Endoxifen for Bipolar Disorder

Recruiting at 11 trial locations

Overseen By Rishi Kakar

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Jina Pharmaceuticals Inc.

Must not be taking: Antidepressants, Benzodiazepines, Estrogens, others

Disqualifiers: Seizure disorder, Personality disorder, Cardiac conditions, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 3 weeks

490 Participants Needed

Trial Summary

What is the purpose of this trial?

Bipolar disorder (BPD) is a chronic debilitating illness characterized by drastic swings in mood, energy and functional ability that affects the adult population. Endoxifen is an active metabolite of the marketed drug Tamoxifen and the present study aims to evaluate the efficacy and safety of 8 mg endoxifen in the Bipolar I disorder patient population compared to a placebo arm. Endoxifen will be compared to a 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. Thus, Endoxifen will be compared to placebo to demonstrate that the test product is safe and active.

Do I need to stop my current medications to join the trial?

Yes, you will need to stop taking your current medications for bipolar disorder 2-7 days before joining the trial, depending on the specific medication. Additionally, certain other medications are not allowed during the study period.

Do I need to stop my current medications for the trial?

Yes, you will need to stop taking your current medications for bipolar disorder 2-7 days before starting the trial, depending on the specific medication. Additionally, certain other medications are prohibited during the study period.

What data supports the effectiveness of the drug Endoxifen for treating bipolar disorder?

Research shows that Endoxifen, a drug related to tamoxifen, has antimanic properties and significantly improved mania symptoms in patients with bipolar I disorder during a 21-day study. Additionally, tamoxifen, a similar drug, has shown effectiveness in reducing manic symptoms in women with bipolar disorder. ^{1 2 3 4 5}

What data supports the effectiveness of the drug Endoxifen for treating bipolar disorder?

Research shows that Endoxifen, a drug related to tamoxifen, has antimanic properties and can help stabilize mood in people with bipolar disorder. In a study, patients taking Endoxifen showed significant improvement in mania symptoms within 4 days, with higher doses leading to better response rates. ^{1 2 3 4 5}

Is endoxifen safe for use in humans?

Endoxifen has been studied in clinical trials for various conditions, including breast cancer and bipolar disorder, and has shown promising safety results. In these studies, it demonstrated good oral bioavailability and did not show significant harmful effects on the endometrium (lining of the uterus) compared to similar drugs. ^{1 2 3 6 7}

Is endoxifen safe for use in humans?

Endoxifen has been studied in clinical trials for various conditions, including breast cancer and bipolar disorder, and has shown promising safety results. It appears to have similar or even greater safety in terms of bone health compared to tamoxifen, with little to no negative effects on the uterus lining. ^{1 2 3 6 7}

How is the drug endoxifen different from other treatments for bipolar disorder?

Endoxifen is unique because it targets the protein kinase C (PKC) signaling system, which plays a role in mood disorders, making it a novel option for treating mania in bipolar disorder. Unlike traditional treatments, endoxifen is an active metabolite of tamoxifen and is administered orally, showing significant improvement in manic symptoms within a few days. ^{1 2 3 8 9}

How is the drug endoxifen unique in treating bipolar disorder?

Endoxifen is unique because it targets the protein kinase C (PKC) signaling system, which plays a role in mood disorders, offering a novel approach for treating mania in bipolar disorder. Unlike traditional treatments, endoxifen has shown significant improvement in manic symptoms within just a few days, making it a promising new option for mood stabilization. ^{1 2 3 8 9}

Eligibility Criteria

This trial is for adults with Bipolar I Disorder, a condition causing extreme mood swings. Participants must meet specific health criteria to join but details are not provided here.

Inclusion Criteria

Patients and/or LAR must agree to comply with all study requirements

I have been diagnosed with bipolar I disorder and am currently experiencing a manic episode.

Patients must have at least one first-degree relative or legally acceptable representative (LAR) to participate

Exclusion Criteria

I have been newly diagnosed with bipolar disorder and haven't received treatment yet.

