Efficacy and Safety of Endoxifen in Bipolar I Disorder Patients

Recruitment Status
ACTIVE, NOT RECRUITING
(See Contacts and Locations)Verified August 2024 by Jina Pharmaceuticals Inc.
Sponsor
Jina Pharmaceuticals Inc.
Information Provided by (Responsible Party)
Jina Pharmaceuticals Inc.
Clinicaltrials.gov Identifier
NCT06608641
Other Study ID Numbers:
72189812
First Submitted
September 17, 2024
First Posted
September 22, 2024
Last Update Posted
March 16, 2025
Last Verified
August 2024

ClinicalTrials.gov processed this data on March 2025. Link to the current ClinicalTrials.gov record .

History of Changes

Study Details

Study Description

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.

Condition or DiseaseIntervention/Treatment
Bipolar 1 Disorder
Drug: Endoxifen enteric-coated tablet (8 mg)Drug: Placebo Tablets

Study Design

Study TypeInterventional
Actual Enrollment490 participants
Design AllocationRandomized
Interventional ModelParallel Assignment
MaskingQuadruple
Primary PurposeTreatment
Official TitleA Double-blind, Oral, Multiple-dose, Parallel, Randomized Study to Evaluate Efficacy and Safety of Endoxifen in Bipolar I Disorder Patients With Acute Mania Episodes With or Without Mixed Features
Study Start DateMarch 18, 2024
Actual Primary Completion DateMay 31, 2025
Actual Study Completion DateNovember 30, 2025

Groups and Cohorts

Group/CohortIntervention/Treatment
Endoxifen Arm
Endoxifen enteric-coated tablet (8 mg). Patients will continue treatment with their initial randomized medication for 3 weeks
Drug: Endoxifen enteric-coated tablet (8 mg)
Patients will continue treatment with their initial randomized medication for 3 weeks
Placebo Arm
Placebo tablets. Patients will continue administration with their initial randomized medication for 3 weeks
Drug: Placebo Tablets
Patients will be treated with Endoxifen Placebo Tablets for 21 days

Outcome Measures

Primary Outcome Measures
  1. Efficacy - mean change from baseline to Day 21 in the total YMRS score
    Primary efficacy endpoint will be the mean change from baseline to Day 21 in the total YMRS score. The point estimate and 95% confidence interval for the mean change from Day 0 (baseline) to Day 21 in total YMRS score for the difference between test and placebo control treatment will be computed and reported for mITT set. Superiority of test over placebo will be claimed if 95% confidence interval for mean change from Day 0 (baseline) to Day 21 in total YMRS score for the difference between test and placebo control treatment will exclude zero for mITT set.
Secondary Outcome Measures
  1. Secondary efficacy endpoints
    * Percentage of patients with improvement of ≥ 50% in total YMRS from baseline. * Clinical Global Impression-Bipolar (CGI-BP) score at the end of study. * Mean change from baseline to the end of treatment in Montgomery-Åsberge Depression Rating Scale (MADRS) total score. * Improvement in Clinical Global Impression-Severity of Illness scale (CGI-S) score. * Columbia-Suicide Severity Rating Scale (C-SSRS) score at the end of treatment. * Percentage of patients needing lorazepam/diazepam for controlling acute agitation/akathisia. * Percentage of patients requiring rescue medications and withdrawal from the study. * To evaluate trough concentrations of Endoxifen.

Eligibility Criteria

Ages Eligible for Study(Adult, Older Adult)
Sexes Eligible for StudyAll
Accepts Healthy VolunteersNo
Inclusion Criteria
1. Male ≥18 to ≤65 years of age and postmenopausal female patients (12 months with no menses without an alternative medical cause) 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. Six months of spontaneous amenorrhea with serum FSH levels \>40 mIU/mL; OR have had surgical bilateral oophorectomy (with or without hysterectomy) at least six months ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment if she is considered not of child-bearing potential. 3. Patients must have a diagnosis of bipolar I disorder and currently display an acute manic episode with or without mixed features according to DSM-5 criteria as judged by the Investigator. 4. Young Mania Rating Scale (YMRS) total score of \> 25 and ≥4 on two of four core items (irritability, speech, content, disruptive/aggressive behavior) at screening and at randomization (baseline). The optimal YMRS23 severity threshold of 25 was chosen as this corresponds to a Positive Predictive Value (PPV) of 83%, signifying that 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 at randomization (baseline). 6. Ready for voluntary hospitalization (along with the accompanying LAR if required and as advised by the Investigator) for the current manic episode for a minimum of 2 days 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 randomization depending 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 adequate contraception, and any female partners must agree to the use of, highly effective contraception. Documentation should be provided for surgical sterilization for male patients not of child begetting potential. 11\. Patient has not taken and agrees not to take any medication or therapy prohibited by the protocol (refer to listing in Section 14.7) for the entire study period. 12\. Patients not having any significant diseases or clinically significant abnormal findings except BPD during screening-including medical history, physical examination, laboratory evaluations, 12-lead ECG and X-ray chest (postero- anterior view) recording, etc. which is likely to adversely affect patient\'s safety and may impact the clinical outcome of the study by participating in the study or study objectives in Investigator\'s opinion. 13\. Subjects judged clinically not to be at serious suicide risk, (all responses to the Baseline 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 for their 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 I Disorder 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 current severity to interfere with conduct of the study 7. Patients with classical premenopausal symptoms were 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
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 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, gastroenterological, 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, (except for 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 (subject responds "Yes" to any category for Baseline C-SSRS) or homicidal ideation per clinical questioning. 21. Participation in a clinical trial of another investigational drug within 30 days prior to screening.

Contacts and Locations

Sponsors and CollaboratorsJina Pharmaceuticals Inc.
Locations
Synexus | Cerritos California, United States, 90703NRC Research Institute | Los Angeles California, United States, 90015NRC Research Institute | Orange California, United States, 92868Medical Research of Westchester, Inc. | Miami Florida, United States, 33165Sunshine Medical Research Studies Inc. | Miami Florida, United States, 33186Innovative Clinical Research, Inc. | Miami Lakes Florida, United States, 33016South Florida Research Phase I-IV, Inc. | Miami Springs Florida, United States, 33166Santos Research Center, CORP | Tampa Florida, United States, 33615Accelerated Clinical Trials, LLC | East Point Georgia, United States, 30344Accelerated Clinical Trials, LLC | Norcross Georgia, United States, 30092Accelerated Clinical Trials, LLC | Peachtree Corners Georgia, United States, 30071Precise Research Centers | Flowood Mississippi, United States, 39232