A Randomized, Double-Blind, Placebo Controlled, Two-Period Cross-Over, Proof of Activity Study to Evaluate the Effects of TAK-041 on Motivational Anhedonia as Add-On to Antipsychotics in Participants With Stable Schizophrenia

• Sponsor: Neurocrine Biosciences (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03319953
• Collaborator: Takeda (Industry)
• Enrollment: 23
• Location: 1
• Arms: 4
• Actual Duration (Months): 22.5
• Patients Per Site Per Month: 1

Study Details

Study Description

Brief Summary

The purpose of the study is to determine whether motivation/reward deficits observed in schizophrenia are attenuated and whether cognitive impairment associated with schizophrenia is improved by add-on TAK-041 administration to antipsychotics in participants with stable schizophrenia.

Condition or Disease	Intervention/Treatment	Phase
Stable Schizophrenia	Drug: TAK-041; Drug: Placebo; Drug: Second Generation Antipsychotics (SGA)	Phase 2

Detailed Description

The drug being tested in this study is called TAK-041. TAK-041 is being tested to treat people who have stable schizophrenia. This study will look whether motivation/reward deficits observed in schizophrenia are attenuated and whether cognitive impairment associated with schizophrenia is improved in people who take TAK-041 in addition to standard care.

The study will enroll approximately 32 patients. Participants will be randomly assigned (by chance, like flipping a coin) in 1:1 ratio to one of the two treatment sequences -which will remain undisclosed to the patient and study doctor during the study (unless there is an urgent medical need) to receive either TAK-041 40 mg or Placebo first and then will be crossed over to receive the opposite Intervention.

All participants will be asked to take oral suspension on Day 1 of each Period. There will be a wash-out Period of 35 days between the dosing days in Period 1 and 2.

This single-center trial will be conducted in the United Kingdom. The overall time to participate in this study is approximately 126 to 154 days. Participants will make multiple visits to the clinic plus a final visit 77 days after receiving their last dose of drug for a follow-up assessment.

Study Design

• Study Type: Interventional
• Actual Enrollment: 23 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-Blind, Placebo Controlled, Two-Period Cross-Over, Proof of Activity Study to Evaluate the Effects of TAK-041 on Motivational Anhedonia as Add-On to Antipsychotics in Subjects With Stable Schizophrenia
• Actual Study Start Date: Dec 21, 2017
• Actual Primary Completion Date: Sep 11, 2019
• Actual Study Completion Date: Nov 6, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment Sequence 1: TAK-041 40 mg/Placebo + Antipsychotics TAK-041 40 milligram (mg), suspension, orally on Day 1 of Treatment Period 1, followed by 35 day Wash-out Period, followed by TAK-041 placebo-matching, suspension, orally on Day 1 of Treatment Period 2. All participants received a stable dose of antipsychotics as per standard of care throughout the duration of the Treatment Period.	Drug: TAK-041; TAK-041 suspension; Drug: Placebo; TAK-041 placebo-matching suspension; Drug: Second Generation Antipsychotics (SGA); Second generation antipsychotics included risperidone, paliperidone, iloperidone, quetiapine, olanzapine, ziprasidone, asenapine and lurasidone.
Experimental: Treatment Sequence 2: Placebo/TAK-041 40 mg + Antipsychotics TAK-041 placebo-matching, suspension, orally on Day 1 of Treatment Period 1, followed by 35 days Wash-out Period, followed by TAK-041 40 mg, suspension, orally on Day 1 of Treatment Period 2. All participants received a stable dose of antipsychotics as per standard of care throughout the duration of the Treatment Period.	Drug: TAK-041; TAK-041 suspension; Drug: Placebo; TAK-041 placebo-matching suspension; Drug: Second Generation Antipsychotics (SGA); Second generation antipsychotics included risperidone, paliperidone, iloperidone, quetiapine, olanzapine, ziprasidone, asenapine and lurasidone.
Experimental: Treatment Sequence 3: TAK-041 160 mg/Placebo + Antipsychotics TAK-041 160 mg, suspension, orally on Day 1 of Treatment Period 1, followed by 35 days Wash-out Period, followed by TAK-041 placebo-matching, suspension, orally on Day 1 of Treatment Period 2. All participants received stable dose of antipsychotics as per standard of care throughout the duration of the Treatment Period.	Drug: TAK-041; TAK-041 suspension; Drug: Placebo; TAK-041 placebo-matching suspension; Drug: Second Generation Antipsychotics (SGA); Second generation antipsychotics included risperidone, paliperidone, iloperidone, quetiapine, olanzapine, ziprasidone, asenapine and lurasidone.
Experimental: Treatment Sequence 4: Placebo/TAK-041 160 mg + Antipsychotics TAK-041 placebo-matching, suspension, orally on Day 1 of Treatment Period 1, followed by 35 days Wash-out Period, followed by TAK-041 160 mg, suspension, orally on Day 1 of Treatment Period 2. All participants received stable dose of antipsychotics as per standard of care throughout the duration of the Treatment Period.	Drug: TAK-041; TAK-041 suspension; Drug: Placebo; TAK-041 placebo-matching suspension; Drug: Second Generation Antipsychotics (SGA); Second generation antipsychotics included risperidone, paliperidone, iloperidone, quetiapine, olanzapine, ziprasidone, asenapine and lurasidone.

