Evaluate Efficacy and Safety of Endoxifen in Bipolar I Disorder Patients
Evaluate Efficacy and Safety of Endoxifen in Bipolar I Disorder Patients
The present study aims to evaluate the efficacy and safety of 8 mg endoxifen in the study
 population. As endoxifen represents a totally new class of drugs in the treatment of the
 bipolar disorder, it is essential to compare the drug against placebo to rule out the
 psychological influence upon study results. More so given the risks to patients and their
 communities from a medication whose efficacy has not been thoroughly evaluated against a
 placebo control. Thus, Endoxifen will be compared to placebo to demonstrate that the test
 product is active and to establish that the study is sufficiently sensitive to detect
 differences between the investigational products.
Protein Kinase C (PKC) plays a major role in the regulation of both pre and postsynaptic
 neurotransmission. Excessive activation of PKC results in symptoms related to bipolar
 disorder. PKC exists as a family of closely related subspecies, has a heterogeneous
 distribution in the brain (with particularly high levels in presynaptic nerve terminals), and
 plays a crucial role in the regulation of neuronal excitability, neurotransmitter release,
 regulation of synaptic plasticity and various forms of learning and memory. Research findings
 show that the PKC pathway can be used as a target for developing treatment strategies for
 bipolar disorder. Endoxifen exhibited activity in inhibiting the PKC activity.

 In patients with acute bipolar mania, rapid reduction of symptoms is a key treatment goal;
 however, there is also a need for effective maintenance of effect treatment beyond the period
 of acute stabilization. The current study will evaluate the efficacy and safety of Endoxifen
 in Bipolar I Disorder patients against a control placebo arm.
Inclusion Criteria:

 1. Male and female patients, 18 to 65 (both inclusive) years of age willing to give
 written informed consent along with at least one first degree relative (the legally
 acceptable representative [LAR]) to participate in the study before initiating any
 study related procedures.

 2. Patients must have a diagnosis of bipolar I disorder and currently display an acute
 manic episodes with or without mixed features according to DSM-5 criteria as judged by
 the Investigator.

 3. Young Mania Rating Scale (YMRS) total score of > 20 and ≥4 on two of four core items
 (irritability, speech, content, disruptive/aggressive behavior) at screening and at
 randomization (baseline).

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

 5. Ready for voluntary hospitalization (along with the accompanying LAR if required and
 as advised by the Investigator) for the current manic episode 2 days prior to
 randomization up to 21 days of in-patient treatment period.

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

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

 8. Male patients of child begetting potential must be practicing adequate contraception.

 9. Females of reproductive potential (which include girls who have entered puberty and
 all women who have a uterus and ovaries and have not completed menopause), must use
 anacceptable and effective method of avoiding pregnancy, starting at least four weeks
 before the first dose of study drug and continuing until at least one month after the
 last dose of study drug.

 10. Subjects judged clinically not to be at serious suicide risk.

 Exclusion Criteria:

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

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

 3. Patients who meet DSM-5 criteria for any psychiatric disorder other than Bipolar I
 Disorder with Acute Mania Episode 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 current
 severity to interfere with conduct of the study

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

 8. Use of the following medications:

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

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

 -  Continuous daily or standing orders use of benzodiazepines during the month
 preceding screening (approximately 5 weeks prior to screening)

 -  Potent cytochrome P450 (CYP) inducers and CYP2D6/CYP3A4 inhibitors 14 days prior
 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 or
 hyperthyroidism

 -  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 the
 Investigator) which prolong QTc interval

 -  Sustained cardiac arrhythmia or history of sustained cardiac arrhythmia

 -  De compensatory 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 thromboembolism
 including 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 of
 the preparation.

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

 17. Drug screen positive for any drug of abuse at screening (with the exception of
 benzodiazepines used in therapeutic dose for management of acute mania), active
 substance abuse in the past 2 months or history of substance dependence (excluding
 nicotine and caffeine) 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 best
 health interest of the subject.

 20. Clinically significant suicidal or homicidal ideation.

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