An Adaptive Phase II/III, Double-Blind, Randomized, Placebo-controlled, Two-Part, Dose-Finding, Multi-center Study of the Safety and Efficacy of NaBen®, a D-Amino Acid Oxidase Inhibitor, as an Add-on Therapy with Clozapine, for Residual Symptoms of Refractory Schizophrenia in Adults

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Syneurx International (Taiwan) Corp.

Participant type

Patients

Age range

18-64 years

Gender

Male and Female

Therapeutic area

Psychiatry and Psychology [F] - Mental Disorders [F03]

Trial duration

26 Nov 2019 → ongoing

Decision date (initial)

2025-01-28

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2024-519237-34-00

EudraCT number

2017-001170-42

ClinicalTrials.gov

NCT03094429

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

Part 1 Objectives:
1. To evaluate, in terms of dose-response, the effectiveness of NaBen® (1000 and 2000 mg/day) compared to Placebo (0 mg/day), when combined with clozapine, in improving the residual symptoms associated with refractory schizophrenia in adults, and; to determine the optimal dose to be used in Part 2 of this study.
2. Sample size re-assessment to evaluate the final sample size needed to proceed with the Part 2 of the study.

Part 2 Objectives:
The primary objective of the Part 2 of this study is to evaluate the effectiveness of NaBen® (at the optimal dose determined in the Part 1 of this study) compared to Placebo (0 mg/day), when combined with clozapine, in improving the residual symptoms associated with refractory schizophrenia in adults.

Secondary objectives 2

1. The secondary objective of the Part 1 of this study is to evaluate the safety and tolerability of NaBen® (1000 and 2000 mg/day) compared to Placebo (0 mg/day), in combination with clozapine.
2. The secondary objective of the Part 2 of this study is to evaluate the safety and tolerability of NaBen® (at the optimal dose determined in the Part 1 of this study) compared to Placebo (0 mg/day), in combination with clozapine.

Conditions and MedDRA coding

Treatment for Refractory Schizophrenia in Adults

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

1. Male or female subjects who are between 18 and 55 years of age inclusive
2. Subject is capable of providing informed consent and is willing to sign the ICF prior to study Screening and agrees to comply with the study protocol requirements, or the subject has a Legally Authorized Representative (LAR) who can provide consent to be enrolled into the study.
3. If female and not infertile (defined below), the subject must agree for the duration of the study to use one of the following forms of contraception 1) systemic hormonal treatment 2) an Intrauterine device (IUD) which was implanted at least 2 months prior to screening or 3) "double-barrier" contraception (condom, diaphragm and spermicide are each considered a barrier). Females are considered to be infertile if they are either a) surgically sterile or b) have had spontaneous amenorrhea for at least the last 2 years and at least 2 years after the onset of amenorrhea while not receiving hormone replacement therapy and had a Follicle-Stimulating Hormone (FSH) level greater than 40 mIU/mL and an estradiol level less than 30 pg/mL
4. The subject has Physician confirmed DSM-V diagnosis of schizophrenia for the past 2 years based on subject’s recorded history and confirmed by psychiatric evaluation and MINI International Neuropsychiatric Interview For Schizophrenia and Psychotic Disorders, version 7.0 (MINI, Version 7.0).
5. The subjects should have refractory schizophrenia as defined below (should meet at least two: either a and b; or a and c; or a and b and c): a. Prior non-response to at least 2 antipsychotic drugs of two different chemical classes for at least 4-6 weeks each at doses ≥ 400 mg equivalents of chlorpromazine or 4 mg/day risperidone, AND b. No period of good functioning in previous 2 years; OR, c. Moderate to severe psychopathology (total PANSS score equal or more than 70): including persistent psychotic symptoms, recurrent mood symptoms, repeated suicide attempts or suicidal ideation, uncontrolled aggressive behavior, moderate to severe positive or negative symptoms or moderate-severe cognitive impairment
6. The subject has been receiving clozapine for a minimum of 6 months with the dose range of 200-900 mg/day. The dose should have remained unchanged for at least 3 months prior to Screening and not expected to change during the study
7. The subject is outpatient, and has been consistently symptomatic without significant fluctuation per the Investigator, with no hospitalization for worsening of schizophrenia within 3 months of the Screening. If the subject is hospitalized during the study for worsening of schizophrenia symptoms the subject will be withdrawn from the study.
8. The subject has a minimum PANSS total score of 70 at the Screening and Baseline Visits (Visit 1 and Visit 2)
9. Without clinically significant abnormalities in physical exam, neurological exam and laboratory assessments (urine/blood routine, biochemical tests and ECG) which would exclude the subject from the study in the opinion of the Investigator. For ALT and AST, clinically significant is defined as above two and a half times the upper limit of normal
10. Body Mass Index (BMI) between 17 and 38 inclusive
11. Subject has a negative routine urine illicit drug screening test (including heroin, amphetamines (including MDMA/ecstasy), cocaine, cannabis or PCP)
12. The subject has a caregiver or some other identified responsible person (e.g., family member, social worker, caseworker or nurse) as determined by the Investigator and per the local regulations. The identified caregiver should be considered reliable by the Investigator and per the local regulations in providing support to the subject to help ensure compliance with study treatment, study visits and protocol procedures who preferably is also able to provide input helpful for completing study rating scales.
13. The subject must not be a danger to themselves or others per the Investigator’s judgment.

