A Study to Evaluate the Safety, Tolerability and Pharmacokinetics of Single Ascending Dose and Multiple Doses With Titration of TAK-935 in Healthy Japanese Participants

• Sponsor: Takeda (Industry)
• Overall Status: Completed
• CT.gov ID: NCT04461483
• Collaborator: (none)
• Enrollment: 33
• Location: 1
• Arms: 8
• Actual Duration (Months): 3.1
• Patients Per Site Per Month: 10.8

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of TAK-935 with single ascending doses (Part 1) and multiple doses with titration (Part 2).

Condition or Disease	Intervention/Treatment	Phase
Healthy Volunteer	Drug: TAK-935; Drug: Placebo	Phase 1

Detailed Description

The drug being tested in this study is called TAK-935 tablet. TAK-935 tablet is being tested in Japanese healthy adult men. This study will evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of TAK-935 with single ascending doses (Part 1) and multiple doses with titration (Part 2).

The study will enroll up to 33 participants in total (Part 1 + 2). In Part 1, participants will be randomly assigned (by chance, like flipping a coin) to one of these treatment cohorts/groups;

• Cohort 1: Single dose of TAK-935 at 200 mg or placebo (fasted)

• Cohort 2: Single dose of TAK-935 at 600 mg or placebo (fasted)

• Cohort 3: Single dose of TAK-935 at 1200 mg or placebo (fasted)

In Part 2, participants will be randomly assigned to one of these treatment groups;

• Cohort 4: Multiple doses with titration of TAK-935 or placebo at 100 mg twice daily (BID) from Day 1 to Day 7, 200 mg BID from Day 8 to Day 14 and 300 mg BID from Day 15 to Day 21 (fasted).

This single-center trial will be conducted in Japan. The overall time to participate in this study is approximately 36 days for Part 1 and 63 days for Part 2. Participants will be hospitalized for 5 days in Part 1 and 26 days in Part 2.

Study Design

• Study Type: Interventional
• Actual Enrollment: 33 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-blind, Placebo-Controlled, Phase 1 Study to Evaluate the Safety, Tolerability and Pharmacokinetics of Single Ascending Dose and Multiple Doses With Titration of TAK-935 in Healthy Japanese Subjects
• Actual Study Start Date: Aug 13, 2020
• Actual Primary Completion Date: Nov 14, 2020
• Actual Study Completion Date: Nov 14, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Part 1, Cohort 1; TAK-935 200 mg Part 1, Cohort 1; TAK-935 200 mg, tablets, orally once on Days 1 in fasted state.	Drug: TAK-935; TAK-935 Tablets
Experimental: Part 1, Cohort 2; TAK-935 600 mg Part 1, Cohort 2; TAK-935 600 mg, tablets, orally once on Days 1 in fasted state.	Drug: TAK-935; TAK-935 Tablets
Experimental: Part 1, Cohort 3; TAK-935 1200 mg Part 1, Cohort 3; TAK-935 1200 mg, tablets, orally once on Days 1 in fasted state.	Drug: TAK-935; TAK-935 Tablets
Placebo Comparator: Part 1, Cohort 1-3; Placebo Part 1, Cohort 1-3; TAK-935 placebo-matching tablets, orally once on Days 1 in fasted state.	Drug: Placebo; TAK-935 placebo-matching tablets
Experimental: Part 2, Cohort 4: TAK-935 100 mg Part 2, Cohort 4: TAK-935 100 mg, tablets, orally twice on Days 1-7 in fasted state with multiple doses with titration.	Drug: TAK-935; TAK-935 Tablets
Experimental: Part 2, Cohort 4: TAK-935 200 mg Part 2, Cohort 4: TAK-935 200 mg, tablets, orally twice on Days 8-14 in fasted state with multiple doses with titration.	Drug: TAK-935; TAK-935 Tablets
Experimental: Part 2, Cohort 4: TAK-935 300 mg Part 2, Cohort 4: TAK-935 300 mg, tablets, orally twice on Days 15-21 in fasted state with multiple doses with titration.	Drug: TAK-935; TAK-935 Tablets
Placebo Comparator: Part 2, Cohort 4: Placebo Part 2, Cohort 4: TAK-935 placebo-matching tablets, orally twice on Days 1-21 in fasted state.	Drug: Placebo; TAK-935 placebo-matching tablets

