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| ID | Type | Description | Link |
|---|---|---|---|
| 2017-001739-38 | EudraCT Number | ||
| U1111-1197-9766 | Other Identifier | World Health Organization | |
| 17/YH/0196 | Registry Identifier | NRES |
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| Name | Class |
|---|---|
| Takeda | INDUSTRY |
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The purpose of this study is to determine whether luvadaxistat is superior to placebo in improving cerebellar function as measured with the average percentage of conditioned responses during the eyeblink conditioning (EBC) test.
The drug being tested in this study is called luvadaxistat. Luvadaxistat is being tested to treat people with schizophrenia.
Participants will be randomly assigned to one of the two treatment sequences which will remain undisclosed to the participant and study doctor during the study (unless there is an urgent medical need):
Participants will receive luvadaxistat 500 mg during the treatment period in which they are assigned to luvadaxistat. Following an interim analysis, there will be a study-wide decision about whether to treat the additional participants with luvadaxistat 500 mg during the active treatment period to or treat them with luvadaxistat 50 mg during this period. After the interim analysis, the participant and study doctor will not be aware of which luvadaxistat dose is being used.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Luvadaxistat 500 mg, then Placebo | Experimental | Participants first received luvadaxistat 500 mg orally once daily (QD) for 8 days during treatment period 1. After a washout of 14 to 21 days, participants then received matching placebo orally QD for 8 days during treatment period 2. |
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| Placebo, then Luvadaxistat 500 mg | Experimental | Participants first received matching placebo orally QD for 8 days during treatment period 1. After a washout of 14 to 21 days, participants then received luvadaxistat 500 mg orally QD for 8 days during treatment period 2. |
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| Luvadaxistat 50 mg, then Placebo | Experimental | Participants first received luvadaxistat 50 mg orally QD for 8 days during treatment period 1. After a washout of 14 to 21 days, participants then received matching placebo orally QD for 8 days during treatment period 2. |
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| Placebo, then Luvadaxistat 50 mg | Experimental | Participants first received matching placebo orally QD for 8 days during treatment period 1. After a washout of 14 to 21 days, participants then received luvadaxistat 50 mg orally QD for 8 days during treatment period 2. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Luvadaxistat | Drug | TAK-831 Tablets. |
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| Measure | Description | Time Frame |
|---|---|---|
| Change From Baseline in Average Percent of Conditioned Responses During the Eye Blink Conditioning (EBC) Test at Day 8 | EBC is a method used to investigate cerebellar-dependent learning. In EBC, a conditioned stimulus, a tone precedes but co-terminates with an unconditioned stimulus, an airpuff to the eyelid. Learning is demonstrated when an eyeblink (the conditioned response) occurs prior to the onset of the unconditioned stimulus. The percentage can range from 0% (no conditioned learning has occurred) to 100% (all responses are conditioned). Results are reported as least squares (LS) means at Day 8, determined using an analysis of variance (ANOVA). | Baseline, Day 8 of each treatment period |
| Measure | Description | Time Frame |
|---|---|---|
| Change From Baseline in the Mean Mismatch Negativity (MMN) at Day 8 | 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 was measured at midline frontal electrode (Fz) of electroencephalogram (EEG). Baseline was defined as the last observation prior to the dose of study treatment in the corresponding period. Results are reported as LS mean change from baseline at Day 8, determined using an ANOVA. |
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Inclusion Criteria:
Exclusion Criteria:
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| CBH Health, LLC | Gaithersburg | Maryland | 20877 | United States |
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This 2-period cross-over study assessed the pharmacodynamic (PD) effects, safety, tolerability and pharmacokinetics (PK) of multiple oral doses of luvadaxistat given once daily (QD) in adult participants with schizophrenia. Effects of 2 dose levels of luvadaxistat (500 milligrams [mg] and 50 mg) or placebo were assessed.
Participants took part in the study at 1 investigative site in the United States from 10 January 2018 to 21 December 2020.
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| ID | Title | Description |
|---|---|---|
| FG000 | Luvadaxistat 500 mg, Then Placebo | Participants first received luvadaxistat 500 mg orally QD for 8 days during treatment period 1. After a washout of 14 to 21 days, participants then received matching placebo orally QD for 8 days during treatment period 2. |
| FG001 | Placebo, Then Luvadaxistat 500 mg | Participants first received matching placebo orally QD for 8 days during treatment period 1. After a washout of 14 to 21 days, participants then received luvadaxistat 500 mg orally QD for 8 days during treatment period 2. |
| FG002 | Luvadaxistat 50 mg, Then Placebo | Participants first received luvadaxistat 50 mg orally QD for 8 days during treatment period 1. After a washout of 14 to 21 days, participants then received matching placebo orally QD for 8 days during treatment period 2. |
| FG003 | Placebo, Then Luvadaxistat 50 mg | Participants first received matching placebo orally QD for 8 days during treatment period 1. After a washout of 14 to 21 days, participants then received luvadaxistat 50 mg orally QD for 8 days during treatment period 2. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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The safety analysis set included all participants who were randomized and received at least 1 dose of double-blind study drug.
