Trial Outcomes & Findings for 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 (NCT NCT03319953)

NCT ID: NCT03319953

Last Updated: 2021-03-19

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

23 participants

Primary outcome timeframe

Baseline (Day -1) and Day 14

Results posted on

2021-03-19

Participant Flow

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

Participant milestones

Participant milestones
Measure	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 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.	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.	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.	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.
Period 1 (Day 1 to 14) STARTED	3	4	9	7
Period 1 (Day 1 to 14) COMPLETED	3	4	9	7
Period 1 (Day 1 to 14) NOT COMPLETED	0	0	0	0
Washout Period (Day 15 to 49) STARTED	3	4	9	7
Washout Period (Day 15 to 49) COMPLETED	3	4	9	7
Washout Period (Day 15 to 49) NOT COMPLETED	0	0	0	0
Period 2 (Day 49 to 154) STARTED	3	4	9	7
Period 2 (Day 49 to 154) Treated	2	4	8	6
Period 2 (Day 49 to 154) COMPLETED	2	4	8	6
Period 2 (Day 49 to 154) NOT COMPLETED	1	0	1	1

Reasons for withdrawal

Reasons for withdrawal
Measure	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 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.	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.	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.	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.
Period 2 (Day 49 to 154) Withdrawal by Subject	1	0	0	0
Period 2 (Day 49 to 154) Reason not Specified	0	0	1	1

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Treatment Sequence 1: TAK-041 40 mg/Placebo + Antipsychotics n=3 Participants 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.	Treatment Sequence 2: Placebo/TAK-041 40 mg + Antipsychotics n=4 Participants 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.	Treatment Sequence 3: TAK-041 160 mg/Placebo + Antipsychotics n=9 Participants 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.	Treatment Sequence 4: Placebo/TAK-041 160 mg + Antipsychotics n=7 Participants 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 n=23 Participants Total of all reporting groups
Age, Continuous	42.0 years STANDARD_DEVIATION 16.5 • n=5 Participants	39.3 years STANDARD_DEVIATION 16.1 • n=7 Participants	46.8 years STANDARD_DEVIATION 12.1 • n=5 Participants	43.4 years STANDARD_DEVIATION 9.6 • n=4 Participants	43.8 years STANDARD_DEVIATION 12.1 • n=21 Participants
Sex: Female, Male Female	0 Participants n=5 Participants	2 Participants n=7 Participants	2 Participants n=5 Participants	2 Participants n=4 Participants	6 Participants n=21 Participants
Sex: Female, Male Male	3 Participants n=5 Participants	2 Participants n=7 Participants	7 Participants n=5 Participants	5 Participants n=4 Participants	17 Participants n=21 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	3 Participants n=5 Participants	4 Participants n=7 Participants	9 Participants n=5 Participants	7 Participants n=4 Participants	23 Participants n=21 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	0 Participants n=4 Participants	1 Participants n=21 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Black or African American	3 Participants n=5 Participants	3 Participants n=7 Participants	4 Participants n=5 Participants	6 Participants n=4 Participants	16 Participants n=21 Participants
Race (NIH/OMB) White	0 Participants n=5 Participants	1 Participants n=7 Participants	4 Participants n=5 Participants	0 Participants n=4 Participants	5 Participants n=21 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants	1 Participants n=21 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Placebo n=21 Participants 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 n=7 Participants 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 n=15 Participants 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.
Change From Baseline in the Brief Assessment of Cognition in Schizophrenia (BACS) Composite Score at Second Testing After TAK-041 Administration Day 14	2.28 t-scale Standard Deviation 6.963	5.35 t-scale Standard Deviation 6.944	1.31 t-scale Standard Deviation 5.618
Change From Baseline in the Brief Assessment of Cognition in Schizophrenia (BACS) Composite Score at Second Testing After TAK-041 Administration Baseline	29.72 t-scale Standard Deviation 12.867	27.35 t-scale Standard Deviation 12.753	27.89 t-scale Standard Deviation 8.214

PRIMARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Placebo n=20 Participants 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 n=6 Participants 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 n=13 Participants 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.
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	0.23 BOLD signal Standard Deviation 0.396	0.23 BOLD signal Standard Deviation 0.202	0.03 BOLD signal Standard Deviation 0.458

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Placebo n=21 Participants 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 n=7 Participants 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 n=15 Participants 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.
Percentage of Participants Who Experience at Least One Treatment Emergent Adverse Event (TEAE)	57.1 percentage of participants	71.4 percentage of participants	53.3 percentage of participants

SECONDARY outcome

Timeframe: 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.

