New Research Study Focused on New Medication for Schizophrenia:
A Study to Evaluate Efficacy, Tolerability, Pharmacodynamic and Pharmacokinetics of Multiple Oral Doses of TAK-831 in Adults With Schizophrenia
Primary Outcome Measures:
Average Percentage of Conditioned Responses During the Eye Blink Conditioning (EBC) Test [ Time Frame: Day 7: For each treatment period ]
EBC is a method used to investigate cerebellar function. In EBC, a conditioned stimulus (CS), a tone precedes but co-terminates with an unconditioned stimulus (US), an airpuff to the eyelid. Learning is demonstrated when an eyeblink (the conditioned response [CR]) occurs prior to the onset of the US. The percentage can range from 0% (no conditioned learning has occurred) to 100% (all responses are conditioned).
Secondary Outcome Measures:
Mean Computed Probability that the Pattern of Functional Magnetic Resonance (fMRI) Blood Oxygen Level-dependent (BOLD) Activation During the Task Set Switching (TSS) Paradigm came from a Participant Receiving add-on TAK-831 Treatment at that Time [ Time Frame: Day 7: For each treatment period ]
TSS Paradigm will assess the effect of TAK-831 on brain function during the performance of an executive function task, which is known to be impaired in schizophrenia. Participants with schizophrenia have lower activity in multiple brain regions and a higher rate of error compared to controls in a task such as TSS which requires shifting of attention to a new but previously irrelevant stimulus, and in some versions reconfiguring responses to the stimuli. It will be performed by functional magnetic resonance imaging (fMRI).
Mean fMRI BOLD Signal in the Ventral Striatum During the Anticipation Period of Reward Trials versus the Anticipation Period of the Neutral Trials of the Monetary Incentive Delay (MID) Task [ Time Frame: Day 7: For each treatment period ]
The MID task is a reward anticipation paradigm that robustly engage the ventral striatum, 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 ventral striatum. In the MID task, participants are instructed to respond as quickly as possible to a light-flash on display screen. The flash is preceded by an icon that informed participants about consequences of their response. Two conditions are included in paradigm, as follows: 1) Win condition: The participant will win a financial reward if response is sufficiently fast. 2) Passive control condition: No response is required.
Mean Mismatch negativity (MMN) [ Time Frame: Day 8: For each treatment period ]
MMN is an event related potential (ERP) evoked in response to unattended changes in background stimulation. MMN reflects an automatic process of detecting a mismatch between a deviant stimulus and a sensory-memory trace. Smaller amplitudes of MMN have been consistently identified in schizophrenia participants. MMN amplitude will be measured at Midline frontal electrode (Fz) of electroencephalogram [EEG].
Mean P300 Amplitude [ Time Frame: Day 8: For each treatment period ]
The P300 wave is an ERP component that is elicited by the presentation of a novel, behaviorally relevant target stimulus embedded among irrelevant stimuli in a manner similar to MMN, but requiring active listening and responding from participants. Auditory stimuli are presented in an oddball paradigm consisting of 1 standard tone and 1 target tone. Participants are instructed to push a button as quickly as possible when they hear the target tone, but not when they hear the standard tone. P300 reflects allocation of attention and activation of immediate memory. P300 amplitude indexes brain actions when the mental representation of the stimulus environment is updated, while P300 latency indexes stimulus classification speed unrelated to response selection processes. P300 amplitude will be measured at midline parietal electrode (Pz) of EEG.
Mean Auditory Steady State Response (ASSR) to 40 Hz stimulation [ Time Frame: Day 8: For each treatment period ]
ASSR are evoked oscillatory responses that are entrained to the frequency and phase of temporally modulated stimuli. Individuals with schizophrenia experience subjective sensory anomalies and objective deficits on assessment of sensory function. These deficits can be produced by abnormal signaling in the sensory pathways and sensory cortex or by later-stage disturbances in the cognitive processing of such inputs. ASSR can be used to assess the integrity of sensory pathways including cortical processing. ASSR will be measured at midline central electrode (Cz) of EEG.
Mean Cerebellar blood flow (CBF) [ Time Frame: Day 7: For each treatment period ]
ASL evaluates effects of drug on blood flow to cerebellar grey matter. CBF will be measured using arterial spin labelling (ASL) in cerebellar grey matter. ASL perfusion is a functional MRI technique which allows quantification of tissue blood flow without the use of an exogenous contrast agent. ASL is performed while a subject is lying quietly in the scanner in the absence of any activity.
Mean Cognitive Battery Composite Score [ Time Frame: Day 8: For each treatment period ]
The neurocognitive test battery includes Continuous Performance Testing, Visual Memory Testing, Verbal Memory Testing, Symbol-Digit Decoding Testing, Shifting Attention Testing, Stroop Test, and Finger Tapping Test. These tests measure how well one perform in five major domains- Memory, Psychomotor Speed, Reaction Time, Complex Attention and Cognitive Flexibility. The primary measure from each cognitive battery test is standardized by creating z-scores whereby the mean of the test session of a healthy participant is set to 0 and the standard deviation set to 1. A composite score is calculated by averaging all 6 standardized primary measures from the cognitive battery, and then calculating a z-score of the composite. The composite z-score indicates how much higher or lower the participant’s cognition is compared to a healthy person.
Mean Concentration of Plasma D-serine and L-serine Levels [ Time Frame: Day 1, 2, 7 and 8: For each treatment period ]
Mean Plasma D-serine to Total Serine Ratio [ Time Frame: Day 1, 2, 7, 8: For each treatment period ]
Mean Plasma Concentration of TAK-831 [ Time Frame: Day 1, 2, 7, 8: For each treatment period ]
Percentage of Participants who Experience at Least 1 Treatment-Emergent Adverse Event (TEAE) [ Time Frame: Within 30 Days after Study Drug ]
An AE is defined as any untoward medical occurrence in a clinical investigation subject who has signed informed consent to participate in a study; it does not necessarily have to have a causal relationship with the treatment.
The drug being tested in this study is called TAK-831. TAK-831 is being tested to treat people with schizophrenia.
The study will enroll approximately 32 patients. Participants will be randomly assigned 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):
TAK-831 500 mg followed by matching placebo
Matching placebo followed by TAK-831 50 mg
The first 16 participants will receive TAK-831 500 mg during the treatment period in which they are assigned to TAK-831. Following an interim analysis, there will be a study-wide decision about whether to treat the additional 16 participants with TAK-831 500 mg during the active treatment period to or treat them with TAK-831 50 mg during this period. After the interim analysis, the participant and study doctor will not be aware of which TAK-831 dose is being used.
This single center trial will be conducted in United Kingdom. The overall time to participate in this study is approximately 81 days. Participants will make multiple visits to the clinic. Each treatment will be administered for a period of 8 consecutive days, separated by a 14 to 21-day washout. After the second treatment period, a final follow-up safety assessment visit will be conducted approximately 10 to 14 days after the last administration of study drug.