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in the Brief Assessment of Cognition in Schizophrenia (BACS) Composite Score at Second Testing After TAK-041 Administration [Baseline (Day -1) and Day 14]

   BACS is a reliable and sensitive measure of cognitive function in schizophrenia. The BACS consists of items across six subtests: Verbal Memory, Digit Sequencing, Token Motor, Verbal Fluency, Symbol Coding, and Tower of London. The subtest scale scores were used to compute a composite BACS t-score of 50 (20) is the mean (standard deviation) of a relevant index population. Higher values indicate better performance. Bayesian normal linear model was used for analysis.

2. Blood-Oxygen-Level-Dependent (BOLD) Signal in the Average Ventral Striatum (VS) Region of Interest (ROI) Activation in the Monetary Incentive Delay (MID) Reward Task at First Testing After TAK-041 Administration [Day 1]

   Blood-oxygen-level-dependent imaging, or BOLD-contrast imaging, is a method used in functional magnetic resonance imaging (fMRI) to observe different areas of the brain or other organs, which are found to be active at any given time. The MID task is a reward anticipation paradigm that robustly engages the VS, a key area associated with coding incentive reward. Dysfunctional processing of reward information is associated with motivational impairments in schizophrenia. Motivational impairment is a key aspect of negative symptoms, and has been associated with reduced activity in the VS. Any change in BOLD signal that comes in fMRI is reported.

Secondary Outcome Measures

1. Percentage of Participants Who Experience at Least One Treatment Emergent Adverse Event (TEAE) [From the first dose of study drug up to 77 days after last dose of study drug (Up to Day 154)]

   An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. A TEAE is defined as an adverse event with an onset that occurs after receiving study drug.

2. Percentage of Participants Who Meet the Markedly Abnormal Criteria for Safety Laboratory Tests at Least Once Post Dose [From the first dose of study drug up to 77 days after last dose of study drug (Up to Day 154)]

   Clinical Laboratory parameters included tests for chemistry, hematology and urinalysis. Markedly abnormal values during treatment period were categorized as: alanine aminotransferase (ALT)>3.0 U/L*upper limit of normal(ULN),albumin<25 g/L*lower limit of normal(LLN), alkaline phosphatase >3.0 U/L*ULN, aspartate aminotransferase >3.0 U/L*ULN, bilirubin >34.2 umol/L*ULN, calcium <1.75 mmol/L, >2.88 mmol/L, chloride <75 mmol/L, >126 mmol/L, creatinine >177umol/L, gamma glutamyl transferase >3 U/L*ULN, glucose <2.8 mmol/L, >19.4 mmol/L, potassium<3 mmol/L, >6 mmol/L, sodium <130 mmol/L, >150 mmol/L,Urea <130 mmol/L, erythrocytes <0.8*LLN >1.2*ULN, hematocrit <0.8*LLN, >1.2*ULN, hemoglobin <0.8 g/L*LLN, >1.2 g/L*ULN, leukocytes <0.5 (10^9/L)*LLN, >1.5 (10^9/L)*ULN, platelets <75(10^9/L), >600(10^9/L).

3. Percentage of Participants Who Meet the Markedly Abnormal Criteria for Vital Sign Measurements At Least Once Post Dose [From the first dose of study drug up to 77 days after last dose of study drug (Up to Day 154)]

   Vital signs included oral body temperature measurement, supine and standing blood pressure, respiration rate, and pulse. Pulse and blood pressure were measured after 5 minutes supine and again at 1 and 3 minutes after standing. The markedly abnormal value (MAV) criteria for vital signs included systolic blood pressure < 85 mmHg, > 180 mmHg; diastolic blood pressure < 50 mmHg, > 110 mmHg; pulse < 50 beats/min, > 120 beats/min; temperature < 35.6 C > 37.7 C.

4. Percentage of Participants Who Meet the Markedly Abnormal Criteria for Safety Electrocardiogram (ECG) at Least Once Post Dose [From the first dose of study drug up to 77 days after last dose of study drug (Up to Day 154)]

   The markedly abnormal value (MAV) criteria for 12-lead ECG parameters included ECG Mean Heart Rate < 50 beats/min, > 120 beats/min; PR Interval, Aggregate <= 80 msec, >= 200 msec; QRS Duration, Aggregate <= 80 msec, >= 180 msec; QTcB Interval, Aggregate <= 300 msec, >= 500 msec OR (>= 30 msec change from baseline and >= 450 msec); QTcF Interval, Aggregate <= 300 msec, >= 500 msec OR (>= 30 msec change from baseline and >= 450 msec).

