Monotherapy Brexpiprazole (OPC-34712) Trial in the Treatment of Adults With Schizophrenia With Impulsivity

To evaluate the effect of brexpiprazole on brain regions activated by impulsive behavior (specifically, activation of the right VLPFC). Assessed by fMRI measurements taken when participants perform tasks designed to assess impulsivity. The tasks to be performed in the scanner included the Go/No-go. Participants were asked to press a button as fast as they could to Stimulus A (eg, neutral face) that appeared on the screen (Go trials) & to NOT press a button to Stimulus B (eg, happy face) that appeared on the screen (No-go trials). The Go trials were presented at a higher frequency (eg, 75% of the time) than the No-go trials to build up a pre-potent response/response bias. Scores were not bounded by a minimum or maximum range, higher fMRI BOLD activation scores indicate increased brain blood flow, which reflects brain activity.

Time frame: At baseline (Day 0), and week 6 (Day 42) of the treatment phase

Population: All participants who had a valid baseline and a Week 6 fMRI scan assessment.

To evaluate the effect of brexpiprazole on brain regions activated by impulsive behavior (specifically, activation of the right VLPFC). Assessed by fMRI measurements taken when participants performed impulsivity assessment tasks. A white circle was shown for 500ms, followed by a left (\<)/right (\>) arrow. When an arrow was presented, participants responded as fast as possible with their index/middle finger. A titration procedure with 4 staircases started with stop signal delay (SSD) values of 100, 150, 200 & 250ms to determine participant's SSRT. The tasks included 3 runs with 166 repetition times (TRs), TR=2s; 5 minutes, 32 seconds/run; 96 go trials, 32 stop trials/ run. The total task duration was 16 minutes & 36 seconds. Scores were not bounded by a minimum or maximum range, higher fMRI BOLD activation scores indicate increased brain blood flow, which reflects brain activity.

Time frame: At baseline (Day 0), and week 6 (Day 42) of the treatment phase

Population: All participants who had a valid baseline and a valid Week 3 or Week 6 fMRI scan assessment.

To assess whether the total improvement was entirely due to drug treatment. The rater or investigator's response choices included: 0 = not assessed, 1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much worse, and 7 = very much worse. The response at a given week was compared to the participant's condition at baseline (last available measurement at the baseline/Day 0 visit before the first dose of IMP).

Time frame: During trial visits from Day 0 to Week 3 (Day 21).

Population: All participants who took at least one dose of brexpiprazole and who had a valid baseline assessment and at least one valid postbaseline efficacy assessment.

A participant-rated scale was used to assess impulsive personality traits. The BIS-11 consisted of 30 items scored on a 4-point scale ranging from 1 (rarely/never) to 4 (almost always/ always) and the scores were used to assess 6 first-order factors (attention, motor, self-control, cognitive complexity, perseverance and cognitive instability impulsiveness) and 3 second-order factors ( motor impulsiveness, nonplanning impulsiveness and attentional impulsiveness). The total score ranged from 30 to 120 with higher scores indicating impulsive personality traits, and took 10 to 15 minutes to complete the BIS-11.

Time frame: At baseline (Day 0), and Week 3 (Day 21) of the treatment.

Population: All participants who took at least one dose of brexpiprazole and who had a valid baseline assessment and at least one valid postbaseline efficacy assessment. All participants who had a valid baseline and a valid Week 3 or Week 6 fMRI scan assessment.

The severity of illness for each participant was assessed. The rater or investigator's response choices included: 0 = not assessed; 1 = normal, not at all ill; 2 = borderline mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; and 7 = among the most extremely ill participants.

Time frame: During trial visits from Day 0 to Week 3 (Day 21).

Population: All participants who took at least one dose of brexpiprazole and who had a valid baseline assessment and at least one valid postbaseline efficacy assessment.

The AX trials were target trials with a valid cue followed by a valid probe X. This feature was intended to encourage participants to expect a valid probe to follow a valid cue. A consequence of this manipulation was that participants developed a prepotency to respond with target responses on trials for which valid cues were presented. The cue was presented for 1000msec, the inter-stimulus interval was 2000msec, and the target was presented for 500msec with a response window of 1500msec. The ITI was 1200msec. Participants had to practice until criteria were obtained. In the AX-CPT task, the subjects were instructed to press the Yes button every time there is a blue letter 'X' (target) following a white letter 'A' (cue). During this task, any letter appears on the screen randomly. The value calculated was the rate of correct response for all the reaction of target trial.

Time frame: During trial visits from Day 0 to Week 3 (Day 21).

