Efficacy and Safety Evaluation of 4-Hydroxy-N-Desmethyltamoxifen in Adult Patients with Bipolar I Disorder Experiencing Acute Mania or Manic Episodes
- Trial ID
- 2024-511829-57-00
- Protocol
- 72189812
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **efficacy** and establish the superiority of Endoxifen 8 mg compared to placebo in the treatment of adult patients with **Bipolar I Disorder** experiencing acute mania or manic episodes, with or without mixed features. This is clinically relevant as it aims to determine the effectiveness of Endoxifen, a potential therapeutic option, in managing symptoms associated with manic episodes in Bipolar I Disorder, which can significantly impact patient quality of life and disease management.
Secondary objectives include evaluating the **safety** and tolerability of the treatments among hospitalized patients with manic episodes, with or without mixed features of Bipolar I Disorder. This is crucial for understanding the risk-benefit profile of Endoxifen, ensuring that it is not only effective but also safe for patient use.
Participants
The clinical trial involves a total of **454 participants** diagnosed with **Bipolar I Disorder**, specifically targeting adult patients experiencing acute manic episodes with or without mixed features. The study population includes both male and postmenopausal female subjects, aged between 18 and 65 years. Participants were selected based on their ability to provide informed consent and the absence of significant comorbidities that could impact the study's outcomes. The trial excludes individuals with a serious suicide or homicidal risk. Participants are required to abstain from medications or therapies prohibited by the study protocol. The trial does not involve a vulnerable population, and lifestyle factors such as diet and physical activity are not specified as part of the selection criteria. The study aims to evaluate the efficacy of Endoxifen 8 mg compared to a placebo in this specific patient group.
Plans and Procedures
The clinical trial is designed as a **randomized**, **double-blind**, placebo-controlled study to evaluate the efficacy and safety of **Endoxifen** in patients with **Bipolar I Disorder** experiencing acute manic episodes. The trial will involve multiple doses administered orally over a period of 21 days. Participants will be randomly assigned to receive either Endoxifen or an identical placebo, with neither the participants nor the investigators aware of the group assignments, ensuring the study's double-blind nature. The primary objective is to assess the mean change from baseline to Day 21 on the Young Mania Rating Scale (YMRS) total score, with secondary endpoints including the percentage of patients with a ≥50% improvement in YMRS, changes in the Clinical Global Impression-Bipolar (CGI-BP) score, and other relevant clinical measures.
The trial will commence with a screening visit to determine eligibility based on specific inclusion criteria, such as age, diagnosis of Bipolar I Disorder, and current manic episodes. Participants must also meet certain health criteria and agree to comply with study requirements. Following successful screening, participants will undergo randomization and begin the treatment phase, which includes regular follow-up visits to monitor safety and efficacy outcomes. These visits will involve assessments such as the YMRS, CGI-BP, and other scales to evaluate mood and behavior changes. The end-of-study visit will occur on Day 21, marking the conclusion of the treatment period and the final collection of data for analysis.
Participant involvement is expected to last approximately 21 days, with the possibility of early termination if specific conditions arise, such as adverse events or non-compliance with study protocols. The trial is anticipated to start recruitment on September 30, 2024, and is estimated to conclude by June 30, 2025. The study aims to provide valuable insights into the therapeutic potential of Endoxifen for managing acute manic episodes in Bipolar I Disorder, contributing to the broader understanding of treatment options for this condition.
Treatment
The clinical trial involves the administration of **Endoxifen**, a pharmaceutical product in the form of a tablet. The active substance in Endoxifen is **4-hydroxy-N-desmethyltamoxifen**, a chemical compound. The tablets are manufactured by Intas Pharmaceuticals Limited. Each tablet contains 8 mg of the active substance, and the maximum daily dose is 8 mg. The total maximum dose over the treatment period is 168 mg, with a maximum treatment duration of 21 days. The route of administration is oral. Endoxifen is classified as an antipsychotic and a nonsteroidal selective estrogen receptor modulator (SERM). Participant compliance with the dosing schedule will be monitored throughout the study.
The study also includes the use of identical placebo tablets, which are manufactured by Intas Pharmaceuticals Limited. These placebo tablets are designed to match the Endoxifen tablets in appearance, being green, round, biconvex, and enteric-coated, with no active substance. The placebo tablets are produced using the same excipients and manufacturing process as the Endoxifen tablets, ensuring that they are indistinguishable from the active treatment. The placebo serves as a comparator treatment to evaluate the efficacy and safety of Endoxifen in patients with Bipolar I Disorder experiencing acute mania or manic episodes, with or without mixed features.
