A Phase 1 Food Effect Study of Azilsartan (TAK-536) Pediatric Formulation

• Sponsor: Takeda (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03434977
• Collaborator: (none)
• Enrollment: 12
• Location: 1
• Arms: 2
• Actual Duration (Days): 25
• Patients Per Site Per Month: 14.6

Study Details

Study Description

Brief Summary

The purpose of this study is to assess the PK of TAK-536 and effect of food on the PK following single oral administration of TAK-536 pediatric formulation in Japanese healthy adult male participants.

Condition or Disease	Intervention/Treatment	Phase
Healthy Volunteers	Drug: TAK-536	Phase 1

Detailed Description

The drug being tested in this study is called TAK-536. TAK-536 is being tested in Japanese healthy adult male participants. This study will look at the PK and effect of food on the PK following single oral administration of TAK-536 pediatric formulation.

The study will enroll 12 healthy participants. Participants will be randomly assigned (by chance, like flipping a coin) to one of the two treatment groups and will receive a single oral dose of 10 mg of TAK-536 pediatric formulation with 200 mL of water according to the following treatments in each period during the study.

• Treatment Group A: single oral administration in the morning under fasted condition (Period 1), followed by single oral administration after breakfast (Period 2)

• Treatment Group B: single oral administration after breakfast (Period 1), followed by in the morning under fasted condition (Period 2)

This single-center trial will be conducted in Japan. The overall time to participate in this study is approximately one month. Participants will make five visits to the clinic and be hospitalized for eight days in total.

Study Design

• Study Type: Interventional
• Actual Enrollment: 12 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized, Open-Label, Cross-over Phase 1 Study to Evaluate the Food Effect of Single Oral Dose of TAK-536 Pediatric Formulation in Healthy Adult Male Subjects
• Actual Study Start Date: Feb 14, 2018
• Actual Primary Completion Date: Mar 11, 2018
• Actual Study Completion Date: Mar 11, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: TAK-536 10 mg (fasted) + TAK-536 10 mg (fed) TAK-536 10 milligram (mg) granule formulation (pediatric formulation), once daily on Day 1 of Period 1 (6 days) in the morning under fasted condition, followed by wash-out (6 days), followed by TAK-536 10 mg granule formulation (pediatric formulation), once daily on Day 1 of Period 2 (6 days) after starting breakfast.	Drug: TAK-536; TAK-536 granule formulation
Experimental: TAK-536 10 mg (fed) + TAK-536 10 mg (fasted) TAK-536 10 mg granule formulation (pediatric formulation), once daily on Day 1 of Period 1 (6 days) after starting breakfast, followed by wash-out (6 days), followed by TAK-536 10 mg granule formulation (pediatric formulation), once daily on Day 1 of Period 2 (6 days) in the morning under fasted condition.	Drug: TAK-536; TAK-536 granule formulation

Outcome Measures

Primary Outcome Measures

1. Cmax: Maximum Observed Plasma Concentration for TAK-536 [Day 1 pre-dose and at multiple time points (up to 48 hours) post-dose]

2. Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-536 [Day 1 pre-dose and at multiple time points (up to 48 hours) post-dose]

3. AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for TAK-536 [Day 1 pre-dose and at multiple time points (up to 48 hours) post-dose]

4. AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for TAK-536 [Day 1 pre-dose and at multiple time points (up to 48 hours) post-dose]

5. T1/2z: Terminal Disposition Phase Half-life for TAK-536 [Day 1 pre-dose and at multiple time points (up to 48 hours) post-dose]

6. MRTlast, ev: Mean Residence Time From Time 0 to the Time of the Last Quantifiable Concentration for TAK-536 [Day 1 pre-dose and at multiple time points (up to 48 hours) post-dose]

7. MRT∞, ev: Mean Residence Time From Time 0 to Infinity for TAK-536 [Day 1 pre-dose and at multiple time points (up to 48 hours) post-dose]

8. λz: Terminal Disposition Phase Rate Constant for TAK-536 [Day 1 pre-dose and at multiple time points (up to 48 hours) post-dose]

9. CL/F: Apparent Clearance for TAK-536 [Day 1 pre-dose and at multiple time points (up to 48 hours) post-dose]

10. Vz/F: Apparent Volume of Distribution for TAK-536 [Day 1 pre-dose and at multiple time points (up to 48 hours) post-dose]

