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

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

Population: 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.

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

Population: 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.

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

Population: 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.

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)

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

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)

Population: 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.

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)

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

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)

Population: 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.