Clinical trial NCT02363738
Conditions: Bipolar Depression
Keywords: Bipolar Disorder Bipolar Depression Inflammation Bipolar
Sponsor: University Health Network, Toronto
Start date: 2015-09-01; Completion date: 2017-04-01
Enrollment: 60 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
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).

Detailed description:

Arms: arm 1: Intravenous infliximab (5mg/kg) at baseline, week 2 and 6 under clinical observation arm 2: Intravenous placebo (saline solution) at baseline, week 2 and 6 under clinical observation. Placebo will be matched to infliximab in color and consistency.
Interventions: intervention 1: Infliximab intervention 2: Saline
Intervention descriptions: intervention 1: 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. intervention 2: 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.

Protocol documents:
Prot_SAP_000.pdf: 
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 A MULTISITE, 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 
 
 
 
INVESTIGATOR: 
Roger S. McIntyre, MD, FRCPC 
Head, Mood Disorders Psychopharmacology Unit  
Toronto Western Hospital 
Main Pavilion 9M-325 
 
416 603 5279 
416 603 5368 
 
 
CO-INVESTIGATORS:   
 
Joanna Soczynska, PhD candidate 
Mood Disorders Psychopharmacology Unit  
Toronto Western Hospital 
Main Pavilion 9M-325 
 
416 603 5800 x3726 
416 603 5368 
 
 
Marion Leboyer, MD, PhD 
University of Paris-Est 
Hôpitaux Universitaires Henri Mondor 
+ 33 1 49 81 30 51 
 
 
Trisha Suppes, MD, PhD 
Stanford University School of Medicine 
3801 Miranda Ave. (151T) 
650-493-5000 x62567 
 
 
Rodrigo Mansur, MD 
Mood Disorders Psychopharmacology Unit  
Toronto Western Hospital 
Main Pavilion 9M-325 
 
416 603 3125 
416 603 5368 
 
 
 
 
 
 
 
 
 
Sidney Kennedy, MD, FRCPC 
Mood Disorders Psychopharmacology Unit  
Toronto General Hospital 
Main Pavilion 9M-329 
 
416 344 3888 
416 603-5368 


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RATIONALE 
 
Disturbances in the immuno-inflammatory system have been implicated in the etiology, 
pathophysiology, phenomenology and comorbidity of Bipolar Disorders (BD). For example, 
preclinical and clinical studies implicate inflammatory networks in the etiology of ‘sickness 
behaviour’, a syndrome phenotypically similar to a major depressive episode. Furthermore, 
increased rates of medical comorbidity (e.g. obesity, abdominal obesity, type 2 diabetes mellitus, 
metabolic syndrome, and cardiovascular disease) relative to age-and sex-matched healthy 
volunteers, point towards common underlying pathophysiology (1). Moreover, preliminary 
evidence from genome-wide association studies, suggests common susceptibility loci for BD and 
several inflammatory-mediated chronic medical disorders (2).   
 
Elevated levels of both circulating and cerebral spinal fluid pro-inflammatory cytokines have 
been consistently replicated in individuals with mood disorders.  Elevated levels of Tumor 
Necrosis Factor-alpha (TNF-α) and its receptors, TNF-R1 and TNF-R2, are amongst the most 
consistently identified pro-inflammatory cytokine abnormalities in BD, across depressive, manic 
and euthymic states. Preliminary evidence suggests that increased inflammation may be 
associated with a more severe illness presentation and illness progression (3;4). Additional 
evidence also suggests that monocytes of individuals with BD have increased inflammatory gene 
expression, which may confer a discriminating mRNA signature in offspring of individuals with 
BD (5). Specifically, evidence suggests that susceptibility to BD may be associated with 
TNFA*2 allele and the –G308A polymorphism of the TNFα gene (6). Disturbances in 
inflammation however, are not evident in all individuals, as mixed results have been reported. 
The foregoing degree of inter-individual variability suggests that immuno-inflammatory 
mechanisms are salient to a subset of individuals with BD.  
 