Population: All participants who took at least one dose of brexpiprazole and who had a valid baseline assessment and at least one valid postbaseline efficacy assessment.

Go/No-go: Participants were to press button fast to Stimulus A (neutral face) (Go trials) & to NOT press button to Stimulus B (happy face) (No-go trials). Task comprised 4 runs of 3 minutes & 8 seconds each. Each run included 36 target (Go) & 13 non target (No-go) stimuli. The stimuli were presented for 500ms with 2 to 14.5 inter-stimulus interval fixation cross in between. Target stimuli were pseudo-randomized across runs so that each participant was presented with 2 Happy Go & 2 Neutral Go conditions. SSRT: White circle was shown for 500ms, followed by left (\<)/right (\>) arrow. When an arrow was presented, participants were to respond fast with their index/middle finger. A titration procedure with 4 staircases that started with stop signal delay (SSD) values of 100, 150, 200 & 250ms determined participant's SSRT. Scores were not bounded by a minimum or maximum range, higher fMRI BOLD activation scores indicate increased brain blood flow, which reflects brain activity.

Time frame: At baseline (Day 0), and week 3 (Day 21) of the treatment phase

Population: All participants who had a valid baseline and a valid Week 3 fMRI scan assessment

Brexpiprazole reduced impulsivity was measured by a change in false alarm rate on the Go/No-go task (a lower false alarm rate was suggestive of better inhibition). Participants were instructed to press a button as fast as they could to Stimulus A (eg, neutral face) that appeared on the screen (Go trials) and to NOT press a button to Stimulus B (eg, happy face) that appeared on the screen (No-go trials). The stimuli were presented randomly. The value calculated was the rate of incorrect response for each condition (Go and No-go).

Time frame: At baseline (Day 0), and week 3 (Day 21) of the treatment phase

Population: All participants who took at least one dose of brexpiprazole and who had a valid baseline assessment and at least one valid postbaseline efficacy assessment.

To measure delay discounting as an index of impulsive behavior. It measured the extent to which the value of a reward decreased as the delay to obtaining that reward increased. The propensity of participants to delay reward was assessed with an MCQ. Discounting rate is estimated using, k= (A/V)1/D, where k is the discounting rate parameter, V is the immediate reward, A is the higher delayed reward and D is the amount of days to the delayed reward. The MCQ consisted of 27 choices between immediate and delayed rewards. The participants chose repeatedly between 2 hypothetical sums of money: a smaller amount now or a larger amount in the future (ex: ''Would you prefer $27 today or $50 in 21 days?). The answers provided an estimate of the participant's discounting rate. The discounting rate parameter takes values between 0 and 1 and higher discounting rates indicated impulsivity.

Time frame: During trial visits from Day 0 to Week 3 (Day 21).

Population: All participants who took at least one dose of brexpiprazole and who had a valid baseline assessment and at least one valid postbaseline efficacy assessment.

PANSS consisted of negative subscale with 7 symptom constructs (blunted affect, emotional withdrawal, poor rapport, passive/apathetic social withdrawal, difficulty in abstract thinking, lack of spontaneity and flow of conversation, and stereotyped thinking). Each item was scored using a scale of 1 to 7 (a higher score indicated increased severity). The maximum subscale score was 49; 7 indicated no symptoms; 49 indicated extreme severity.

Time frame: During trial visits from Day 0 to Week 3 (Day 21).

Population: All participants who took at least one dose of brexpiprazole and who had a valid baseline assessment and at least one valid postbaseline efficacy assessment.

PANSS consisted of positive subscales with 7 symptom constructs (delusions, conceptual disorganization, hallucinatory behavior, excitement, grandiosity, suspiciousness/persecution, and hostility). Each item was scored using a scale of 1 to 7 (a higher score indicated increased severity). The maximum subscale score was 49; 7 indicated no symptoms; 49 indicated extreme severity.

Time frame: During trial visits from Day 0 to Week 3 (Day 21).

Population: All participants who took at least one dose of brexpiprazole and who had a valid baseline assessment and at least one valid postbaseline efficacy assessment.

The PANSS consisted of 3 subscales containing 30 symptom constructs. For each symptom construct, severity was rated on a 7-point scale, with a score of 1 indicating the absence of symptoms and a score of 7 indicating extremely severe symptoms. PANSS Positive and Negative subscale scores symptom constructs consisted of positive subscale (7 positive symptom constructs), negative subscale (7 negative symptom constructs), and general psychopathology subscale (16 symptom constructs). The possible maximum PANSS total score was 210; 30 indicating no symptoms; 210 indicating extremely severe symptoms.

