Schizophrenia
Conditions
Keywords
Drug Therapy
Brief summary
The purpose of this study is to determine whether improvement in P50 (a pharmacodynamic marker) in auditory sensory gating is demonstrated after administration of TAK-058 and ondansetron compared to placebo in participants with schizophrenia.
Detailed description
The drug being tested in this study is called TAK-058. TAK-058 is being tested to evaluate its effects on P50 auditory gating in people who have stable schizophrenia. This study will look at the effect of TAK-058 on P50 auditory gaiting of people with schizophrenia. This study will be performed in a sequential manner progressing from an optimization (screening) phase in healthy volunteers, to screening of subjects with schizophrenia in part 1, to a 3 period crossover treatment phase in part 2. In the screening phase, 15 healthy volunteers will be enrolled to optimize the settings for the measurement of neurophysiological markers prior to any dosing in participants with schizophrenia. If optimization is not reached, the study will be terminated. In part 1 participants with schizophrenia will receive 2 P50 electroencephalography (EEG) sessions. A measurable deficit in auditory P50 gating S2/S1 ratio greater than (\>) 0.5 will be established during this phase. The intraclass correlation coefficient (ICC) will be calculated for the P50 auditory gating S2/S1 ratios collected during the 2 sessions. If these P50 auditory gating S2/S1 ratio measurements are found to have at least a fair level of agreement within individuals (that is, ICC \> 0.5), part 2 of the study will begin. 12 participants demonstrating P50 impairment in part 1, will be randomly assigned (by chance, like flipping a coin) to one of the six treatment crossover sequences -which will remain undisclosed to the patient and study doctor during the study (unless there is an urgent medical need): * Placebo + TAK-058 + Ondansetron * TAK-058 + Placebo + Ondansetron * Ondansetron + Placebo + TAK-058 * Placebo + Ondansetron + TAK-058 * TAK-058 + Ondansetron + Placebo * Ondansetron + TAK-058 + Placebo All participants will be asked to take one dose of capsule, followed 1 hour later by one dose of solution on Day 1 of each intervention period. This single-center trial will be conducted in the United States. The overall time to participate in this study is approximately 118 days. Participants will make be confined to the clinic for 3 days (Day -1 through Day 2 of each period), a final visit for schizophrenic participants in Part 2 after receiving TAK-058, on Day 2 of Period 3 (no final visit for optimization phase healthy participants), and a telephonic follow up assessment 21 days after last dose of study drug.
Interventions
DRUGTAK-058
TAK-058 oral solution.
DRUGOndansetron
Ondansetron capsule.
DRUGTAK-058 Placebo
TAK-058 placebo-matching, solution.
Ondansetron placebo-matching, capsule.
Sponsors
Takeda
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
OTHER
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
Yes
Inclusion criteria
1. 18 to 60 years of healthy and schizophrenic participants, inclusive, at the time of informed consent. 2. Has acceptable clinical laboratory evaluations (including clinical chemistry, hematology and complete urinalysis). 3. Meets schizophrenia criteria as defined by the Diagnostic & Statistical Manual of Mental Disorders, 5th Edition (DSM-V). 4. Are on a stable dose of single second-generation antipsychotics (SGA) for at least 2 months prior to Screening as documented by medical history and assessed by site staff. 5. Demonstrates Positive and Negative Syndrome Scale (PANSS) total score of less than equal to (\<=) 85. 6. Has a P50 ratio of \> 0.5 at both screening assessments.