Secondary Outcome Measures

1. Number of Participants Who Experienced at Least One Treatment-emergent Adverse Event (TEAE) [Baseline up to Day 18 (End of Period 2)]

2. Number of Participants With TEAE Related to Vital Sign [Baseline up to Day 18 (End of Period 2)]

3. Number of Participants With TEAE Related to Body Weight [Baseline up to Day 18 (End of Period 2)]

4. Number of Participants With TEAE Related to Clinical Laboratory Tests (Eosinophil Count Increased) [Baseline up to Day 18 (End of Period 2)]

5. Number of Participants With TEAE Related to 12-lead Electrocardiograms (ECGs) [Baseline up to Day 18 (End of Period 2)]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 20 Years to 35 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 Japanese healthy adult male.

4. The participant ages 20 to 35 years inclusive at the time of informed consent.

5. The participant weighs at least 50.0 kilogram (kg), and has a Body Mass Index (BMI) between 18.5 and 25.0 kilogram per square meter (kg/m^2), inclusive, at Screening.

Exclusion Criteria:

1. The participant has suspected hypotension with associated physical findings, such as dizziness postural, facial pallor, or cold sweats based on evaluation/physical examination at Screening, on the day before the study drug administration (Day -1) in Period 1, or up to the study drug administration in Period 1.

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

3. The participant has received TAK-536 or TAK-491 in a previous clinical study or as a therapeutic agent.

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

5. The participant has a hypersensitivity to any component of the formulation of TAK-536 or any ARB.

6. The participant has a positive urine drug result for drugs of abuse (defined as any illicit drug use) at Screening.

7. The participant has a history of drug abuse (defined as any illicit drug use) or a history of 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, dietary products or food products during the specified time periods.

9. The participant has any current or recent (within 6 months prior to the start of the study drug administration in Period 1) gastrointestinal diseases that would be expected to influence the absorption of drugs (that is, 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 of Period 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 the 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 the study drug administration in Period 1.

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

16. The participant has an abnormal (clinically significant) ECG at Screening or prior to the study drug administration in Period 1.

17. The participant has abnormal laboratory values that suggest a clinically significant underlying disease, or participant with the following laboratory abnormalities at Screening or prior to the study drug administration in Period 1: Alanine Aminotransferase (ALT) and/or Aspartate Transaminase (AST) greater than (>) 1.5× the upper limits of normal (ULN).

18. 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	Fukuoka Mirai Hospital	Fukuoka		Japan

Sponsors and Collaborators

• Takeda

Investigators

• Study Director: Study Director, Takeda

Study Documents (Full-Text)

• Study Protocol - Dec 8, 2017
• Statistical Analysis Plan - Jan 10, 2018

More Information

Publications

None provided.

• Responsible Party: Takeda
• ClinicalTrials.gov Identifier: NCT03434977
• Other Study ID Numbers: Azilsartan-1005; U1111-1206-5973; JapicCTI-183856
• First Posted: Feb 15, 2018
• Last Update Posted: Jun 10, 2019
• Last Verified: Jun 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: Azilsartan medoxomil

Study Results

Participant Flow

Recruitment Details	Participants took part in the study at 1 investigative site in Japan from 14 February 2018 to 11 March 2018.
Pre-assignment Detail	Healthy male participants were enrolled in 1 of the 2 treatment sequences of this 2-period cross-over study to receive pediatric formulation of TAK-536 10 milligram (mg) granules under fasted or fed condition.