Conventional mood stabilizers (e.g. lithium. antipsychotics, anticonvulsants) act in varying 
capacities to down-regulate the production of pro-inflammatory cytokine mRNA and protein 
gene expression (5;7). In keeping with this view, double-blind, randomized, placebo-controlled 
studies have documented significant antidepressant effects following adjunctive treatment with 
the anti-inflammatory agent, celecoxib, in individuals with BD and MDD (8-10). Although 
favorable results have been reported with non-steroidal anti-inflammatory drugs (NSAIDs), not 
all studies have been positive and the effect sizes are of questionable clinical significance. It 
could be hypothesized that antagonism of TNF-α, notably in individuals who manifest signs of 
inflammation, may exert more specific and superior efficacy in mitigating symptoms of bipolar 
depression.  
 
Tumor Necrosis Factor Alpha  


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Tumor necrosis factor alpha is a 157 amino acid pro-inflammatory cytokine synthesized and 
secreted by disparate cells types including macrophages, lymphocytes, astrocytes, and microglia. 
Its expression is increased in response to injury as well as inflammatory and infectious stimuli. 
Tumor necrosis factor alpha serves a homeostatic function in both innate and adaptive immune 
responses, and is capable of exerting salutary, as well as detrimental effects on immune function. 
For example, acute modest elevations of TNF-α concentrations augment host defense 
mechanisms, while chronically elevated concentrations may contribute to allostatic load (11). 
 
Tumor necrosis factor alpha is released from cells as a soluble cytokine (sTNF, a homotrimer of 
17 kDa) after being enzymatically cleaved from its cell surface-bound precursor [transmembrane 
TNF (tmTNF), a homotrimer of 26-kDa monomers] by TNFα-converting enzyme (TACE). Both 
sTNF and tmTNF ligands are biologically active and exert their effects by binding to TNF 
receptors: TNF-R1 and TNF-R2. Both TNF receptors are membrane glycoproteins that 
specifically bind TNF-α and lymphotoxin alpha-3 (11;12). TNF-R1 mediates apoptosis, cytokine 
production, activation of transcription factors (e.g. NF-kB), as well as inflammatory gene 
activation. Activation of TNF-R1 has been shown to trigger a dual signaling cascade leading to 
apoptosis, proliferation, differentiation, or survival of different cell types. Reverse signaling can 
be initiated by TNF-R2 or TNF-α antagonist binding to cell surface tmTNF, resulting in cytokine 
suppression or apoptosis.  
 
Postmortem studies indicate that individuals with BD exhibit regional abnormalities in the size, 
shape, and density of neurons and glia. Tumor necrosis factor alpha may via activation of 
caspase 3 mediate the observed regional abnormalities in BD. Cellular and biochemical studies 
indicate that TNF-α binding to its canonical receptors subsequently activates an intracellular 
cascade that results in recruitment of the TNF receptor associated death domain. This adapter 
protein subsequently recruits Fas-associated death domain that leads to caspase-3 activation (11). 
Caspase-3 activation is part of the ‘pro-apoptotic’ machinery that possibly mediates neuronal and 
glial apoptosis in BD. Taken together, these observations provide a framework for hypothesizing 
that activated pro-inflammatory cytokines are integral to the neurotoxic process in BD. 
 
Anti-TNF Antagonists 
There are several commercially available biologic agents that specifically inhibit TNF-α, and 
have approved indications for several inflammatory-based diseases, including rheumatoid 
arthritis, Crohn’s disease, ankylosing spondylitis, psoratic arthritis, and ulcerative colitis (12). 
There are no commercially available biosimilar agents to the available TNF antagonists in North 
America. Infliximab is a chimeric monoclonal antibody that has recently been shown to mitigate 
depressive symptoms in individuals treated for other medical conditions, with only preliminary 
evidence for its efficacy in a subgroup of individuals with treatment resistant depression.   
 


