BezafibrateTreatment for Bipolar Depression: A Proof of Concept Study

Study Overview
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Brief Summary
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We propose to test the hypothesis that bezafibrate, a pan-PPAR agonist, may be effective and safe for bipolar depression with the following specific aims: Aim #1. Proof-of-Concept Safety and Tolerability Aim: To assess the safety and tolerability of bezafibrate added to anti-manic medication for bipolar depression, especially with regard to worsening manic symptoms and suicidal ideation. We will conduct a phase IIa, 8-week, open pilot trial of bezafibrate added to FDA-approved anti-manic medication in 30 participants with bipolar depression. We will monitor changes in manic symptoms (Young Mania Rating Scale), suicidal ideation, cognitive functioning specifically in attention and verbal memory, and treatment emergent adverse events (SAFTEE). We will also monitor changes in the Framingham Cardiovascular Risk Score. Aim #2. Preliminary Assessment of Efficacy: To assess the antidepressant efficacy of bezafibrate added to anti-manic medication for acute bipolar I major depressive episodes. Hypothesis: The bezafibrate group will have a statistically significant decrease in the Montgomery Asberg Rating Scale (MADRS) Scores over 8 weeks. The results of this proof-of concept phase IIa study will help us to plan a placebo-controlled randomized trial. In summary, we propose an 8-week, proof-of-concept open pilot trial of an adjunctive pan-PPAR agonist, bezafibrate, for 30 patients with an acute bipolar I major depressive episode. The study may have a profound impact on the development of a novel treatment consistent with the mitochondrial dysregulation hypothesis of bipolar disorder and, to the best of our knowledge, will be the first proof-of-concept trial to assess a pan-PPAR agonist for bipolar disorder.

Official Title
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A Pan-PPAR Agonist Treatment for Bipolar Depression: A Proof of Concept Study

Conditions
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Bipolar Disorder, Depressive Episode

Intervention / Treatment
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* Drug: Bezafibrate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men or women between the ages of 18 and 65 (inclusive) DSM IV diagnosis of Bipolar Disorder Type I or Bipolar Disorder Type II Ability to sign the Informed Consent Form Taking an adequate dose of any FDA-approved anti-manic medication for at least two weeks prior to enrollment Agrees not to change medications during the study Meets criteria for a current major depressive episode as defined and operationalized by the MINI and by a MADRS score of >18 at screen and baseline (randomization) Does not meet criteria for current hypomanic or manic episode as defined and operationalized by the MINI Exclusion Criteria: The following DSM-IV diagnoses: (1) Bipolar NOS, (2) Cyclothymia, (3) Schizoaffective Disorder, (4) organic mental disorders, (5) substance use disorders, including alcohol, active within the 3 months, (6) schizophrenia, (7) delusional disorder, (8) psychotic disorders not elsewhere classified, (9) acute bereavement, (10) severe borderline or antisocial personality disorder, (11) OCD or OCD-spectrum disorders Primary diagnosis of anxiety disorders or patients where the anxiety disorder is the primary focus of treatment Patients with mood congruent or mood incongruent psychotic features Pregnant women or women of child bearing potential who are not using a medically accepted means of contraception (e.g. oral contraceptives, intrauterine device, barrier methods, or total abstinence from intercourse; Depo Provera is acceptable if it is started 3 months prior to enrollment). Women who are nursing Patients who are a serious suicide or homicide risk Suspected or known clinically unstable systemic medical disorder including epilepsy, untreated endocrine disease, unstable angina, recent ulcers or significant esophagitis Conditions which may be negatively affected by bezafibrate treatment, such as hepatobiliary disease Clinical or laboratory evidence of hypothyroidism (if maintained on thyroid medication must be euthyroid for at least 1 month before Visit 1) Subjects having failed two or more trials of somatic therapy (i.e., medications for bipolar depression or FDA-approved devices) during the current bipolar depressive episode Current use of a fibrate or history of anaphylactic reaction or intolerance to fibrates or any component of the preparation History of significant treatment non-adherence or situations where the subjects is unlikely to adhere to treatment, in the opinion of the investigator History of stroke or cerebrovascular disease Type 1 or Type II Diabetes requiring medication treatment treated with Pioglitazone or any other PPAR agonist medication. Current use of of MAO Inhibitors, statins, and anticoagulants (e.g. warfarin)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Bipolar I and Bipolar II Disorder<br>30 currently depressed patients with DSM-IV bipolar I or bipolar II disorder who are currently taking an adequate dose of an FDA-approved anti-manic medication will receive Bezafibrate treatment. | Drug: Bezafibrate<br>* 30 patients with Bipolar I or Bipolar II disorder who are experiencing an acute bipolar depressive episode will be given bezafibrate XR 400 mg daily added on to adequate doses of an FDA-approved anti-manic medication.<br>* Other names: Bezalip;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline to Week 8 in Montgomery-Åsberg Depression Rating Scale (MADRS) | The primary efficacy measure will be the change in MADRS score. | Baseline and Week 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline to Week 8 in Clinical Global Impressions Bipolar Scale (CGI-BP-S) score | Secondary efficacy measure will be change in CGI-BP-S score. | Baseline and Week 8 | 
| Adiponectin Level at Baseline and Week 8 | We will measure adiponectin as a well-established biomarker for the effect of bezafibrate on PPAR and examine changes in adiponectin as a mediator of changes in mood symptoms. | Baseline and Week 8 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Bipolar Disorder, Bezafibrate, Depressive Episode