Arm/Group Title	TAK-536 10 mg Granules Fasted + TAK-536 10 mg Granules Fed	TAK-536 10 mg Granules Fed + TAK-536 10 mg Granules Fasted
Arm/Group Description	TAK-536 10 mg, granules (pediatric formulation), orally, under fasted condition, once on Day 1 of Period 1, followed by a washout period of at least 6 days, further followed by TAK-536 10 mg, granules (pediatric formulation), orally, under fed condition, once on Day 1 of Period 2.	TAK-536 10 mg, granules (pediatric formulation), orally, under fed condition, once on Day 1 of Period 1, followed by a washout period of at least 6 days, further followed by TAK-536 10 mg, granules (pediatric formulation), orally, under fasted condition, once on Day 1 of Period 2.
Period Title: Intervention Period 1 (6 Days)
STARTED	6	6
COMPLETED	6	6
NOT COMPLETED	0	0
Period Title: Intervention Period 1 (6 Days)
STARTED	6	6
COMPLETED	6	5
NOT COMPLETED	0	1
Period Title: Intervention Period 1 (6 Days)
STARTED	6	5
COMPLETED	6	5
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	TAK-536 10 mg Granules Fasted + TAK-536 10 mg Granules Fed	TAK-536 10 mg Granules Fed + TAK-536 10 mg Granules Fasted	Total
Arm/Group Description	TAK-536 10 mg, granules (pediatric formulation), orally, under fasted condition, once on Day 1 of Period 1, followed by a washout period of at least 6 days, further followed by TAK-536 10 mg, granules (pediatric formulation), orally, under fed condition, once on Day 1 of Period 2.	TAK-536 10 mg, granules (pediatric formulation), orally, under fed condition, once on Day 1 of Period 1, followed by a washout period of at least 6 days, further followed by TAK-536 10 mg, granules (pediatric formulation), orally, under fasted condition, once on Day 1 of Period 2.	Total of all reporting groups
Overall Participants	6	6	12
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	22.7 (2.73)	24.3 (5.57)	23.5 (4.27)
Sex: Female, Male (Count of Participants)
Female	0 0%	0 0%	0 0%
Male	6 100%	6 100%	12 100%
Race and Ethnicity Not Collected (Count of Participants)
Count of Participants [Participants]	0 0%
Region of Enrollment (Count of Participants)
Japan	6 100%	6 100%	12 100%
Height (centimeter (cm)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [centimeter (cm)]	175.7 (7.31)	173.2 (5.71)	174.4 (6.39)
Weight (kilogram (kg)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilogram (kg)]	66.88 (5.712)	64.02 (11.129)	65.45 (8.566)
Body Mass Index (BMI) (kilogram per square meter (kg/m^2)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilogram per square meter (kg/m^2)]	21.72 (2.036)	21.23 (2.392)	21.47 (2.133)
Smoking Classification (Count of Participants)
Never smoked	4 66.7%	1 16.7%	5 41.7%
Current smoker	1 16.7%	5 83.3%	6 50%
Former smoker	1 16.7%	0 0%	1 8.3%
Alcohol Classification (Count of Participants)
Drank a few times per month	5 83.3%	5 83.3%	10 83.3%
Never drank	1 16.7%	1 16.7%	2 16.7%
Caffeine Classification (Count of Participants)
Had caffeine consumption	3 50%	0 0%	3 25%
Had no caffeine consumption	3 50%	6 100%	9 75%

Outcome Measures

1. Primary Outcome

Title	Cmax: Maximum Observed Plasma Concentration for TAK-536
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 the study drug, completed the minimum protocol-specified procedures without any major protocol deviations, and were evaluable for PK.

Arm/Group Title	TAK-536 10 mg Granules Fasted	TAK-536 10 mg Granules Fed
Arm/Group Description	TAK-536 10 mg, granules (pediatric formulation), orally, under fasted condition, once on Day 1 of either Period 1 or 2.	TAK-536 10 mg, granules (pediatric formulation), orally, under fed condition, once on Day 1 of either Period 1 or 2.
Measure Participants	11	11
Mean (Standard Deviation) [nanogram per milliliter (ng/mL)]	652.6 (78.03)	609.4 (103.92)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TAK-536 10 mg Granules Fasted, TAK-536 10 mg Granules Fed
	Comments	The shown data were ratio of fed conditions divided by fasted conditions, taking anti-logs of the least square (LS) means difference (fed-fasted) or confidence interval (CI). The difference in LS means between treatment conditions (fed-fasted) and two-sided 90% CI were provided using a crossover analysis of variance (ANOVA) model. ANOVA model included log-transformed (natural log) PK parameters Cmax as dependent variable, and treatment condition, group, and period as independent variables.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.937
	Confidence Interval	(2-Sided) 90%; 0.890 to 0.986
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-536
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 the study drug, completed the minimum protocol-specified procedures without any major protocol deviations, and were evaluable for PK.

