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

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

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).

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:

1. 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.

2. 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.

3. Inflammatory bowel disorder (Ulcerative Colitis, Crohn's disease).

4. Rheumatological disorders (rheumatoid arthiristis); Psoriasis.

5. Smoking cigarettes (daily - minimum of ½ pack).

6. 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