Time frame: During trial visits from Day 0 to Week 3 (Day 21).

Population: All participants who took at least one dose of brexpiprazole and who had a valid baseline assessment and at least one valid postbaseline efficacy assessment

Brexpiprazole reduced impulsivity was measured by a change in Stop Signal Reaction Time (SSRT) on the SSRT task (a lower SSRT was suggestive of better inhibition). A white circle was shown for 500ms, followed by a left (\<)/right (\>) arrow. When an arrow was presented, participants responded as fast as possible with their index/middle finger. A titration procedure with 4 staircases started with stop signal delay (SSD) values of 100, 150, 200 & 250ms to determine participant's SSRT. The tasks included 3 runs with 166 repetition times (TRs), TR=2s; 5 minutes, 32 seconds/run; 96 go trials, 32 stop trials/ run. The total task duration was 16 minutes & 36 seconds. During scanning, the SSD was dynamically adjusted to yield a 50% successful inhibition rate, so that SSRT could be estimated for each participant. This resulted in approximately equal proportions of stop trials with & without a response

Time frame: During trial visits from Day 0 to Week 3 (Day 21).

Population: All participants who had a valid baseline and a valid Week 3 fMRI scan assessment

A participant-rated scale was used to assess impulsive personality traits. The BIS-11 consisted of 30 items scored on a 4-point scale ranging from 1 (rarely/never) to 4 (almost always/ always) and the scores were used to assess 6 first-order factors (attention, motor, self-control, cognitive complexity, perseverance and cognitive instability impulsiveness) and 3 second-order factors ( motor impulsiveness, nonplanning impulsiveness and attentional impulsiveness). The total score ranged from 30 to 120 with higher scores indicating impulsive personality traits, and took 10 to 15 minutes to complete the BIS-11.

Time frame: At baseline (Day 0), and Week 6 (Day 42) of the treatment.

Population: The full analysis set consisted of all participants who took at least one dose of brexpiprazole and who had a valid baseline assessment and at least one valid postbaseline efficacy assessment. Change from baseline data were presented for participant count of 16, 12 for 2mg and 4mg arms, respectively.

The severity of illness for each participant was assessed. The rater or investigator's response choices included: 0 = not assessed; 1 = normal, not at all ill; 2 = borderline mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; and 7 = among the most extremely ill participants.

Time frame: During trial visits from Day 0 to Week 6 (Day 42).

Population: All participants who took at least one dose of brexpiprazole and who had a valid baseline assessment and at least one valid postbaseline efficacy assessment.

The AX trials were target trials with a valid cue followed by a valid probe X. This feature was intended to encourage participants to expect a valid probe to follow a valid cue. A consequence of this manipulation was that participants developed a prepotency to respond with target responses on trials for which valid cues were presented. The cue was presented for 1000msec, the inter-stimulus interval was 2000msec, and the target was presented for 500msec with a response window of 1500msec. The ITI was 1200msec. Participants had to practice until criteria were obtained. In the AX-CPT task, the subjects were instructed to press the Yes button every time there is a blue letter 'X' (target) following a white letter 'A' (cue). During this task, any letter appears on the screen randomly. The value calculated was the rate of correct response for all the reaction of target trial.

Time frame: During trial visits from Day 0 to Week 6 (Day 42).

Population: All participants who took at least one dose of brexpiprazole and who had a valid baseline assessment and at least one valid postbaseline efficacy assessment

Brexpiprazole reduced impulsivity was measured by a change in false alarm rate on the Go/No-go task (a lower false alarm rate was suggestive of better inhibition). Participants were instructed to press a button as fast as they could to Stimulus A (eg, neutral face) that appeared on the screen (Go trials) and to NOT press a button to Stimulus B (eg, happy face) that appeared on the screen (No-go trials). The stimuli were presented randomly. The value calculated was the rate of incorrect response for each condition (Go and No-go).

Time frame: At baseline (Day 0), week 6 (Day 42) of the treatment phase

Population: All participants who took at least one dose of brexpiprazole and who had a valid baseline assessment and at least one valid postbaseline efficacy assessment.

To measure delay discounting as an index of impulsive behavior. It measured the extent to which the value of a reward decreased as the delay to obtaining that reward increased. The propensity of participants to delay reward was assessed with an MCQ. Discounting rate is estimated using, k= (A/V)1/D, where k is the discounting rate parameter, V is the immediate reward, A is the higher delayed reward and D is the amount of days to the delayed reward. The MCQ consisted of 27 choices between immediate and delayed rewards. The participants chose repeatedly between 2 hypothetical sums of money: a smaller amount now or a larger amount in the future (ex: ''Would you prefer $27 today or $50 in 21 days?). The answers provided an estimate of the participant's discounting rate. The discounting rate parameter takes values between 0 and 1 and higher discounting rates indicated impulsivity. It took 5 to10 minutes to complete the MCQ

Time frame: During trial visits from Day 0 to Week 6 (Day 42).