Arm/Group Title	TAK-536 10 mg Granules Fasted	TAK-536 10 mg Granules Fed
Arm/Group Description	TAK-536 10 mg, granules (pediatric formulation), orally, under fasted condition, once on Day 1 of either Period 1 or 2.	TAK-536 10 mg, granules (pediatric formulation), orally, under fed condition, once on Day 1 of either Period 1 or 2.
Measure Participants	11	11
Median (Full Range) [hours]	2.000	3.000

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TAK-536 10 mg Granules Fasted, TAK-536 10 mg Granules Fed
	Comments	The difference in the LS means between treatment conditions (fed-fasted) and the two-sided 90% CI were provided using a crossover ANOVA model. The ANOVA model included log-transformed (non-natural log) PK parameters tmax as dependent variable, and treatment condition, group, and period as independent variables.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS-Means Difference
	Estimated Value	0.9083
	Confidence Interval	(2-Sided) 90%; 0.1821 to 1.6345
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Primary Outcome

Title	AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for TAK-536
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 the study drug, completed the minimum protocol-specified procedures without any major protocol deviations, and were evaluable for PK.

Arm/Group Title	TAK-536 10 mg Granules Fasted	TAK-536 10 mg Granules Fed
Arm/Group Description	TAK-536 10 mg, granules (pediatric formulation), orally, under fasted condition, once on Day 1 of either Period 1 or 2.	TAK-536 10 mg, granules (pediatric formulation), orally, under fed condition, once on Day 1 of either Period 1 or 2.
Measure Participants	11	11
Mean (Standard Deviation) [hour*nanogram per milliliter (h*ng/mL)]	5275.3 (1044.49)	5220.7 (881.13)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TAK-536 10 mg Granules Fasted, TAK-536 10 mg Granules Fed
	Comments	The shown data were the ratio of the fed conditions divided by the fasted conditions, taking anti-logs of the LS means difference (fed-fasted) or CI. The difference in the LS means between treatment conditions (fed-fasted) and the two-sided 90% CI were provided using a crossover ANOVA model. The ANOVA model included log-transformed (natural log) PK parameters AUClast as dependent variable, and treatment condition, group, and period as independent variables.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.998
	Confidence Interval	(2-Sided) 90%; 0.943 to 1.056
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Primary Outcome

Title	AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for TAK-536
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 the study drug, completed the minimum protocol-specified procedures without any major protocol deviations, and were evaluable for PK.

Arm/Group Title	TAK-536 10 mg Granules Fasted	TAK-536 10 mg Granules Fed
Arm/Group Description	TAK-536 10 mg, granules (pediatric formulation), orally, under fasted condition, once on Day 1 of either Period 1 or 2.	TAK-536 10 mg, granules (pediatric formulation), orally, under fed condition, once on Day 1 of either Period 1 or 2.
Measure Participants	11	11
Mean (Standard Deviation) [h*ng/mL]	5440.1 (1109.74)	5377.8 (918.96)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TAK-536 10 mg Granules Fasted, TAK-536 10 mg Granules Fed
	Comments	The shown data were the ratio of the fed conditions divided by the fasted conditions, taking anti-logs of the LS means difference (fed-fasted) or CI. The difference in the LS means between treatment conditions (fed-fasted) and the two-sided 90% CI were provided using a crossover ANOVA model. The ANOVA model included log-transformed (natural log) PK parameters AUC∞ as dependent variable, and treatment condition, group, and period as independent variables.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.997
	Confidence Interval	(2-Sided) 90%; 0.942 to 1.056
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Primary Outcome

Title	T1/2z: Terminal Disposition Phase Half-life for TAK-536
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 the study drug, completed the minimum protocol-specified procedures without any major protocol deviations, and were evaluable for PK.

Arm/Group Title	TAK-536 10 mg Granules Fasted	TAK-536 10 mg Granules Fed
Arm/Group Description	TAK-536 10 mg, granules (pediatric formulation), orally, under fasted condition, once on Day 1 of either Period 1 or 2.	TAK-536 10 mg, granules (pediatric formulation), orally, under fed condition, once on Day 1 of either Period 1 or 2.
Measure Participants	11	11
Mean (Standard Deviation) [hours]	11.11 (0.90050)	10.96 (0.85065)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TAK-536 10 mg Granules Fasted, TAK-536 10 mg Granules Fed
	Comments	The shown data were the ratio of the fed conditions divided by the fasted conditions, taking anti-logs of the LS means difference (fed-fasted) or CI. The difference in the LS means between treatment conditions (fed-fasted) and the two-sided 90% CI were provided using a crossover ANOVA model. The ANOVA model included log-transformed (natural log) PK parameters T1/2z as dependent variable, and treatment condition, group, and period as independent variables.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.985
	Confidence Interval	(2-Sided) 90%; 0.932 to 1.041
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Primary Outcome

Title	MRTlast, ev: Mean Residence Time From Time 0 to the Time of the Last Quantifiable Concentration for TAK-536
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 the study drug, completed the minimum protocol-specified procedures without any major protocol deviations, and were evaluable for PK.

