dose and at multiple time points (up to 48 hours) post-dose]

5. Study 1, AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for Unchanged Aspirin [Day 1 pre-dose and at multiple time points (up to 12 hours) post-dose]

6. Study 1, Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Unchanged Aspirin [Day 1 pre-dose and at multiple time points (up to 12 hours) post-dose]

7. Study 1, MRT (Infinity,ev): Mean Residence Time From Time 0 to Infinity for Unchanged Aspirin [Day 1 pre-dose and at multiple time points (up to 12 hours) post-dose]

8. Study 1, Lambda (z): Terminal Disposition Phase Rate Constant for Unchanged Aspirin [Day 1 pre-dose and at multiple time points (up to 12 hours) post-dose]

9. Study 2, AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for TAK-438F and Its Metabolites (M) (M-I, M-II, M-III and M-IV-Sul) [Day 1 pre-dose and at multiple time points (up to 48 hours) post-dose]

10. Study 2, AUC(0-48): Area Under the Plasma Concentration-time Curve From Time 0 to Time 48 Hours Over the Dosing Interval for TAK-438F and Its Metabolites (M-I, M-II, M-III and M-IV-Sul) [Day 1 pre-dose and at multiple time points (up to 48 hours) post-dose]

11. Study 2, AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for TAK-438F and Its Metabolites (M-I, M-II, M-III and M-IV-Sul) [Day 1 pre-dose and at multiple time points (up to 48 hours) post-dose]

12. Study 2, Cmax: Maximum Observed Plasma Concentration for TAK-438F and Its Metabolites (M-I, M-II, M-III and M-IV-Sul) [Day 1 pre-dose and at multiple time points (up to 48 hours) post-dose]

13. Study 2, Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-438F and Its Metabolites (M-I, M-II, M-III and M-IV-Sul) [Day 1 pre-dose and at multiple time points (up to 48 hours) post-dose]

14. Study 2, T1/2z: Terminal Disposition Phase Half-life for TAK-438F and Its Metabolites (M-I, M-II, M-III and M-IV-Sul) [Day 1 pre-dose and at multiple time points (up to 48 hours) post-dose]

15. Study 2, AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for Unchanged Aspirin and Its Metabolite (Salicylic Acid) [Day 1 pre-dose and at multiple time points (up to 24 hours) post-dose]

16. Study 2, AUC(0-24): Area Under the Plasma Concentration-time Curve From Time 0 to Time 24 Hours Over the Dosing Interval for Unchanged Aspirin and Its Metabolite (Salicylic Acid) [Day 1 pre-dose and at multiple time points (up to 24 hours) post-dose]

17. Study 2, AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Unchanged Aspirin and Its Metabolite (Salicylic Acid) [Day 1 pre-dose and at multiple time points (up to 24 hours) post-dose]

18. Study 2, Cmax: Maximum Observed Plasma Concentration for Unchanged Aspirin and Its Metabolite (Salicylic Acid) [Day 1 pre-dose and at multiple time points (up to 24 hours) post-dose]

19. Study 2, Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Unchanged Aspirin and Its Metabolite (Salicylic Acid) [Day 1 pre-dose and at multiple time points (up to 24 hours) post-dose]

20. Study 2, T1/2z: Terminal Disposition Phase Half-life for Unchanged Aspirin and Its Metabolite (Salicylic Acid) [Day 1 pre-dose and at multiple time points (up to 24 hours) post-dose]

21. Study 2, Ae(0-48): Amount of Drug Excreted in Urine From Time 0 to 48 Hours for TAK-438F and Its Metabolites (M-I, M-II, M-III, and M-IV-Sul) [Day 1 pre-dose and at multiple time points (up to 48 hours) post-dose]

22. Study 2, Fe(0-48): Fraction of Administered Dose Excreted Into Urine From Time 0 to Time 48 Hours for TAK-438F and Its Metabolites (M-I, M-II, M-III and M-IV-Sul) [Day 1 pre-dose and at multiple time points (up to 48 hours) post-dose]

23. Study 2, CLR: Renal Clearance for TAK-438F and Its Metabolites (M-I, M-II, M-III, and M-IV-Sul) [Day 1 pre-dose and at multiple time points (up to 48 hours) post-dose]

24. Study 2, Ae(0-24): Amount of Drug Excreted in Urine From Time 0 to 24 Hours for Unchanged Aspirin and Its Metabolites (Salicylic Acid and Salicyluric Acid) [Day 1 pre-dose and at multiple time points (up to 24 hours) post-dose]

25. Study 2, Fe(0-24): Fraction of Administered Dose Excreted Into Urine From Time 0 to Time 24 Hours for Unchanged Aspirin and Its Metabolites (Salicylic Acid and Salicyluric Acid) [Day 1 pre-dose and at multiple time points (up to 24 hours) post-dose]

26. Study 2, CLR: Renal Clearance for Unchanged Aspirin and Its Metabolites (Salicylic Acid and Salicyluric Acid) [Day 1 pre-dose and at multiple time points (up to 24 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, participants are capable of understanding the procedures required for the study and complying with its requirements.

2. Participants sign and date an informed consent form by themselves prior to the initiation of any study procedures.

3. Japanese healthy men aged greater than or equal to (>=) 20 and less than or equal to (=<) 60, inclusive, at the time of consent.

4. Body weight >=50 kilogram (kg) as well as body mass index (BMI) >=18.5 kilogram per meter square (kg/m^{2) and =<25.0 kg/m}2 at screening test.

Exclusion Criteria:

1. Participants who received study drug within 16 weeks (112 days) prior to the start of study treatment in Period 1.

2. Participants who received TAK-438 or aspirin in a previous study.

3. Staffs at the study site and their family, or participants who depend on the study-related staffs at the study site (example, husband and wife, parents, children, brothers and sisters), or participants who may be constrained to consent to the study.

4. Participants with uncontrolled and clinically significant neurological, cardiovascular, lung, hepatic, renal, metabolic, gastrointestinal, urinary or endocrine disease, or other abnormalities (except for diseases investigated) that might affect the study participation or impact the results of the study.

5. Participants with a previous or current history of aspirin asthma (asthmatic attack induced by non-steroidal anti-inflammatory drugs, etc.).

6. Participants with hypersensitivity for components of TAK-438 tablet or aspirin enteric-coated tablet, or salicylic acid-based products.

7. Positive result in urinary test for illegal drug abuse at screening.

8. Participants who have a history of illegal drug abuse or alcoholism within the past 2 years prior to the screening visit, or who are not willing to refrain from alcohol consumption and drug use during the study period.

9. Participants who ingested a medicine, a supplement or food forbidden to be used in combination during the specified time period.

10. Participants with a current history or recent episodes (within the past 6 months) of gastrointestinal diseases (malabsorption, gastroesophageal reflux, peptic ulcer disease, erosive oesophagitis), frequent (at least once per week) heartburn or surgical intervention that might affect drug absorption.

11. Participants with a history of cancer, except for basal cell carcinoma in remission for >=5 years prior to Day 1.

12. Positive results at screening for hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) antibody, human immunodeficiency virus (HIV) antibody/antigen, or serological test for syphilis.

13. Participants who have difficulties in blood draw from peripheral veins.

14. Participants who had >=200 milliliter (mL) of whole blood drawn within 4 weeks (28 days) prior to the start of study treatment in Period 1 or who had >=400 mL of whole blood drawn within 12 weeks (84 days) prior to the start of study treatment in Period

16. Participants who had a total of >=800 mL of whole blood drawn within 52 weeks (364 days) prior to the start of study treatment in Period 1.

17. Participants who had blood components drawn within 2 weeks (14 days) prior to the start of study treatment in Period 1.

18. Clinically significant abnormalities in electrocardiogram at screening or admission (Day -1).

19. Participants with abnormal laboratory parameters suggestive of clinically significant underlying diseases or who have abnormal values in the following measures at screening: alanine aminotransferase (ALT) or aspartate aminotransferase (AST) over the upper limit of normal.

20. Participants who are unlikely to comply with the protocol or deemed ineligible due to other reasons by the principal investigator or other investigators.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Fukuoka Mirai Hospital	Fukuoka		Japan

Sponsors and Collaborators

• Takeda

Investigators

• Study Director: Study Director, Takeda

Study Documents (Full-Text)

• Study Protocol - Feb 9, 2018
• Statistical Analysis Plan - Jul 25, 2018

More Information

Publications

None provided.

• Responsible Party: Takeda
• ClinicalTrials.gov Identifier: NCT03456960
• Other Study ID Numbers: TAK-438ASA-1001; U1111-1208-7631; JapicCTI-183885
• First Posted: Mar 7, 2018
• Last Update Posted: Nov 19, 2019
• Last Verified: Nov 1, 2019

• 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
• Additional relevant MeSH terms: Aspirin

Study Results

Participant Flow

Recruitment Details	Participants took part in the study at 1 investigative site in Japan from 8 March 2018 to 12 October 2018.
Pre-assignment Detail	Healthy male participants were enrolled in this 2-period cross-over design study to receive 1 of the 2 treatment sequences: fixed dose combination (FDC) of TAK-438 and aspirin (TAK-438ASA) or a free combination of TAK-438 and aspirin in Study 1, and to receive 1 of the 2 sequences: FDC of TAK-438ASA under fasted or fed conditions in Study 2.