5. Number of Participants With Suicidal Ideation or Suicidal Behavior as Measured Using Columbia-Suicide Severity Rating Scale (C-SSRS) [Baseline (Day -1) and Days 14, 35 and 77]

   Treatment-emergent suicidal ideation (SI) or suicidal behavior (SB) compared to baseline will be measured by an increase in suicidal ideation category (1-5 on the C-SSRS) or suicidal behavior category (6-10 on the C-SSRS) during treatment from the maximum suicidal ideation/behavior category at baseline, or any suicidal ideation/behavior during treatment if there is none at baseline. C-SSRS is used to assess whether participant experienced suicidal ideation (1: wish to be dead; 2: non-specific active suicidal thoughts; 3: active suicidal ideation with any methods (not plan) without intent to act; 4: active suicidal ideation with some intent to act, without specific plan; 5: active suicidal ideation with specific plan and intent) and suicidal behavior (6: actual attempt; 7: interrupted attempt; 8: aborted attempt; 9: preparatory acts or behavior; 10: suicidal behavior).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 60 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Is on a stable dose of antipsychotics for at least 2 months as documented by medical history and assessed by site staff (other than those on the excluded medication list).

2. Meets schizophrenia criteria as defined by the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) by the Mini International Neuropsychiatric Interview (MINI).

3. Have Positive and Negative Syndrome Scale (PANSS) total score less than or equal to (<=) 90 and PANSS Negative Symptom Factor Score ([NSFS]; Sum of PANSS N1, N2, N3, N4, N6, G7, and G16) greater than or equal to (>=) 15 at screening and baseline (Day -1).

4. Has stable Screening and baseline (Day-1) PANSS and NSFS total scores (less than [<] 20 percent [%] change).

5. Have had a structural brain magnetic resonance imaging (MRI) within the preceding year or during screening indicating no concerning structural brain abnormalities or other abnormalities that would interfere with interpretation of functional brain imaging results.

Exclusion Criteria:

1. Has a history of cancer (malignancy).

2. Has a positive alcohol and/ or positive drug screen at Screening or Day -1.

3. Is positive for hepatitis B surface antigen (HBsAg), hepatitis C (HCV) antibody, or human immunodeficiency virus (HIV) antibody/antigen (confirmatory testing is allowed; most sensitive test should take precedence).

4. Had major surgery, or donated or lost 1 unit of blood (approximately 500 milliliters [mL]) within 4 weeks prior to the pretrial/Screening Visit.

5. Has abnormal Screening or baseline laboratory values (>upper limit of normal [ULN] for the respective serum chemistries) of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBILI), alkaline phosphatase (ALP), γ-glutamyl transferase (GGT) confirmed upon repeat testing, 5'-nucleotidase (Screening only), and/or abnormal urine osmolality, confirmed upon repeat testing.

6. Meets DSM-5 criteria for substance use disorder or history of alcohol abuse within 1 month prior to Screening Visit.

7. Has a history of claustrophobia or inability to tolerate mock scanner environment during habituation/screening session.

8. Fulfills any of the MRI contraindications on the site standard radiography screening document.

9. Has a history in the last year from the randomization visit or is currently receiving treatment with clozapine.

10. Has a current diagnosis of a significant psychiatric illness other than schizophrenia, per DSM-5 and is in an acute phase or episode.

11. Has a risk of suicide according to the investigator's clinical judgment (example, per C-SSRS positive answers on questions 4 or 5 or has made a suicide attempt within 6 months prior to screening visit).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Kings College London	London		United Kingdom	SE58AF

Sponsors and Collaborators

• Neurocrine Biosciences
• Takeda

Investigators

• Study Director: Medical Director Clinical Science, Takeda

Study Documents (Full-Text)

• Study Protocol - Aug 10, 2018
• Statistical Analysis Plan - Jun 13, 2019

More Information

Publications

None provided.

• Responsible Party: Neurocrine Biosciences
• ClinicalTrials.gov Identifier: NCT03319953
• Other Study ID Numbers: TAK-041-2001; U1111-1191-6915; 2017-001084-20; 17/YH/0195; 03319953
• First Posted: Oct 24, 2017
• Last Update Posted: Mar 19, 2021
• Last Verified: Mar 1, 2021

• 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 Neurocrine Biosciences: Drug therapy
• Additional relevant MeSH terms: Anhedonia; Schizophrenia; Antipsychotic Agents

Study Results

Participant Flow

Recruitment Details	Participants took part in the study at single investigative sites in United Kingdom from 21 December 2017 to 06 November 2019.