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Infliximab is a chimeric IgG1k monoclonal antibody for TNF-α with a molecular weight of 150 
kDa. It is composed of human constant and murine variable regions of the antibody. Infliximab 
is supplied as a sterile, white, lyophilized powder for intravenous injection; following 
reconstitution with 10 mL of sterile water for injection with a pH of approximately 7.2. Each 
single-use vile contains 100 mg of infliximab, 50 mg sucrose, 0.5 mg polysorbate 80, 2.2 mg 
monobasic sodium phosphate, monohydrate, and 6.1 mg d dibasic sodium phosphate, dehydrate, 
with no added preservatives (12). Infliximab binds with high affinity to the soluble and 
transmembrane forms of TNF- α and inhibits binding of TNF- α with its receptors (12). 
Treatment with infliximab reduces the access of inflammatory cells into inflamed areas in 
particular inflamed joints or intestine areas in patients with rheumatoid arthritis and Crohn’s 
disease, respectively. Decreases in serum IL-6 and C-reactive protein have also been reported 
following infliximab treatment (13).  
 
Single intravenous (i.v.) infusion of infliximab results in a linear increase between the maximum 
serum concentration and dose of administration (3–20 mg/kg). Infliximab is primarily distributed 
in the vascular compartment. Its volume of distribution at steady state is independent of dose. 
Single dose infusion of 3–10 mg/kg indicates that the median terminal half-life is 8.0–9.5 days. 
Repeated infusions of infliximab at 2 and 6 weeks result in predictable concentration-time 
profiles following each treatment. No systemic accumulation occurs at 4- or 8-week intervals 
with 3–10 mg/kg dosing. At 8 weeks, mean serum concentrations of infliximab range from 0.5 to 
6.0 mcg/mL (12). 
 
TNF Antagonists in Depression 
Several lines of trans-disciplinary evidence indicate that TNF antagonists improve measures of 
depression in individuals with psoriasis, rheumatoid arthritis, Crohn’s disease and ankylosing 
spondylitis. Treatment with TNF antagonists has been associated with lower rates of MDD and 
anxiety disorders in individuals with rheumatoid arthritis, as compared to individuals who did 
not receive these medications (14). In a 6-week, open-label study, infliximab (5 mg/kg 
administered at 0, 2 weeks and 6 weeks) was associated with reduced depressive and anxious 
symptom severity in individuals with ankylosing spondylitis (15). In a single-dose study of 
infliximab, a significantly smaller proportion of subjects met criteria for depression at 4 weeks 
(16% vs. 24%) as compared to baseline (16). In a single-blinded study of patients with Crohn’s 
disease (n = 14), each of whom received placebo (i.e. saline) at baseline, followed by infliximab 
(5 mg/kg) at 2 weeks, demonstrated a significant effect of infliximab on depressive symptom 
severity at 4 weeks (17). In patients with advanced cancer (n = 17), open-label infliximab was 
associated with improvements in fatigue, anxiety and depression subscores (18). Taken together, 
the results demonstrate that infliximab at 5 mg/kg may offer therapeutic benefit for depressive 
symptoms associated with BD.  
 


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Studies with other TNF antagonists also provide support for their putative antidepressant 
properties.   In an animal model of depression, 5 weeks of etanercept treatment was 
demonstrated to exert antidepressant-like effects on the Forced Swim Test (19). In clinical trials, 
12 weeks of etanercept was demonstrated to result in a reduction of depressive symptom severity 
on the Hamilton Depression Rating scale (HAMD) and Beck Depression Inventory (BDI) in 
individuals with plaque psoriasis (20;21). Significant improvement in depressive symptom 
severity has also been demonstrated in individuals with Crohn’s disease following adalimumab 
maintenance therapy (40 mg every other week) (22).  
 
To our knowledge, there is only one published study that has evaluated the effects of infliximab 
in a primary depressed population. Individuals with treatment resistant depression (N=60; MDD: 
n=51; BD: n=9) were enrolled in a 12-week, randomized, double-blind, placebo-controlled study 
with infliximab (5 mg/kg). Infliximab was administered at baseline, week 2 and week 6. 
Infliximab was superior to placebo in mitigating depressive symptom severity on the HAMD, 
only in individuals who exhibited elevated inflammation at baseline [i.e. high sensitivity C-
reactive protein (hsCRP) level of > 5mg/L].  This subgroup also exhibited a significantly higher 
response rate following treatment with infliximab as compared to placebo (62% and 33%). No 
significant time by drug interaction was observed in the full analysis set. Infliximab was well 
tolerated; the most commonly reported side effect was headaches (67%), followed by coughing 
and insomnia (17%), sore throat, upper respiratory infection, rash, and sinus congestion (13%), 
diarrhea and yeast infection (10%), panic attacks (7%) and fever (3%) (23). 
 