Arm/Group Title	Pilot Study 1, Sequence A: TAK-438ASA + TAK-438 and Aspirin	Pilot Study 1, Sequence B: TAK-438 and Aspirin + TAK-438ASA	Pivotal Study 1, Sequence A: TAK-438ASA + TAK-438 and Aspirin	Pivotal Study 1, Sequence B: TAK-438 and Aspirin + TAK-438ASA	Study 2, Sequence C: TAK-438ASA (Fasted + Fed Condition)	Study 2, Sequence D: TAK-438ASA (Fed + Fasted Condition)
Arm/Group Description	TAK-438 10 milligram (mg) and aspirin 100 mg FDC (TAK-438ASA), tablet, orally, under fasted condition, once on Day 1 of Period 1, followed by a washout period of at least 14 days, further followed by TAK-438 10 mg, tablet and aspirin 100 mg, tablet (free combination), orally, under fasted condition, once on Day 1 of Period 2.	TAK-438 10 mg, tablet and aspirin 100 mg, tablet (free combination), orally, under fasted condition, once on Day 1 of Period 1, followed by a washout period of at least 14 days, further followed by TAK-438 10 mg and aspirin 100 mg FDC (TAK-438ASA), tablet, orally, under fasted condition, once on Day 1 of Period 2.	TAK-438 10 mg and aspirin 100 mg FDC (TAK-438ASA), tablet, orally, under fasted condition, once on Day 1 of Period 1, followed by a washout period of at least 14 days, further followed by TAK-438 10 mg, tablet and aspirin 100 mg, tablet (free combination), orally, under fasted condition, once on Day 1 of Period 2.	TAK-438 10 mg, tablet and aspirin 100 mg, tablet (free combination), orally, under fasted condition, once on Day 1 of Period 1, followed by a washout period of at least 14 days, further followed by TAK-438 10 mg and aspirin 100 mg FDC (TAK-438ASA), tablet, orally, under fasted condition, once on Day 1 of Period 2.	TAK-438 10 mg and aspirin 100 mg FDC (TAK-438ASA), tablet, orally, under fasted condition, once on Day 1 of Period 1, followed by a washout period of at least 14 days, further followed by TAK-438 10 mg and aspirin 100 mg FDC (TAK-438ASA), tablet, orally, under fed condition, once on Day 1 of Period 2.	TAK-438 10 mg and aspirin 100 mg FDC (TAK-438ASA), tablet, orally, under fed condition, once on Day 1 of Period 1, followed by a washout period of at least 14 days, further followed by TAK-438 10 mg and aspirin 100 mg FDC (TAK-438ASA), tablet, orally, under fasted condition, once on Day 1 of Period 2.
Period Title: Period 1 (1 Day)
STARTED	12	12	120	120	6	6
COMPLETED	12	12	120	120	6	6
NOT COMPLETED	0	0	0	0	0	0
Period Title: Period 1 (1 Day)
STARTED	12	12	120	120	6	6
COMPLETED	12	12	119	118	6	6
NOT COMPLETED	0	0	1	2	0	0
Period Title: Period 1 (1 Day)
STARTED	12	12	119	118	6	6
COMPLETED	11	12	119	117	6	6
NOT COMPLETED	1	0	0	1	0	0

Baseline Characteristics

Arm/Group Title	Pilot Study 1, Sequence A: TAK-438ASA + TAK-438 and Aspirin	Pilot Study 1, Sequence B: TAK-438 and Aspirin + TAK-438ASA	Pivotal Study 1, Sequence A: TAK-438ASA + TAK-438 and Aspirin	Pivotal Study 1, Sequence B: TAK-438 and Aspirin + TAK-438ASA	Study 2, Sequence C: TAK-438ASA (Fasted + Fed Condition)	Study 2, Sequence D: TAK-438ASA (Fed + Fasted Condition)	Total
Arm/Group Description	TAK-438 10 milligram (mg) and aspirin 100 mg FDC (TAK-438ASA), tablet, orally, under fasted condition, once on Day 1 of Period 1, followed by a washout period of at least 14 days, further followed by TAK-438 10 mg, tablet and aspirin 100 mg, tablet (free combination), orally, under fasted condition, once on Day 1 of Period 2.	TAK-438 10 mg, tablet and aspirin 100 mg, tablet (free combination), orally, under fasted condition, once on Day 1 of Period 1, followed by a washout period of at least 14 days, further followed by TAK-438 10 mg and aspirin 100 mg FDC (TAK-438ASA), tablet, orally, under fasted condition, once on Day 1 of Period 2.	TAK-438 10 mg and aspirin 100 mg FDC (TAK-438ASA), tablet, orally, under fasted condition, once on Day 1 of Period 1, followed by a washout period of at least 14 days, further followed by TAK-438 10 mg, tablet and aspirin 100 mg, tablet (free combination), orally, under fasted condition, once on Day 1 of Period 2.	TAK-438 10 mg, tablet and aspirin 100 mg, tablet (free combination), orally, under fasted condition, once on Day 1 of Period 1, followed by a washout period of at least 14 days, further followed by TAK-438 10 mg and aspirin 100 mg FDC (TAK-438ASA), tablet, orally, under fasted condition, once on Day 1 of Period 2.	TAK-438 10 mg and aspirin 100 mg FDC (TAK-438ASA), tablet, orally, under fasted condition, once on Day 1 of Period 1, followed by a washout period of at least 14 days, further followed by TAK-438 10 mg and aspirin 100 mg FDC (TAK-438ASA), tablet, orally, under fed condition, once on Day 1 of Period 2.	TAK-438 10 mg and aspirin 100 mg FDC (TAK-438ASA), tablet, orally, under fed condition, once on Day 1 of Period 1, followed by a washout period of at least 14 days, further followed by TAK-438 10 mg and aspirin 100 mg FDC (TAK-438ASA), tablet, orally, under fasted condition, once on Day 1 of Period 2.	Total of all reporting groups
Overall Participants	12	12	120	120	6	6	276
Age, Customized (Count of Participants)
Less than (<) 20 years	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Between 20 and 60 years	12 100%	12 100%	120 100%	120 100%	6 100%	6 100%	276 100%
Greater than (>) 60 years	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Sex: Female, Male (Count of Participants)
Female	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Male	12 100%	12 100%	120 100%	120 100%	6 100%	6 100%	276 100%
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%	120 100%	120 100%	6 100%	6 100%	276 100%
Consumption of caffeine (Count of Participants)
Had caffeine consumption	6 50%	5 41.7%	23 19.2%	18 15%	2 33.3%	1 16.7%	55 19.9%
Had no caffeine consumption	6 50%	7 58.3%	97 80.8%	102 85%	4 66.7%	5 83.3%	221 80.1%
Consumption of alcohol (Count of Participants)
Drank daily	2 16.7%	0 0%	1 0.8%	3 2.5%	0 0%	0 0%	6 2.2%
Drank a few times per week	2 16.7%	2 16.7%	9 7.5%	9 7.5%	0 0%	0 0%	22 8%
Drank a few times per month	3 25%	5 41.7%	72 60%	68 56.7%	3 50%	3 50%	154 55.8%
Never drank	5 41.7%	5 41.7%	38 31.7%	40 33.3%	3 50%	3 50%	94 34.1%
Smoking classification (Count of Participants)
Never smoked	7 58.3%	6 50%	81 67.5%	76 63.3%	4 66.7%	4 66.7%	178 64.5%
Current smoker	2 16.7%	0 0%	9 7.5%	12 10%	1 16.7%	1 16.7%	25 9.1%
Ex-smoker	3 25%	6 50%	30 25%	32 26.7%	1 16.7%	1 16.7%	73 26.4%

Outcome Measures

1. Primary Outcome

Title	Study 1, AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Free Base of TAK-438 (TAK-438F)
Time Frame	Day 1 pre-dose and at multiple time points (up to 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, who had no major protocol deviation, and whose PK data were evaluable. Samples were not collected for Pivotal Study 1 because sufficient results were available for TAK-438F from the Pilot Study 1.

Arm/Group Title	Pilot Study 1: TAK-438ASA	Pilot Study 1: TAK-438 and Aspirin	Pivotal Study 1: TAK-438ASA	Pivotal Study 1: TAK-438 and Aspirin
Arm/Group Description	TAK-438 10 mg and aspirin 100 mg FDC (TAK-438ASA), tablet, orally, under fasted condition, once on Day 1 of either Period 1 or 2.	TAK-438 10 mg, tablet and aspirin 100 mg, tablet (free combination), orally, under fasted condition, once on Day 1 of either Period 1 or 2.	TAK-438 10 mg and aspirin 100 mg FDC (TAK-438ASA), tablet, orally, under fasted condition, once on Day 1 of either Period 1 or 2.	TAK-438 10 mg, tablet and aspirin 100 mg, tablet (free combination), orally, under fasted condition, once on Day 1 of either Period 1 or 2.
Measure Participants	23	23	0	0
Geometric Mean (Standard Deviation) [hour*nanogram per milliliter (h*ng/mL)]	92.46 (32.128)	91.95 (31.431)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pilot Study 1: TAK-438ASA, Pilot Study 1: TAK-438 and Aspirin
	Comments
	Type of Statistical Test	Equivalence
	Comments	The difference in the least square means (LSM) between study medications (TAK-438ASA tablet - concomitant administration of TAK-438 tablet and aspirin enteric-coated tablet) and the two-sided 90 percent (%) confidence interval (CI) were provided using a crossover analysis of variance (ANOVA) model. The ANOVA model included a log-transformed (natural log) analysis variable as the dependent variable, and study medication, sequence, and period as independent variables.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LSM Difference
	Estimated Value	0.0059
	Confidence Interval	(2-Sided) 90%; -0.0340 to 0.0458
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Study 1, Cmax: Maximum Observed Plasma Concentration for TAK-438F
Time Frame	Day 1 pre-dose and at multiple time points (up to 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, who had no major protocol deviation, and whose PK data were evaluable. Samples were not collected for Pivotal Study 1 because sufficient results were available for TAK-438F from the Pilot Study 1.