Exclusion criteria
1. Has a history in the last year or currently receiving treatment with clozapine or olanzapine. 2. Has taken any excluded medications, supplements or food products. 3. Has a history of gastrointestinal disease that would influence the absorption of study drug or have a significant medical history of any disease that would contraindicate the administration of TAK-058, ondansetron, or a similar compound. 4. Has substance abuse or dependence within previous 12 months, unstable mood or anxiety disorder. 5. Has a current diagnosis of a significant psychiatric illness other than schizophrenia per DSM-V and is in an acute phase/episode. 6. Has clinically meaningful hearing loss per investigator's judgment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in P50 Ratio S2/S1 at Central (Cz) Electrode Following Administration of TAK-058 | Part 2: Day 1 pre-dose and at multiple time points (up to 2 hours) post-dose in each period. | Participants were planned to check for P50 gating ratio. Stimulus signal of 90 decibel pulses of 0.1 millisecond (msec) was to be generated and recorded the event-related potential waveforms. 32 pairs of auditory clicks were to be presented every 10 seconds, with a 500 msec interclick interval. S1 is defined as the conditioning P50 wave with the most positive peak between 30 and 90 msec after the conditioning stimulus. S2 is defined as the test P50 wave with the positive peak after the test stimulus that was closest in latency to the conditioning P50. Amplitude is the difference between the positive peak and the preceding negative trough for both waves. The data from the vertex (Cz site) was to be collected and the P50 gating ratio (S2/S1) was to be calculated as the ratio of the test P50 amplitude to the conditioning P50 amplitude. |
Secondary
| Measure | Time frame |
|---|---|
| Percentage of Participants Who Experience at Least One Treatment Emergent Adverse Event (TEAE) | Part 2: Day 1 of Intervention Period 1 up to Day 21 |
Countries
United States
Participant flow
Recruitment details
Participants took part in the study at 1 investigative site in the United States from 09 December 2015 to 29 April 2016.
Pre-assignment details
Participants with a diagnosis of schizophrenia were enrolled in this 2-part study comprised of Part-1, screening and Part-2, treatment phase. Part-2 was not initiated because in Part-1 (sequential step 2), the P50 auditory gating (stimulus\[S\]2/S1) ratio for alpha and beta frequency bands demonstrated high variability and the study was terminated.
Participants by arm
| Arm | Count |
|---|---|
| Part-1: Screening Phase Participants received 2 P50 electroencephalography (EEG) sessions, first session was conducted in the morning, and second session was conducted in the afternoon. Participants did not receive any study medication in Screening Phase (Part-1) of the study. | 11 |
| Total | 11 |
Baseline characteristics
| Characteristic | Part-1: Screening Phase |
|---|---|
| Age, Continuous | 46.5 years STANDARD_DEVIATION 4.63 |
| Body Mass Index (BMI) | 29.93 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 4.929 |
| Caffeine Consumption Consumed Caffeine | 9 participants |
| Caffeine Consumption Did not Consume Caffeine | 2 participants |
| Female Reproductive Status Have Childbearing Potential | 3 participants |
| Female Reproductive Status Not Applicable | 6 participants |
| Female Reproductive Status Postmenopausal | 1 participants |
| Female Reproductive Status Surgically Sterile | 1 participants |
| Height | 170.7 centimeter (cm) STANDARD_DEVIATION 12.39 |
| Race/Ethnicity, Customized Black or African American | 11 participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 11 participants |
| Region of Enrollment United States | 11 participants |
| Sex: Female, Male Female | 5 Participants |
| Sex: Female, Male Male | 6 Participants |
| Smoking Classification Current Smoker | 5 participants |
| Smoking Classification Never Smoked | 6 participants |
| Weight | 87.75 kilogram (kg) STANDARD_DEVIATION 19.351 |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 0 / 0 |
| serious Total, serious adverse events | 0 / 0 |
Outcome results
Primary
Change From Baseline in P50 Ratio S2/S1 at Central (Cz) Electrode Following Administration of TAK-058
Participants were planned to check for P50 gating ratio. Stimulus signal of 90 decibel pulses of 0.1 millisecond (msec) was to be generated and recorded the event-related potential waveforms. 32 pairs of auditory clicks were to be presented every 10 seconds, with a 500 msec interclick interval. S1 is defined as the conditioning P50 wave with the most positive peak between 30 and 90 msec after the conditioning stimulus. S2 is defined as the test P50 wave with the positive peak after the test stimulus that was closest in latency to the conditioning P50. Amplitude is the difference between the positive peak and the preceding negative trough for both waves. The data from the vertex (Cz site) was to be collected and the P50 gating ratio (S2/S1) was to be calculated as the ratio of the test P50 amplitude to the conditioning P50 amplitude.
Time frame: Part 2: Day 1 pre-dose and at multiple time points (up to 2 hours) post-dose in each period.
Population: Part 2 was not initiated because it was not possible to calculate an ICC due to the magnitude of the intrasubject variability in relation to the intersubject variability.
Secondary
Percentage of Participants Who Experience at Least One Treatment Emergent Adverse Event (TEAE)
Time frame: Part 2: Day 1 of Intervention Period 1 up to Day 21
Population: Part 2 was not initiated because it was not possible to calculate an ICC due to the magnitude of the intrasubject variability in relation to the intersubject variability.