A Study to Evaluate Efficacy, Tolerability, Pharmacodynamic and Pharmacokinetics of Multiple Oral Doses of TAK-831 in Adults With Schizophrenia

• Sponsor: Neurocrine Biosciences (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03359785
• Collaborator: Takeda (Industry)
• Enrollment: 31
• Location: 1
• Arms: 2
• Actual Duration (Months): 36
• Patients Per Site Per Month: 0.9

Study Details

Study Description

Brief Summary

The purpose of this study is to determine whether TAK-831 is superior to placebo in improving cerebellar function as measured with the average percentage of conditioned responses during the eyeblink conditioning (EBC) test.

Condition or Disease	Intervention/Treatment	Phase
Schizophrenia	Drug: Luvadaxistat; Drug: Matching Placebo	Phase 2

Detailed Description

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 States of America. The overall time to participate in this study is approximately 81 days. Two treatment periods will be administered for 8 consecutive days, separated by a 14 to 21-day washout. Participants will be admitted to the clinic for two overnight stays at the beginning of each treatment period and one night at the end of each treatment period. 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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 31 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official 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
• Actual Study Start Date: Dec 21, 2017
• Actual Primary Completion Date: Dec 21, 2020
• Actual Study Completion Date: Dec 21, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Luvadaxistat 500 mg + Luvadaxistat 50 mg Luvadaxistat 500 milligrams (mg) or matching Placebo tablets, orally, once daily for 8 days in period 1, followed by 14-21 day washout period, followed by Luvadaxistat 50 mg or matching Placebo tablets, orally, once daily for up to 8 days in period 2.	Drug: Luvadaxistat; TAK-831 Tablets.; Other Names: TAK-831 ; Drug: Matching Placebo; Matching Placebo Tablets.
Experimental: Luvadaxistat 50 mg + Luvadaxistat 500 mg Luvadaxistat 50 mg or matching Placebo tablets, orally, once daily for 8 days in period 1, followed by 14-21 day washout period, followed by Luvadaxistat 500 mg or matching Placebo tablets, orally, once daily for up to 8 days in period 2.	Drug: Luvadaxistat; TAK-831 Tablets.; Other Names: TAK-831 ; Drug: Matching Placebo; Matching Placebo Tablets.

Outcome Measures

Primary Outcome Measures

1. Average Percentage of Conditioned Responses During the Eye Blink Conditioning (EBC) Test at Day 8 [Day 8: 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

1. Mean Mismatch Negativity (MMN) at Day 8 [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].

2. Mean P300 Amplitude at Day 8 [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.

3. Mean Auditory Steady State Response (ASSR) to 40 Hz Stimulation at Day 8 [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.

4. Brief Assessment of Cognition in Schizophrenia (BACS) Cognitive Battery Composite Score at Day 7 [Day 7: For each treatment period]

   BACS is specifically designed to measure treatment- related improvements in cognition and includes alternate forms. The battery of tests in the BACS includes brief assessments of reasoning and problem solving, verbal fluency, attention, verbal memory, working memory, and motor speed. The primary measure from each test of the BACS 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 was calculated by averaging all of the 6 standardized primary measures from the BACS, 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.

5. Mean Concentration of Plasma D-serine and L-serine Levels at Day 8 [Day 8: For each treatment period]

6. Mean Plasma D-serine to Total Serine Ratio at Day 8 [Day 8: For each treatment period]

7. Mean Plasma Concentration of TAK-831 [Day 1, 7 and 8: For each treatment period]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 60 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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 subject 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 TAK-831.

• 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	CBH Health, LLC	Gaithersburg	Maryland	United States	20877

Sponsors and Collaborators

• Neurocrine Biosciences
• Takeda

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Neurocrine Biosciences
• ClinicalTrials.gov Identifier: NCT03359785
• Other Study ID Numbers: TAK-831-2001; 2017-001739-38; U1111-1197-9766; 17/YH/0196
• First Posted: Dec 2, 2017
• Last Update Posted: Dec 10, 2021
• Last Verified: Dec 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Neurocrine Biosciences: Drug therapy
• Additional relevant MeSH terms: Schizophrenia

Study Results

No Results Posted as of Dec 10, 2021