Arm/Group Title	Pilot Study 1: TAK-438ASA	Pilot Study 1: TAK-438 and Aspirin	Pivotal Study 1: TAK-438ASA	Pivotal Study 1: TAK-438 and Aspirin
Arm/Group Description	TAK-438 10 mg and aspirin 100 mg FDC (TAK-438ASA), tablet, orally, under fasted condition, once on Day 1 of either Period 1 or 2.	TAK-438 10 mg, tablet and aspirin 100 mg, tablet (free combination), orally, under fasted condition, once on Day 1 of either Period 1 or 2.	TAK-438 10 mg and aspirin 100 mg FDC (TAK-438ASA), tablet, orally, under fasted condition, once on Day 1 of either Period 1 or 2.	TAK-438 10 mg, tablet and aspirin 100 mg, tablet (free combination), orally, under fasted condition, once on Day 1 of either Period 1 or 2.
Measure Participants	23	23	0	0
Geometric Mean (Standard Deviation) [nanogram per milliliter (ng/mL)]	13.87 (5.0945)	13.22 (5.0778)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pilot Study 1: TAK-438ASA, Pilot Study 1: TAK-438 and Aspirin
	Comments
	Type of Statistical Test	Equivalence
	Comments	The difference in the LSM between study medications (TAK-438ASA tablet - concomitant administration of TAK-438 tablet and aspirin enteric-coated tablet) and the two-sided 90% CI were provided using a crossover ANOVA model. The ANOVA model included a log-transformed (natural log) analysis variable as the dependent variable, and study medication, sequence, and period as independent variables.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LSM Difference
	Estimated Value	0.0508
	Confidence Interval	(2-Sided) 90%; -0.0079 to 0.1096
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Primary Outcome

Title	Study 1, AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Unchanged Aspirin
Time Frame	Day 1 pre-dose and at multiple time points (up to 12 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, who had no major protocol deviation, and whose PK data were evaluable.

Arm/Group Title	Pilot Study 1: TAK-438ASA	Pilot Study 1: TAK-438 and Aspirin	Pivotal Study 1: TAK-438ASA	Pivotal Study 1: TAK-438 and Aspirin
Arm/Group Description	TAK-438 10 mg and aspirin 100 mg FDC (TAK-438ASA), tablet, orally, under fasted condition, once on Day 1 of either Period 1 or 2.	TAK-438 10 mg, tablet and aspirin 100 mg, tablet (free combination), orally, under fasted condition, once on Day 1 of either Period 1 or 2.	TAK-438 10 mg and aspirin 100 mg FDC (TAK-438ASA), tablet, orally, under fasted condition, once on Day 1 of either Period 1 or 2.	TAK-438 10 mg, tablet and aspirin 100 mg, tablet (free combination), orally, under fasted condition, once on Day 1 of either Period 1 or 2.
Measure Participants	23	23	233	233
Geometric Mean (Standard Deviation) [h*ng/mL]	873.5 (220.94)	831.9 (350.69)	912.3 (327.58)	832.7 (323.46)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pilot Study 1: TAK-438ASA, Pilot Study 1: TAK-438 and Aspirin
	Comments
	Type of Statistical Test	Equivalence
	Comments	Pilot Study 1: The difference in the LSM between study medications (TAK-438ASA tablet - concomitant administration of TAK-438 tablet and aspirin enteric-coated tablet) and the two-sided 90% CI were provided using a crossover ANOVA model. The ANOVA model included a log-transformed (natural log) analysis variable as the dependent variable, and study medication, sequence, and period as independent variables.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LSM Difference
	Estimated Value	0.0546
	Confidence Interval	(2-Sided) 90%; -0.0941 to 0.2034
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Pivotal Study 1: TAK-438ASA, Pivotal Study 1: TAK-438 and Aspirin
	Comments
	Type of Statistical Test	Equivalence
	Comments	Pivotal Study 1: The difference in the LSM between study medications (TAK-438ASA tablet - concomitant administration of TAK-438 tablet and aspirin enteric-coated tablet) and the two-sided 90% CI were provided using a crossover ANOVA model. The ANOVA model will include a log-transformed (natural log) analysis variable as the dependent variable, and study medication, sequence, and period as independent variables.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LSM Difference
	Estimated Value	0.0912
	Confidence Interval	(2-Sided) 90%; 0.0399 to 0.1424
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Primary Outcome

Title	Study 1, Cmax: Maximum Observed Plasma Concentration for Unchanged Aspirin
Time Frame	Day 1 pre-dose and at multiple time points (up to 12 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, who had no major protocol deviation, and whose PK data were evaluable.

Arm/Group Title	Pilot Study 1: TAK-438ASA	Pilot Study 1: TAK-438 and Aspirin	Pivotal Study 1: TAK-438ASA	Pivotal Study 1: TAK-438 and Aspirin
Arm/Group Description	TAK-438 10 mg and aspirin 100 mg FDC (TAK-438ASA), tablet, orally, under fasted condition, once on Day 1 of either Period 1 or 2.	TAK-438 10 mg, tablet and aspirin 100 mg, tablet (free combination), orally, under fasted condition, once on Day 1 of either Period 1 or 2.	TAK-438 10 mg and aspirin 100 mg FDC (TAK-438ASA), tablet, orally, under fasted condition, once on Day 1 of either Period 1 or 2.	TAK-438 10 mg, tablet and aspirin 100 mg, tablet (free combination), orally, under fasted condition, once on Day 1 of either Period 1 or 2.
Measure Participants	23	23	233	233
Geometric Mean (Standard Deviation) [ng/mL]	647.6 (326.77)	597.5 (507.90)	701.8 (349.18)	558.0 (404.26)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pilot Study 1: TAK-438ASA, Pilot Study 1: TAK-438 and Aspirin
	Comments
	Type of Statistical Test	Equivalence
	Comments	Pilot Study 1: The difference in the LSM between study medications (TAK-438ASA tablet - concomitant administration of TAK-438 tablet and aspirin enteric-coated tablet) and the two-sided 90% CI were provided using a crossover ANOVA model. The ANOVA model included a log-transformed (natural log) analysis variable as the dependent variable, and study medication, sequence, and period as independent variables.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LSM Difference
	Estimated Value	0.0916
	Confidence Interval	(2-Sided) 90%; -0.1330 to 0.3162
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Pivotal Study 1: TAK-438ASA, Pivotal Study 1: TAK-438 and Aspirin
	Comments
	Type of Statistical Test	Equivalence
	Comments	Pivotal Study 1: The difference in the LSM between study medications (TAK-438ASA tablet - concomitant administration of TAK-438 tablet and aspirin enteric-coated tablet) and the two-sided 90% CI were provided using a crossover ANOVA model. The ANOVA model included a log-transformed (natural log) analysis variable as the dependent variable, and study medication, sequence, and period as independent variables.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LSM Difference
	Estimated Value	0.2293
	Confidence Interval	(2-Sided) 90%; 0.1519 to 0.3068
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Study 1, 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) post-dose

Outcome Measure Data

Analysis Population Description

The PK analysis set included all participants who received at least one dose of study drug, who had no major protocol deviation, and whose PK data were evaluable. Samples were not collected for Pivotal Study 1 because sufficient results were available for TAK-438F from the Pilot Study 1.

Arm/Group Title	Pilot Study 1: TAK-438ASA	Pilot Study 1: TAK-438 and Aspirin	Pivotal Study 1: TAK-438ASA	Pivotal Study 1: TAK-438 and Aspirin
Arm/Group Description	TAK-438 10 mg and aspirin 100 mg FDC (TAK-438ASA), tablet, orally, under fasted condition, once on Day 1 of either Period 1 or 2.	TAK-438 10 mg, tablet and aspirin 100 mg, tablet (free combination), orally, under fasted condition, once on Day 1 of either Period 1 or 2.	TAK-438 10 mg and aspirin 100 mg FDC (TAK-438ASA), tablet, orally, under fasted condition, once on Day 1 of either Period 1 or 2.	TAK-438 10 mg, tablet and aspirin 100 mg, tablet (free combination), orally, under fasted condition, once on Day 1 of either Period 1 or 2.
Measure Participants	23	23	0	0
Geometric Mean (Standard Deviation) [h*ng/mL]	94.71 (32.334)	93.78 (31.828)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pilot Study 1: TAK-438ASA, Pilot Study 1: TAK-438 and Aspirin
	Comments
	Type of Statistical Test	Equivalence
	Comments	The difference in the LSM between study medications (TAK-438ASA tablet - concomitant administration of TAK-438 tablet and aspirin enteric-coated tablet) and the two-sided 90% CI were provided using a crossover ANOVA model. The ANOVA model included a log-transformed (natural log) analysis variable as the dependent variable, and study medication, sequence, and period as independent variables.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LSM Difference
	Estimated Value	0.0100
	Confidence Interval	(2-Sided) 90%; -0.0299 to 0.0500
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Study 1, Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-438F
Time Frame	Day 1 pre-dose and at multiple time points (up to 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, who had no major protocol deviation, and whose PK data were evaluable. Samples were not collected for Pivotal Study 1 because sufficient results were available for TAK-438F from the Pilot Study 1.