Safety and toxicity concerns 
The major risk associated with TNF-antagonists is an increased propensity for infections. As a 
result, treatment should not be initiated in patients who demonstrate evidence of acute or chronic 
infections. Patients must be monitored closely for clinical presentations suggestive of infection 
while receiving a TNF antagonist. Allergic reactions have been reported in approximately 1% of 
patients; serious allergic reactions are rare. Also, in rare cases patients treated with TNF-
antagonists may develop antibodies against the biologic agent and very rarely develop a lupus-
like syndrome. Other rare side-effects include: increased risk of serious infections, risk of 
demyelinating disorders (e.g. multiple sclerosis), psychosis, decrease in WBC and RBC count, 
and less than 1% risk of developing malignancy. Common side-effects include: mild skin 
reaction at the injection site (itchiness, redness, and mild swelling), nausea, abdominal pain, 
headache, rash and upper respiratory tract infections (such as sinusitis). 
 
Microbial Changes (optional participation) 
Every human harbors complex microbial communities (collectively, the human ‘microbiome’) 
that cover the skin and the body’s mucosal surfaces. These communities have a profound effect 
on our well-being. For instance, recent studies have outlined distinct associations between gut 
microbial communities and obesity, inflammatory bowel disease, nationality and aging. 


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Emerging research on axenic and gnotobiotic mice indicates that the influence of the intestinal 
microbiome extends well beyond the gut to involve organs that include the skin, liver and brain.  
Research on an animal model of depression has also shown that oral administration of a probiotic 
increased plasma tryptophan levels and decreased serotonin metabolite concentrations in the 
frontal cortex and decreased dopamine metabolite concentrations in the amygdaloid cortex. To 
date, there is no data on the nature of the microbiome of patients with BD. 
As part of this investigation into the efficacy of Infliximab, we will also look at the biomarker of 
changes in the gut microbiome.  
 
HYPOTHESIS 
Primary Hypothesis 
Adjunctive treatment with intravenous infliximab (5 mg/kg) will significantly mitigate 
depressive symptoms in individuals with DSM-5-defined bipolar I/II depression as compared to 
intravenous placebo (saline). 
 
Secondary Hypothesis 
Reduction in depressive symptom severity following infliximab treatment will be mediated by 
reduction in the levels of pro-inflammatory mediators, notably TNF-α. 
Reduction in levels of pro-inflammatory mediators, notably TNF- α, following treatment with 
infliximab mediates: 
 reduction in depressive symptom severity 
 favorable changes in cold and hot cognition 
 improvements in quality of life and functioning 
 alteration in central glutamate neurotransmission 
OBJECTIVES 
Primary Objective 
The primary objective is to evaluate the efficacy of adjunctive treatment with intravenous 
infliximab (5 mg/kg) in mitigating depressive symptoms in individuals with DSM-5-defined 
bipolar I/II depression as compared to intravenous placebo (saline) as measured by the mean 
change in Montgomery-Asberg Depression Rating Scale (MADRS) total scores. 
 
Secondary Objectives 
Secondary objectives are (1) to evaluate the effect of infliximab/cytokine milieu on measures of 
cognitive function including cold cognition and hot cognition (i.e., anhedonia) (2) to evaluate the 
effect of infliximab/cytokine milieu on the neuroprogression in BD as measured by prefrontal N-
Acetyl Aspartate and choline levels as well as hippocampal and whole brain gray matter volume 
using MRS and MRI, respectively (3) to evaluate the effect of treatment on quality of life and 
functioning as measured by 36-Item Short Form Health Survey (SF-36), Sheehan Disability 