Patients with personality disorders interfering with study conduct

My mood disorder symptoms have improved recently.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Endoxifen or placebo for 3 weeks to evaluate efficacy and safety in treating acute mania episodes

3 weeks

Weekly visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Endoxifen

Trial Overview The study tests the effectiveness and safety of an 8 mg endoxifen tablet against a placebo in managing symptoms of Bipolar I Disorder. Endoxifen is derived from Tamoxifen, which is already on the market.

Participant Groups

Group I: Endoxifen Arm Experimental Treatment 1 Intervention

Endoxifen enteric-coated tablet (8 mg). Patients will continue treatment with their initial randomized medication for 3 weeks

Group II: Placebo Arm Placebo Group 1 Intervention

Placebo tablets. Patients will continue administration with their initial randomized medication for 3 weeks

Endoxifen is already approved in India for the following indications:

Approved in India as Endoxifen for:

• Bipolar I disorder

Who Is Running the Clinical Trial?

Jina Pharmaceuticals Inc.

Lead Sponsor

Trials

7

Recruited

1,700+

Novum Pharmaceutical Research Services

Industry Sponsor

Trials

18

Recruited

6,700+

Findings from Research

Z-endoxifen, a potent metabolite of tamoxifen, shows promising antitumor activity in patients with various cancers, including endocrine-refractory metastatic breast cancer, and has substantial oral bioavailability.

Unlike tamoxifen, Z-endoxifen appears to have beneficial effects on bone health while causing little to no endometrial proliferation, making it a potentially safer alternative for breast cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Endoxifen, an Estrogen Receptor Targeted Therapy: From Bench to Bedside. Jayaraman, S., Reid, JM., Hawse, JR., et al.[2022]

In a double-blind study involving 84 patients with bipolar I disorder, endoxifen demonstrated significant antimanic effects, with improvements in mania observed as early as 4 days and sustained over 21 days.

Response rates for endoxifen were notable, with 44.44% for the 4 mg/day dose and 64.29% for the 8 mg/day dose, indicating its potential as a novel treatment for managing manic episodes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Endoxifen, a New Treatment Option for Mania: A Double-Blind, Active-Controlled Trial Demonstrates the Antimanic Efficacy of Endoxifen. Ahmad, A., Sheikh, S., Shah, T., et al.[2019]

In a 28-day study involving 13 women with acute Bipolar Affective Disorder, those treated with tamoxifen showed significant improvement in manic symptoms compared to the placebo group.

The group receiving medroxyprogesterone acetate (MPA) also demonstrated improvement over the placebo, suggesting both hormonal agents may be beneficial adjuncts in treating acute mania.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A pilot study of hormone modulation as a new treatment for mania in women with bipolar affective disorder. Kulkarni, J., Garland, KA., Scaffidi, A., et al.[2022]

Tamoxifen, while used for treating breast cancer, can lead to significant psychiatric side effects, including worsening depressive symptoms and suicidal thoughts in male patients with a history of mood disorders, as seen in a case study of a 45-year-old man.

Discontinuation of Tamoxifen resulted in a rapid and sustained improvement in the patient's depressive symptoms and suicidal ideation over a one-year follow-up, highlighting the need for careful monitoring of psychiatric effects in patients receiving this medication.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Suicidality and Illness Course Worsening in a Male Patient with Bipolar Disorder during Tamoxifen Treatment for ER+/HER2+ Breast Cancer. Carmassi, C., Pardini, F., Dell'Oste, V., et al.[2022]

A new high-performance liquid chromatography-tandem mass spectrometry assay has been developed and validated to accurately measure endoxifen levels in serum, which is crucial for personalized tamoxifen therapy in breast cancer patients.

In a study of over 500 patients, 32.7% had endoxifen levels below the therapeutic threshold of 5.9 ng/mL, indicating a significant number of patients may be at risk for breast cancer recurrence due to subtherapeutic drug levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fast and Adequate Liquid Chromatography-Tandem Mass Spectrometric Determination of Z-endoxifen Serum Levels for Therapeutic Drug Monitoring. de Krou, S., Rosing, H., Nuijen, B., et al.[2017]

In a phase III study involving 116 patients with bipolar I disorder, endoxifen significantly reduced mania symptoms, as measured by the Young Mania Rating Scale, demonstrating strong efficacy (YMRS score decreased from 33.1 to 17.8).