Arm/Group Title	Pilot Study 1: TAK-438ASA	Pilot Study 1: TAK-438 and Aspirin	Pivotal Study 1: TAK-438ASA	Pivotal Study 1: TAK-438 and Aspirin
Arm/Group Description	TAK-438 10 mg and aspirin 100 mg FDC (TAK-438ASA), tablet, orally, under fasted condition, once on Day 1 of either Period 1 or 2.	TAK-438 10 mg, tablet and aspirin 100 mg, tablet (free combination), orally, under fasted condition, once on Day 1 of either Period 1 or 2.	TAK-438 10 mg and aspirin 100 mg FDC (TAK-438ASA), tablet, orally, under fasted condition, once on Day 1 of either Period 1 or 2.	TAK-438 10 mg, tablet and aspirin 100 mg, tablet (free combination), orally, under fasted condition, once on Day 1 of either Period 1 or 2.
Measure Participants	23	23	0	0
Median (Full Range) [hour]	1.500	1.500

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pilot Study 1: TAK-438ASA, Pilot Study 1: TAK-438 and Aspirin
	Comments
	Type of Statistical Test	Equivalence
	Comments	The difference in the LSM between study medications (TAK-438ASA tablet - concomitant administration of TAK-438 tablet and aspirin enteric-coated tablet) and the two-sided 90% CI were provided using a crossover ANOVA model. The ANOVA model included a log-transformed (natural log) analysis variable as the dependent variable, and study medication, sequence, and period as independent variables.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LSM Difference
	Estimated Value	-0.0281
	Confidence Interval	(2-Sided) 90%; -0.1662 to 0.1100
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Study 1, MRT (Infinity,ev): Mean Residence Time From Time 0 to Infinity for TAK-438F
Time Frame	Day 1 pre-dose and at multiple time points (up to 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, who had no major protocol deviation, and whose PK data were evaluable. Samples were not collected for Pivotal Study 1 because sufficient results were available for TAK-438F from the Pilot Study 1.

Arm/Group Title	Pilot Study 1: TAK-438ASA	Pilot Study 1: TAK-438 and Aspirin	Pivotal Study 1: TAK-438ASA	Pivotal Study 1: TAK-438 and Aspirin
Arm/Group Description	TAK-438 10 mg and aspirin 100 mg FDC (TAK-438ASA), tablet, orally, under fasted condition, once on Day 1 of either Period 1 or 2.	TAK-438 10 mg, tablet and aspirin 100 mg, tablet (free combination), orally, under fasted condition, once on Day 1 of either Period 1 or 2.	TAK-438 10 mg and aspirin 100 mg FDC (TAK-438ASA), tablet, orally, under fasted condition, once on Day 1 of either Period 1 or 2.	TAK-438 10 mg, tablet and aspirin 100 mg, tablet (free combination), orally, under fasted condition, once on Day 1 of either Period 1 or 2.
Measure Participants	23	23	0	0
Mean (Standard Deviation) [hour]	9.610 (1.2440)	9.751 (1.3853)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pilot Study 1: TAK-438ASA, Pilot Study 1: TAK-438 and Aspirin
	Comments
	Type of Statistical Test	Equivalence
	Comments	The difference in the LSM between study medications (TAK-438ASA tablet - concomitant administration of TAK-438 tablet and aspirin enteric-coated tablet) and the two-sided 90% CI were provided using a crossover ANOVA model. The ANOVA model included a log-transformed (natural log) analysis variable as the dependent variable, and study medication, sequence, and period as independent variables.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LSM Difference
	Estimated Value	-0.0150
	Confidence Interval	(2-Sided) 90%; -0.0448 to 0.0149
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Study 1, Lambda (z): Terminal Disposition Phase Rate Constant for TAK-438F
Time Frame	Day 1 pre-dose and at multiple time points (up to 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, who had no major protocol deviation, and whose PK data were evaluable. Samples were not collected for Pivotal Study 1 because sufficient results were available for TAK-438F from the Pilot Study 1.

Arm/Group Title	Pilot Study 1: TAK-438ASA	Pilot Study 1: TAK-438 and Aspirin	Pivotal Study 1: TAK-438ASA	Pivotal Study 1: TAK-438 and Aspirin
Arm/Group Description	TAK-438 10 mg and aspirin 100 mg FDC (TAK-438ASA), tablet, orally, under fasted condition, once on Day 1 of either Period 1 or 2.	TAK-438 10 mg, tablet and aspirin 100 mg, tablet (free combination), orally, under fasted condition, once on Day 1 of either Period 1 or 2.	TAK-438 10 mg and aspirin 100 mg FDC (TAK-438ASA), tablet, orally, under fasted condition, once on Day 1 of either Period 1 or 2.	TAK-438 10 mg, tablet and aspirin 100 mg, tablet (free combination), orally, under fasted condition, once on Day 1 of either Period 1 or 2.
Measure Participants	23	23	0	0
Mean (Standard Deviation) [1 per hour]	0.08565 (0.0090230)	0.08788 (0.013025)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pilot Study 1: TAK-438ASA, Pilot Study 1: TAK-438 and Aspirin
	Comments
	Type of Statistical Test	Equivalence
	Comments	The difference in the LSM between study medications (TAK-438ASA tablet - concomitant administration of TAK-438 tablet and aspirin enteric-coated tablet) and the two-sided 90% CI were provided using a crossover ANOVA model. The ANOVA model included a log-transformed (natural log) analysis variable as the dependent variable, and study medication, sequence, and period as independent variables.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LSM Difference
	Estimated Value	-0.0195
	Confidence Interval	(2-Sided) 90%; -0.0676 to 0.0286
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Secondary Outcome

Title	Study 1, AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for Unchanged Aspirin
Time Frame	Day 1 pre-dose and at multiple time points (up to 12 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, who had no major protocol deviation, and whose PK data were evaluable. The PK analysis set where data at specified time points was available.

Arm/Group Title	Pilot Study 1: TAK-438ASA	Pilot Study 1: TAK-438 and Aspirin	Pivotal Study 1: TAK-438ASA	Pivotal Study 1: TAK-438 and Aspirin
Arm/Group Description	TAK-438 10 mg and aspirin 100 mg FDC (TAK-438ASA), tablet, orally, under fasted condition, once on Day 1 of either Period 1 or 2.	TAK-438 10 mg, tablet and aspirin 100 mg, tablet (free combination), orally, under fasted condition, once on Day 1 of either Period 1 or 2.	TAK-438 10 mg and aspirin 100 mg FDC (TAK-438ASA), tablet, orally, under fasted condition, once on Day 1 of either Period 1 or 2.	TAK-438 10 mg, tablet and aspirin 100 mg, tablet (free combination), orally, under fasted condition, once on Day 1 of either Period 1 or 2.
Measure Participants	23	23	231	221
Geometric Mean (Standard Deviation) [h*ng/mL]	876.5 (221.10)	834.6 (349.28)	915.8 (328.82)	855.4 (322.27)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pilot Study 1: TAK-438ASA, Pilot Study 1: TAK-438 and Aspirin
	Comments
	Type of Statistical Test	Equivalence
	Comments	Pilot Study 1: The difference in the LSM between study medications (TAK-438ASA tablet - concomitant administration of TAK-438 tablet and aspirin enteric-coated tablet) and the two-sided 90% CI were provided using a crossover ANOVA model. The ANOVA model included a log-transformed (natural log) analysis variable as the dependent variable, and study medication, sequence, and period as independent variables.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LSM Difference
	Estimated Value	0.0547
	Confidence Interval	(2-Sided) 90%; -0.0937 to 0.2032
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Pivotal Study 1: TAK-438ASA, Pivotal Study 1: TAK-438 and Aspirin
	Comments
	Type of Statistical Test	Equivalence
	Comments	Pivotal Study 1: The difference in the LSM between study medications (TAK-438ASA tablet - concomitant administration of TAK-438 tablet and aspirin enteric-coated tablet) and the two-sided 90% CI were provided using a crossover ANOVA model. The ANOVA model included a log-transformed (natural log) analysis variable as the dependent variable, and study medication, sequence, and period as independent variables.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LSM Difference
	Estimated Value	0.0654
	Confidence Interval	(2-Sided) 90%; 0.0141 to 0.1167
	Parameter Dispersion	Type: Value:
	Estimation Comments

10. Secondary Outcome

Title	Study 1, Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Unchanged Aspirin
Time Frame	Day 1 pre-dose and at multiple time points (up to 12 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, who had no major protocol deviation, and whose PK data were evaluable.