Outcome Measures

Primary Outcome Measures

1. Parts 1 and 2: Percentage of Participants With at Least One Treatment-emergent Adverse Event (TEAE) [Part 1: Baseline up to Day 8; Part 2: Baseline up to Day 35]

Secondary Outcome Measures

1. Part 1, Cmax: Maximum Observed Plasma Concentration for TAK-935 [Day 1 pre-dose and at multiple time points (up to 48 hours) post-dose]

2. Part 2, Cmax: Maximum Observed Plasma Concentration for TAK-935 [Days 7, 14, and 21 pre-dose and at multiple time points (up to 12 hours) post-dose]

3. Part 1, AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to Time of the Last Quantifiable Concentration for TAK-935 [Day 1 pre-dose and at multiple time points (up to 48 hours) post-dose]

4. Part 1, AUCinf: Area Under the Plasma Concentration-time Curve From Time 0 to Time of Infinity for TAK-935 [Day 1 pre-dose and at multiple time points (up to 48 hours) post-dose]

5. Part 1, AUC(0-24): Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours Post-dose for TAK-935 [Day 1 pre-dose and at multiple time points (up to 24 hours) post-dose]

6. Part 2, AUCtau,ss: Area Under the Plasma Concentration-time Curve During the Dosing Interval at Steady State for TAK-935 [Days 7, 14, and 21 pre-dose and at multiple time points (up to 12 hours) post-dose]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 20 Years to 55 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

1. The participant must understand the study procedures and agree to participate by providing written informed consent.

2. The participant must be willing and able to comply with all study procedures and restrictions.

3. The participant must be a Japanese healthy adult male or female, aged 20 to 55 years, inclusive, at the time of informed consent.

4. The participant must have a body mass index (BMI) >=18.5 and =<25.0 kg/m^2 at the Screening Visit.

5. The participant must be a current nonsmoker who has not used tobacco- or nicotine-containing products (eg, nicotine patch) for at least 6 months prior to the first dose of study drug or first invasive procedure.

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

7. The participant must meet the following birth control requirements:

• Is a male participant who is sterile or agrees to use an appropriate method of contraception, including a condom with spermicidal cream or jelly, from the first dose of study drug until 90 days after the last dose of study drug. No restrictions are required for a vasectomized male participant provided the participant is at least 1-year postbilateral vasectomy procedure prior to the first dose of study drug. A male participant whose vasectomy procedure was performed less than 1 year prior to the first dose of study drug must follow the same restrictions as a nonvasectomized man. Appropriate documentation of surgical procedure should be provided.

• Is a male participant who agrees to not donate sperm from the first dose of study drug until 90 days after the last dose of study drug.

• Is a female participant of nonchildbearing potential, defined by at least 1 of the following criteria:

1. Postmenopausal (defined as 12 months of spontaneous amenorrhea in females aged >45 years or >=6 months of spontaneous amenorrhea in females aged >45 years with serum follicle-stimulating hormone [FSH] levels >40 mIU/mL). Appropriate documentation of follicle-stimulating hormone levels should be required.

2. Hysterectomy and/or bilateral oophorectomy with appropriate documentation of surgical procedure.

3. Had a tubal ligation with appropriate documentation of surgical procedure.

4. Congenital conditions such as uterine aplasia etc.

Exclusion Criteria:

1. Has a history of clinically significant endocrine, gastrointestinal (including motility disorder and intestinal obstruction), cardiovascular (including arrhythmia), hematological, hepatic, immunological, renal, respiratory, genitourinary, major neurological (including stroke, epileptic seizure), or degenerative ophthalmological abnormalities or diseases

2. Has participated in another investigational trial within 4 weeks or 5 half-lives (whichever is longer) before the pretrial visit (Screening). The 4-week or 5 half-lives window will be derived from the date of the last trial procedure and/or AE related to the trial procedure in the previous trial to the pretrial/Screening Visit of the current trial.

3. Is an employee or immediate family member (eg, spouse, parent, child, sibling) of the sponsor.

4. Has a history of cancer (malignancy).

5. Has any lifetime history of a suicide attempt, or have suicidal ideation or, any suicidal behavior within 12 months, or who are at significant risk to commit suicide, as judged by the investigator using the Columbia Suicide Severity Rating Scale (C-SSRS) or is clinically judged by the investigator to be at risk for suicide.

