A Study to Evaluate 3 Dose Levels of Luvadaxistat of Adults With Negative Symptoms of Schizophrenia

Schizophrenia Clinical Trial

Official title:

A Phase 2, 12-Week, Randomized, Double-Blind, Placebo-Controlled, Parallel Study to Evaluate Efficacy, Safety, Tolerability, and Pharmacokinetics of 3 Dose Levels of TAK-831 in Adjunctive Treatment of Adult Subjects With Negative Symptoms of Schizophrenia

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03382639
• Other study ID #: TAK-831-2002
• Secondary ID: 2017-003471-54U1
• Status: Completed
• Phase: Phase 2
• Start date: January 4, 2018
• Est. completion date: January 12, 2021

Study information

• Verified date: January 2024
• Source: Neurocrine Biosciences
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to determine whether add-on luvadaxistat is superior to placebo on the Positive and Negative Syndrome Scale Negative Symptom Factor Score (PANSS NSFS).

Description:

The drug being tested in this study is called luvadaxistat. Luvadaxistat is being tested to treat negative symptoms in participants who have schizophrenia.

Participants will be randomly assigned (by chance, like flipping a coin) to one of the four treatment groups in the double-blind period-which will remain undisclosed to the participant and study doctor during the study (unless there is an urgent medical need):

• Luvadaxistat 50 mg once daily

• Luvadaxistat 125 mg once daily

• Luvadaxistat 500 mg once daily

• Placebo once daily

Recruitment information / eligibility

• Status: Completed
• Enrollment: 256
• Est. completion date: January 12, 2021
• Est. primary completion date: December 29, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 60 Years

Eligibility

Inclusion Criteria:

1. Has a current diagnosis of schizophrenia as defined by the Mini International Neuropsychiatric Interview (MINI) 7.0.2 for Psychotic Disorders for the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) and the general psychiatric evaluation.

2. Initial diagnosis must be greater than or equal to (>=1) year from screening.

3. Is receiving primary background antipsychotic therapy (other than clozapine) at a total daily dose between 2 and 6 mg of risperidone equivalents. Concomitant treatment with a sub-therapeutic dose of a second antipsychotic may be permitted with sponsor or designee approval if used to treat specific symptoms, such as insomnia or anxiety (for example, quetiapine 25-50 mg or its equivalent as needed for anxiety), but not if it is used for refractory positive psychosis symptoms.

4. Is treated with a stable regimen of psychotropic medications with no clinically meaningful change (no increase in dose, less than or equal to [<=] 25 percent [%] decrease in dose for tolerability) in the prescribed dose for 2 months before the screening visit and no dose adjustment is anticipated throughout study participation up to the Day 84/early termination visit.

5. Has a BNSS total score (12-item, excluding number 4) >=28; stable Single-blind Placebo Run-in and baseline BNSS total (12-item, excluding number 4) scores (<= 20% change from the screening score).

6. Has no more than moderate-severe (<=5) rating on PANSS positive symptom items P1, P3, P4, P5, P6, or unusual thought content (G9), with a maximum of 2 of these items rated '5'; no more than moderate (<=4) rating on conceptual disorganization (P2).

7. There is evidence that the participant has stable symptomatology >=3 months prior to the screening visit (example, no hospitalizations for schizophrenia, no emergency room admission due to symptoms of schizophrenia, no increase in level of psychiatric care due to worsening of symptoms of schizophrenia).

8. Have an adult informant who will be able to provide input for completing study rating scales, including the PANSS and SCoRS (for example, a family member, social worker, caseworker, residential facility staff, or nurse who spends >=4 hours/week with the participant) and is considered reliable by the investigator. The informant must be able and willing to provide written informed consent and to participate in at least 1 in-person interview, then be able to provide continuing input by attending each clinical assessment visit or via participating in a telephone interview for other study visits that include the PANSS or SCoRS endpoints.

Exclusion Criteria:

1. Has a lifetime diagnosis of schizoaffective disorder; a lifetime diagnosis of bipolar disorder; or a lifetime diagnosis of obsessive compulsive disorder based on the MINI combined with the general psychiatric evaluation.

2. Has a recent (within the last 6 months) occurrence of panic disorder, depressive episode, or other comorbid psychiatric conditions currently requiring clinical attention based on the MINI for DSM-5 and the general psychiatric evaluation.

3. Has a diagnosis of substance use disorder (with the exception of nicotine dependence) within the preceding 6 months based on the MINI for DSM-5 and the general psychiatric evaluation.