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| ID | Title | Description |
|---|---|---|
| BG000 | Luvadaxistat 500 mg, Then Placebo | Participants first received luvadaxistat 500 mg orally QD for 8 days during treatment period 1. After a washout of 14 to 21 days, participants then received matching placebo orally QD for 8 days during treatment period 2. |
| BG001 | Placebo, Then Luvadaxistat 500 mg |
| Units | Counts |
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| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Change From Baseline in Average Percent of Conditioned Responses During the Eye Blink Conditioning (EBC) Test at Day 8 | EBC is a method used to investigate cerebellar-dependent learning. In EBC, a conditioned stimulus, a tone precedes but co-terminates with an unconditioned stimulus, an airpuff to the eyelid. Learning is demonstrated when an eyeblink (the conditioned response) occurs prior to the onset of the unconditioned stimulus. The percentage can range from 0% (no conditioned learning has occurred) to 100% (all responses are conditioned). Results are reported as least squares (LS) means at Day 8, determined using an analysis of variance (ANOVA). | The PD set consisted of all randomized participants who received at least 1 dose of study treatment and had at least 1 post- dose PD result. Here, 'Overall number of participants analyzed' = participants evaluable for this outcome measure. | Posted | Least Squares Mean | Standard Error | Percent of Conditioned Responses | Baseline, Day 8 of each treatment period |
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8-day treatment period for each of treatment periods 1 and 2 (separated by washout of up to 21 days) and up to 30 days follow-up after last dose of study treatment. Up to a maximum of 67 days for overall timeframe.
Treatment-emergent adverse events were defined as adverse events that occurred after the first dose of study treatment and up to 30 days after the last dose or early termination. The safety analysis set included all randomized participants who received at least 1 dose of study treatment.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Placebo | Participants who received matching placebo orally QD for 8 days during either treatment periods 1 or 2 of the study. Placebo treatment was pooled for participants receiving 50 mg and 500 mg luvadaxistat. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Dyspepsia | Gastrointestinal disorders | MedDRA 23.0 | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Neurocrine Medical Information Call Center | Neurocrine Biosciences | 877-641-3461 | medinfo@neurocrine.com |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Jan 14, 2020 | Dec 5, 2023 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Feb 5, 2021 | Dec 5, 2023 | SAP_001.pdf |
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| ID | Term |
|---|---|
| D012559 | Schizophrenia |
| ID | Term |
|---|---|
| D019967 | Schizophrenia Spectrum and Other Psychotic Disorders |
| D001523 | Mental Disorders |
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| Matching Placebo | Drug | Matching Placebo Tablets. |
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| Baseline, Day 8 of each treatment period |
| Change From Baseline in the Mean P300 Amplitude at Day 8 | 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 was measured at midline parietal electrode (Pz) of EEG. Baseline was defined as the last observation prior to the dose of study treatment in the corresponding period. Results are reported as LS mean change from baseline at Day 8, determined using an ANOVA. | Baseline, Day 8 of each treatment period |
| Change From Baseline in the Mean Auditory Steady State Response (ASSR) at Day 8 | ASSRs 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. The ASSR applied a frequency stimulus of 40 hertz (Hz) and was measured at midline central electrode (Cz) of EEG. Baseline was defined as the last observation prior to the dose of study treatment in the corresponding period. Results are reported as LS mean change from baseline at Day 8, determined using an ANOVA. | Baseline, Day 8 of each treatment period |
| Change From Baseline on the Brief Assessment of Cognition in Schizophrenia (BACS) Composite Score at Day 7 | BACS is a cognition assessment battery and includes brief assessments of reasoning and problem solving, verbal fluency, attention, verbal memory, working memory and motor speed. The primary measure from each test is standardized by creating z-scores whereby the mean of the test session of a healthy person is set to 0 and the standard deviation set to 1. A Z-score of 0 represents the population mean. A composite score was calculated by averaging the 4 measures from the BACS used in the study and then calculating a z-score of the composite. The composite z-score indicates how much higher or lower the participants cognition is compared to a healthy person. Lower z-scores are indicative of lower cognitive performance. Baseline was defined as the last observation prior to the dose of study treatment in the corresponding period. Results are reported as LS mean change from baseline at Day 7, determined using an ANOVA. | Baseline, Day 7 of each treatment period |