Arm/Group Title	Treatment Sequence 1: TAK-041 40 mg/Placebo + Antipsychotics	Treatment Sequence 2: Placebo/TAK-041 40 mg + Antipsychotics	Treatment Sequence 3: TAK-041 160 mg/Placebo + Antipsychotics	Treatment Sequence 4: Placebo/TAK-041 160 mg + Antipsychotics
Arm/Group Description	TAK-041 40 milligram (mg), suspension, orally on Day 1 of Treatment Period 1, followed by 35 days wash-out Period, followed by TAK-041 placebo-matching, suspension, orally on Day 1 of Treatment Period 2. All participants received a stable dose of antipsychotics as per standard of care throughout the duration of the Treatment Period.	TAK-041 placebo-matching, suspension, orally on Day 1 of Treatment Period 1, followed by 35 days Wash-out Period, followed by TAK-041 40 mg, suspension, orally on Day 1 of Treatment Period 2. All participants received a stable dose of antipsychotics as per standard of care throughout the duration of the Treatment Period.	TAK-041 160 mg, suspension, orally on Day 1 of Treatment Period 1, followed by 35 days Wash-out Period, followed by TAK-041 placebo-matching, suspension, orally on Day 1 of Treatment Period 2. All participants received stable dose of antipsychotics as per standard of care throughout the duration of the Treatment Period.	TAK-041 placebo-matching, suspension, orally on Day 1 of Treatment Period 1, followed by 35 days Wash-out Period, followed by TAK-041 160 mg, suspension, orally on Day 1 of Treatment Period 2. All participants received stable dose of antipsychotics as per standard of care throughout the duration of the Treatment Period.
Period Title: Period 1 (Day 1 to 14)
STARTED	3	4	9	7
COMPLETED	3	4	9	7
NOT COMPLETED	0	0	0	0
Period Title: Period 1 (Day 1 to 14)
STARTED	3	4	9	7
COMPLETED	3	4	9	7
NOT COMPLETED	0	0	0	0
Period Title: Period 1 (Day 1 to 14)
STARTED	3	4	9	7
Treated	2	4	8	6
COMPLETED	2	4	8	6
NOT COMPLETED	1	0	1	1

Baseline Characteristics

Arm/Group Title	Treatment Sequence 1: TAK-041 40 mg/Placebo + Antipsychotics	Treatment Sequence 2: Placebo/TAK-041 40 mg + Antipsychotics	Treatment Sequence 3: TAK-041 160 mg/Placebo + Antipsychotics	Treatment Sequence 4: Placebo/TAK-041 160 mg + Antipsychotics	Total
Arm/Group Description	TAK-041 40 milligram (mg), suspension, orally on Day 1 of Treatment Period 1, followed by 35 days wash-out Period, followed by TAK-041 placebo-matching, suspension, orally on Day 1 of Treatment Period 2. All participants received a stable dose of antipsychotics as per standard of care throughout the duration of the Treatment Period.	TAK-041 placebo-matching, suspension, orally on Day 1 of Treatment Period 1, followed by 35 days Wash-out Period, followed by TAK-041 40 mg, suspension, orally on Day 1 of Treatment Period 2. All participants received a stable dose of antipsychotics as per standard of care throughout the duration of the Treatment Period.	TAK-041 160 mg, suspension, orally on Day 1 of Treatment Period 1, followed by 35 days Wash-out Period, followed by TAK-041 placebo-matching, suspension, orally on Day 1 of Treatment Period 2. All participants received stable dose of antipsychotics as per standard of care throughout the duration of the Treatment Period.	TAK-041 placebo-matching, suspension, orally on Day 1 of Treatment Period 1, followed by 35 days Wash-out Period, followed by TAK-041 160 mg, suspension, orally on Day 1 of Treatment Period 2. All participants received stable dose of antipsychotics as per standard of care throughout the duration of the Treatment Period.	Total of all reporting groups
Overall Participants	3	4	9	7	23
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	42.0 (16.5)	39.3 (16.1)	46.8 (12.1)	43.4 (9.6)	43.8 (12.1)
Sex: Female, Male (Count of Participants)
Female	0 0%	2 50%	2 22.2%	2 28.6%	6 26.1%
Male	3 100%	2 50%	7 77.8%	5 71.4%	17 73.9%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%	0 0%	0 0%
Not Hispanic or Latino	3 100%	4 100%	9 100%	7 100%	23 100%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	1 11.1%	0 0%	1 4.3%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	3 100%	3 75%	4 44.4%	6 85.7%	16 69.6%
White	0 0%	1 25%	4 44.4%	0 0%	5 21.7%
More than one race	0 0%	0 0%	0 0%	1 14.3%	1 4.3%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in the Brief Assessment of Cognition in Schizophrenia (BACS) Composite Score at Second Testing After TAK-041 Administration
Description	BACS is a reliable and sensitive measure of cognitive function in schizophrenia. The BACS consists of items across six subtests: Verbal Memory, Digit Sequencing, Token Motor, Verbal Fluency, Symbol Coding, and Tower of London. The subtest scale scores were used to compute a composite BACS t-score of 50 (20) is the mean (standard deviation) of a relevant index population. Higher values indicate better performance. Bayesian normal linear model was used for analysis.
Time Frame	Baseline (Day -1) and Day 14