4. Is participating in a formal structured nonpharmacological psychosocial therapeutic treatment program (cognitive remediation, cognitive-behavioral therapy, intensive symptom/vocational rehabilitation) for a duration of less than (<) 3 months before randomization. In addition, initiation of such nonpharmacological treatment programs is not permitted during study participation through the Day 84 visit.

5. The participant exhibits more than a minimal level of antipsychotic-induced parkinsonism symptoms, as documented by a score on the modified Simpson Angus Scale (SAS) (excluding item number 10, Akathisia) greater than (>) 6.

6. Has evidence of depression as measured by a Calgary Depression Scale Score (CDSS) > 9.

7. Is considered by the investigator to be at imminent risk of suicide or injury to self, others, or property, or the participant has attempted suicide within the past year prior to screening. Participants who have positive answers on item number 4 or 5 on the Columbia-Suicide Severity Rating Scale (C-SSRS) (based on the past year) prior to randomization are excluded.

8. Has a history of brain trauma associated with loss of consciousness for >15 minutes.

9. Diagnosis of schizophrenia occurred prior to 12 years of age.

10. Has received electroconvulsive therapy within 6 months (180 days) before Screening.

11. Has a history of developmental intellectual disability or mental retardation.

12. Antipsychotic plasma levels for the participant's primary background antipsychotic are below the minimum acceptable concentration criteria per the Antipsychotic Reference document at the screening or placebo run-in visits. This criterion is not applicable to participants on a primary background antipsychotic for which a clinical assay is unavailable.

13. Is treatment resistant. Treatment resistance is defined as prior nonresponse of positive symptoms of schizophrenia to 2 courses of treatment with antipsychotics of different chemical classes for at least 4 weeks, each at doses considered to be effective.

14. Does not have a stable residence or is homeless.

Related Conditions & MeSH terms

• Schizophrenia

Intervention

Drug:
• Luvadaxistat
TAK-831 tablets.
• Placebo
Luvadaxistat placebo-matching tablets.

Locations

Country	Name	City	State
Bulgaria	State Psychiatric Hospital - Lovech	Lovech
Bulgaria	State Psychiatric Hospital "Sv. Ivan Rilski", Novi Iskar	Novi Iskar
Bulgaria	UMHAT 'Dr. Georgi Stranski', EAD	Pleven
Bulgaria	DCC "Sv. Vrach and Sv. Sv. Kuzma and Damyan", OOD	Sofia
Bulgaria	Medical Centre "Sv. Naum"	Sofia
Bulgaria	DCC "Mladost M" - Varna, OOD	Varna
Bulgaria	Mental Health CenterVratsa EOOD	Vratsa
Czechia	Narodni ustav dusevniho zdravi	Klecany
Czechia	A-SHINE s.r.o.	Plzen
Czechia	CLINTRIAL s.r.o.	Praha 10
Czechia	PRAGTIS s.r.o.	Praha 2
Czechia	Vseobecna fakultni nemocnice v Praze	Praha 2
Czechia	MUDr. Simona Papezova s.r.o.	Praha 9
Germany	Charite Universitaetsmedizin Berlin - Campus Charite Mitte	Berlin
Germany	Universitaetsklinikum Leipzig AoeR	Leipzig	Sachsen
Germany	Zentralinstitut fuer Seelische Gesundheit	Mannheim	Baden Wuerttemberg
Germany	Studienzentrum Nordwest	Westerstede	Niedersachsen
Italy	Azienda Ospedaliero Universitaria Consorziale Policlinico di Bari	Bari
Italy	Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia (Presidio Spedali Civili)	Brescia
Italy	Azienda Ospedaliera Universitaria- Universita degli Studi della Campania Luigi Vanvitelli	Napoli
Italy	Azienda Ospedaliera di Padova	Padova
Italy	Azienda Ospedaliera Citta della Salute e della Scienza di Torino	Torino
Poland	Przychodnia Srodmiescie Sp. z o. o.	Bydgoszcz
Poland	NZOZ Syntonia	Gdynia
Poland	Care Clinic	Katowice
Poland	NZOZ Poradnia Zdrowia Psychicznego	Kobierzyce
Poland	Centrum Medyczne Plejady	Krakow
Poland	Medycyna Milorzab	Lodz
Poland	Centrum Medyczne "Luxmed" Sp. z o.o.	Lublin
Spain	Hospital Clinic de Barcelona	Barcelona
Spain	Hospital Universitario 12 de Octubre	Madrid
Ukraine	Regional Psychoneurological Hospital #3	Ivano Frankivsk
Ukraine	CIH Kharkiv Regional Clinical Psychiatric Hospital #3	Kharkiv
Ukraine	Kyiv CH on Railway Transport #2 of Branch Center of Healthcare Public Company Ukr Railway	Kyiv
Ukraine	CI Kirovograd RPH Male dept#11,Female dep#17 Donetsk NMU	Nove, Kropyvnytskiy
Ukraine	Ternopil RCCPH Depts of Psychiatry #2 (m) & Psychiatry #4 (f) Ternopil I.Ya. Gorbachevskyi SMU	Ternopil
Ukraine	Transcarpathian Regional Narcological Dispensary	Uzhgorod
Ukraine	Zhytomyr Regional Psychiatric Hospital #1	Zarichany Vil.
United States	Atlanta Center for Medical Research	Atlanta	Georgia
United States	Augusta University	Augusta	Georgia
United States	Community Clinical Research, Inc.	Austin	Texas
United States	Core Clinical Research	Everett	Washington
United States	Center for Behavioral Health, LLC	Gaithersburg	Maryland
United States	Collaborative Neuroscience Network, LLC	Garden Grove	California
United States	Cherry Health	Grand Rapids	Michigan
United States	The Dr. Alan & Diane Breier Prevention and Recovery Center for Early Psychosis	Indianapolis	Indiana
United States	Synergy Clinical Research Center	Lemon Grove	California
United States	Semel Institute for Neuroscience and Human Behavior	Los Angeles	California
United States	Research Strategies of Memphis, LLC	Memphis	Tennessee
United States	Connecticut Mental Health Center - Yale University	New Haven	Connecticut
United States	Manhattan Psychiatric Center	New York	New York
United States	Excell Research	Oceanside	California
United States	NRC Research Institute	Orange	California
United States	Artemis Institute for Clinical Research, LLC	San Diego	California