Arm/Group Title	TAK-536 10 mg Granules Fasted	TAK-536 10 mg Granules Fed
Arm/Group Description	TAK-536 10 mg, granules (pediatric formulation), orally, under fasted condition, once on Day 1 of either Period 1 or 2.	TAK-536 10 mg, granules (pediatric formulation), orally, under fed condition, once on Day 1 of either Period 1 or 2.
Measure Participants	11	11
Mean (Standard Deviation) [hours]	9.419 (1.0233)	9.836 (0.61518)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TAK-536 10 mg Granules Fasted, TAK-536 10 mg Granules Fed
	Comments	The shown data were the ratio of the fed conditions divided by the fasted conditions, taking anti-logs of the LS means difference (fed-fasted) or CI. The difference in the LS means between treatment conditions (fed-fasted) and the two-sided 90% CI were provided using a crossover ANOVA model. The ANOVA model included log-transformed (natural log) PK parameters MRTlast, ev as dependent variable, and treatment condition, group, and period as independent variables.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	1.047
	Confidence Interval	(2-Sided) 90%; 1.006 to 1.091
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Primary Outcome

Title	MRT∞, ev: Mean Residence Time From Time 0 to Infinity for TAK-536
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 the study drug, completed the minimum protocol-specified procedures without any major protocol deviations, and were evaluable for PK.

Arm/Group Title	TAK-536 10 mg Granules Fasted	TAK-536 10 mg Granules Fed
Arm/Group Description	TAK-536 10 mg, granules (pediatric formulation), orally, under fasted condition, once on Day 1 of either Period 1 or 2.	TAK-536 10 mg, granules (pediatric formulation), orally, under fed condition, once on Day 1 of either Period 1 or 2.
Measure Participants	11	11
Mean (Standard Deviation) [hours]	11.02 (1.3931)	11.40 (0.90089)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TAK-536 10 mg Granules Fasted, TAK-536 10 mg Granules Fed
	Comments	The shown data were the ratio of the fed conditions divided by the fasted conditions, taking anti-logs of the LS means difference (fed-fasted) or CI. The difference in the LS means between treatment conditions (fed-fasted) and the two-sided 90% CI were provided using a crossover ANOVA model. The ANOVA model included log-transformed (natural log) PK parameters MRT∞, ev as dependent variable, and treatment condition, group, and period as independent variables.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	1.037
	Confidence Interval	(2-Sided) 90%; 0.996 to 1.081
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Primary Outcome

Title	λz: Terminal Disposition Phase Rate Constant for TAK-536
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 the study drug, completed the minimum protocol-specified procedures without any major protocol deviations, and were evaluable for PK.

Arm/Group Title	TAK-536 10 mg Granules Fasted	TAK-536 10 mg Granules Fed
Arm/Group Description	TAK-536 10 mg, granules (pediatric formulation), orally, under fasted condition, once on Day 1 of either Period 1 or 2.	TAK-536 10 mg, granules (pediatric formulation), orally, under fed condition, once on Day 1 of either Period 1 or 2.
Measure Participants	11	11
Mean (Standard Deviation) [1 per hour (1/h)]	0.06285 (0.0048845)	0.06355 (0.0047738)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TAK-536 10 mg Granules Fasted, TAK-536 10 mg Granules Fed
	Comments	The shown data were the ratio of the fed conditions divided by the fasted conditions, taking anti-logs of the LS means difference (fed-fasted) or CI. The difference in the LS means between treatment conditions (fed-fasted) and the two-sided 90% CI were provided using a crossover ANOVA model. The ANOVA model included log-transformed (natural log) PK parameters λz as dependent variable, and treatment condition, group, and period as independent variables.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	1.014
	Confidence Interval	(2-Sided) 90%; 0.959 to 1.071
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Primary Outcome

Title	CL/F: Apparent Clearance for TAK-536
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 the study drug, completed the minimum protocol-specified procedures without any major protocol deviations, and were evaluable for PK.