Arm/Group Title	Pilot Study 1: TAK-438ASA	Pilot Study 1: TAK-438 and Aspirin	Pivotal Study 1: TAK-438ASA	Pivotal Study 1: TAK-438 and Aspirin
Arm/Group Description	TAK-438 10 mg and aspirin 100 mg FDC (TAK-438ASA), tablet, orally, under fasted condition, once on Day 1 of either Period 1 or 2.	TAK-438 10 mg, tablet and aspirin 100 mg, tablet (free combination), orally, under fasted condition, once on Day 1 of either Period 1 or 2.	TAK-438 10 mg and aspirin 100 mg FDC (TAK-438ASA), tablet, orally, under fasted condition, once on Day 1 of either Period 1 or 2.	TAK-438 10 mg, tablet and aspirin 100 mg, tablet (free combination), orally, under fasted condition, once on Day 1 of either Period 1 or 2.
Measure Participants	23	23	233	233
Median (Full Range) [hour]	4.000	4.500	4.000	4.500

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pilot Study 1: TAK-438ASA, Pilot Study 1: TAK-438 and Aspirin
	Comments
	Type of Statistical Test	Equivalence
	Comments	Pilot Study 1: The difference in the LSM between study medications (TAK-438ASA tablet - concomitant administration of TAK-438 tablet and aspirin enteric-coated tablet) and the two-sided 90% CI were provided using a crossover ANOVA model. The ANOVA model included a log-transformed (natural log) analysis variable as the dependent variable, and study medication, sequence, and period as independent variables.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LSM Difference
	Estimated Value	-0.1460
	Confidence Interval	(2-Sided) 90%; -0.2478 to -0.0443
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Pivotal Study 1: TAK-438ASA, Pivotal Study 1: TAK-438 and Aspirin
	Comments
	Type of Statistical Test	Equivalence
	Comments	Pivotal Study 1: The difference in the LSM between study medications (TAK-438ASA tablet - concomitant administration of TAK-438 tablet and aspirin enteric-coated tablet) and the two-sided 90% CI were provided using a crossover ANOVA model. The ANOVA model included a log-transformed (natural log) analysis variable as the dependent variable, and study medication, sequence, and period as independent variables.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LSM Difference
	Estimated Value	-0.1674
	Confidence Interval	(2-Sided) 90%; -0.2084 to -0.1264
	Parameter Dispersion	Type: Value:
	Estimation Comments

11. Secondary Outcome

Title	Study 1, MRT (Infinity,ev): Mean Residence Time From Time 0 to Infinity for Unchanged Aspirin
Time Frame	Day 1 pre-dose and at multiple time points (up to 12 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, who had no major protocol deviation, and whose PK data were evaluable. The PK analysis set where data at specified time points was available.

Arm/Group Title	Pilot Study 1: TAK-438ASA	Pilot Study 1: TAK-438 and Aspirin	Pivotal Study 1: TAK-438ASA	Pivotal Study 1: TAK-438 and Aspirin
Arm/Group Description	TAK-438 10 mg and aspirin 100 mg FDC (TAK-438ASA), tablet, orally, under fasted condition, once on Day 1 of either Period 1 or 2.	TAK-438 10 mg, tablet and aspirin 100 mg, tablet (free combination), orally, under fasted condition, once on Day 1 of either Period 1 or 2.	TAK-438 10 mg and aspirin 100 mg FDC (TAK-438ASA), tablet, orally, under fasted condition, once on Day 1 of either Period 1 or 2.	TAK-438 10 mg, tablet and aspirin 100 mg, tablet (free combination), orally, under fasted condition, once on Day 1 of either Period 1 or 2.
Measure Participants	23	23	231	221
Mean (Standard Deviation) [hour]	4.629 (1.4634)	5.194 (1.5154)	4.398 (1.0552)	5.152 (2.0334)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pilot Study 1: TAK-438ASA, Pilot Study 1: TAK-438 and Aspirin
	Comments
	Type of Statistical Test	Equivalence
	Comments	Pilot Study 1: The difference in the LSM between study medications (TAK-438ASA tablet - concomitant administration of TAK-438 tablet and aspirin enteric-coated tablet) and the two-sided 90% CI were provided using a crossover ANOVA model. The ANOVA model included a log-transformed (natural log) analysis variable as the dependent variable, and study medication, sequence, and period as independent variables.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LSM Difference
	Estimated Value	-0.1193
	Confidence Interval	(2-Sided) 90%; -0.2179 to -0.0206
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Pivotal Study 1: TAK-438ASA, Pivotal Study 1: TAK-438 and Aspirin
	Comments
	Type of Statistical Test	Equivalence
	Comments	Pivotal Study 1: The difference in the LSM between study medications (TAK-438ASA tablet - concomitant administration of TAK-438 tablet and aspirin enteric-coated tablet) and the two-sided 90% CI were provided using a crossover ANOVA model. The ANOVA model included a log-transformed (natural log) analysis variable as the dependent variable, and study medication, sequence, and period as independent variables.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LSM Difference
	Estimated Value	-0.1366
	Confidence Interval	(2-Sided) 90%; -0.1730 to -0.1002
	Parameter Dispersion	Type: Value:
	Estimation Comments

12. Secondary Outcome

Title	Study 1, Lambda (z): Terminal Disposition Phase Rate Constant for Unchanged Aspirin
Time Frame	Day 1 pre-dose and at multiple time points (up to 12 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, who had no major protocol deviation, and whose PK data were evaluable. The PK analysis set where data at specified time points was available.

Arm/Group Title	Pilot Study 1: TAK-438ASA	Pilot Study 1: TAK-438 and Aspirin	Pivotal Study 1: TAK-438ASA	Pivotal Study 1: TAK-438 and Aspirin
Arm/Group Description	TAK-438 10 mg and aspirin 100 mg FDC (TAK-438ASA), tablet, orally, under fasted condition, once on Day 1 of either Period 1 or 2.	TAK-438 10 mg, tablet and aspirin 100 mg, tablet (free combination), orally, under fasted condition, once on Day 1 of either Period 1 or 2.	TAK-438 10 mg and aspirin 100 mg FDC (TAK-438ASA), tablet, orally, under fasted condition, once on Day 1 of either Period 1 or 2.	TAK-438 10 mg, tablet and aspirin 100 mg, tablet (free combination), orally, under fasted condition, once on Day 1 of either Period 1 or 2.
Measure Participants	23	23	231	221
Mean (Standard Deviation) [1 per hour]	1.734 (0.30398)	1.703 (0.30765)	1.754 (0.32224)	1.795 (0.35228)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pilot Study 1: TAK-438ASA, Pilot Study 1: TAK-438 and Aspirin
	Comments
	Type of Statistical Test	Equivalence
	Comments	Pilot Study 1: The difference in the LSM between study medications (TAK-438ASA tablet - concomitant administration of TAK-438 tablet and aspirin enteric-coated tablet) and the two-sided 90% CI were provided using a crossover ANOVA model. The ANOVA model included a log-transformed (natural log) analysis variable as the dependent variable, and study medication, sequence, and period as independent variables.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LSM Difference
	Estimated Value	0.0148
	Confidence Interval	(2-Sided) 90%; -0.0734 to 0.1030
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Pivotal Study 1: TAK-438ASA, Pivotal Study 1: TAK-438 and Aspirin
	Comments
	Type of Statistical Test	Equivalence
	Comments	Pivotal Study 1: The difference in the LSM between study medications (TAK-438ASA tablet - concomitant administration of TAK-438 tablet and aspirin enteric-coated tablet) and the two-sided 90% CI were provided using a crossover ANOVA model. The ANOVA model included a log-transformed (natural log) analysis variable as the dependent variable, and study medication, sequence, and period as independent variables.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LSM Difference
	Estimated Value	-0.0020
	Confidence Interval	(2-Sided) 90%; -0.0463 to 0.0424
	Parameter Dispersion	Type: Value:
	Estimation Comments

13. Secondary Outcome

Title	Study 2, AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for TAK-438F and Its Metabolites (M) (M-I, M-II, M-III and M-IV-Sul)
Time Frame	Day 1 pre-dose and at multiple time points (up to 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, who had no major protocol deviation, and whose PK data were evaluable. The PK analysis set where data at specified time points was available.

Arm/Group Title	Study 2: TAK-438ASA Fasted	Study 2: TAK-430ASA Fed
Arm/Group Description	TAK-438 10 mg and aspirin 100 mg FDC (TAK-438ASA), tablet, orally, under fasted condition, once on Day 1 of either Period 1 or 2.	TAK-438 10 mg and aspirin 100 mg FDC (TAK-438ASA), tablet, orally, under fed condition, once on Day 1 of either Period 1 or 2.
Measure Participants	12	12
TAK-438F	84.26 (16.890)	104.3 (19.470)
M-I	290.4 (50.706)	266.9 (44.125)
M-II	50.77 (19.175)	58.29 (63.088)
M-III	83.59 (15.202)	80.25 (22.318)
M-IV-Sul	115.9 (37.933)	97.60 (40.882)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pilot Study 1: TAK-438ASA, Pilot Study 1: TAK-438 and Aspirin
	Comments
	Type of Statistical Test	Equivalence
	Comments	TAK-438F: The difference in the LSM between dosing condition (TAK-438ASA tablet taken in a fed [30 minutes after starting breakfast] - TAK-438ASA tablet taken in a fasted [without breakfast] condition) and the two-sided 90% CI were provided using a crossover ANOVA model. The ANOVA model included a log-transformed (natural log) analysis variable as the dependent variable, and dosing condition, sequence, and period as independent variables.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LSM Difference
	Estimated Value	0.2138
	Confidence Interval	(2-Sided) 90%; 0.1609 to 0.2667
	Parameter Dispersion	Type: Value:
	Estimation Comments

14. Secondary Outcome

Title	Study 2, AUC(0-48): Area Under the Plasma Concentration-time Curve From Time 0 to Time 48 Hours Over the Dosing Interval for TAK-438F and Its Metabolites (M-I, M-II, M-III and M-IV-Sul)
Time Frame	Day 1 pre-dose and at multiple time points (up to 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, who had no major protocol deviation, and whose PK data were evaluable.