6. Has a history of significant multiple and/or severe allergies (eg, food, drug, latex allergy) or has had an anaphylactic reaction or significant intolerability to prescription or nonprescription drugs or food.

7. Has a positive alcohol or drug screen.

8. Had major surgery, donated or lost whole blood prior to the start of study drug administration as any of below:

For both male and female participants, >=200 mL within 4 weeks (28 days) For male participants, >=400 mL within 12 weeks (84 days), >=800 mL in total within 52 weeks (364 days) For female participants, >=400 mL within 16 weeks (112 days). >=400 mL in total within 52 weeks (364 days)

1. Had gastrointestinal surgery that could impact the absorption of study drug.

2. Has a history of a major psychiatric disorder as diagnosed utilizing Diagnostic and Statistical Manual of Mental Disorders, 5th Edition criteria.

3. Has a known hypersensitivity to any component of the formulation of TAK-935 or related compounds.

4. Is unable to refrain from or anticipates the use of any medication, including prescription and nonprescription drugs or herbal remedies, beginning approximately 7 days before administration of the initial dose of study drug, throughout the trial (including washout intervals between trial periods), until the Follow-up Visit.

5. Has a history of drug abuse (defined as any illicit drug use) or a history of alcohol abuse within 1 year prior to the Screening visit or is unwilling to agree to abstain from alcohol and drugs throughout the study.

6. Consumes excessive amounts, defined as greater than 6 servings (1 serving is approximately equivalent to 120 mg of caffeine) of coffee, tea, cola, energy drinks, or other caffeinated beverages per day.

7. Has a substance abuse disorder.

8. Has a QTcF >450 msec confirmed with one repeat testing, at the Screening Visit.

9. Had abnormal Screening or Day -1 laboratory values that suggested a clinically significant underlying disease or participant with the following laboratory abnormalities: ALT and/or AST >1.5 time ULN.

10. Has tested positive for hepatitis B virus surface antigen (HBsAg), hepatitis C virus (HCV) antibody, HIV antibody/antigen, or serologic reactions for syphilis at Screening.

11. In the opinion of the 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	Clinical Research Hospital Tokyo	Shinjuku-ku	Tokyo	Japan

Sponsors and Collaborators

• Takeda

Investigators

• Study Director: Study Director, Takeda

Study Documents (Full-Text)

• Study Protocol - Jul 2, 2020
• Statistical Analysis Plan - Nov 20, 2020

More Information

Publications

None provided.

• Responsible Party: Takeda
• ClinicalTrials.gov Identifier: NCT04461483
• Other Study ID Numbers: TAK-935-1004; U1111-1252-8555; JapicCTI-205349
• First Posted: Jul 8, 2020
• Last Update Posted: Jan 11, 2022
• Last Verified: Nov 1, 2020

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

Study Results

Participant Flow

Recruitment Details	Participants took part in the study at 1 investigative site in Japan from 13 August 2020 to 14 November 2020.
Pre-assignment Detail	Healthy Japanese participants were enrolled in the study into two parts: Single Ascending Dose (SAD) (Part 1) and Multiple Dose (MD) titration (Part 2) to receive TAK-935 tablets or TAK-935 placebo-matching tablets.

Arm/Group Title	Part 1, SAD, Cohorts 1 to 3: Placebo	Part 1, SAD, Cohort 1: TAK-935 200 mg	Part 1, SAD, Cohort 2: TAK-935 600 mg	Part 1, SAD, Cohort 3: TAK-935 1200 mg	Part 2, MD, Cohort 4: Placebo	Part 2, MD, Cohort 4: TAK-935
Arm/Group Description	TAK-935 placebo-matching tablet, orally, once on Day 1 in fasted state.	TAK-935 200 milligram (mg), tablet, orally, once on Day 1 in fasted state.	TAK-935 600 mg, tablet, orally, once on Day 1 in fasted state.	TAK-935 1200 mg, tablet, orally, once on Day 1 in fasted state.	TAK-935 placebo-matching tablets, orally, twice daily on Days 1 to 21 in fasted state.	TAK-935 100 mg, tablets, orally, twice daily on Days 1 to 7, then up-titrated to TAK-935 200 mg, tablets, orally, twice daily, on Days 8 to 14, further up-titrated to TAK-935 300 mg, tablets, orally, twice daily on Days 15 to 21 as multiple doses with titration in the fasted state.
Period Title: Part 1 (Day 1)
STARTED	6	6	6	6	0	0
COMPLETED	6	6	6	6	0	0
NOT COMPLETED	0	0	0	0	0	0
Period Title: Part 1 (Day 1)
STARTED	0	0	0	0	3	6
COMPLETED	0	0	0	0	3	6
NOT COMPLETED	0	0	0	0	0	0