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Scale (SDS) and Endicott Workplace Productivity Scale (EWPS), respectively (4) To evaluate if 
the gut microbial signature changes with treatment. This will be done by comparing changes pre- 
and post- treatment with Infliximab, as well as comparing the treatment group to the placebo 
group.  
STUDY DESIGN 
This is a phase II, 12-week, fixed dose, multisite, randomized, double-blind, placebo-controlled 
study of the efficacy, safety, and tolerability of adjunctive infliximab for the treatment of 
individuals with bipolar I/II depression. 
RECRUITMENT 
The two sites, Mood Disorder Psychopharmacology Unit, and Stanford University School of 
Medicine provide psychiatric assessment to approximately 20 new patients with BD per week. 
Based on experience from other interventional studies, we expect to recruit approximately 1-3 
participants per month per site for this study for a period of 2 years. An attrition rate of 30 
percent is expected; we anticipate that approximately 78 individual will be enrolled for a total of 
60 evaluable subjects. 
 
The study will be approved by the respective institutional review boards as well as Health 
Canada and FDA.  
SELECTION OF SUBJECTS  
Male and female outpatients (N=60; n=55 at Toronto Western Hospital and n=5 at Stanford 
University) between the ages of 18 and 65 who meet DSM-5 criteria for a current major 
depressive episode as part bipolar I/II disorder and are able to provide written informed consent 
will be eligible for inclusion in the study. The diagnosis of BD will be confirmed clinically 
according to DSM-5. At study entry, eligible subjects will be required to have a minimum 
Hamilton Depression Rating scale 17- item (HAMD-17) total score of >20 and Young Mania 
Rating Scale (YMRS) total score of <12; have previously failed a trial of a CANMAT BD 
guideline/FDA-approved first-line treatment for the depressive phase of BD during the index 
episode and/or during a prior episode. Treatment failure will be adjudicated either historically or 
prospectively. Female participants of childbearing potential must test negative for pregnancy and 
must be using adequate birth control measures (e.g., abstinence, oral contraceptives, intrauterine 
device, barrier method with spermicide, or surgical sterilization) throughout the study and must 
continue such precautions for 6 months after receiving the last study drug administration. 
Enrollment will be stratified based on indicators of inflammation; subjects will be randomized to 
treatment if they meet any one of the following criteria:  
 


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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. Migraines (as per the International Headache Society guidelines) (24;25) 
 
7. CRP ≥5 mg/L  
 
Country/Ethnic Specific Values for Waist Circumference* 
Country/Ethnic Group 
 
Waist Circumference  
(as Measure of Central Obesity) 
 
Europeans 
 
Male ≥94 cm  
Female ≥80 cm 
South Asians 
 
Male ≥90 cm  
Female ≥80 cm 
Chinese 
Male ≥90 cm  
Female ≥80 cm 
Japanese 
 
Male ≥85 cm  
Female ≥90 cm 
*These are pragmatic cut points and better data are required to link them to risk. Ethnicity 
should be the basis for classification, not the country of residence. 
 
Participants will be excluded from the study if according to clinician judgment, they have 
another concurrent psychiatric disorder that requires primary clinical attention, a history of 
schizophrenia, active psychotic symptoms; meet criteria for substance abuse and/or dependence 
within 6 months; have received electroconvulsive therapy in the past 6 months, are actively 
suicidal or evaluated as being a suicide risk (a score of ≥3 on the HAMD-17 suicide item; a score 


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of > 4 on the MADRS and/or according to clinical judgment using the Columbia-Suicide 
Severity Rating Scale). Participants will also be excluded if they have a clinically significant 
unstable medical illness, a history of tuberculosis (confirmed by chest radiography, a positive 
tuberculin skin test, or a blood test; as per Canadian TB standards) or a high risk of tuberculosis 
exposure; severe infections such as sepsis, abscesses, tuberculosis and opportunistic infections; 
viral hepatitis B (assessed using Public Health of Canada hepatitis B screening 
recommendation); a history of hepatitis C infection; documented or suspected human 
immunodeficiency virus (HIV) infection (confirmed by laboratory testing); any unstable 
autoimmune disorder; active fungal infection; a history of recurrent viral or bacterial infections; 
received within 3 months prior to screening or are expected to receive any live viral (e.g., 
smallpox) or live bacterial vaccinations during the trial or up to 3 months after the last 
administration of study agent; have had a C.difficile infection within the past 4 months; have a 
history of lymphoproliferative disease; a 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; a concomitant diagnosis or any history of congestive heart 
failure; and/or are concomitantly treated with non-steroidal and steroidal anti-inflammatory 
medications or other biologics; have current or past exposure to anti-TNF biologics; a 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 will 
also be excluded from this study.  
TREATMENT AND DOSING 
Infliximab will be prescribed adjunctively to a conventional mood stabilizer or atypical 
antipsychotic agent. Eligible participants will have received conventional treatment for bipolar 
depression for a minimum of 4 weeks prior to randomization to infliximab or placebo. The 
choice and dosing of mood stabilizing agents will remain unchanged throughout the trial; 
allowing for adjunctive treatment with mechanistically dissimilar mood stabilizing agents, which 
foster recruitment.   
 