Outcome Measure Data

Analysis Population Description

Pharmacodynamic (PD) Analysis Set included all participants who received at least 1 dose of study drug and had at least 1 evaluable primary or exploratory PD measurement. Number analyzed is the number of participants with data available for analyses.

Arm/Group Title	Placebo	TAK-041 40 mg	TAK-041 160 mg
Arm/Group Description	TAK-041 placebo-matching, suspension, orally on Day 1 of Treatment Period 1 or 2. All participants took a stable dose of antipsychotics as per standard of care throughout the duration of the Treatment Period.	TAK-041 40 mg, suspension, orally on Day 1 of Treatment Period 1 or 2. All participants took a stable dose of antipsychotics as per standard of care throughout the duration of the Treatment Period.	TAK-041 160 mg, suspension, orally on Day 1 of Treatment Period 1 or 2. All participants took a stable dose of antipsychotics as per standard of care throughout the duration of the Treatment Period.
Measure Participants	21	7	15
Baseline	29.72 (12.867)	27.35 (12.753)	27.89 (8.214)
Day 14	2.28 (6.963)	5.35 (6.944)	1.31 (5.618)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-041 40 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2079
	Comments	Bayesian method was used to calculate the posterior probability. High posterior probability of a difference between TAK-041 and placebo >2.0.
	Method	Bayesian Normal Linear Model
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-041 160 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0633
	Comments	Bayesian method was used to calculate the posterior probability. High posterior probability of a difference between TAK-041 and placebo >2.0.
	Method	Bayesian Normal Linear Model
	Comments

2. Primary Outcome

Title	Blood-Oxygen-Level-Dependent (BOLD) Signal in the Average Ventral Striatum (VS) Region of Interest (ROI) Activation in the Monetary Incentive Delay (MID) Reward Task at First Testing After TAK-041 Administration
Description	Blood-oxygen-level-dependent imaging, or BOLD-contrast imaging, is a method used in functional magnetic resonance imaging (fMRI) to observe different areas of the brain or other organs, which are found to be active at any given time. The MID task is a reward anticipation paradigm that robustly engages the VS, a key area associated with coding incentive reward. Dysfunctional processing of reward information is associated with motivational impairments in schizophrenia. Motivational impairment is a key aspect of negative symptoms, and has been associated with reduced activity in the VS. Any change in BOLD signal that comes in fMRI is reported.
Time Frame	Day 1

Outcome Measure Data

Analysis Population Description

PD Analysis Set included all participants who received at least 1 dose of study drug and had at least 1 evaluable primary or exploratory PD measurement. Overall number of participants analyzed is the number of participants with data available for analyses.

Arm/Group Title	Placebo	TAK-041 40 mg	TAK-041 160 mg
Arm/Group Description	TAK-041 placebo-matching, suspension, orally on Day 1 of Treatment Period 1 or 2. All participants took a stable dose of antipsychotics as per standard of care throughout the duration of the Treatment Period.	TAK-041 40 mg, suspension, orally on Day 1 of Treatment Period 1 or 2. All participants took a stable dose of antipsychotics as per standard of care throughout the duration of the Treatment Period.	TAK-041 160 mg, suspension, orally on Day 1 of Treatment Period 1 or 2. All participants took a stable dose of antipsychotics as per standard of care throughout the duration of the Treatment Period.
Measure Participants	20	6	13
Mean (Standard Deviation) [BOLD signal]	0.23 (0.396)	0.23 (0.202)	0.03 (0.458)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-041 40 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1706
	Comments	Bayesian method was used to calculate the posterior probability. High posterior probability of a difference between TAK-041 and placebo >0.09.
	Method	Bayesian Normal Linear Model
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-041 160 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0373
	Comments	Bayesian method was used to calculate the posterior probability. High posterior probability of a difference between TAK-041 and placebo >0.09.
	Method	Bayesian Normal Linear Model
	Comments

3. Secondary Outcome

Title	Percentage of Participants Who Experience at Least One Treatment Emergent Adverse Event (TEAE)
Description	An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. A TEAE is defined as an adverse event with an onset that occurs after receiving study drug.
Time Frame	From the first dose of study drug up to 77 days after last dose of study drug (Up to Day 154)

Outcome Measure Data

Analysis Population Description

Safety analysis set included all participants who were enrolled and received at least 1 dose of study drug.