| Change From Baseline in the Mean Plasma Concentrations of D-serine and L-serine at Day 8 | Blood samples were collected at pre-specified timepoints and plasma concentrations of D-serine and L-serine were measured. Results are reported as LS mean change from baseline at Day 8, determined using a mixed model for repeated measures (MMRM). | Day 1 and at multiple time points (up to 6 hours) to Day 8 pre-dose |
| Change From Baseline in the Mean Plasma D-serine to Total Serine Ratio at Day 8 | Blood samples were collected at pre-specified timepoints and plasma concentrations of D-serine and total serine were measured. Plasma D-serine to total serine ratios were then calculated. Results are reported as LS mean change from baseline at Day 8, determined using a MMRM. | Baseline and Day 8 of each treatment period |
| Mean Plasma Concentration of Luvadaxistat | Blood samples were collected at pre-specified timepoints and plasma concentrations of luvadaxistat were measured. | Day 1 0.25 to 2 hours and 3 to 6 hours post-dose, Day 7 pre-dose, 0.25 to 2 hours and 3 to 6 hours post-dose, and Day 8 pre-dose |
| Early study termination due to study pause |
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| Withdrawal by Subject |
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Participants first received matching placebo orally QD for 8 days during treatment period 1. After a washout of 14 to 21 days, participants then received luvadaxistat 500 mg orally QD for 8 days during treatment period 2. |
| BG002 | Luvadaxistat 50 mg, Then Placebo | Participants first received luvadaxistat 50 mg orally QD for 8 days during treatment period 1. After a washout of 14 to 21 days, participants then received matching placebo orally QD for 8 days during treatment period 2. |
| BG003 | Placebo, Then Luvadaxistat 50 mg | Participants first received matching placebo orally QD for 8 days during treatment period 1. After a washout of 14 to 21 days, participants then received luvadaxistat 50 mg orally QD for 8 days during treatment period 2. |
| BG004 | Total | Total of all reporting groups |
| Participants |
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| Sex: Female, Male | Count of Participants | Participants |
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| Ethnicity (NIH/OMB) | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
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| Luvadaxistat 50 mg |
Participants received luvadaxistat 50 mg orally QD for 8 days during either treatment periods 1 or 2 of the study. |
| OG001 | Placebo (Reference for Luvadaxistat 50 mg) | Participants received matching placebo orally QD for 8 days during either treatment periods 1 or 2 of the study. Placebo treatment in this arm corresponds to participants who received 50 mg luvadaxistat in the alternative treatment period (that is, participants receiving 50 mg and 500 mg luvadaxistat were analyzed separately and placebo treatment was not pooled). |
| OG002 | Luvadaxistat 500 mg | Participants received luvadaxistat 500 mg orally QD for 8 days during either treatment periods 1 or 2 of the study. |
| OG003 | Placebo (Reference for Luvadaxistat 500 mg) | Participants received matching placebo orally QD for 8 days during either treatment periods 1 or 2 of the study. Placebo treatment in this arm corresponds to participants who received 500 mg luvadaxistat in the alternative treatment period (that is, participants receiving 50 mg and 500 mg luvadaxistat were analyzed separately and placebo treatment was not pooled). |
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| Secondary | Change From Baseline in the Mean Mismatch Negativity (MMN) at Day 8 | 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 was measured at midline frontal electrode (Fz) of electroencephalogram (EEG). Baseline was defined as the last observation prior to the dose of study treatment in the corresponding period. Results are reported as LS mean change from baseline at Day 8, determined using an ANOVA. | The PD set consisted of all randomized participants who received at least 1 dose of study treatment and had at least 1 post- dose PD result. Here, 'Overall number of participants analyzed' = participants evaluable for this outcome measure. | Posted | Least Squares Mean | Standard Error | microvolts | Baseline, Day 8 of each treatment period |
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| Secondary | Change From Baseline in the Mean P300 Amplitude at Day 8 | 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 was measured at midline parietal electrode (Pz) of EEG. Baseline was defined as the last observation prior to the dose of study treatment in the corresponding period. Results are reported as LS mean change from baseline at Day 8, determined using an ANOVA. | The PD set consisted of all randomized participants who received at least 1 dose of study treatment and had at least 1 post- dose PD result. Here, 'Overall number of participants analyzed' = participants evaluable for this outcome measure. | Posted | Least Squares Mean | Standard Error | microvolts | Baseline, Day 8 of each treatment period |
