Dose-Finding Clinical Trial to Evaluate the Efficacy and Safety of LV232 Capsules in the Treatment of MDD

This multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-finding Phase II clinical trial aimed to determine the optimal dose of LV232 capsules for treating MDD, evaluate preliminary efficacy and safety, and provide a basis for Phase III trial design and dosing regimen determination.

This study adopts a multicenter, randomized, double-blind, placebo- and active-controlled parallel-group clinical trial design, aiming to evaluate the efficacy and safety of LV232 capsules ( 40 mg, and 60 mg, once daily) in patients with major depressive disorder (MDD).

The trial plans to enroll 400 subjects, stratified by first episode or recurrence of the disease. Participants will be randomized in a 1:1:1:1 ratio into five groups: LV232 capsules 40 mg, 60 mg, placebo, and active control, with 100 subjects in each group. The treatment will be administered once daily for 8 consecutive weeks.

Eligibility Criteria:
Inclusion Criteria:

1. Fully understand the purpose, content, and potential adverse reactions of this trial, voluntarily participate in the clinical trial and sign a written informed consent form, able to complete the entire trial process as required and comply with the trial regulations;
2. Gender unrestricted, at screening: 18 years old ≤ age ≤ 65 years old;
3. Meet the DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, 5th Edition) diagnostic criteria for depression according to the Mini International Neuropsychiatric Interview (M.I.N.I. 7.0.2), currently experiencing a single or multiple episodes;
4. For first-episode patients, the duration of the current depressive episode must be ≥3 months; for recurrent patients, the duration of the current depressive episode must be ≥1 month (each month is counted as 30 days, the same applies below);
5. During the screening and baseline periods, the total score on the Montgomery-Asberg Depression Rating Scale (MADRS) must be ≥26, and the Clinical Global Impression-Severity (CGI-S) score must be ≥4;
6. At screening and baseline visits, the score on the first item (depressed mood) of the HAMD-17 scale must be ≥2;
7. Female or male subjects of childbearing potential agree and commit to using effective contraception from the signing of the informed consent form until 3 months after the last administration of the trial drug.

Exclusion Criteria:

1. Treatment-resistant depression (failure to respond to an adequate dose and duration of treatment, at least 8 weeks, with two antidepressants of different mechanisms) or failure to respond to an adequate dose and duration of treatment with escitalopram oxalate;
2. Meeting the diagnostic criteria for other mental disorders as per DSM-5 (such as schizophrenia spectrum and other psychotic disorders, bipolar and related disorders, generalized anxiety disorder, obsessive-compulsive and related disorders, somatic symptom and related disorders, etc.);
3. Meeting the DSM-5 criteria for substance use disorder;
4. Organic mental disorders, such as depression caused by hypothyroidism;
5. Depression induced by psychoactive substances or non-addictive substances;
6. Presence of depressive symptoms due to other diseases or other types of mental disorders;
7. A reduction of ≥25% in the MADRS score at baseline compared to the screening period;
8. Assessed by the Columbia Suicide Severity Rating Scale (C-SSRS) and judged by the investigator to be at risk of suicide, or having suicidal behavior within the 6 months prior to screening;
9. Presence of severe physical illnesses deemed by the investigator as grounds for exclusion, such as uncontrolled hypertension or severe unstable cardiovascular diseases, severe liver diseases, kidney diseases, blood diseases, endocrine diseases, neurological diseases, etc.;
10. Diseases affecting oral drug absorption, such as active bowel disease, partial or complete intestinal obstruction, chronic diarrhea, etc.;
11. Active malignancy or a history of malignancy within 5 years prior to screening (except for completely resected and cured squamous cell carcinoma, cervical carcinoma in situ, etc.);
12. History of increased intraocular pressure or narrow-angle glaucoma;
13. Individuals with allergic constitution, such as those allergic to two or more drugs or known to be allergic to escitalopram oxalate;
14. Use of drugs that alter the activity of liver enzymes (CYP2C19 and CYP2D6) within 4 weeks (or 5 half-lives, whichever is longer) prior to randomization (see Appendix 2);
15. Previous treatment with vagus nerve stimulation (VNS) and deep brain stimulation (DBS), or modified electroconvulsive therapy (MECT) within 3 months prior to randomization, or systematic psychotherapy (interpersonal therapy, dynamic therapy, cognitive behavioral therapy), transcranial magnetic stimulation (TMS), and light therapy within 1 month prior to randomization, or judged by the investigator to currently require such treatments;
16. Systematic antidepressant treatment within 2 weeks prior to randomization (not less than 30 days for fluoxetine), or discontinuation of psychotropic drugs for less than 5 half-lives prior to randomization (except for stable doses of sleep aids received within 4 weeks prior to randomization, including benzodiazepines (limited to estazolam, alprazolam, and oxazepam) and non-benzodiazepines);
17. Use of monoamine oxidase inhibitors such as phenelzine, isocarboxazid, tranylcypromine, etc., and linezolid, methylene blue, etc., within 2 weeks prior to randomization;
18. Second or third-degree atrioventricular block, long QT syndrome, or QTcF \> 450 ms (male)/460 ms (female) on 12-lead ECG at screening;
19. Discontinuation of drugs that prolong the QT interval (such as levofloxacin, fluconazole, ondansetron, amiodarone, metronidazole, erythromycin, and haloperidol, etc.) or drugs that may cause QT interval prolongation and induce torsade de pointes (TdP) for less than 5 half-lives at randomization;
20. ALT or AST above 2 times the upper limit of normal; creatinine above 1.5 times the upper limit of normal; 2 or more abnormal indicators in thyroid function tests (TSH, FT3, FT4, TT3, or TT4 below 0.9 times the lower limit of normal or above 1.1 times the upper limit of normal) at screening;
21. Positive for Treponema pallidum antibody and HIV antibody at screening;
22. Substance abuse (including alcohol, drugs, and other psychoactive substances) within 3 months prior to screening;
23. Female subjects who are breastfeeding or have a positive pregnancy test at screening or during the trial;
24. Participation in any interventional clinical trial and use of investigational drugs or medical devices within 3 months prior to screening, or currently participating in other clinical trials;
25. Other factors deemed by the investigator as unsuitable for participation in the trial.