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Completed

NCT Number: NCT03359785

A Study to Evaluate Multiple Oral Doses of Luvadaxistat in Adults With Schizophrenia

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.

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Key information

Conditions

Schizophrenia Mental Disorders Schizophrenia Spectrum and Other Psychotic Disorders

Age range

18 year–60 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 2

Primary location

CBH Health, LLC

Gaithersburg, Maryland, 20877, United States

About this study

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):

  • Luvadaxistat 500 milligrams (mg) followed by matching placebo
  • Matching placebo followed by luvadaxistat 50 mg

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Have a body mass index (BMI) greater than or equal to (>=) 18.5 and less than or equal to (<=) 40.0 (kilogram per square meter [kg/m^2]) at the Screening Visit.
  • With a current Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) diagnosis of schizophrenia who are receiving stable antipsychotic therapy (no increase, no decrease greater than [>] 20% in dose in the preceding 2 months).
  • Positive and Negative Syndrome Scale (PANSS) negative symptom factor score (NSFS) >= 15, stable screening and baseline PANSS NSFS (< 25% change).
  • PANSS total score <= 90; stable screening and baseline PANSS total score (less than [<] 20% change).
  • Receiving stable (no increase, no decrease > 25% in dose in the preceding 2 months)antipsychotic medication at doses not to exceed risperidone 6 mg or its equivalent. Concomitant treatment with a subtherapeutic dose of a second antipsychotic may be permitted with sponsor or designee approval if used as a hypnotic (maximum of quetiapine 300 mg or its equivalent once daily at bedtime) and participants does not show morning sedation as per the investigator opinion, but not if it is used for refractory positive psychosis symptoms. Under this exception, the total daily dose the second antipsychotic will not have to be included in the calculation of the 6 mg/day risperidone-equivalent limit.

Exclusion criteria

  • Has a history of cancer (malignancy) excluding treated basal cell carcinoma or treated stage 0 (in situ) cervical carcinoma.
  • Has a history of significant multiple and/or severe allergies (example [eg], food, drug, latex allergy) or has had an anaphylactic reaction or significant intolerability to prescription or nonprescription drugs or food.
  • Has a QT interval with Fridericia's correction method (QTcF) > 450 milliseconds [ms] (males) or > 470 ms (females) confirmed with one repeat testing, at the Screening Visit or Check-in.
  • Has a positive alcohol or drug screen for disallowed substances, including amphetamines, barbiturates, cocaine, marijuana, methadone, methamphetamine, 3,4-methylenedioxymethamphetamine, phencyclidine, or nonprescribed benzodiazepines or opiates.
  • Is positive for hepatitis B surface antigen (HBsAg), hepatitis C antibodies, or has HIV by history (confirmatory testing is allowed; most sensitive test should take precedence).
  • Had major surgery, donated or lost 250 milliliter [mL] of blood within 4 weeks prior to the prestudy (screening) visit.
  • Has a known hypersensitivity to any component of the formulation of luvadaxistat.
  • Has a history of significant skin reactions (hypersensitivity) to adhesives, metals or plastic.
  • Is considered by the investigator to be at imminent risk of suicide or injury to self, others, or property, or participants who within the past year prior to Screening have attempted suicide. Participants who have positive answers on item 4 or 5 on the Columbia Suicide Severity Rating Scale (C-SSRS) (based on the past year) prior to randomization are excluded.

Treatment and study plan

Luvadaxistat

Drug

TAK-831 Tablets.

Other names: TAK-831, NBI-1065844

Matching Placebo

Drug

Matching Placebo Tablets.

Primary outcomes

  1. Change From Baseline in Average Percent of Conditioned Responses During the Eye Blink Conditioning (EBC) Test at Day 8

    Time frame: Baseline, Day 8 of each treatment period

    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).

Secondary outcomes

  1. Change From Baseline in the Mean Mismatch Negativity (MMN) at Day 8

    Time frame: Baseline, Day 8 of 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 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.

  2. Change From Baseline in the Mean P300 Amplitude at Day 8

    Time frame: Baseline, Day 8 of 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 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.

  3. Change From Baseline in the Mean Auditory Steady State Response (ASSR) at Day 8

    Time frame: Baseline, Day 8 of each treatment period

    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.

  4. Change From Baseline on the Brief Assessment of Cognition in Schizophrenia (BACS) Composite Score at Day 7

    Time frame: Baseline, Day 7 of each treatment period

    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.

  5. Change From Baseline in the Mean Plasma Concentrations of D-serine and L-serine at Day 8

    Time frame: Day 1 and at multiple time points (up to 6 hours) to Day 8 pre-dose

    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).

  6. Change From Baseline in the Mean Plasma D-serine to Total Serine Ratio at Day 8

    Time frame: Baseline and Day 8 of each treatment period

    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.

  7. Mean Plasma Concentration of Luvadaxistat

    Time frame: 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

    Blood samples were collected at pre-specified timepoints and plasma concentrations of luvadaxistat were measured.

Sponsors and collaborators

Lead sponsor

Neurocrine Biosciences

Industry

Collaborators

  • Takeda

Registry information

Official study title

A Phase 2 Randomized, Double-Blind, Placebo-Controlled, Cross-Over Study to Evaluate Pharmacodynamic Effects, Safety, Tolerability, and Pharmacokinetics of Multiple Oral Doses of TAK-831 in Adult Subjects With Schizophrenia

Important dates

Study start
2018
Primary completion
2020
Study completion
2020
First posted
Dec 2, 2017
Registry last updated
Feb 28, 2024

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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