The Research of Ammoxetine Hydrochloride Enteric-coated Tablets in Subjects With Depression

Efficacy and Safety of Ammoxetine Hydrochloride Enteric-coated Tablets in Subjects With Depression: A Multicenter, Randomized, Double-blind, Double-Dummy, Placebo-controlled and Sertraline Active-controlled, Parallel-group, Phase III Study

The purpose of this study is to evaluate the efficacy and safety of Ammoxetine hydrochloride enteric-coated tablets in subjects with depression.

In this study, a randomized, double-blind, double-dummy, placebo-controlled and Sertraline active-controlled multicenter study will be conducted to evaluate the efficacy and safety of different doses of Ammoxetine hydrochloride enteric coated tablets in the treatment of depression.

Inclusion Criteria:

• 1. Subjects aged 18 and 65 years (inclusive), no gender limitation;
• 2. Subject has recurrent Major Depressive Disorder (MDD) as the primary diagnosis according to Diagnostic and Statistical Manual of Mental Disorders (DSM-5, 5th Edition), single episode or recurrent episodes (classification code 296.2/296.3).The duration of the current depressive episode should be ≥3 months for first-episode patients and ≥1 month for relapsing patients;
• 3. Subjects with a Montgomery-Asberg Depression Rating Scale (MADRS) score ≥ 26 at screening and baseline. Subjects with Clinical Global Impression Scale Disease Severity CGI-S severity score ≥ 4 at screening and baseline. Score of first item (depressed mood) of the HAMD-17 scale ≥2 at the screening and baseline.
• Be able to read and understand the study procedures and trial requirements, agree to abide by the restrictions of the trial and return to the site on time for evaluation, and sign the informed consent form prior to the trial.

Exclusion Criteria:

• 1. Subjects with ≥ 25% reduction in MADRS score in the baseline period compared to the screening period;

• 2. There is a clinically significant risk of suicide or risk of self-injury and harm to others. Those who meet any of the following:

  1. A score of ≥4 on item 10 (Suicidal Ideation) of the MADRS scale;
  2. Subjects who in the judgment of the investigator, are at significant risk for suicide (e.g., participant answered "yes" to question 4 (active suicidal ideation with intent to act but no specific plan) or question 5 (active suicidal ideation with a specific plan and intent) on the Screening C-SSRS and the most recent suicidal intent or suicidal plan occurred within the last six months);
  3. Attempted suicide during the current depressive episode;

• 3. Subjects meet DSM-5 diagnostic criteria for other mental disorders (Schizophrenia spectrum and other psychotic disorders, bipolar and related disorders, anxiety disorders, obsessive-compulsive and related disorders, somatic symptoms and related disorders, substance-related and addiction disorders, etc.)

• 4. Subjects who meet any of the following diagnoses of depressive disorders:

  1. Those who have been determined by the investigator to have TRD (current or prior use of 2 or more antidepressants with different mechanisms that have not been effective with a full course (at least 8 weeks) of treatment at the full dosage (the maximum recommended amount of the instructions);
  2. Subjects with depressive disorders due to other types of mental disorders or somatic diseases (e.g., depressive disorders due to hypothyroidism);
  3. Subjects with depressive disorders due to substances/drugs;

• 5. Subjects who stopped using the following drugs for less than 5 half-lives prior to randomization:

  1. CYP2C19 and CYP3A4 strong inducers and strong inhibitors (e.g., fluoxetine, rifampicin, carbamazepine, etc.);
  2. Combined use of drugs that cause QTc interval prolongation (e.g., levofloxacin, fluconazole, ondansetron, amiodarone, metronidazole, erythromycin, and haloperidol, etc.) or drugs that can cause QTc interval prolongation and may induce torsade de pointes ventricular tachycardia;
  3. Antipsychotics, antidepressants, or mood stabilizers;

• 6. Subjects who have failed previous treatment with a full course (at least 8 weeks) of sertraline at the maximum recommended dose or who have a known allergy to sertraline;

• 7. Subjects who stopped using MAOI (e.g., phenelzine, isocarbazide, antiphencyclidine, linezolid, methylene blue, etc.) for less than 2 weeks before randomization;

• 8. Subjects on long half-life antipsychotics;

• 9. Subjects who have received any of the following non-pharmacologic treatments within 3 months prior to screening:

  1. Electroconvulsive therapy (ECT)
  2. Systemic psychotherapy (e.g., interpersonal therapy, motivational therapy, cognitive behavioral therapy, etc.)
  3. Transcranial magnetic stimulation therapy (TMS)
  4. Vagus Nerve Stimulation (VNS)
  5. Light therapy, etc.
  6. Or those who, in the judgment of the investigator, currently require the above treatments

• 10. Participation in any clinical trial within 3 months prior to screening;

• 11. Those with degree II or III AV block, long QT syndrome, or QTcF >450 ms (males)/460 ms (females) on 12-lead ECG at the time of screening, or those deemed unsuitable for enrollment by the investigator (e.g., tachyarrhythmias requiring clinical management, etc.)

• 12. Screening subjects with ALT or AST greater than 2 times the upper limit of laboratory normal; Severe subclinical hypothyroidism (thyroid function indices only with abnormally elevated TSH and TSH ≥ 10.0 mIU/L); Abnormalities in 2 or more of the 5 thyroid function parameters (TSH, FT3, FT4, TT3, or TT4 values less than 0.9 times the lower limit of normal or more than 1.1 times the upper limit of normal);

• 13. Allergic constitution (e.g. allergic to two or more drugs or to SNRIs);

• 14. Prior history of seizures; or any other condition that increases the risk of seizures (e.g., stroke, severe head trauma, significant metabolic disorders, etc.);

• 15. By the judgment of the investigator, presence of any clinically significant hematologic, endocrine/metabolic, cardiovascular, respiratory, renal, hepatic, gastrointestinal, infectious, or neurological disease or the presence of an unstable or progressive chronic disease that unsuitable for entry into the study;

• 16. History of malignancy, including solid tumors, hematologic malignancies, and carcinoma in situ (except completely resected and cured basal cell carcinoma of the skin, squamous cell carcinoma, and carcinoma in situ of the cervix), within 5 years prior to screening;

• 17. Previous history of increased intraocular pressure or narrow-angle glaucoma;

• 18. Subjects with conditions that interfere with the absorption of oral medications, such as active enteropathy, partial or complete intestinal obstruction, and chronic diarrhea, etc;

• 19. Female subjects who are breastfeeding or have a positive pregnancy test during the screening period or during the study;

• 20. Alcohol or drug dependence within 3 months before screening;

• 21. Male or female with fertility do not agree to use an effective method of contraception during the study and for 1 month after the end of the trial to ensure that contraception is effective for the sexual partner or for themselves;

• 22. Subjects who in the opinion of the investigator, have any other condition that makes them unsuitable for participation in this trial.