Exclusion criteria 17

1. Meets the DSM-V criteria at Screening for intellectual disability, dissociative disorder, bipolar disorder, major depressive disorder, schizoaffective disorder, schizophreniform disorder, autistic disorder, primary substance-induced psychotic disorder, dementia, or any other comorbid mental disorders that in the opinion of the Investigator may interfere with study conduct and results interpretation
2. Initiation or dose change of lithium, antidepressant or other mood stabilizers within 16 weeks prior to Screening
3. Initiation or dose change of benzodiazepines or sleep medications, or any other psychotropic medications due to worsening of schizophrenia symptoms or medication side effects within four (4) weeks prior to Screening
4. The subject has previously received NaBen®
5. History of epilepsy, major head trauma, or any neurological illness other than Tourette’s syndrome which might impair the subject’s cognition or psychiatric functioning per the Investigator’s judgment
6. History of allergic reaction to sodium benzoate
7. Serious medical illnesses such as end-stage renal disease, liver failure or heart failure that, in the opinion of the Investigator, may interfere with the conduct of the study
8. Any significant gastrointestinal disorders that, in the opinion of the Investigator, markedly alter the absorption, metabolism or elimination of sodium benzoate
9. Any movement disorder that might affect the ratings on the EPS scales (e.g. Parkinson’s disease) or any movement disorder that is due to antipsychotic medications and is not currently controlled with anti-EPS medications
10. Current substance abuse, or history of meeting criteria for moderate or severe substance abuse and/or substance dependence (including alcohol, but excluding nicotine and caffeine) in the past six (6) months prior to Screening
11. Female subjects who are pregnant (as confirmed by serum pregnancy test performed at Screening Visit) or are breast feeding
12. History of cancer not in remission for the last three (3) years except for basal cell carcinoma and squamous cell carcinoma
13. Participation in a clinical trial within 3 months prior to Screening or more than two clinical trials within 12 months
14. Electroconvulsive Therapy (ECT) within 6 months prior to Screening
15. The subject started a new non-medication treatment for schizophrenia or other psychiatric condition within the last 3 months prior to Screening (e.g. individual psychotherapy, cognitive behavioral therapy or rehabilitative therapy)
16. The subject’s anti-EPS medications dose or regimen has changed within 2 weeks prior to Screening
17. The subject’s PANSS total score has decreased more than 20 percent using PANSS score evaluations at Visit 1 and Visit 2

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Mean change from baseline in Positive and Negative Syndrome Scale (PANSS) total score after 8 weeks of randomized treatment

Secondary endpoints 8

1. Percent change from baseline in PANSS total score after 8 weeks of treatment
2. Percentage of subjects with 20% or more reduction from baseline in PANSS total score after 8 weeks of treatment
3. Percent change in PANSS sub-scales and Marder PANSS factor scores
4. Percent change in Personal and Social Performance (PSP) scale
5. Percent change in Schizophrenia Quality of Life Scale (SQLS)
6. Percent change in Clinical Global Impression-Severity (CGI-S) and -improvement (CGI-I)
7. Percent change in Hamilton Depression Rating Scale (HDRS)
8. Serum pharmacokinetic evaluations

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Syneurx International (Taiwan) Corp.

Sponsor organisation

Syneurx International (Taiwan) Corp.

Address

20f 8 No. 99, Xin Tai 5th Rd. Sec 1, Xizhi Dist. Xin Tai 5th Rd. Sec 1 Xizhi Dist.

City

New Taipei City

Postcode

221416

Country

Taiwan

Scientific contact point

Organisation

Syneurx International (Taiwan) Corp.

Contact name

SyneuRx_Clinical

Public contact point

Organisation

Syneurx International (Taiwan) Corp.

Contact name

SyneuRx_Clinical

Third parties 2

Locations

1 EU/EEA country · 4 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 4 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications