A Phase II Clinical Study to Evaluate the Efficacy and Safety of NS-136 in the Treatment of Schizophrenia

A Randomized, Double-blind, Placebo-controlled Phase II Clinical Study to Evaluate the Efficacy and Safety of NS-136 in the Treatment of Schizophrenia

This is a randomized, double-blind, placebo-controlled, parallel-group Phase II study to preliminarily evaluate the efficacy and safety of NS-136 in patients with schizophrenia. The study consists of a screening period, baseline period, treatment period, and follow-up period, with the screening period lasting up to 21 days.

Eligible subjects will be randomized in a 1:1:1 ratio to the 80 mg (QD) group, 120 mg (QD) group, or placebo group. The study drug treatment will last for 5 weeks, followed by a 2-week safety follow-up after completion of the study.

Inclusion Criteria:

1. Male or female aged 18-65 years (inclusive) with body mass index (BMI) of 18-34 kg/m2 (inclusive);
2. No participation in other clinical studies within 60 days prior to signing the informed consent form (ICF);
3. Patients diagnosed with schizophrenia according to DSM-5 criteria;
4. During the screening and baseline periods, subjects should have a PANSS total score of 80 or above, CGI-S score of 4 or above, moderate-to-severe illness severity, and at least 2 positive symptoms;
5. Trial participants are willing to discontinue all prohibited antipsychotic medications in order to meet the wash-out period required by the study protocol;
6. Trial participants are in a state of relapse or acute exacerbation of psychotic symptoms prior to signing the ICF;
7. Women of childbearing potential must have a negative serum pregnancy test during the screening period. All subjects should agree to use effective contraception (see Appendix 1 for details) from the time of signing the ICF until at least 3 months after the last dose of the study drug, with no plans for sperm or egg donation;
8. Subjects should fully understand the study objectives, nature, procedures, and potential adverse reactions, voluntarily participate as subjects, and sign the ICF before any study procedures are initiated.

Exclusion Criteria:

1. DSM-5 Diagnosis: Subjects with the following psychiatric diagnoses should be excluded, including but not limited to intellectual disability, schizoaffective disorder, schizotypal disorder, depressive psychosis, major depressive disorder, bipolar disorder, post-traumatic stress disorder, generalized anxiety disorder, obsessive-compulsive disorder, eating disorders (bulimia nervosa, anorexia nervosa) or other anxiety disorders (except anxiety symptoms secondary to schizophrenia); dementia, dementia-like symptoms, amnesia or other cognitive disorders; borderline personality disorder, paranoid personality disorder, histrionic personality disorder, schizoid personality disorder, apathetic personality disorder or antisocial personality disorder;

2. Subjects with treatment-resistant schizophrenia who have shown no response or improvement after receiving adequate doses (clinically tolerable effective doses) of two different classes of antipsychotic drugs for a minimum treatment duration of 6 weeks; or subjects who are unresponsive to clozapine treatment or responsive only to clozapine treatment;

3. Subjects with unstable extrapyramidal symptoms requiring dose adjustments and/or new medication treatments within 6 months prior to signing the ICF;

4. Subjects with current or past history of significant pulmonary, gastrointestinal, renal, hepatic, metabolic, endocrine (including newly diagnosed diabetes or known diabetes with HbA1c >7.5%), hematologic, immunologic, psychiatric (except schizophrenia), or neurological disorders, dysphagia, or hypersensitivity to the study drug or any of its components;

5. Subjects with current or past history of major cardiovascular diseases, including any of the following: ischemic heart disease, myocardial infarction, valvular heart disease, cardiac surgical revascularization (coronary artery bypass grafting, stent placement or percutaneous transluminal coronary angioplasty), hypertension, receiving antihypertensive medications, orthostatic hypotension, angina pectoris, unstable angina, cerebrovascular accident or stroke or transient ischemic attack, pacemaker, atrial fibrillation, flutter or nonsustained or sustained ventricular tachycardia, pulmonary hypertension, sick sinus syndrome, second- or third-degree atrioventricular block, congestive heart failure, personal or family history of sudden death or long QT syndrome, unexplained syncope or syncope within the past 3 years;

6. Subjects presenting with first-episode schizophrenia symptoms as judged by the investigator;

7. Subjects who, in the investigator's judgment, have exhibited acute depressive symptoms within the last 30 days requiring antidepressant treatment;

8. Subjects with a history of epilepsy or seizures, excluding single seizure episodes (e.g., childhood febrile seizures) or seizures associated with trauma or alcohol withdrawal;

9. Subjects with central nervous system infections, demyelinating diseases, progressive neurological disorders, intellectual disability, or any central nervous system condition deemed progressive;

10. Subjects who have received systemic electroconvulsive therapy within 60 days prior to screening;

11. Subjects who answer "Yes" to item 4 of the C-SSRS suicidal ideation section (active suicidal ideation without specific plan) with the most recent episode meeting this C-SSRS item 4 criterion occurring within the past 6 months, as well as those who answer "Yes" to item 5 of the C-SSRS suicidal ideation section (active suicidal ideation with specific plan and intent);

12. Subjects with positive results in any of the following screening tests: hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (Anti-HCV), human immunodeficiency virus antibody (Anti-HIV), or serological testing for syphilis antibody;

13. Subjects with any of the following abnormal clinical laboratory test results during the screening period (one retest is permitted at the investigator's discretion):

    • AST or ALT ≥3×ULN
    • Total bilirubin ≥2×ULN

14. Subjects with alcohol abuse or weekly alcohol consumption exceeding 14 units (1 unit equals 17.5 mL or 14 g pure alcohol; alcohol content of different beverages is labeled by volume percentage; 1 alcohol unit approximately equals 35 mL of 50° liquor or 350 mL of 5° beer) within 4 weeks prior to screening;

15. Subjects with a history of drug abuse within 1 year prior to the first dose, or positive results in the multi-drug test panel (urine) during screening (except for benzodiazepines);

16. Subjects who have used moderate or strong CYP3A4 inducers or inhibitors within 2 weeks prior to the first dose, or are expected to require moderate or strong CYP3A4 inducers or inhibitors during study participation;

17. Subjects deemed by the investigator to have other factors unsuitable for study participation.