Arm/Group Title	Placebo	TAK-041 40 mg	TAK-041 160 mg
Arm/Group Description	TAK-041 placebo-matching, suspension, orally on Day 1 of Treatment Period 1 or 2. All participants took a stable dose of antipsychotics as per standard of care throughout the duration of the Treatment Period.	TAK-041 40 mg, suspension, orally on Day 1 of Treatment Period 1 or 2. All participants took a stable dose of antipsychotics as per standard of care throughout the duration of the Treatment Period.	TAK-041 160 mg, suspension, orally on Day 1 of Treatment Period 1 or 2. All participants took a stable dose of antipsychotics as per standard of care throughout the duration of the Treatment Period.
Measure Participants	21	7	15
Number [percentage of participants]	57.1 1903.3%	71.4 1785%	53.3 592.2%

4. Secondary Outcome

Title	Percentage of Participants Who Meet the Markedly Abnormal Criteria for Safety Laboratory Tests at Least Once Post Dose
Description	Clinical Laboratory parameters included tests for chemistry, hematology and urinalysis. Markedly abnormal values during treatment period were categorized as: alanine aminotransferase (ALT)>3.0 U/L*upper limit of normal(ULN),albumin<25 g/L*lower limit of normal(LLN), alkaline phosphatase >3.0 U/L*ULN, aspartate aminotransferase >3.0 U/L*ULN, bilirubin >34.2 umol/L*ULN, calcium <1.75 mmol/L, >2.88 mmol/L, chloride <75 mmol/L, >126 mmol/L, creatinine >177umol/L, gamma glutamyl transferase >3 U/L*ULN, glucose <2.8 mmol/L, >19.4 mmol/L, potassium<3 mmol/L, >6 mmol/L, sodium <130 mmol/L, >150 mmol/L,Urea <130 mmol/L, erythrocytes <0.8*LLN >1.2*ULN, hematocrit <0.8*LLN, >1.2*ULN, hemoglobin <0.8 g/L*LLN, >1.2 g/L*ULN, leukocytes <0.5 (10^9/L)*LLN, >1.5 (10^9/L)*ULN, platelets <75(10^9/L), >600(10^9/L).
Time Frame	From the first dose of study drug up to 77 days after last dose of study drug (Up to Day 154)

Outcome Measure Data

Analysis Population Description

Safety analysis set included all participants who were enrolled and received at least 1 dose of study drug.

Arm/Group Title	Placebo	TAK-041 40 mg	TAK-041 160 mg
Arm/Group Description	TAK-041 placebo-matching, suspension, orally on Day 1 of Treatment Period 1 or 2. All participants took a stable dose of antipsychotics as per standard of care throughout the duration of the Treatment Period.	TAK-041 40 mg, suspension, orally on Day 1 of Treatment Period 1 or 2. All participants took a stable dose of antipsychotics as per standard of care throughout the duration of the Treatment Period.	TAK-041 160 mg, suspension, orally on Day 1 of Treatment Period 1 or 2. All participants took a stable dose of antipsychotics as per standard of care throughout the duration of the Treatment Period.
Measure Participants	21	7	15
Number [percentage of participants]	0 0%	0 0%	0 0%

5. Secondary Outcome

Title	Percentage of Participants Who Meet the Markedly Abnormal Criteria for Vital Sign Measurements At Least Once Post Dose
Description	Vital signs included oral body temperature measurement, supine and standing blood pressure, respiration rate, and pulse. Pulse and blood pressure were measured after 5 minutes supine and again at 1 and 3 minutes after standing. The markedly abnormal value (MAV) criteria for vital signs included systolic blood pressure < 85 mmHg, > 180 mmHg; diastolic blood pressure < 50 mmHg, > 110 mmHg; pulse < 50 beats/min, > 120 beats/min; temperature < 35.6 C > 37.7 C.
Time Frame	From the first dose of study drug up to 77 days after last dose of study drug (Up to Day 154)

Outcome Measure Data

Analysis Population Description

Safety analysis set included all participants who were enrolled and received at least 1 dose of study drug. Only categories with at least one participant are reported.

Arm/Group Title	Placebo	TAK-041 40 mg	TAK-041 160 mg
Arm/Group Description	TAK-041 placebo-matching, suspension, orally on Day 1 of Treatment Period 1 or 2. All participants took a stable dose of antipsychotics as per standard of care throughout the duration of the Treatment Period.	TAK-041 40 mg, suspension, orally on Day 1 of Treatment Period 1 or 2. All participants took a stable dose of antipsychotics as per standard of care throughout the duration of the Treatment Period.	TAK-041 160 mg, suspension, orally on Day 1 of Treatment Period 1 or 2. All participants took a stable dose of antipsychotics as per standard of care throughout the duration of the Treatment Period.
Measure Participants	21	7	15
<35.6 C	0 0%	0 0%	6.7 74.4%
>37.7 C	4.8 160%	0 0%	0 0%