Sponsors (2)

Lead Sponsor	Collaborator
Neurocrine Biosciences	Takeda

Countries where clinical trial is conducted

United States,  Bulgaria,  Czechia,  Germany,  Italy,  Poland,  Spain,  Ukraine, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change From Baseline on the PANSS NSFS at Week 12	PANSS assesses the positive symptoms, negative symptoms and general psychopathology associated with schizophrenia. The scale consists of 30 items. Each item is rated on a scale from 1 (symptom not present) to 7 (symptoms extremely severe). Here, the PANSS NSFS subscale consists of 7 items which assess the negative symptoms with subscale score ranging from 7 to 49, where a higher score indicates greater severity. Baseline was defined as the last observed value before the first dose of study treatment. Results are reported as least squares (LS) mean change from baseline at Week 12, determined using a mixed model for repeated measures (MMRM). A negative change from baseline indicates improvement.	Baseline and Week 12
Secondary	Change From Baseline on the PANSS NSFS at Week 4 and Week 8	PANSS assesses the positive symptoms, negative symptoms and general psychopathology associated with schizophrenia. The scale consists of 30 items. Each item is rated on a scale from 1 (symptom not present) to 7 (symptoms extremely severe). Here, the PANSS NSFS subscale consists of 7 items which assess the negative symptoms with subscale score ranging from 7 to 49, where a higher score indicates greater severity. Baseline was defined as the last observed value before the first dose of study treatment. Results are reported as LS mean change from baseline at Weeks 4 and 8, determined using a MMRM. A negative change from baseline indicates improvement.	Baseline and Weeks 4 and 8
Secondary	Change From Baseline on the Brief Negative Symptom Scale (BNSS) Total Score (12-item) at Week 12	The BNSS is a 13-item instrument that measures 5 domains of negative symptoms: blunted affect, alogia, asociality, anhedonia and avolition. All items in the BNSS are rated on a 7-point (0-6) scale, with anchor points generally ranging from symptoms being absent (0) to severe (6). Here, the BNSS total score (12-item, excluding item 4) was calculated by summing the 12 individual items; total score range of 0 to 72, where a higher score indicates higher severity of negative symptoms. Participants required a BNSS total score =28 to be eligible for the study (excluding item 4). Baseline was defined as the last observed value before the first dose of study treatment. Results are reported as LS mean change from baseline at Week 12, determined using a MMRM. A negative change from baseline indicates improvement.	Baseline and Week 12
Secondary	Change From Baseline on the Brief Assessment of Cognition in Schizophrenia (BACS) Composite Score at Week 12	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 T-scores whereby the mean of the test session of a healthy person is set to 50 and the standard deviation set to 10. A composite T-score is calculated by averaging the 6 standardized primary measures. The composite T-score indicates how much higher or lower the participants cognition is compared to a healthy person. Lower T-scores are indicative of lower cognitive performance. Baseline was defined as the last observed value before the first dose of study treatment. Results are reported as LS mean change from baseline at Day 12, determined using a MMRM.	Baseline and Week 12
Secondary	Change From Baseline on the Clinical Global Impression-Schizophrenia Severity (CGI-SCH-S) Negative Symptoms Score at Week 12	The CGI-SCH scale is an adapted version of the CGI scale that is designed to assess global illness status in participants with schizophrenia. CGI-SCH-S is a 7-point scale that requires the investigator to rate the severity of the participant's illness at the time of assessment. Here, CGI-SCH-S negative symptoms score assesses the severity of illness for negative symptoms on the following 7-point scale: 1. normal, not at all ill; 2. borderline mentally ill; 3. mildly ill; 4. moderately ill; 5. markedly ill; 6. severely ill; or 7. among the most extremely ill. Baseline was defined as the last observed value before the first dose of study treatment. The number of participants with each CGI-SCH-S negative symptoms score at baseline and at Week 12 is reported.	Baseline and Week 12