Baseline Characteristics

Arm/Group Title	Part 1, SAD, Cohorts 1 to 3: Placebo	Part 1, SAD, Cohort 1: TAK-935 200 mg	Part 1, SAD, Cohort 2: TAK-935 600 mg	Part 1, SAD, Cohort 3: TAK-935 1200 mg	Part 2, MD, Cohort 4: Placebo	Part 2, MD, Cohort 4: TAK-935	Total
Arm/Group Description	TAK-935 placebo-matching tablet, orally, once on Day 1 in fasted state.	TAK-935 200 mg, tablet, orally, once on Day 1 in fasted state.	TAK-935 600 mg, tablet, orally, once on Day 1 in fasted state.	TAK-935 1200 mg, tablet, orally, once on Day 1 in fasted state.	TAK-935 placebo-matching tablets, orally, twice daily on Days 1 to 21 in fasted state.	TAK-935 100 mg, tablets, orally, twice daily on Days 1 to 7, then up-titrated to TAK-935 200 mg, tablets, orally, twice daily, on Days 8 to 14, further up-titrated to TAK-935 300 mg, tablets, orally, twice daily on Days 15 to 21 as multiple doses with titration in the fasted state.	Total of all reporting groups
Overall Participants	6	6	6	6	3	6	33
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	39.8 (12.43)	39.0 (12.71)	31.5 (14.11)	41.5 (11.20)	37.7 (8.39)	33.5 (7.48)	37.1 (11.28)
Sex: Female, Male (Count of Participants)
Female	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Male	6 100%	6 100%	6 100%	6 100%	3 100%	6 100%	33 100%
Race/Ethnicity, Customized (Count of Participants)
Asian	6 100%	6 100%	6 100%	6 100%	3 100%	6 100%	33 100%
Region of Enrollment (Count of Participants)
Japan	6 100%	6 100%	6 100%	6 100%	3 100%	6 100%	33 100%
Height (centimeter (cm)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [centimeter (cm)]	170.5 (6.95)	169.8 (4.02)	167.0 (8.39)	173.3 (5.61)	173.7 (1.53)	168.2 (2.64)	170.1 (5.74)
Weight (kilogram (kg)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilogram (kg)]	63.78 (4.392)	59.88 (4.212)	58.75 (5.410)	65.47 (7.750)	65.70 (1.778)	61.38 (2.865)	62.2 (5.311)
Body-mass Index (BMI) (kilogram per square meter (kg/m^2)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilogram per square meter (kg/m^2)]	21.98 (1.755)	20.77 (1.206)	21.05 (0.822)	21.75 (1.473)	21.77 (0.306)	21.75 (1.571)	21.49 (1.326)
Smoking Classification (Count of Participants)
Never Smoked	5 83.3%	3 50%	6 100%	4 66.7%	3 100%	4 66.7%	25 75.8%
Former Smoker	1 16.7%	3 50%	0 0%	2 33.3%	0 0%	2 33.3%	8 24.2%
Alcohol Classification (Count of Participants)
Had Daily Consumption	0 0%	0 0%	0 0%	2 33.3%	0 0%	0 0%	2 6.1%
Had a Few Times Per Week	0 0%	1 16.7%	1 16.7%	2 33.3%	0 0%	2 33.3%	6 18.2%
Had a Few Times Per Month	4 66.7%	2 33.3%	3 50%	2 33.3%	0 0%	1 16.7%	12 36.4%
Had no Consumption	2 33.3%	3 50%	2 33.3%	0 0%	3 100%	3 50%	13 39.4%
Caffeine Classification (Count of Participants)
Had Caffeine	2 33.3%	3 50%	0 0%	3 50%	1 33.3%	1 16.7%	10 30.3%
Had no Caffeine	4 66.7%	3 50%	6 100%	3 50%	2 66.7%	5 83.3%	23 69.7%

Outcome Measures

1. Primary Outcome

Title	Parts 1 and 2: Percentage of Participants With at Least One Treatment-emergent Adverse Event (TEAE)
Time Frame	Part 1: Baseline up to Day 8; Part 2: Baseline up to Day 35

Outcome Measure Data

Analysis Population Description

The safety analysis set included all participants who received at least 1 dose of study drug.

Arm/Group Title	Part 1, SAD, Cohorts 1 to 3: Placebo	Part 1, SAD, Cohort 1: TAK-935 200 mg	Part 1, SAD, Cohort 2: TAK-935 600 mg	Part 1, SAD, Cohort 3: TAK-935 1200 mg	Part 2, MD, Cohort 4: Placebo	Part 2, MD, Cohort 4: TAK-935 100 mg	Part 2, MD, Cohort 4: TAK-935 200 mg	Part 2, MD, Cohort 4: TAK-935 300 mg
Arm/Group Description	TAK-935 placebo-matching tablet, orally, once on Day 1 in fasted state.	TAK-935 200 mg, tablet, orally, once on Day 1 in fasted state.	TAK-935 600 mg, tablet, orally, once on Day 1 in fasted state.	TAK-935 1200 mg, tablet, orally, once on Day 1 in fasted state.	TAK-935 placebo-matching tablets, orally, twice daily on Days 1 to 21 in fasted state.	TAK-935 100 mg, tablets, orally, twice daily on Days 1 to 7 in fasted state.	TAK-935 200 mg, tablets, orally, twice daily on Days 8 to 14 in fasted state following TAK-935 100 mg, tablet, orally, twice daily.	TAK-935 300 mg, tablets, orally, twice daily on Days 15 to 21 in fasted state following TAK-935 200 mg, tablet, orally, twice daily.
Measure Participants	6	6	6	6	3	6	6	6
Number [percentage of participants]	0 0%	0 0%	0 0%	0 0%	0 0%	33.33 555.5%	16.7 50.6%	33.33 NaN

2. Secondary Outcome

Title	Part 1, Cmax: Maximum Observed Plasma Concentration for TAK-935
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 included all participants who received at least 1 dose of study drug and had at least 1 estimable PK parameter.

Arm/Group Title	Part 1, SAD, Cohort 1: TAK-935 200 mg	Part 1, SAD, Cohort 2: TAK-935 600 mg	Part 1, SAD, Cohort 3: TAK-935 1200 mg
Arm/Group Description	TAK-935 200 mg, tablet, orally, once on Day 1 in fasted state.	TAK-935 600 mg, tablet, orally, once on Day 1 in fasted state.	TAK-935 1200 mg, tablet, orally, once on Day 1 in fasted state.
Measure Participants	6	6	6
Geometric Mean (Geometric Coefficient of Variation) [nanogram per milliliter (ng/mL)]	413.2 (202.4)	3001 (47.3)	9278 (48.1)

3. Secondary Outcome

Title	Part 2, Cmax: Maximum Observed Plasma Concentration for TAK-935
Time Frame	Days 7, 14, and 21 pre-dose and at multiple time points (up to 12 hours) post-dose

Outcome Measure Data

Analysis Population Description

The PK analysis set included all participants who received at least 1 dose of study drug and had at least 1 estimable PK parameter. As planned data for this outcome measure was collected, analyzed and reported for dose level TAK-935-100 mg on Day 7, dose level TAK-935-200 mg on Day 14, and TAK-935-300 mg on Day 21.

Arm/Group Title	Part 2, MD, Cohort 4: TAK-935 100 mg	Part 2, MD, Cohort 4: TAK-935 200 mg	Part 2, MD, Cohort 4: TAK-935 300 mg
Arm/Group Description	TAK-935 100 mg, tablets, orally, twice daily on Days 1 to 7 in fasted state.	TAK-935 200 mg, tablets, orally, twice daily on Days 8 to 14 in fasted state following TAK-935 100 mg, tablet, orally, twice daily.	TAK-935 300 mg, tablets, orally, twice daily on Days 15 to 21 in fasted state following TAK-935 200 mg, tablet, orally, twice daily.
Measure Participants	6	6	6
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	146.5 (113.1)	835.5 (73.8)	1945 (37.7)

4. Secondary Outcome

Title	Part 1, AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to Time of the Last Quantifiable Concentration for TAK-935
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 1 dose of study drug and had at least 1 estimable PK parameter.

Arm/Group Title	Part 1, SAD, Cohort 1: TAK-935 200 mg	Part 1, SAD, Cohort 2: TAK-935 600 mg	Part 1, SAD, Cohort 3: TAK-935 1200 mg
Arm/Group Description	TAK-935 200 mg, tablet, orally, once on Day 1 in fasted state.	TAK-935 600 mg, tablet, orally, once on Day 1 in fasted state.	TAK-935 1200 mg, tablet, orally, once on Day 1 in fasted state.
Measure Participants	6	6	6
Geometric Mean (Geometric Coefficient of Variation) [hour*nanogram per milliliter (h*ng/mL)]	512.7 (100.8)	3538 (45.8)	10590 (42.1)

5. Secondary Outcome

Title	Part 1, AUCinf: Area Under the Plasma Concentration-time Curve From Time 0 to Time of Infinity for TAK-935
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 1 dose of study drug and had at least 1 estimable PK parameter.

Arm/Group Title	Part 1, SAD, Cohort 1: TAK-935 200 mg	Part 1, SAD, Cohort 2: TAK-935 600 mg	Part 1, SAD, Cohort 3: TAK-935 1200 mg
Arm/Group Description	TAK-935 200 mg, tablet, orally, once on Day 1 in fasted state.	TAK-935 600 mg, tablet, orally, once on Day 1 in fasted state.	TAK-935 1200 mg, tablet, orally, once on Day 1 in fasted state.
Measure Participants	6	6	6
Geometric Mean (Geometric Coefficient of Variation) [h*ng/mL]	539.2 (97.2)	3603 (45.1)	10660 (42.0)

6. Secondary Outcome

Title	Part 1, AUC(0-24): Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours Post-dose for TAK-935
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 1 dose of study drug and had at least 1 estimable PK parameter.

Arm/Group Title	Part 1, SAD, Cohort 1: TAK-935 200 mg	Part 1, SAD, Cohort 2: TAK-935 600 mg	Part 1, SAD, Cohort 3: TAK-935 1200 mg
Arm/Group Description	TAK-935 200 mg, tablet, orally, once on Day 1 in fasted state.	TAK-935 600 mg, tablet, orally, once on Day 1 in fasted state.	TAK-935 1200 mg, tablet, orally, once on Day 1 in fasted state.
Measure Participants	6	6	6
Geometric Mean (Geometric Coefficient of Variation) [h*ng/mL]	517.8 (99.4)	3538 (45.8)	10540 (41.0)

7. Secondary Outcome

Title	Part 2, AUCtau,ss: Area Under the Plasma Concentration-time Curve During the Dosing Interval at Steady State for TAK-935
Time Frame	Days 7, 14, and 21 pre-dose and at multiple time points (up to 12 hours) post-dose

Outcome Measure Data

Analysis Population Description

The PK analysis set included all participants who received at least 1 dose of study drug and had at least 1 estimable PK parameter. As planned data for this outcome measure was collected, analyzed and reported for dose level TAK-935-100 mg on Day 7, dose level TAK-935-200 mg on Day 14, and TAK-935-300 mg on Day 21.

Arm/Group Title	Part 2, MD, Cohort 4: TAK-935 100 mg	Part 2, MD, Cohort 4: TAK-935 200 mg	Part 2, MD, Cohort 4: TAK-935 300 mg
Arm/Group Description	TAK-935 100 mg, tablets, orally, twice daily on Days 1 to 7 in fasted state.	TAK-935 200 mg, tablets, orally, twice daily on Days 8 to 14 in fasted state following TAK-935 100 mg, tablet, orally, twice daily.	TAK-935 300 mg, tablets, orally, twice daily on Days 15 to 21 in fasted state following TAK-935 200 mg, tablet, orally, twice daily.
Measure Participants	6	6	6
Geometric Mean (Geometric Coefficient of Variation) [h*ng/mL]	202.3 (54.6)	788.6 (48.9)	1960 (27.7)

