Efficacy and Safety Study of Levomilnacipran Hydrochloride Extended-Release Capsules in Major Depressive Disorder

A Randomized, Double-Blind, Active-Controlled, Multicenter Phase III Clinical Trial Evaluating the Efficacy and Safety of Levomilnacipran Hydrochloride Extended-Release Capsules in the Treatment of Patients With Major Depressive Disorder (MDD)

The purpose of this study is using Duloxetine Hydrochloride Enteric Capsules as the positive control, to evaluate the efficacy and safety of Levomilnacipran Hydrochloride Extended-Release Capsules in patients with Major Depressive Disorder (MDD).

Inclusion Criteria:

1. Outpatient patients aged 18 to 65 years (inclusive of 18 but exclusive of 65), regardless of gender;
2. Meet the diagnostic criteria for depression as per the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), with a duration of at least 3 months for first-episode cases (30 days per month);
3. Current depressive episode confirmed using the Mini-International Neuropsychiatric Interview (M.I.N.I.) version 7.0.0 or higher;
4. Total HAMD17 score ≥18 at screening and baseline visits;
5. CGI-S score ≥4 at screening and baseline visits;
6. Agree to use effective contraception during the trial and for 30 days after the last dose (women of childbearing potential must have a negative pregnancy test before dosing and not be breastfeeding), and men and women must have no plans to donate sperm or eggs, respectively;
7. Voluntarily participate in the trial and sign the informed consent form.

Exclusion Criteria:

1. Meet DSM-5 diagnostic criteria for other mental disorders (including but not limited to schizophrenia spectrum and other psychotic disorders, bipolar and related disorders, obsessive-compulsive and related disorders, somatic symptom and related disorders);
2. Previous failure to respond to adequate dose and duration (maximum recommended dose for MDD as per label for at least 4 weeks) of serotonin and norepinephrine reuptake inhibitors (including but not limited to milnacipran, levomilnacipran, duloxetine, venlafaxine, desvenlafaxine), or failure to respond to adequate dose and duration of at least two antidepressant drugs;
3. Allergic to milnacipran, levomilnacipran, duloxetine, or excipients of the trial drug, or have an allergic constitution;
4. History of suicide attempt within 1 year prior to screening; suicidal or self-harming behavior during screening; HAMD17 item 3 (suicide) score ≥3; currently at high suicide risk;
5. Depression secondary to other diseases;
6. History of epileptic seizures (except for febrile convulsions in childhood);
7. Received systematic electroconvulsive therapy, transcranial magnetic stimulation, transcranial direct current stimulation, systematic psychotherapy, or other treatments with antidepressant effects within 3 months prior to screening; received electroconvulsive therapy within 1 month prior to screening;
8. Discontinuation of psychotropic drugs or their active metabolites less than 5 half-lives, or monoamine oxidase inhibitors less than 2 weeks, before randomization;
9. Required to use drugs with clinically significant interactions with the trial drug during the trial (including but not limited to monoamine oxidase inhibitors, other serotonergic drugs, drugs affecting coagulation, strong CYP3A4/CYP1A2/CYP2D6 inhibitors or inducers, alcohol, linezolid, and intravenous methylene blue);
10. Conditions affecting drug swallowing or absorption, as judged by the investigator;
11. Risk factors for angle-closure glaucoma, as judged by the investigator;
12. Abnormal and clinically significant results from physical examinations or laboratory tests at screening or baseline, as judged by the investigator, including but not limited to ALT, AST, total bilirubin, or serum creatinine >1.5 times the upper limit of normal, or thyroid-stimulating hormone outside the normal range;
13. Current or past medical history of diseases or dysfunctions affecting the trial, as judged by the investigator, including but not limited to chronic or acute diseases of the nervous, motor, circulatory, respiratory, digestive, urinary, endocrine, reproductive, or immune systems;
14. Clinically significant cardiovascular diseases, as judged by the investigator, including but not limited to atrial fibrillation, second- or third-degree atrioventricular block, myocardial infarction within 12 months, or NYHA heart function class III or above;
15. ECG QTcF interval ≥450 ms (males) or ≥470 ms (females), or other factors increasing the risk of QTcF prolongation or arrhythmic events (including but not limited to heart failure, hypokalemia, family history of long QT syndrome), or ECG heart rate <50 bpm or >120 bpm (Note: QTcF = QT/(RR^0.33));
16. Resting seated systolic blood pressure <90 mmHg or >140 mmHg, or diastolic blood pressure <50 mmHg or >90 mmHg;
17. Diagnosed with end-stage renal disease at screening or previously, as judged by the investigator;
18. History of malignant tumors, as judged by the investigator at screening or previously;
19. Positive virological screening for hepatitis B surface antigen (HBsAg), hepatitis C antibody (HCVAb), syphilis antibody, or human immunodeficiency virus (HIV) antibody during screening;
20. History of drug or alcohol abuse;
21. Weekly alcohol consumption exceeding 14 units in the 6 months prior to screening (1 unit = 360 mL beer, 45 mL 40% liquor, or 150 mL wine);
22. Inability to comply with medication instructions, as judged by the investigator;
23. Physiological or psychological conditions that may increase trial risks, affect protocol compliance, or prevent trial completion, as judged by the investigator;
24. Participation in any clinical trial (received investigational drugs or medical devices) within 30 days before signing the informed consent form;
25. Concomitant diseases that may interfere with trial procedures or assessments, or other conditions deemed unsuitable for trial participation by the investigator.