Population: All participants who took at least one dose of brexpiprazole and who had a valid baseline assessment and at least one valid postbaseline efficacy assessment.

PANSS consisted of negative subscale with 7 symptom constructs (blunted affect, emotional withdrawal, poor rapport, passive/apathetic social withdrawal, difficulty in abstract thinking, lack of spontaneity and flow of conversation, and stereotyped thinking). Each item was scored using a scale of 1 to 7 (a higher score indicated increased severity). The maximum subscale score was 49; 7 indicated no symptoms; 49 indicated extreme severity.

Time frame: During trial visits from Day 0 to Week 6 (Day 42).

Population: All participants who took at least one dose of brexpiprazole and who had a valid baseline assessment and at least one valid postbaseline efficacy assessment

PANSS consisted of positive subscales with 7 symptom constructs (delusions, conceptual disorganization, hallucinatory behavior, excitement, grandiosity, suspiciousness/persecution, and hostility). Each item was scored using a scale of 1 to 7 (a higher score indicated increased severity). The maximum subscale score was 49; 7 indicated no symptoms; 49 indicated extreme severity.

Time frame: During trial visits from Day 0 to Week 6 (Day 42).

Population: All participants who took at least one dose of brexpiprazole and who had a valid baseline assessment and at least one valid postbaseline efficacy assessment.

A validated clinician-rated scale that measured personal and social functioning in 4 domains: socially useful activities (eg, work and study), personal and social relationships, self-care, and disturbing and aggressive behaviors. Impairment was rated as absent, mild, manifest, marked, severe, or very severe and were converted to a total score on a 100-point scale: 71 to 100 - mild functional difficulty, 31 to 70 - manifest disabilities of various degrees and 1 to 30 - minimal functioning that required intense support and/or supervision.

Time frame: During trial visits from Day 0 to Week 6 (Day 42).

Population: All participants who took at least one dose of brexpiprazole and who had a valid baseline assessment and at least one valid postbaseline efficacy assessment

The PANSS consisted of 3 subscales containing 30 symptom constructs. For each symptom construct, severity was rated on a 7-point scale, with a score of 1 indicating the absence of symptoms and a score of 7 indicating extremely severe symptoms. PANSS Positive and Negative subscale scores symptom constructs consisted of positive subscale (7 positive symptom constructs), negative subscale (7 negative symptom constructs), and general psychopathology subscale (16 symptom constructs). The possible maximum PANSS total score was 210; 30 indicating no symptoms; 210 indicating extremely severe symptoms.

Time frame: During trial visits from Day 0 to Week 6 (Day 42).

Population: All participants who took at least one dose of brexpiprazole and who had a valid baseline assessment and at least one valid postbaseline efficacy assessment

Brexpiprazole reduced impulsivity was measured by a change in Stop Signal Reaction Time (SSRT) on the SSRT task (a lower SSRT was suggestive of better inhibition). A white circle was shown for 500ms, followed by a left (\<)/right (\>) arrow. When an arrow was presented, participants responded as fast as possible with their index/middle finger. A titration procedure with 4 staircases started with stop signal delay (SSD) values of 100, 150, 200 & 250ms to determine participant's SSRT. The tasks included 3 runs with 166 repetition times (TRs), TR=2s; 5 minutes, 32 seconds/run; 96 go trials, 32 stop trials/ run. The total task duration was 16 minutes & 36 seconds. During scanning, the SSD was dynamically adjusted to yield a 50% successful inhibition rate, so that SSRT could be estimated for each participant. This resulted in approximately equal proportions of stop trials with & without a response

Time frame: At baseline (Day 0), and Week 6 (Day 42).

Population: All participants who had a valid baseline and a valid Week 6 fMRI scan assessment

To assess whether the total improvement was entirely due to drug treatment. The rater or investigator's response choices included: 0 = not assessed, 1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much worse, and 7 = very much worse. The response at a given week was compared to the participant's condition at baseline (last available measurement at the baseline/Day 0 visit before the first dose of IMP).

Time frame: During trial visits from Day 0 to Week 6 (Day 42).

Population: All participants who took at least one dose of brexpiprazole and who had a valid baseline assessment and at least one valid postbaseline efficacy assessment.