Adverse Events

Time Frame	TEAEs were adverse events that started after the first dose of study drug (Baseline) up to Day 8 in Part 1, and up to Day 35 in Part 2
Adverse Event Reporting Description	At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Arm/Group Title	Part 1, SAD, Cohort 1-3: Placebo		Part 1, SAD, Cohort 1: TAK-935 200 mg		Part 1, SAD, Cohort 2: TAK-935 600 mg		Part 1, SAD, Cohort 3: TAK-935 1200 mg		Part 2, MD, Cohort 4: Placebo		Part 2, MD, Cohort 4: TAK-935 100 mg		Part 2, MD, Cohort 4: TAK-935 200 mg		Part 2, MD, Cohort 4: TAK-935 300 mg
Arm/Group Description	TAK-935 placebo-matching tablet, orally, once on Day 1 in fasted state.		TAK-935 200 mg, tablet, orally, once on Day 1 in fasted state.		TAK-935 600 mg, tablet, orally, once on Day 1 in fasted state.		TAK-935 1200 mg, tablet, orally, once on Day 1 in fasted state.		TAK-935 placebo-matching tablets, orally, twice daily on Days 1to 21 in fasted state.		TAK-935 100 mg, tablets, orally, twice daily on Days 1 to 7 in fasted state.		TAK-935 200 mg, tablets, orally, twice daily on Days 8 to 14 in fasted state following TAK-935 100 mg, tablet, orally, twice daily.		TAK-935 300 mg, tablets, orally, twice daily on Days 15 to 21 in fasted state following TAK-935 200 mg, tablet, orally, twice daily.
All Cause Mortality
	Part 1, SAD, Cohort 1-3: Placebo		Part 1, SAD, Cohort 1: TAK-935 200 mg		Part 1, SAD, Cohort 2: TAK-935 600 mg		Part 1, SAD, Cohort 3: TAK-935 1200 mg		Part 2, MD, Cohort 4: Placebo		Part 2, MD, Cohort 4: TAK-935 100 mg		Part 2, MD, Cohort 4: TAK-935 200 mg		Part 2, MD, Cohort 4: TAK-935 300 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	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	0/6 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/3 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)
Serious Adverse Events
	Part 1, SAD, Cohort 1-3: Placebo		Part 1, SAD, Cohort 1: TAK-935 200 mg		Part 1, SAD, Cohort 2: TAK-935 600 mg		Part 1, SAD, Cohort 3: TAK-935 1200 mg		Part 2, MD, Cohort 4: Placebo		Part 2, MD, Cohort 4: TAK-935 100 mg		Part 2, MD, Cohort 4: TAK-935 200 mg		Part 2, MD, Cohort 4: TAK-935 300 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	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	0/6 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/3 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)
Other (Not Including Serious) Adverse Events
	Part 1, SAD, Cohort 1-3: Placebo		Part 1, SAD, Cohort 1: TAK-935 200 mg		Part 1, SAD, Cohort 2: TAK-935 600 mg		Part 1, SAD, Cohort 3: TAK-935 1200 mg		Part 2, MD, Cohort 4: Placebo		Part 2, MD, Cohort 4: TAK-935 100 mg		Part 2, MD, Cohort 4: TAK-935 200 mg		Part 2, MD, Cohort 4: TAK-935 300 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	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	0/6 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/3 (0%)		2/6 (33.3%)		1/6 (16.7%)		2/6 (33.3%)
Gastrointestinal disorders
Diarrhoea	0/6 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/3 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)
Respiratory, thoracic and mediastinal disorders
Hiccups	0/6 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/3 (0%)		0/6 (0%)		0/6 (0%)		1/6 (16.7%)
Skin and subcutaneous tissue disorders
Alopecia areata	0/6 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/3 (0%)		0/6 (0%)		0/6 (0%)		1/6 (16.7%)
Dry skin	0/6 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/3 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)
Rash	0/6 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/3 (0%)		0/6 (0%)		1/6 (16.7%)		0/6 (0%)

Limitations/Caveats

[Not Specified]

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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.