Arm/Group Title	TAK-536 10 mg Granules Fasted	TAK-536 10 mg Granules Fed
Arm/Group Description	TAK-536 10 mg, granules (pediatric formulation), orally, under fasted condition, once on Day 1 of either Period 1 or 2.	TAK-536 10 mg, granules (pediatric formulation), orally, under fed condition, once on Day 1 of either Period 1 or 2.
Measure Participants	11	11
Mean (Standard Deviation) [Liter per hour (L/h)]	1.912 (0.40241)	1.909 (0.31980)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TAK-536 10 mg Granules Fasted, TAK-536 10 mg Granules Fed
	Comments	The shown data were the ratio of the fed conditions divided by the fasted conditions, taking anti-logs of the LS means difference (fed-fasted) or CI. The difference in the LS means between treatment conditions (fed-fasted) and the two-sided 90% CI were provided using a crossover ANOVA model. The ANOVA model included log-transformed (natural log) PK parameters CL/F as dependent variable, and treatment condition, group, and period as independent variables.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	1.003
	Confidence Interval	(2-Sided) 90%; 0.947 to 1.062
	Parameter Dispersion	Type: Value:
	Estimation Comments

10. Primary Outcome

Title	Vz/F: Apparent Volume of Distribution for TAK-536
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 the study drug, completed the minimum protocol-specified procedures without any major protocol deviations, and were evaluable for PK.

Arm/Group Title	TAK-536 10 mg Granules Fasted	TAK-536 10 mg Granules Fed
Arm/Group Description	TAK-536 10 mg, granules (pediatric formulation), orally, under fasted condition, once on Day 1 of either Period 1 or 2.	TAK-536 10 mg, granules (pediatric formulation), orally, under fed condition, once on Day 1 of either Period 1 or 2.
Measure Participants	11	11
Mean (Standard Deviation) [liter]	30.35 (5.5177)	30.14 (5.2637)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TAK-536 10 mg Granules Fasted, TAK-536 10 mg Granules Fed
	Comments	The shown data were the ratio of the fed conditions divided by the fasted conditions, taking anti-logs of the LS means difference (fed-fasted) or CI. The difference in the LS means between treatment conditions (fed-fasted) and the two-sided 90% CI were provided using a crossover ANOVA model. The ANOVA model included log-transformed (natural log) PK parameters Vz/F as dependent variable, and treatment condition, group, and period as independent variables.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.989
	Confidence Interval	(2-Sided) 90%; 0.916 to 1.068
	Parameter Dispersion	Type: Value:
	Estimation Comments

11. Secondary Outcome

Title	Number of Participants Who Experienced at Least One Treatment-emergent Adverse Event (TEAE)
Time Frame	Baseline up to Day 18 (End of Period 2)

Outcome Measure Data

Analysis Population Description

The safety analysis set was defined as all participants who received at least one dose of the study drug. Out of 12 participants, only 11 participants received study drug under fasted condition, since 1 participant discontinued the study due to adverse event (AE) before the start of Period 2.

Arm/Group Title	TAK-536 10 mg Granules Fasted	TAK-536 10 mg Granules Fed
Arm/Group Description	TAK-536 10 mg, granules (pediatric formulation), orally, under fasted condition, once on Day 1 of either Period 1 or 2.	TAK-536 10 mg, granules (pediatric formulation), orally, under fed condition, once on Day 1 of either Period 1 or 2.
Measure Participants	11	12
Count of Participants [Participants]	0 0%	1 16.7%

12. Secondary Outcome

Title	Number of Participants With TEAE Related to Vital Sign
Time Frame	Baseline up to Day 18 (End of Period 2)

Outcome Measure Data

Analysis Population Description

The safety analysis set was defined as all participants who received at least one dose of the study drug. Out of 12 participants, only 11 participants received study drug under fasted condition, since 1 participant discontinued the study due to AE before the start of Period 2.