Arm/Group Title	Study 2: TAK-438ASA Fasted	Study 2: TAK-430ASA Fed
Arm/Group Description	TAK-438 10 mg and aspirin 100 mg FDC (TAK-438ASA), tablet, orally, under fasted condition, once on Day 1 of either Period 1 or 2.	TAK-438 10 mg and aspirin 100 mg FDC (TAK-438ASA), tablet, orally, under fed condition, once on Day 1 of either Period 1 or 2.
Measure Participants	12	12
TAK-438F	82.89 (16.467)	102.9 (18.851)
M-I	272.1 (49.341)	251.9 (44.461)
M-II	30.80 (14.808)	24.17 (12.927)
M-III	82.96 (14.931)	79.69 (22.117)
M-IV-Sul	111.5 (38.376)	93.20 (41.338)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pilot Study 1: TAK-438ASA, Pilot Study 1: TAK-438 and Aspirin
	Comments
	Type of Statistical Test	Equivalence
	Comments	TAK-438F: The difference in the LSM between dosing condition (TAK-438ASA tablet taken in a fed [30 minutes after starting breakfast] - TAK-438ASA tablet taken in a fasted [without breakfast] condition) and the two-sided 90% CI were provided using a crossover ANOVA model. The ANOVA model included a log-transformed (natural log) analysis variable as the dependent variable, and dosing condition, sequence, and period as independent variables.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LSM Difference
	Estimated Value	0.2161
	Confidence Interval	(2-Sided) 90%; 0.1652 to 0.2671
	Parameter Dispersion	Type: Value:
	Estimation Comments

15. Secondary Outcome

Title	Study 2, AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for TAK-438F and Its Metabolites (M-I, M-II, M-III and M-IV-Sul)
Time Frame	Day 1 pre-dose and at multiple time points (up to 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, who had no major protocol deviation, and whose PK data were evaluable.

Arm/Group Title	Study 2: TAK-438ASA Fasted	Study 2: TAK-438ASA Fed
Arm/Group Description	TAK-438 10 mg and aspirin 100 mg FDC (TAK-438ASA), tablet, orally, under fasted condition, once on Day 1 of either Period 1 or 2.	TAK-438 10 mg and aspirin 100 mg FDC (TAK-438ASA), tablet, orally, under fed condition, once on Day 1 of either Period 1 or 2.
Measure Participants	12	12
TAK-438F	82.23 (16.775)	102.4 (19.138)
M-I	258.6 (49.384)	239.5 (44.950)
M-II	26.86 (12.921)	20.66 (10.882)
M-III	81.92 (15.032)	78.69 (21.959)
M-IV-Sul	108.4 (36.884)	89.48 (39.843)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pilot Study 1: TAK-438ASA, Pilot Study 1: TAK-438 and Aspirin
	Comments
	Type of Statistical Test	Equivalence
	Comments	TAK-438F: The difference in the LSM between dosing condition (TAK-438ASA tablet taken in a fed [30 minutes after starting breakfast] - TAK-438ASA tablet taken in a fasted [without breakfast] condition) and the two-sided 90% CI were provided using a crossover ANOVA model. The ANOVA model included a log-transformed (natural log) analysis variable as the dependent variable, and dosing condition, sequence, and period as independent variables.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LSM Difference
	Estimated Value	0.2190
	Confidence Interval	(2-Sided) 90%; 0.1675 to 0.2706
	Parameter Dispersion	Type: Value:
	Estimation Comments

16. Secondary Outcome

Title	Study 2, Cmax: Maximum Observed Plasma Concentration for TAK-438F and Its Metabolites (M-I, M-II, M-III and M-IV-Sul)
Time Frame	Day 1 pre-dose and at multiple time points (up to 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, who had no major protocol deviation, and whose PK data were evaluable.

Arm/Group Title	Study 2: TAK-438ASA Fasted	Study 2: TAK-438ASA Fed
Arm/Group Description	TAK-438 10 mg and aspirin 100 mg FDC (TAK-438ASA), tablet, orally, under fasted condition, once on Day 1 of either Period 1 or 2.	TAK-438 10 mg and Aspirin 100 mg FDC (TAK-438ASA), tablet, orally, under fed condition, once on Day 1 of either Period 1 or 2.
Measure Participants	12	12
TAK-438F	12.73 (2.5465)	18.35 (5.4137)
M-I	41.26 (9.0261)	35.22 (9.6886)
M-II	2.820 (0.83815)	2.131 (0.57491)
M-III	15.38 (2.7078)	14.90 (2.2273)
M-IV-Sul	28.52 (7.8634)	23.09 (7.4466)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pilot Study 1: TAK-438ASA, Pilot Study 1: TAK-438 and Aspirin
	Comments
	Type of Statistical Test	Equivalence
	Comments	TAK-438F: The difference in the LSM between dosing condition (TAK-438ASA tablet taken in a fed [30 minutes after starting breakfast] - TAK-438ASA tablet taken in a fasted [without breakfast] condition) and the two-sided 90% CI were provided using a crossover ANOVA model. The ANOVA model included a log-transformed (natural log) analysis variable as the dependent variable, and dosing condition, sequence, and period as independent variables.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LSM Difference
	Estimated Value	0.3653
	Confidence Interval	(2-Sided) 90%; 0.2180 to 0.5126
	Parameter Dispersion	Type: Value:
	Estimation Comments

17. Secondary Outcome

Title	Study 2, Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-438F and Its Metabolites (M-I, M-II, M-III and M-IV-Sul)
Time Frame	Day 1 pre-dose and at multiple time points (up to 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, who had no major protocol deviation, and whose PK data were evaluable.

Arm/Group Title	Study 2: TAK-438ASA Fasted	Study 2: TAK-438ASA Fed
Arm/Group Description	TAK-438 10 mg and aspirin 100 mg FDC (TAK-438ASA), tablet, orally, under fasted condition, once on Day 1 of either Period 1 or 2.	TAK-438 10 mg and aspirin 100 mg FDC (TAK-438ASA), tablet, orally, under fed condition, once on Day 1 of either Period 1 or 2.
Measure Participants	12	12
TAK-438F	1.500	1.500
M-I	1.500	1.500
M-II	4.000	4.000
M-III	1.750	2.000
M-IV-Sul	1.500	2.000

18. Secondary Outcome

Title	Study 2, T1/2z: Terminal Disposition Phase Half-life for TAK-438F and Its Metabolites (M-I, M-II, M-III and M-IV-Sul)
Time Frame	Day 1 pre-dose and at multiple time points (up to 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, who had no major protocol deviation, and whose PK data were evaluable. The PK analysis set where data at specified time points was available.

Arm/Group Title	Study 2: TAK-438ASA Fasted	Study 2: TAK-438ASA Fed
Arm/Group Description	TAK-438 10 mg and aspirin 100 mg FDC (TAK-438ASA), tablet, orally, under fasted condition, once on Day 1 of either Period 1 or 2.	TAK-438 10 mg and aspirin 100 mg FDC (TAK-438ASA), tablet, orally, under fed condition, once on Day 1 of either Period 1 or 2.
Measure Participants	12	12
TAK-438F	8.293 (1.1254)	7.951 (0.82489)
M-I	9.653 (1.3591)	9.153 (1.0688)
M-II	12.92 (10.029)	27.52 (38.721)
M-III	6.797 (2.1059)	6.826 (1.5924)
M-IV-Sul	4.067 (1.4194)	4.543 (1.6209)

19. Secondary Outcome

Title	Study 2, AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for Unchanged Aspirin and Its Metabolite (Salicylic Acid)
Time Frame	Day 1 pre-dose and at multiple time points (up to 24 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, who had no major protocol deviation, and whose PK data were evaluable.

Arm/Group Title	Study 2: TAK-438ASA Fasted	Study 2: TAK-438ASA Fed
Arm/Group Description	TAK-438 10 mg and aspirin 100 mg FDC (TAK-438ASA), tablet, orally, under fasted condition, once on Day 1 of either Period 1 or 2.	TAK-438 10 mg and aspirin 100 mg FDC (TAK-438ASA), tablet, orally, under fed condition, once on Day 1 of either Period 1 or 2.
Measure Participants	12	12
Unchanged aspirin	817.9 (296.13)	1008 (221.75)
Salicylic acid	20010 (5299.3)	20290 (5048.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pilot Study 1: TAK-438ASA, Pilot Study 1: TAK-438 and Aspirin
	Comments
	Type of Statistical Test	Equivalence
	Comments	Unchanged aspirin: The difference in the LSM between dosing condition (TAK-438ASA tablet taken in a fed [30 minutes after starting breakfast] - TAK-438ASA tablet taken in a fasted [without breakfast] condition) and the two-sided 90% CI were provided using a crossover ANOVA model. The ANOVA model included a log-transformed (natural log) analysis variable as the dependent variable, and dosing condition, sequence, and period as independent variables.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LSM Difference
	Estimated Value	0.2089
	Confidence Interval	(2-Sided) 90%; -0.0061 to 0.4239
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Pilot Study 1: TAK-438ASA, Pilot Study 1: TAK-438 and Aspirin
	Comments
	Type of Statistical Test	Equivalence
	Comments	Salicylic acid: The difference in the LSM between dosing condition (TAK-438ASA tablet taken in a fed [30 minutes after starting breakfast] - TAK-438ASA tablet taken in a fasted [without breakfast] condition) and the two-sided 90% CI were provided using a crossover ANOVA model. The ANOVA model included a log-transformed (natural log) analysis variable as the dependent variable, and dosing condition, sequence, and period as independent variables.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LSM Difference
	Estimated Value	0.0140
	Confidence Interval	(2-Sided) 90%; -0.0639 to 0.0918
	Parameter Dispersion	Type: Value:
	Estimation Comments

20. Secondary Outcome

Title	Study 2, AUC(0-24): Area Under the Plasma Concentration-time Curve From Time 0 to Time 24 Hours Over the Dosing Interval for Unchanged Aspirin and Its Metabolite (Salicylic Acid)
Time Frame	Day 1 pre-dose and at multiple time points (up to 24 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, who had no major protocol deviation, and whose PK data were evaluable.