Endoxifen was well-tolerated with no patients requiring rescue medication or withdrawing due to side effects, indicating a favorable safety profile compared to the standard treatment, divalproex.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Endoxifen: A new, protein kinase C inhibitor to treat acute and mixed mania associated with bipolar I disorder. Ahmad, A., Sheikh, S., Khan, MA., et al.[2022]

Tamoxifen has shown significant efficacy in treating acute mania in bipolar disorder, with a strong effect size (SMD -2.14) and higher response rates compared to placebo in five randomized controlled trials lasting three to six weeks.

The acceptability of tamoxifen as a treatment was similar to that of placebo, suggesting it may be a safe option for patients, but further research is needed to explore its long-term effects and potential use alongside other medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tamoxifen for bipolar disorder: Systematic review and meta-analysis. Palacios, J., Yildiz, A., Young, AH., et al.[2020]

(Z)-Endoxifen is a more potent selective estrogen receptor modulator than tamoxifen, showing significant tumor growth inhibition in a preclinical model with female athymic mice at doses of 4-8 mg/kg.

The study confirmed the active configuration of (Z)-endoxifen and developed a validated HPLC method for quality control, ensuring accurate quantitation and impurity profiling, which is crucial for its therapeutic evaluation in ER+ breast cancer patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Characterization of the isomeric configuration and impurities of (Z)-endoxifen by 2D NMR, high resolution LC⬜MS, and quantitative HPLC analysis. Elkins, P., Coleman, D., Burgess, J., et al.[2021]

Endoxifen, a potent metabolite of tamoxifen, shows promise as an alternative therapy in breast cancer, but current research primarily focuses on its use in metastatic cases, indicating a need for further studies to establish its therapeutic role.

Pharmacogenetic factors, particularly CYP2D6 genotypes, significantly impact tamoxifen metabolism and clinical outcomes, suggesting that personalized treatment approaches based on genetic testing may be necessary, although evidence for monitoring endoxifen concentrations is still limited.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical pharmacokinetics and pharmacogenetics of tamoxifen and endoxifen. Sanchez-Spitman, AB., Swen, JJ., Dezentje, VO., et al.[2019]

References

1. United States pubmed.ncbi.nlm.nih.gov

Endoxifen, an Estrogen Receptor Targeted Therapy: From Bench to Bedside. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

Endoxifen, a New Treatment Option for Mania: A Double-Blind, Active-Controlled Trial Demonstrates the Antimanic Efficacy of Endoxifen. [2019]

3. England pubmed.ncbi.nlm.nih.gov

A pilot study of hormone modulation as a new treatment for mania in women with bipolar affective disorder. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

Suicidality and Illness Course Worsening in a Male Patient with Bipolar Disorder during Tamoxifen Treatment for ER+/HER2+ Breast Cancer. [2022]

5. United States pubmed.ncbi.nlm.nih.gov

Fast and Adequate Liquid Chromatography-Tandem Mass Spectrometric Determination of Z-endoxifen Serum Levels for Therapeutic Drug Monitoring. [2017]

6. Denmark pubmed.ncbi.nlm.nih.gov

Endoxifen: A new, protein kinase C inhibitor to treat acute and mixed mania associated with bipolar I disorder. [2022]

7. United States pubmed.ncbi.nlm.nih.gov

Tamoxifen for bipolar disorder: Systematic review and meta-analysis. [2020]

8. England pubmed.ncbi.nlm.nih.gov

Characterization of the isomeric configuration and impurities of (Z)-endoxifen by 2D NMR, high resolution LC⬜MS, and quantitative HPLC analysis. [2021]

9. England pubmed.ncbi.nlm.nih.gov

Clinical pharmacokinetics and pharmacogenetics of tamoxifen and endoxifen. [2019]