Arm/Group Title	TAK-536 10 mg Granules Fasted	TAK-536 10 mg Granules Fed
Arm/Group Description	TAK-536 10 mg, granules (pediatric formulation), orally, under fasted condition, once on Day 1 of either Period 1 or 2.	TAK-536 10 mg, granules (pediatric formulation), orally, under fed condition, once on Day 1 of either Period 1 or 2.
Measure Participants	11	12
Count of Participants [Participants]	0 0%	0 0%

13. Secondary Outcome

Title	Number of Participants With TEAE Related to Body Weight
Time Frame	Baseline up to Day 18 (End of Period 2)

Outcome Measure Data

Analysis Population Description

The safety analysis set was defined as all participants who received at least one dose of the study drug. Out of 12 participants, only 11 participants received study drug under fasted condition, since 1 participant discontinued the study due to AE before the start of Period 2.

Arm/Group Title	TAK-536 10 mg Granules Fasted	TAK-536 10 mg Granules Fed
Arm/Group Description	TAK-536 10 mg, granules (pediatric formulation), orally, under fasted condition, once on Day 1 of either Period 1 or 2.	TAK-536 10 mg, granules (pediatric formulation), orally, under fed condition, once on Day 1 of either Period 1 or 2.
Measure Participants	11	12
Count of Participants [Participants]	0 0%	0 0%

14. Secondary Outcome

Title	Number of Participants With TEAE Related to Clinical Laboratory Tests (Eosinophil Count Increased)
Time Frame	Baseline up to Day 18 (End of Period 2)

Outcome Measure Data

Analysis Population Description

The safety analysis set was defined as all participants who received at least one dose of the study drug. Out of 12 participants, only 11 participants received study drug under fasted condition, since 1 participant discontinued the study due to AE before the start of Period 2.

Arm/Group Title	TAK-536 10 mg Granules Fasted	TAK-536 10 mg Granules Fed
Arm/Group Description	TAK-536 10 mg, granules (pediatric formulation), orally, under fasted condition, once on Day 1 of either Period 1 or 2.	TAK-536 10 mg, granules (pediatric formulation), orally, under fed condition, once on Day 1 of either Period 1 or 2.
Measure Participants	11	12
Count of Participants [Participants]	0 0%	1 16.7%

15. Secondary Outcome

Title	Number of Participants With TEAE Related to 12-lead Electrocardiograms (ECGs)
Time Frame	Baseline up to Day 18 (End of Period 2)

Outcome Measure Data

Analysis Population Description

The safety analysis set was defined as all participants who received at least one dose of the study drug. Out of 12 participants, only 11 participants received study drug under fasted condition, since 1 participant discontinued the study due to AE before the start of Period 2.

Arm/Group Title	TAK-536 10 mg Granules Fasted	TAK-536 10 mg Granules Fed
Arm/Group Description	TAK-536 10 mg, granules (pediatric formulation), orally, under fasted condition, once on Day 1 of either Period 1 or 2.	TAK-536 10 mg, granules (pediatric formulation), orally, under fed condition, once on Day 1 of either Period 1 or 2.
Measure Participants	11	12
Count of Participants [Participants]	0 0%	0 0%

Adverse Events

Time Frame	TEAEs are adverse events that started after the first dose of study drug until the follow up examination on Day 6 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. Out of 12 participants, only 11 participants received study drug under fasted condition, since 1 participant discontinued the study due to AE before the start of Period 2.
Arm/Group Title	TAK-536 10 mg Granules Fasted		TAK-536 10 mg Granules Fed
Arm/Group Description	TAK-536 10 mg, granules (pediatric formulation), orally, under fasted condition, once on Day 1 of either Period 1 or 2.		TAK-536 10 mg, granules (pediatric formulation), orally, under fed condition, once on Day 1 of either Period 1 or 2.
All Cause Mortality
	TAK-536 10 mg Granules Fasted		TAK-536 10 mg Granules Fed
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/11 (0%)		0/12 (0%)
Serious Adverse Events
	TAK-536 10 mg Granules Fasted		TAK-536 10 mg Granules Fed
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/11 (0%)		0/12 (0%)
Other (Not Including Serious) Adverse Events
	TAK-536 10 mg Granules Fasted		TAK-536 10 mg Granules Fed
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/11 (0%)		1/12 (8.3%)
Investigations
Eosinophil count increased	0/11 (0%)		1/12 (8.3%)

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.