6. Secondary Outcome

Title	Percentage of Participants Who Meet the Markedly Abnormal Criteria for Safety Electrocardiogram (ECG) at Least Once Post Dose
Description	The markedly abnormal value (MAV) criteria for 12-lead ECG parameters included ECG Mean Heart Rate < 50 beats/min, > 120 beats/min; PR Interval, Aggregate <= 80 msec, >= 200 msec; QRS Duration, Aggregate <= 80 msec, >= 180 msec; QTcB Interval, Aggregate <= 300 msec, >= 500 msec OR (>= 30 msec change from baseline and >= 450 msec); QTcF Interval, Aggregate <= 300 msec, >= 500 msec OR (>= 30 msec change from baseline and >= 450 msec).
Time Frame	From the first dose of study drug up to 77 days after last dose of study drug (Up to Day 154)

Outcome Measure Data

Analysis Population Description

Safety analysis set included all participants who were enrolled and received at least 1 dose of study drug. Categories with at least one participant are reported. Number analyzed is the number of participants with data available for analyses.

Arm/Group Title	Placebo	TAK-041 40 mg	TAK-041 160 mg
Arm/Group Description	TAK-041 placebo-matching, suspension, orally on Day 1 of Treatment Period 1 or 2. All participants took a stable dose of antipsychotics as per standard of care throughout the duration of the Treatment Period.	TAK-041 40 mg, suspension, orally on Day 1 of Treatment Period 1 or 2. All participants took a stable dose of antipsychotics as per standard of care throughout the duration of the Treatment Period.	TAK-041 160 mg, suspension, orally on Day 1 of Treatment Period 1 or 2. All participants took a stable dose of antipsychotics as per standard of care throughout the duration of the Treatment Period.
Measure Participants	21	7	15
ECG Mean Heart Rate: <50 beats per minute	0 0%	0 0%	6.7 74.4%
PR Interval: >=200 milliseconds	10.5 350%	20.0 500%	13.3 147.8%
QRS Duration: <=80 milliseconds	36.8 1226.7%	20.0 500%	33.3 370%

7. Secondary Outcome

Title	Number of Participants With Suicidal Ideation or Suicidal Behavior as Measured Using Columbia-Suicide Severity Rating Scale (C-SSRS)
Description	Treatment-emergent suicidal ideation (SI) or suicidal behavior (SB) compared to baseline will be measured by an increase in suicidal ideation category (1-5 on the C-SSRS) or suicidal behavior category (6-10 on the C-SSRS) during treatment from the maximum suicidal ideation/behavior category at baseline, or any suicidal ideation/behavior during treatment if there is none at baseline. C-SSRS is used to assess whether participant experienced suicidal ideation (1: wish to be dead; 2: non-specific active suicidal thoughts; 3: active suicidal ideation with any methods (not plan) without intent to act; 4: active suicidal ideation with some intent to act, without specific plan; 5: active suicidal ideation with specific plan and intent) and suicidal behavior (6: actual attempt; 7: interrupted attempt; 8: aborted attempt; 9: preparatory acts or behavior; 10: suicidal behavior).
Time Frame	Baseline (Day -1) and Days 14, 35 and 77

Outcome Measure Data

Analysis Population Description

Safety analysis set included all participants who were enrolled and received at least 1 dose of study drug. Only categories with at least one participant are reported. Number analyzed is the number of participants with data available for analyses.

Arm/Group Title	Placebo	TAK-041 40 mg	TAK-041 160 mg
Arm/Group Description	TAK-041 placebo-matching, suspension, orally on Day 1 of Treatment Period 1 or 2. All participants took a stable dose of antipsychotics as per standard of care throughout the duration of the Treatment Period.	TAK-041 40 mg, suspension, orally on Day 1 of Treatment Period 1 or 2. All participants took a stable dose of antipsychotics as per standard of care throughout the duration of the Treatment Period.	TAK-041 160 mg, suspension, orally on Day 1 of Treatment Period 1 or 2. All participants took a stable dose of antipsychotics as per standard of care throughout the duration of the Treatment Period.
Measure Participants	21	7	15
SI-Wish to be Dead, Day -1	3 100%	0 0%	1 11.1%
SI-Wish to be Dead, Day 14	1 33.3%	0 0%	0 0%
SI-Wish to be Dead, Day 77	1 33.3%	0 0%	1 11.1%
SB-Non-suicidal Self-injurious Behaviour, Day 77	1 33.3%	0 0%