Efficacy
The efficacy of Endoxifen in the treatment of **Bipolar I Disorder** will be assessed through a double-blind, placebo-controlled, multiple-dose, parallel, randomized clinical trial. The primary endpoint for evaluating efficacy is the mean change from baseline to Day 21 on the Young Mania Rating Scale (YMRS) Total Score. Secondary endpoints include the percentage of patients with a ≥50% improvement in total YMRS from baseline, the Clinical Global Impression-Bipolar (CGI-BP) score at the end of the study, and the mean change from baseline to the end of treatment (Day 21) in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score. Additional secondary endpoints involve improvement in the Clinical Global Impression-Severity of Illness scale (CGI-S) score, the Columbia-Suicide Severity Rating Scale (C-SSRS) score at the end of treatment, the percentage of patients needing lorazepam/diazepam for controlling acute agitation/akathisia, the percentage of patients requiring rescue medications and withdrawal from the study, and the evaluation of trough concentrations of Endoxifen.
These efficacy parameters will be measured and collected at specified timepoints, including baseline and Day 21, using validated scales such as the YMRS, CGI-BP, MADRS, and C-SSRS. The analysis will focus on comparing the changes in these scores between the Endoxifen and placebo groups to determine the drug's efficacy in managing acute manic episodes in patients with Bipolar I Disorder. The trial is designed to establish the superiority of Endoxifen over placebo in this patient population.
Inclusion and Exclusion Criteria
Inclusion Criteria
- 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.
- 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.
- Patients must have a diagnosis of Bipolar I Disorder and currently display acute manic episodes with or without mixed features according to DSM-5 criteria as judged by the Investigator.
- 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 YMRS 23 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”.
- 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).
- 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 up to 21 days of in-patient treatment period.
- 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.
- Patient and / or LAR understand and agree to comply with all the study requirements.
- Male patients of child begetting potential must be practicing, 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.
- 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.
- 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 may impact the clinical outcome of the study by participating in the study or study objectives in the Investigator's opinion.
- 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
- Newly diagnosed patients and not having any suitable treatment exposure in past for their Bipolar mood disorder.
- > 20% improvement in YMRS total scores between screening and randomization visits.
- Patients who meet DSM-5 criteria for any psychiatric disorder other than Bipolar I Disorder with Acute Mania Episode with or without mixed features.
- Patients with seizure disorder.
- Obsessive compulsive disorder or any other co-morbid Axis I anxiety disorder.
- Patients with borderline or anti-social personality disorder of sufficient current severity to interfere with conduct of the study.
- Patients with classical premenopausal symptoms were found at risk of developing intolerable hot flushes, irregular vaginal bleeding.
- 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
- 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
- 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
- Presence of a coagulation disorder; active or past history of venous thromboembolism including deep venous thrombosis or pulmonary embolism.
- Current prolonged immobilization.
- History or current presence of retinal pathology including retinal vein thrombosis
- Increased risk of stroke as per the Investigator’s discretion.
- History of hypersensitivity or intolerance to tamoxifen or any other ingredients of the preparation.
- 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.
- 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.
- History of breast or uterine cancer, or abnormal uterine bleeding.
- Current leukopenia or thrombocytopenia as judged by the Investigator in the best health interest of the subject.
- Clinically significant suicidal (subject responds “Yes” to any category for Baseline C- SSRS) or homicidal ideation per clinical questioning.
- Participation in a clinical trial of another investigational drug within 30 days prior to screening.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Romania | Not Recruiting | 30 Sept 2024 | 27 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Endoxifen | Test | TABLET | ORAL | 8.0 | 21 | PRD11213009 |
Identical placebo tablets of Endoxifen manufactured by Intas Pharmaceuticals Limited, India. The placebo tablets were manufactured using the same excipients and the manufacturing process of endoxifen tablets. Like endoxifen 8 mg tablets, the placebo tablets are green coloured, round shape, biconvex, enteric coated tablets plain on both sides. The placebo for Endoxifen Tablets 8 mg was manufactured following the same procedure as the drug product without using endoxifen citrate. | Placebo | N/A | — | — | — | N/A |