Participants will be randomized to receive intravenous infliximab (5 mg/kg) or placebo (saline 
solution) at baseline, week 2 and 6 under clinical observation. Placebo will be matched to 
infliximab in color and consistency. The dosing and dosing schedule are identical to a previously 
published RCT with infliximab in MDD.  
 
 


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CONCOMITANT TREATMENTS:  
Prohibited medications: 
 Anakinra 
 Abatacept 
 Other biologics 
 Nonsteroidal and steroidal anti-inflammatory medications (exception: 81 mg aspirin if 
medically indicated) 
 
Restricted medications: 
 Medications taken on a prn basis will be reviewed and may be restricted at certain time 
points during the study (e.g., medications that interfere with cognitive function). 
 
 
SUBJECT DISCONTINUATION 
Subjects may be discontinued from the study participation at any time.   
 
Reasons for discontinuation include: 
1. Voluntary discontinuation by the subject without prejudice to further treatment. 
2. Worsened depression on 2 consecutive visits as measured by MADRS. 
3. Onset of hypo/manic symptoms, i.e., YMRS >12 on 2 consecutive visits.  
 
 
PROCEDURES 
Participants will be enrolled at the Mood Disorders Psychopharmacology Unit, University Health 
Network, University of Toronto, Canada and Department of Psychiatry, Veterans’ affairs 
Hospital, USA. 
 
A written, signed and dated informed consent should be obtained from the subject before any 
study-related procedures are performed. A member of the research staff will explain the study in 
full detail to any prospective subject in understandable, non-medical terms.  The research staff, 
as well as the investigator, will answer any questions raised and ensure that the prospective 
participant understands all the procedures and risks involved. Once the subject has had some 
time to consider the study (usually up to 24 hrs) and decides that they wish to participate, the 
study staff will confirm the subject’s voluntary and informed participation in the study.  A copy 
of the signed consent form will be given to the patient for their reference. 
The subject should then be assigned a subject number.  
 


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Screening Visit 
Screening procedures will be performed within -28 days of the baseline (day 0) visit, unless 
approved by the principal investigator. 
 
The following information/assessments will be collected: 
 Subject demography and social characteristics 
o Date of birth (mmm/yyyy), sex, race, ethnicity 
o Marital status, employment status, education 
 Physical Activity History: International Physical Activity Questionnaire (IPAQ) 
 Medical history: Illness characteristics will be obtained from patient interview and 
hospital medical records. 
 Current medication(s) and the daily dosages will be recorded. 
 Psychiatric history and evaluation: 
o Diagnosis of Bipolar Disorder I/II will be confirmed with the Structured Clinical 
Interview for DSM Disorders (SCID). 
o Comorbid psychiatric disorders will be assessed with the MINI International 
Neuropsychiatric Interview (MINI).  
o Active psychotic symptoms as well as substance abuse/dependence will be 
assessed with the MINI.  
o Symptoms of depression will be assessed using Montgomery-Asberg Depression 
Rating Scale (MADRS) and Hamilton Depression Rating Scale (HAMD-17). 
 Other assessments 
o Symptoms of hypo/mania will be assessed using the Young Mania Rating Scale 
(YMRS). 
o Risk of suicide will be assessed using the Columbia Suicide Severity Rating Scale 
(C-SSRS). 
o Symptom severity will be assessed using the CGI-Severity. 
o Chronic stress and episodic life events will be assessed using the UCLA Life 
Stress Interview. 
 Spontaneously reported adverse events will be recorded. 
 Anthropometric measures will be recorded. 
o Height 
o Weight 
 Vital signs will be recorded. 
o Blood Pressure 
o Pulse rate 
 