Secondary	Clinical Global Impression Schizophrenia Improvement (CGI-SCH-I) Negative Symptoms Score at Week 12	The CGI-SCH-I assesses the participant's improvement (or worsening). CGI-SCH-I requires the investigator to assess the participant's condition relative to baseline on a 7-point scale. Here, CGI-SCH-I negative symptoms score assesses the improvement for negative symptoms on the following scale: very much improved; 2. much improved; 3. minimally improved; 4. no change; 5. minimally worse; 6. much worse; or 7. very much worse. Baseline was defined as the last observed value before the first dose of study treatment. The number of participants with each CGI-SCH-I negative symptoms score at Week 12 is reported.	Baseline up to Week 12
Secondary	Change From Baseline on the Schizophrenia Cognition Rating Scale (SCoRS) Interviewer Total Score at Week 12	The SCoRS is an interview-based measure of cognitive functioning that is developed to specifically assess aspects of cognitive functioning in participants with schizophrenia. The items assess the 7 cognitive domains of attention, memory, reasoning and problem solving, working memory, processing speed, language functions and social cognition. The SCoRS total score is the sum of the 20 items and varies from 20 to 80 with 20 being the best outcome and 80 being the worst. Baseline was defined as the last observed value before the first dose of study treatment. Results are reported as LS mean change from baseline at Week 12, determined using a MMRM.	Baseline and Week 12
Secondary	Change From Baseline on the PANSS Total Score at Week 12	PANSS assesses the positive symptoms, negative symptoms and general psychopathology associated with schizophrenia. The scale consists of 30 items. Each item is rated on a scale from 1 (symptom not present) to 7 (symptoms extremely severe). The sum of the 30 items is defined as the PANSS total score and ranges from 30 to 210, where a higher score indicates greater severity. Baseline was defined as the last observed value before the first dose of study treatment. Results are reported as LS mean change from baseline at Week 12, determined using a MMRM. A negative change from baseline indicates improvement.	Baseline and Week 12
Secondary	Change From Baseline on the PANSS Positive Symptom Factor Score (PSFS) at Week 12	PANSS assesses the positive symptoms, negative symptoms and general psychopathology associated with schizophrenia. The scale consists of 30 items. Each item is rated on a scale from 1 (symptom not present) to 7 (symptoms extremely severe). Here, the PANSS PSFS subscale consists of 7 items which assess the positive symptoms with subscale score ranging from 7 to 49, where a higher score indicates greater severity. Baseline was defined as the last observed value before the first dose of study treatment. Results are reported as LS mean change from baseline at Week 12, determined using a MMRM. A negative change from baseline indicates improvement.	Baseline and Week 12
Secondary	Luvadaxistat Plasma Concentrations	Blood samples were collected at pre-specified timepoints and plasma concentrations of luvadaxistat were measured. At Week 4, assessments were categorized as pre-dose or post-dose according to actual sampling time. Due to this, some participants may have had more than 1 record summarized for Week 4 pre-dose or Week 4 post-dose. Mean concentration on each visit was averaged from the observations over the time span of 24 hours post-dose or pre-dose.	Pre-dose on Day 1 and Week 4 and post-dose on Weeks 4, 6, 8 and 12