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| Secondary | Change From Baseline in the Mean Auditory Steady State Response (ASSR) at Day 8 | ASSRs 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. The ASSR applied a frequency stimulus of 40 hertz (Hz) and was measured at midline central electrode (Cz) of EEG. Baseline was defined as the last observation prior to the dose of study treatment in the corresponding period. Results are reported as LS mean change from baseline at Day 8, determined using an ANOVA. | The PD set consisted of all randomized participants who received at least 1 dose of study treatment and had at least 1 post- dose PD result. Here, 'Overall number of participants analyzed' = participants evaluable for this outcome measure. | Posted | Least Squares Mean | Standard Error | microvolts-squared | Baseline, Day 8 of each treatment period |
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| Secondary | Change From Baseline on the Brief Assessment of Cognition in Schizophrenia (BACS) Composite Score at Day 7 | BACS is a cognition assessment battery and includes brief assessments of reasoning and problem solving, verbal fluency, attention, verbal memory, working memory and motor speed. The primary measure from each test is standardized by creating z-scores whereby the mean of the test session of a healthy person is set to 0 and the standard deviation set to 1. A Z-score of 0 represents the population mean. A composite score was calculated by averaging the 4 measures from the BACS used in the study and then calculating a z-score of the composite. The composite z-score indicates how much higher or lower the participants cognition is compared to a healthy person. Lower z-scores are indicative of lower cognitive performance. Baseline was defined as the last observation prior to the dose of study treatment in the corresponding period. Results are reported as LS mean change from baseline at Day 7, determined using an ANOVA. | The PD set consisted of all randomized participants who received at least 1 dose of study treatment and had at least 1 post- dose PD result. Here, 'Overall number of participants analyzed' = participants evaluable for this outcome measure. | Posted | Least Squares Mean | Standard Error | z-score | Baseline, Day 7 of each treatment period |
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| Secondary | Change From Baseline in the Mean Plasma Concentrations of D-serine and L-serine at Day 8 | Blood samples were collected at pre-specified timepoints and plasma concentrations of D-serine and L-serine were measured. Results are reported as LS mean change from baseline at Day 8, determined using a mixed model for repeated measures (MMRM). | The PK analysis set included all randomized participants who received at least 1 dose of study treatment and who had any available plasma concentration data. Here, 'Overall number of participants analyzed' = participants evaluable for this outcome measure. | Posted | Least Squares Mean | Standard Error | mg / liter | Day 1 and at multiple time points (up to 6 hours) to Day 8 pre-dose |
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| Secondary | Change From Baseline in the Mean Plasma D-serine to Total Serine Ratio at Day 8 | Blood samples were collected at pre-specified timepoints and plasma concentrations of D-serine and total serine were measured. Plasma D-serine to total serine ratios were then calculated. Results are reported as LS mean change from baseline at Day 8, determined using a MMRM. | The PK analysis set included all randomized participants who received at least 1 dose of study treatment and who had any available plasma concentration data. Here, 'Overall number of participants analyzed' = participants evaluable for this outcome measure. | Posted | Least Squares Mean | Standard Error | ratio | Baseline and Day 8 of each treatment period |
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| Secondary | Mean Plasma Concentration of Luvadaxistat | Blood samples were collected at pre-specified timepoints and plasma concentrations of luvadaxistat were measured. | The PK analysis set included all randomized participants who received at least 1 dose of study treatment and who had any available plasma concentration data. Here, 'Overall number of participants analyzed' = participants evaluable for this outcome measure. | Posted | Mean | Standard Deviation | nanograms / milliliter | Day 1 0.25 to 2 hours and 3 to 6 hours post-dose, Day 7 pre-dose, 0.25 to 2 hours and 3 to 6 hours post-dose, and Day 8 pre-dose |
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| 0 |
| 29 |
| 0 |
| 29 |
| 0 |
| 29 |
| EG001 | Luvadaxistat 500 mg | Participants received luvadaxistat 500 mg orally QD for 8 days during either treatment periods 1 or 2 of the study. | 0 | 15 | 0 | 15 | 0 | 15 |
| EG002 | Luvadaxistat 50 mg | Participants received luvadaxistat 50 mg orally QD for 8 days during either treatment periods 1 or 2 of the study. | 0 | 14 | 0 | 14 | 1 | 14 |
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| L-serine |
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| Day 1 - Post-dose (3 to 6 hours) |
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| Day 7 - Pre-dose |
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| Day 7 - Post-dose (0.25 to 2 hours) |
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| Day 7 - Post-dose (3 to 6 hours) |
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| Day 8 - Pre-dose |
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