Adverse Events

Time Frame	From the first dose of study drug up to 77 days after last dose of study drug (Up to Day 154)
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. Safety analysis set included all participants who were enrolled and received at least 1 dose of study drug.
Arm/Group Title	Placebo		TAK-041 40 mg		TAK-041 160 mg
Arm/Group Description	TAK-041 placebo-matching, suspension, orally on Day 1 of Treatment Period 1 or 2. All participants took a stable dose of antipsychotics as per standard of care throughout the duration of the Treatment Period.		TAK-041 40 mg, suspension, orally on Day 1 of Treatment Period 1 or 2. All participants took a stable dose of antipsychotics as per standard of care throughout the duration of the Treatment Period.		TAK-041 160 mg, suspension, orally on Day 1 of Treatment Period 1 or 2. All participants took a stable dose of antipsychotics as per standard of care throughout the duration of the Treatment Period.
All Cause Mortality
	Placebo		TAK-041 40 mg		TAK-041 160 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/21 (0%)		0/7 (0%)		0/15 (0%)
Serious Adverse Events
	Placebo		TAK-041 40 mg		TAK-041 160 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/21 (0%)		0/7 (0%)		0/15 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		TAK-041 40 mg		TAK-041 160 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	12/21 (57.1%)		5/7 (71.4%)		8/15 (53.3%)
Blood and lymphatic system disorders
Neutropenia	2/21 (9.5%)		0/7 (0%)		0/15 (0%)
Gastrointestinal disorders
Vomiting	1/21 (4.8%)		0/7 (0%)		1/15 (6.7%)
Gastrooesophageal Reflux Disease	0/21 (0%)		0/7 (0%)		1/15 (6.7%)
Nausea	1/21 (4.8%)		0/7 (0%)		0/15 (0%)
General disorders
Fatigue	2/21 (9.5%)		0/7 (0%)		1/15 (6.7%)
Chest Pain	1/21 (4.8%)		0/7 (0%)		1/15 (6.7%)
Catheter Site Pain	1/21 (4.8%)		0/7 (0%)		0/15 (0%)
Infections and infestations
Nasopharyngitis	3/21 (14.3%)		1/7 (14.3%)		0/15 (0%)
Upper Respiratory Tract Infection	2/21 (9.5%)		0/7 (0%)		0/15 (0%)
Pharyngitis	0/21 (0%)		0/7 (0%)		1/15 (6.7%)
Injury, poisoning and procedural complications
Fall	0/21 (0%)		0/7 (0%)		1/15 (6.7%)
Muscle Strain	0/21 (0%)		0/7 (0%)		1/15 (6.7%)
Procedural Headache	0/21 (0%)		1/7 (14.3%)		0/15 (0%)
Investigations
Alanine Aminotransferase Increased	0/21 (0%)		0/7 (0%)		1/15 (6.7%)
Aspartate Aminotransferase Increased	0/21 (0%)		0/7 (0%)		1/15 (6.7%)
Lymphocyte Count Decreased	0/21 (0%)		1/7 (14.3%)		0/15 (0%)
Metabolism and nutrition disorders
Hypokalaemia	0/21 (0%)		1/7 (14.3%)		0/15 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/21 (4.8%)		0/7 (0%)		1/15 (6.7%)
Back Pain	0/21 (0%)		1/7 (14.3%)		1/15 (6.7%)
Myalgia	2/21 (9.5%)		0/7 (0%)		0/15 (0%)
Muscle Spasms	1/21 (4.8%)		0/7 (0%)		0/15 (0%)
Neck Pain	0/21 (0%)		0/7 (0%)		1/15 (6.7%)
Nervous system disorders
Headache	2/21 (9.5%)		1/7 (14.3%)		1/15 (6.7%)
Somnolence	1/21 (4.8%)		0/7 (0%)		1/15 (6.7%)
Syncope	0/21 (0%)		0/7 (0%)		1/15 (6.7%)
Psychiatric disorders
Anxiety	1/21 (4.8%)		0/7 (0%)		0/15 (0%)
Insomnia	1/21 (4.8%)		0/7 (0%)		0/15 (0%)
Panic Attack	1/21 (4.8%)		0/7 (0%)		0/15 (0%)
Paranoia	1/21 (4.8%)		0/7 (0%)		0/15 (0%)
Schizophrenia	0/21 (0%)		0/7 (0%)		1/15 (6.7%)
Respiratory, thoracic and mediastinal disorders
Cough	0/21 (0%)		2/7 (28.6%)		0/15 (0%)
Nasal Congestion	1/21 (4.8%)		0/7 (0%)		0/15 (0%)
Oropharyngeal Pain	1/21 (4.8%)		0/7 (0%)		0/15 (0%)
Rhinorrhoea	1/21 (4.8%)		0/7 (0%)		0/15 (0%)
Skin and subcutaneous tissue disorders
Dry Skin	1/21 (4.8%)		0/7 (0%)		0/15 (0%)
Social circumstances
Pregnancy Of Partner	1/21 (4.8%)		0/7 (0%)		0/15 (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.