12-Week Study Evaluating the Efficacy, Safety, and Tolerability of Adjunctive Infliximab for Bipolar I/II Depression

Study Overview
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Brief Summary
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Studies show the presence of immuno-inflammatory disturbances in individuals with Bipolar Disorders (BD). Increased levels of circulating proteins known as cytokines that promote inflammation have been consistently reported in individuals with bipolar disorders. A particular cytokine referred to as Tumor Necrosis Factor (TNF)-alpha is among those cytokines that have been consistently identified across depressive, manic, and euthymic periods. Disturbances in inflammation however, are not seen in all individual with bipolar disorder. Those individuals with signs of inflammation also often present with higher prevalence of medical disorders that are also associated with inflammation. Those individuals with significant signs of inflammation may respond to anti-inflammatory treatments. In this study, individuals with bipolar depression who exhibit signs of high inflammation will be enrolled and treated with either an anti-inflammatory biologic known as infliximab or placebo (saline).

Official Title
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A Multisite, Fixed Dose, Randomized, Double-Blind, Placebo-Controlled 12-Week Study Evaluating the Efficacy, Safety, and Tolerability of Adjunctive Infliximab for the Treatment of Bipolar I/II Depression

Conditions
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Bipolar Depression

Intervention / Treatment
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* Drug: Infliximab
* Other: Saline


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Fifth edition of Diagnostic and Statistical Manual for Mental Disorders (DSM-5) criteria for major depressive episode as part of bipolar I/II disorder and are able to provide written informed consent HAMD-17 score >= 20 Young Mania Rating Scale score < 12 Previous failed trial (i.e., inefficacy) of quetiapine and one other Canadian Network for Mood and Anxiety Treatments (CANMAT) BD guideline/FDA approved first line treatment for the depressive phase of BD during the index episode and/or during a prior episode Currently prescribed conventional mood stabilizer or atypical antipsychotic agent Received conventional treatment for bipolar depression for a minimum of 4 weeks prior to randomization Females of childbearing potential must test negative for pregnancy and must be using adequate birth control measures throughout the study and must continue such precautions for 6 months after receiving the last study drug administration. Participants will also need to meet one of the following inflammatory indicators: Central Obesity (ethnicity-specific waist circumference - see table below for specific values) OR BMI ≥30 kg/m2. AND Raised triglycerides: ≥1.7 mmol/L (150 mg/dL) or specific treatment for this lipid abnormality OR Reduced HDL-cholesterol: <1.03 mmol/L (40 mg/dL) in males; <1.29 mmol/L (50 mg/dL) in females or specific treatment for this lipid abnormality OR Raised Blood Pressure: Raised blood pressure Systolic: ≥130 mm Hg or diastolic: ≥85 mm Hg or treatment of previously diagnosed hypertension. Diabetes: 8-hour fasting plasma glucose ≥ 7.0 mmol/L or Hb-A1C test ≥ 6.5% (as per the 2013 CDA diagnostic criteria) or previously diagnosed type 1 or 2 diabetes (current prescription medication for diabetes acceptable of diagnosis). Participants with child onset of diabetes will be excluded. Inflammatory bowel disorder (Ulcerative Colitis, Crohn's disease). Rheumatological disorders (rheumatoid arthiristis); Psoriasis. Smoking cigarettes (daily - minimum of ½ pack). High sensitivity C-reactive protein level of ≥5 mg/L via blood test at screening Exclusion Criteria: Another concurrent psychiatric disorder that requires primary clinical attention History of schizophrenia Active psychotic symptoms Substance abuse and/or dependence within past 6 months Electroconvulsive therapy in the past 6 months Actively suicidal or evaluated as being a suicide risk [HAMD-17 suicide item >= 3 or Montogomery Asberg Depression Rating Scale (MADRS) suicide item >= 4, or according to clinical judgement using the C-SSRS] Clinically significant unstable medical illness Severe infections such as sepsis, abscess, tuberculosis and opportunistic infections Viral hepatitis B History of Hepatitis C ( documented or suspected) Any autoimmune disorder History of tuberculosis or a high risk of tuberculosis exposure Human Immunodeficiency Virus confirmed by laboratory testing Active fungal infection History of recurrent viral or bacterial infections Received within 3 months prior to screening or are expected to receive any live viral vaccine or live bacterial vaccinations during the trial or up to 3 months after the last administration of study agent C. difficile infection within the past 4 months History of lymphoproliferative disease History of cancer, excluding basal cell or squamous cell carcinoma of the skin (fully excised with no recurrence) Unstable cardiovascular, endocrinological, hematological, hepatic, renal or neurological disease determined by physical examination and laboratory testing Concomitant diagnosis or any history of congestive heart failure Concomitant treatment with non-steroidal and steroidal anti-inflammatory medications or other biologics Current or past exposure to anti-TNF biologics Previous immediate hypersensitivity response, including anaphylaxis to an immunoglobulin product (plasma-derived or recombinant, e.g. monoclonal antibody) Known allergies, hypersensitivity or intolerance to infliximab or its excipients Known allergy to murine proteins or other chimeric proteins Currently on or have used any investigational drug within 30 days prior to screening, or within 5 half-lives of the investigational agent Females who are pregnant or breastfeeding

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Infliximab<br>Intravenous infliximab (5mg/kg) at baseline, week 2 and 6 under clinical observation | Drug: Infliximab<br>* Intravenous infliximab (5mg/kg) at baseline, week 2 and 6 under clinical observation. Infliximab will be prescribed adjunctively to a conventional mood stabilizer or atypical antipsychotic agent.<br>* Other names: Remicade;|
| Placebo Comparator: Saline (Placebo)<br>Intravenous placebo (saline solution) at baseline, week 2 and 6 under clinical observation. Placebo will be matched to infliximab in color and consistency. | Other: Saline<br>* Intravenous placebo (saline solution) at baseline, week 2 and 6 under clinical observation. Placebo will be matched to infliximab in color and consistency and will be administered adjunctively to conventional mood stabilizer or atypical antipsychotic agent.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Baseline and Week 12 Montgomery-Asberg Depression Rating Scale (MADRS) Scores | Baseline and Week 12 Montgomery-Asberg Depression Rating Scale scores are provided, with the range of possible values on the scale from 0 to 60. The higher the score, the worse the overall depressive symptoms. | Up to 12 weeks | 
| Baseline and Week 6 Montgomery-Asberg Depression Rating Scale (MADRS) Scores | Baseline and Week 6 Montgomery-Asberg Depression Rating Scale (MADRS) scores, where the range of possible values on the scale is from 0 to 60. The higher the score, the worse the overall depressive symptoms. | Up to 6 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in Brain N-acetylaspartate Levels | Changes in prefrontal metabolites concentration of N-acetylaspartate, using proton-magnetic resonance spectroscopy (1H-MRS), adjusted for age, sex, baseline values and % gray matter in the spectroscopic region of interest. | Baseline to Week 12 | 
| Changes in Anhedonia | Change in the Snaith-Hamilton Pleasure Scale (SHAPS) total score. Total score range of 14 to 56, with greater scores indicative of greater hedonic capacity. | Baseline to 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Bipolar Disorder, Bipolar Depression, Inflammation, Bipolar