Arm/Group Title	Study 2: TAK-438ASA Fasted	Study 2: TAK-438ASA Fed
Arm/Group Description	TAK-438 10 mg and aspirin 100 mg FDC (TAK-438ASA), tablet, orally, under fasted condition, once on Day 1 of either Period 1 or 2.	TAK-438 10 mg and aspirin 100 mg FDC (TAK-438ASA), tablet, orally, under fed condition, once on Day 1 of either Period 1 or 2.
Measure Participants	12	12
Unchanged aspirin	816.7 (295.55)	1007 (222.08)
Salicylic acid	20070 (5318.8)	20340 (5119.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pilot Study 1: TAK-438ASA, Pilot Study 1: TAK-438 and Aspirin
	Comments
	Type of Statistical Test	Equivalence
	Comments	Unchanged aspirin: The difference in the LSM between dosing condition (TAK-438ASA tablet taken in a fed [30 minutes after starting breakfast] - TAK-438ASA tablet taken in a fasted [without breakfast] condition) and the two-sided 90% CI were provided using a crossover ANOVA model. The ANOVA model included a log-transformed (natural log) analysis variable as the dependent variable, and dosing condition, sequence, and period as independent variables.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LSM Difference
	Estimated Value	0.2099
	Confidence Interval	(2-Sided) 90%; -0.0048 to 0.4246
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Pilot Study 1: TAK-438ASA, Pilot Study 1: TAK-438 and Aspirin
	Comments
	Type of Statistical Test	Equivalence
	Comments	Salicylic acid: The difference in the LSM between dosing condition (TAK-438ASA tablet taken in a fed [30 minutes after starting breakfast] - TAK-438ASA tablet taken in a fasted [without breakfast] condition) and the two-sided 90% CI were provided using a crossover ANOVA model. The ANOVA model included a log-transformed (natural log) analysis variable as the dependent variable, and dosing condition, sequence, and period as independent variables.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LSM Difference
	Estimated Value	0.0137
	Confidence Interval	(2-Sided) 90%; -0.0712 to 0.0986
	Parameter Dispersion	Type: Value:
	Estimation Comments

21. Secondary Outcome

Title	Study 2, AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Unchanged Aspirin and Its Metabolite (Salicylic Acid)
Time Frame	Day 1 pre-dose and at multiple time points (up to 24 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, who had no major protocol deviation, and whose PK data were evaluable.

Arm/Group Title	Study 2: TAK-438ASA Fasted	Study 2: TAK-438ASA Fed
Arm/Group Description	TAK-438 10 mg and aspirin 100 mg FDC (TAK-438ASA), tablet, orally, under fasted condition, once on Day 1 of either Period 1 or 2.	TAK-438 10 mg and aspirin 100 mg FDC (TAK-438ASA), tablet, orally, under fed condition, once on Day 1 of either Period 1 or 2.
Measure Participants	12	12
Unchanged aspirin	816.5 (295.68)	1007 (222.45)
Salicylic acid	19370 (5108.5)	19760 (4853.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pilot Study 1: TAK-438ASA, Pilot Study 1: TAK-438 and Aspirin
	Comments
	Type of Statistical Test	Equivalence
	Comments	Unchanged aspirin: The difference in the LSM between dosing condition (TAK-438ASA tablet taken in a fed [30 minutes after starting breakfast] - TAK-438ASA tablet taken in a fasted [without breakfast] condition) and the two-sided 90% CI were provided using a crossover ANOVA model. The ANOVA model included a log-transformed (natural log) analysis variable as the dependent variable, and dosing condition, sequence, and period as independent variables.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LSM Difference
	Estimated Value	0.2096
	Confidence Interval	(2-Sided) 90%; -0.0054 to 0.4246
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Pilot Study 1: TAK-438ASA, Pilot Study 1: TAK-438 and Aspirin
	Comments
	Type of Statistical Test	Equivalence
	Comments	Salicylic acid: The difference in the LSM between dosing condition (TAK-438ASA tablet taken in a fed [30 minutes after starting breakfast] - TAK-438ASA tablet taken in a fasted [without breakfast] condition) and the two-sided 90% CI were provided using a crossover ANOVA model. The ANOVA model included a log-transformed (natural log) analysis variable as the dependent variable, and dosing condition, sequence, and period as independent variables.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LSM Difference
	Estimated Value	0.0201
	Confidence Interval	(2-Sided) 90%; -0.0690 to 0.1092
	Parameter Dispersion	Type: Value:
	Estimation Comments

22. Secondary Outcome

Title	Study 2, Cmax: Maximum Observed Plasma Concentration for Unchanged Aspirin and Its Metabolite (Salicylic Acid)
Time Frame	Day 1 pre-dose and at multiple time points (up to 24 hours) post-dose

Outcome Measure Data

Analysis Population Description

The PK analysis set included all participants who received at least one dose of study drug, who had no major protocol deviation, and whose PK data were evaluable.

Arm/Group Title	Study 2: TAK-438ASA Fasted	Study 2: TAK-438ASA Fed
Arm/Group Description	TAK-438 10 mg and aspirin 100 mg FDC (TAK-438ASA), tablet, orally, under fasted condition, once on Day 1 of either Period 1 or 2.	TAK-438 10 mg and aspirin 100 mg FDC (TAK-438ASA), tablet, orally, under fed condition, once on Day 1 of either Period 1 or 2.
Measure Participants	12	12
Unchanged aspirin	632.5 (286.18)	949.0 (415.75)
Salicylic acid	4414 (930.76)	5374 (1119.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pilot Study 1: TAK-438ASA, Pilot Study 1: TAK-438 and Aspirin
	Comments
	Type of Statistical Test	Equivalence
	Comments	Unchanged aspirin: The difference in the LSM between dosing condition (TAK-438ASA tablet taken in a fed [30 minutes after starting breakfast] - TAK-438ASA tablet taken in a fasted [without breakfast] condition) and the two-sided 90% CI were provided using a crossover ANOVA model. The ANOVA model included a log-transformed (natural log) analysis variable as the dependent variable, and dosing condition, sequence, and period as independent variables.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LSM Difference
	Estimated Value	0.4058
	Confidence Interval	(2-Sided) 90%; 0.0803 to 0.7312
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Pilot Study 1: TAK-438ASA, Pilot Study 1: TAK-438 and Aspirin
	Comments
	Type of Statistical Test	Equivalence
	Comments	Salicylic acid: The difference in the LSM between dosing condition (TAK-438ASA tablet taken in a fed [30 minutes after starting breakfast] - TAK-438ASA tablet taken in a fasted [without breakfast] condition) and the two-sided 90% CI were provided using a crossover ANOVA model. The ANOVA model included a log-transformed (natural log) analysis variable as the dependent variable, and dosing condition, sequence, and period as independent variables.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LSM Difference
	Estimated Value	0.1969
	Confidence Interval	(2-Sided) 90%; 0.1065 to 0.2873
	Parameter Dispersion	Type: Value:
	Estimation Comments

23. Secondary Outcome

Title	Study 2, Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Unchanged Aspirin and Its Metabolite (Salicylic Acid)
Time Frame	Day 1 pre-dose and at multiple time points (up to 24 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, who had no major protocol deviation, and whose PK data were evaluable.

Arm/Group Title	Study 2: TAK-438ASA Fasted	Study 2: TAK-438ASA Fed
Arm/Group Description	TAK-438 10 mg and aspirin 100 mg FDC (TAK-438ASA), tablet, orally, under fasted condition, once on Day 1 of either Period 1 or 2.	TAK-438 10 mg and aspirin 100 mg FDC (TAK-438ASA), tablet, orally, under fed condition, once on Day 1 of either Period 1 or 2.
Measure Participants	12	12
Unchanged aspirin	4.500	4.000
Salicylic acid	5.500	4.500

24. Secondary Outcome

Title	Study 2, T1/2z: Terminal Disposition Phase Half-life for Unchanged Aspirin and Its Metabolite (Salicylic Acid)
Time Frame	Day 1 pre-dose and at multiple time points (up to 24 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, who had no major protocol deviation, and whose PK data were evaluable.

Arm/Group Title	Study 2: TAK-438ASA Fasted	Study 2: TAK-438ASA Fed
Arm/Group Description	TAK-438 10 mg and aspirin 100 mg FDC (TAK-438ASA), tablet, orally, under fasted condition, once on Day 1 of either Period 1 or 2.	TAK-438 10 mg and aspirin 100 mg FDC (TAK-438ASA), tablet, orally, under fed condition, once on Day 1 of either Period 1 or 2.
Measure Participants	12	12
Unchanged aspirin	0.3749 (0.042784)	0.4373 (0.10311)
Salicylic acid	2.050 (0.32982)	1.901 (0.26555)

25. Secondary Outcome

Title	Study 2, Ae(0-48): Amount of Drug Excreted in Urine From Time 0 to 48 Hours for TAK-438F and Its Metabolites (M-I, M-II, M-III, and M-IV-Sul)
Time Frame	Day 1 pre-dose and at multiple time points (up to 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, who had no major protocol deviation, and whose PK data were evaluable.