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).

Outcome measures

Outcome measures
Measure	Placebo n=21 Participants 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 n=7 Participants 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 n=15 Participants 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.
Percentage of Participants Who Meet the Markedly Abnormal Criteria for Safety Laboratory Tests at Least Once Post Dose	0 percentage of participants	0 percentage of participants	0 percentage of participants

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Placebo n=21 Participants 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 n=7 Participants 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 n=15 Participants 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.
Percentage of Participants Who Meet the Markedly Abnormal Criteria for Vital Sign Measurements At Least Once Post Dose <35.6 C	0 percentage of participants	0 percentage of participants	6.7 percentage of participants
Percentage of Participants Who Meet the Markedly Abnormal Criteria for Vital Sign Measurements At Least Once Post Dose >37.7 C	4.8 percentage of participants	0 percentage of participants	0 percentage of participants

SECONDARY outcome

Timeframe: 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.

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).

Outcome measures

Outcome measures
Measure	Placebo n=21 Participants 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 n=7 Participants 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 n=15 Participants 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.
Percentage of Participants Who Meet the Markedly Abnormal Criteria for Safety Electrocardiogram (ECG) at Least Once Post Dose PR Interval: >=200 milliseconds	10.5 percentage of participants	20.0 percentage of participants	13.3 percentage of participants
Percentage of Participants Who Meet the Markedly Abnormal Criteria for Safety Electrocardiogram (ECG) at Least Once Post Dose QRS Duration: <=80 milliseconds	36.8 percentage of participants	20.0 percentage of participants	33.3 percentage of participants
Percentage of Participants Who Meet the Markedly Abnormal Criteria for Safety Electrocardiogram (ECG) at Least Once Post Dose ECG Mean Heart Rate: <50 beats per minute	0 percentage of participants	0 percentage of participants	6.7 percentage of participants

SECONDARY outcome

Timeframe: 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.

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).

Outcome measures

Outcome measures
Measure	Placebo n=21 Participants 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 n=7 Participants 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 n=15 Participants 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.
Number of Participants With Suicidal Ideation or Suicidal Behavior as Measured Using Columbia-Suicide Severity Rating Scale (C-SSRS) SI-Wish to be Dead, Day -1	3 Participants	0 Participants	1 Participants
Number of Participants With Suicidal Ideation or Suicidal Behavior as Measured Using Columbia-Suicide Severity Rating Scale (C-SSRS) SI-Wish to be Dead, Day 14	1 Participants	0 Participants	0 Participants
Number of Participants With Suicidal Ideation or Suicidal Behavior as Measured Using Columbia-Suicide Severity Rating Scale (C-SSRS) SI-Wish to be Dead, Day 77	1 Participants	0 Participants	1 Participants
Number of Participants With Suicidal Ideation or Suicidal Behavior as Measured Using Columbia-Suicide Severity Rating Scale (C-SSRS) SB-Non-suicidal Self-injurious Behaviour, Day 77	—	1 Participants	0 Participants

Adverse Events

Placebo

Serious events: 0 serious events

Other events: 12 other events

Deaths: 0 deaths

TAK-041 40 mg

Serious events: 0 serious events

Other events: 5 other events

Deaths: 0 deaths

TAK-041 160 mg

Serious events: 0 serious events

Other events: 8 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Additional Information

Medical Director

Takeda

Phone: +1-877-825-3327

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee 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.
Publication restrictions are in place

Restriction type: OTHER