Efficacy and Safety of Endoxifen in Bipolar I Disorder Patients

Inclusion Criteria:

1. Male ≥18 to ≤65 years of age and postmenopausal female patients (12 months with nomenses without an alternative medical cause) willing to give written informedconsent along with at least one first degree relative (the legally acceptablerepresentative [LAR]) to participate in the study before initiating any studyrelated procedures.

2. Six months of spontaneous amenorrhea with serum FSH levels >40 mIU/mL; OR havehad surgical bilateral oophorectomy (with or without hysterectomy) at least sixmonths ago. In the case of oophorectomy alone, only when the reproductive status ofthe woman has been confirmed by follow up hormone level assessment if she isconsidered not of child-bearing potential.

3. Patients must have a diagnosis of bipolar I disorder and currently display an acutemanic episode with or without mixed features according to DSM-5 criteria as judgedby the Investigator.

4. Young Mania Rating Scale (YMRS) total score of > 25 and ≥4 on two of four coreitems (irritability, speech, content, disruptive/aggressive behavior) at screeningand at randomization (baseline). The optimal YMRS23 severity threshold of 25 waschosen as this corresponds to a Positive Predictive Value (PPV) of 83%, signifyingthat 83% of patients with a baseline score ≥ 25 are at least "Markedly ill".

5. Score of >4 in Severity of illness criteria of Clinical Global Impressions-bipolar disorder (CGI-BP) Scale for overall illness at screening and atrandomization (baseline).

6. Ready for voluntary hospitalization (along with the accompanying LAR if required andas advised by the Investigator) for the current manic episode for a minimum of 2days prior to randomization through 21 days of in-patient treatment period.

7. Last intake of the medication(s) for BPD should be 2-7 days prior to randomizationdepending upon the individual drug's plasma half-life.

8. Patient and / or LAR understand and agree to comply with all the study requirements.

9. Male patients of child begetting potential must be practicing adequatecontraception, and any female partners must agree to the use of, highly effectivecontraception. Documentation should be provided for surgical sterilization for malepatients not of child begetting potential.

10. Patient has not taken and agrees not to take any medication or therapy prohibited bythe protocol (refer to listing in Section 14.7) for the entire study period.

11. Patients not having any significant diseases or clinically significant abnormalfindings except BPD during screening-including medical history, physicalexamination, laboratory evaluations, 12-lead ECG and X-ray chest (postero- anteriorview) recording, etc. which is likely to adversely affect patient's safety andmay impact the clinical outcome of the study by participating in the study or studyobjectives in Investigator's opinion.

12. Subjects judged clinically not to be at serious suicide risk, (all responses to theBaseline C-SSRS as "No"), or homicidal risk per clinical questioning.

Exclusion Criteria:

1. Newly diagnosed patients not having any suitable treatment exposure in the past fortheir bipolar mood disorder.

2. ≥ 20% improvement in YMRS total scores between screening and randomization visits.

3. Patients who meet DSM-5criteria for any psychiatric disorder other than Bipolar IDisorder with Acute manic episodes with or without mixed features

4. Patients with seizure disorder

5. Obsessive compulsive disorder or any other co-morbid Axis I anxiety disorder

6. Patients with borderline or anti-social personality disorder of sufficient currentseverity to interfere with conduct of the study

7. Patients with classical premenopausal symptoms were found at risk of developingintolerable hot flushes, irregular vaginal bleeding.

8. Use of the following medications:

• Antihypertensive agents if stable dose has not been administered for at least 1month before randomization

• Antidepressants in the week (or a period of 5 half-lives of the drug) prior torandomization

• Continuous daily or standing orders use of benzodiazepines during the monthpreceding screening (approximately 5 weeks prior to screening)

• Potent cytochrome P450 (CYP) inducers and CYP2D6/CYP3A4 inhibitors 14 daysprior to randomization

• Depot antipsychotic medications within 1 dosing interval prior to randomization

• Use of systemic estrogens 6 weeks prior to randomization

• Patients currently on carbapenem agents

9. Any of the following laboratory abnormalities

• Serum bilirubin ≥ 1.5 times ULN

• Serum AST/ALT ≥ 2.5 times ULN

• Serum TSH >10% above the ULN, regardless of treatment for hypothyroidism orhyperthyroidism

• Serum triglyceride level > 2.5 times ULN

10. Patients with the following cardiac conditions are excluded:

• Recent myocardial infarction (<12 months)

• QTc prolongation (screening electrocardiogram with QTc > 450 msec for men,QTc > 470 msec for women)

• History of QTc prolongation or using concomitant medications (as judged by theInvestigator) which prolong QTc interval

• Sustained cardiac arrhythmia or history of sustained cardiac arrhythmia

• Decompensatory congestive heart failure

• Complete left bundle branch block

• First-degree heart block with PR interval > 0.22 seconds

11. Presence of a coagulation disorder; active or past history of venous thromboembolismincluding deep venous thrombosis or pulmonary embolism

12. Current prolonged immobilization

13. History or current presence of retinal pathology including retinal vein thrombosis

14. Increased risk of stroke as per the Investigator's discretion

15. History of hypersensitivity or intolerance to tamoxifen, or any other ingredients ofthe preparation

16. Serious, unstable illnesses including hepatic, renal, gastroenterological,respiratory, cardiovascular (including ischemic heart disease), endocrinologic,neurologic, immunologic, or hematologic disease as per history and medicalexamination.

17. Drug screen positive for any drug of abuse at screening, (except for benzodiazepinesused in therapeutic dose for management of acute mania), active substance abuse inthe past 2 months or history of substance dependence (excluding nicotine andcaffeine) within 3 months of screening.

18. History of breast or uterine cancer, or abnormal uterine bleeding.

19. Current leukopenia or thrombocytopenia as judged by the Investigator in the besthealth interest of the subject.

20. Clinically significant suicidal (subject responds "Yes" to any category for BaselineC-SSRS) or homicidal ideation per clinical questioning.

21. Participation in a clinical trial of another investigational drug within 30 daysprior to screening.