Arm/Group Title	Study 2: TAK-438ASA Fasted	Study 2: TAK-438ASA Fed
Arm/Group Description	TAK-438 10 mg and aspirin 100 mg FDC (TAK-438ASA), tablet, orally, under fasted condition, once on Day 1 of either Period 1 or 2.	TAK-438 10 mg and aspirin 100 mg FDC (TAK-438ASA), tablet, orally, under fed condition, once on Day 1 of either Period 1 or 2.
Measure Participants	12	12
TAK-438F	433.3 (63.305)	583.1 (110.83)
M-I	150.1 (99.765)	153.4 (61.628)
M-II	0.000 (0.0000)	0.000 (0.0000)
M-III	0.000 (0.0000)	0.000 (0.0000)
M-IV-Sul	237.0 (56.783)	196.8 (59.876)

26. Secondary Outcome

Title	Study 2, Fe(0-48): Fraction of Administered Dose Excreted Into Urine From Time 0 to Time 48 Hours for TAK-438F and Its Metabolites (M-I, M-II, M-III and M-IV-Sul)
Time Frame	Day 1 pre-dose and at multiple time points (up to 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, who had no major protocol deviation, and whose PK data were evaluable.

Arm/Group Title	Study 2: TAK-438ASA Fasted	Study 2: TAK-438ASA Fed
Arm/Group Description	TAK-438 10 mg and aspirin 100 mg FDC (TAK-438ASA), tablet, orally, under fasted condition, once on Day 1 of either Period 1 or 2.	TAK-438 10 mg and aspirin 100 mg FDC (TAK-438ASA), tablet, orally, under fed condition, once on Day 1 of either Period 1 or 2.
Measure Participants	12	12
TAK-438F	4.333 (0.63305)	5.831 (1.1083)
M-I	1.499 (0.99551)	1.529 (0.61494)
M-II	0.000 (0.0000)	0.000 (0.0000)
M-III	0.000 (0.0000)	0.000 (0.0000)
M-IV-Sul	1.854 (0.44353)	1.539 (0.46709)

27. Secondary Outcome

Title	Study 2, CLR: Renal Clearance for TAK-438F and Its Metabolites (M-I, M-II, M-III, and M-IV-Sul)
Time Frame	Day 1 pre-dose and at multiple time points (up to 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, who had no major protocol deviation, and whose PK data were evaluable.

Arm/Group Title	Study 2: TAK-438ASA Fasted	Study 2: TAK-438ASA Fed
Arm/Group Description	TAK-438 10 mg and aspirin 100 mg FDC (TAK-438ASA), tablet, orally, under fasted condition, once on Day 1 of either Period 1 or 2.	TAK-438 10 mg and aspirin 100 mg FDC (TAK-438ASA), tablet, orally, under fed condition, once on Day 1 of either Period 1 or 2.
Measure Participants	12	12
TAK-438F	5.213 (0.65760)	5.604 (0.55389)
M-I	0.5577 (0.38695)	0.6018 (0.21705)
M-II	0.000 (0.0000)	0.000 (0.0000)
M-III	0.000 (0.0000)	0.000 (0.0000)
M-IV-Sul	2.148 (0.59016)	2.126 (0.66434)

28. Secondary Outcome

Title	Study 2, Ae(0-24): Amount of Drug Excreted in Urine From Time 0 to 24 Hours for Unchanged Aspirin and Its Metabolites (Salicylic Acid and Salicyluric Acid)
Time Frame	Day 1 pre-dose and at multiple time points (up to 24 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, who had no major protocol deviation, and whose PK data were evaluable.

Arm/Group Title	Study 2: TAK-438ASA Fasted	Study 2: TAK-438ASA Fed
Arm/Group Description	TAK-438 10 mg and aspirin 100 mg FDC (TAK-438ASA), tablet, orally, under fasted condition, once on Day 1 of either Period 1 or 2.	TAK-438 10 mg and aspirin 100 mg FDC (TAK-438ASA), tablet, orally, under fed condition, once on Day 1 of either Period 1 or 2.
Measure Participants	12	12
Unchanged aspirin	481.3 (173.04)	817.3 (403.78)
Salicylic acid	2318 (1904.7)	2076 (1159.4)
Salicyluric acid	80180 (9852.2)	83800 (4019.7)

29. Secondary Outcome

Title	Study 2, Fe(0-24): Fraction of Administered Dose Excreted Into Urine From Time 0 to Time 24 Hours for Unchanged Aspirin and Its Metabolites (Salicylic Acid and Salicyluric Acid)
Time Frame	Day 1 pre-dose and at multiple time points (up to 24 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, who had no major protocol deviation, and whose PK data were evaluable.

Arm/Group Title	Study 2: TAK-438ASA Fasted	Study 2: TAK-438ASA Fed
Arm/Group Description	TAK-438 10 mg and aspirin 100 mg FDC (TAK-438ASA), tablet, orally, under fasted condition, once on Day 1 of either Period 1 or 2.	TAK-438 10 mg and aspirin 100 mg FDC (TAK-438ASA), tablet, orally, under fed condition, once on Day 1 of either Period 1 or 2.
Measure Participants	12	12
Unchanged aspirin	0.4813 (0.17304)	0.8173 (0.40378)
Salicylic acid	3.025 (2.4834)	2.708 (1.5127)
Salicyluric acid	74.02 (9.0984)	77.34 (3.7218)

30. Secondary Outcome

Title	Study 2, CLR: Renal Clearance for Unchanged Aspirin and Its Metabolites (Salicylic Acid and Salicyluric Acid)
Time Frame	Day 1 pre-dose and at multiple time points (up to 24 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, who had no major protocol deviation, and whose PK data were evaluable. Data for CLR of Salicyluric acid was not calculated since the plasma concentration of Salicyluric acid was not measured.

Arm/Group Title	Study 2: TAK-438ASA Fasted	Study 2: TAK-438ASA Fed
Arm/Group Description	TAK-438 10 mg and aspirin 100 mg FDC (TAK-438ASA), tablet, orally, under fasted condition, once on Day 1 of either Period 1 or 2.	TAK-438 10 mg and aspirin 100 mg FDC (TAK-438ASA), tablet, orally, under fed condition, once on Day 1 of either Period 1 or 2.
Measure Participants	12	12
Unchanged aspirin	0.6181 (0.28917)	0.7818 (0.29682)
Salicylic acid	0.1135 (0.083534)	0.1022 (0.055826)

Adverse Events

Time Frame	Treatment-emergent adverse events are adverse events (AE) that started after the first dose of study drug and no more than 2 days after the last dose of study drug in Period 2 (Day 18)
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. Two participants discontinued the study due to an AE in Period 2 pre-dose and did not receive the study drug for Period 2.
Arm/Group Title	Pilot Study 1: TAK-438ASA		Pilot Study 1: TAK-438 and Aspirin		Pivotal Study 1: TAK-438ASA		Pivotal Study 1: TAK-438 and Aspirin		Study 2: TAK-438ASA Fasted		Study 2: TAK-438ASA Fed
Arm/Group Description	TAK-438 10 mg and aspirin 100 mg FDC (TAK-438ASA), tablet, orally, under fasted condition, once on Day 1 of either Period 1 or 2.		TAK-438 10 mg, tablet and aspirin 100 mg, tablet (free combination), orally, under fasted condition, once on Day 1 of either Period 1 or 2.		TAK-438 10 mg and aspirin 100 mg FDC (TAK-438ASA), tablet, orally, under fasted condition, once on Day 1 of either Period 1 or 2.		TAK-438 10 mg, tablet and aspirin 100 mg, tablet (free combination), orally, under fasted condition, once on Day 1 of either Period 1 or 2.		TAK-438 10 mg and aspirin 100 mg FDC (TAK-438ASA), tablet, orally, under fasted condition, once on Day 1 of either Period 1 or 2.		TAK-438 10 mg and aspirin 100 mg FDC (TAK-438ASA), tablet, orally, under fed condition, once on Day 1 of either Period 1 or 2.
All Cause Mortality
	Pilot Study 1: TAK-438ASA		Pilot Study 1: TAK-438 and Aspirin		Pivotal Study 1: TAK-438ASA		Pivotal Study 1: TAK-438 and Aspirin		Study 2: TAK-438ASA Fasted		Study 2: TAK-438ASA Fed
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/24 (0%)		0/23 (0%)		0/237 (0%)		0/239 (0%)		0/12 (0%)		0/12 (0%)
Serious Adverse Events
	Pilot Study 1: TAK-438ASA		Pilot Study 1: TAK-438 and Aspirin		Pivotal Study 1: TAK-438ASA		Pivotal Study 1: TAK-438 and Aspirin		Study 2: TAK-438ASA Fasted		Study 2: TAK-438ASA Fed
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/24 (0%)		0/23 (0%)		0/237 (0%)		0/239 (0%)		0/12 (0%)		0/12 (0%)
Other (Not Including Serious) Adverse Events
	Pilot Study 1: TAK-438ASA		Pilot Study 1: TAK-438 and Aspirin		Pivotal Study 1: TAK-438ASA		Pivotal Study 1: TAK-438 and Aspirin		Study 2: TAK-438ASA Fasted		Study 2: TAK-438ASA Fed
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/24 (4.2%)		0/23 (0%)		8/237 (3.4%)		3/239 (1.3%)		1/12 (8.3%)		0/12 (0%)
Infections and infestations
Upper respiratory tract infection	1/24 (4.2%)		0/23 (0%)		0/237 (0%)		0/239 (0%)		1/12 (8.3%)		0/12 (0%)
Pharyngitis	0/24 (0%)		0/23 (0%)		6/237 (2.5%)		2/239 (0.8%)		0/12 (0%)		0/12 (0%)
Nasopharyngitis	0/24 (0%)		0/23 (0%)		2/237 (0.8%)		0/239 (0%)		0/12 (0%)		0/12 (0%)
Investigations
Liver function test abnormal	0/24 (0%)		0/23 (0%)		0/237 (0%)		1/239 (0.4%)		0/12 (0%)		0/12 (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.