Laboratory samples will be collected. 
o TB skin test; chest x-ray (if indicated) 
o HIV test 
o Hep B test 


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o Hep C test 
o Hematology: hemoglobin, hematocrit, total and differential WBC count, platelet 
count 
o Chemistry: blood urea nitrogen/urea, creatinine, sodium, potassium, calcium, 
alkaline phosphatise, total protein, albumin, AST, ALT, total bilirubin 
o Lipid panel: triglycerides, HDL, LDL, total cholesterol 
o Insulin 
o Glucose 
o Lithium 
o Valproate 
o hCG 
o Urine drug test 
 participants will be given a stool collection kit to collect stool sample for microbial 
profile which is to be submitted within 24 hours of collection at baseline visit (optional 
participation) 
 
Baseline / Endpoint Evaluation 
The baseline visit is on day 0 of the study.  
 
The endpoint visit is on day 84 of the study. 
 
The following assessments will be completed in the aforementioned visits: 
 Symptoms of depression will be assessed using Montgomery-Asberg Depression Rating 
Scale (MADRS), Hamilton Depression Rating Scale (HAMD-17) and the Quick 
Inventory of Depressive Symptomatology – Self Report (QIDS-SR). The HAMD-17 will 
be administered at baseline. 
 Symptoms of hypo/mania will be assessed using YMRS and the Hypomania Check List 
(HCL). 
 Risk of suicide will be assessed using the Columbia – Suicide Severity Rating Scale (C-
SSRS). 
 Symptom severity will be assessed using the CGI-Severity at baseline and endpoint 
whereas symptom improvement will be assessed using CGI-Improvement at endpoint. 
 Quality of life will be assessed using Short Form - 36 (SF-36), Sheehan Disability Scale 
(SDS) and Endicott Work Place Productivity Scale (EWPS). 
 The Snaith Hamilton Pleasure Scale (SHAPS) will be administered. 
 History of childhood adversity will be assessed using the Childhood Trauma 
Questionnaire (CTQ) at baseline. 
 Digit Symbol Substitution Test (DSST) from the WAIS-III and the Rey Auditory Verbal 
Learning Test (RAVLT) will be administered. 


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 The Perceived Deficits Questionnaire for Depression – 20 item will be administered. 
 Diet will be assessed using the Brief Diet Questionnaire (BDQ). 
 Spontaneously reported adverse events will be recorded. 
 All prescription or non-prescription drugs, herbal or nutritional supplements will be 
recorded. 
 Vital signs as well as waist circumference and weight will be measured and recorded. 
 Laboratory specimens will be collected (endpoint only). 
 Anatomical and functional magnetic resonance imaging (MRI) scan and a single voxel 
proton magnetic resonance spectroscopy (MRS) scanning will be conducted. 
 Stool sample will be collected (optional participation). 
 
Follow-up Visits 
All follow-up visits will be scheduled within ± 2 days of visit date to allow for variations in 
subject schedules, unless approved by the principal investigator. The overall treatment period in 
the protocol will be maintained. 
The following assessments will be completed in the aforementioned visits: 
 Symptoms of depression will be assessed using MADRS, the Quick Inventory of 
Depressive Symptomatology – Self Report (QIDS-SR)and the HAMD-17 (Baseline, 
Week 0 and Week 12) 
 Symptoms of hypo/mania will be assessed using YMRS and the Hypomania Check List 
(HCL). 
 Risk of suicide will be assessed using the Columbia – Suicide Severity Rating Scale (C-
SSRS). 
 Symptom severity and improvement will be assessed using the CGI-Severity and CGI-—
Improvement, respectively, at all follow-up visits. 
 Quality of life will be assessed using Short Form - 36 (SF-36) at Week 4.  
 Sheehan Disability Scale (SDS) will be administered. 
 The Snaith Hamilton Pleasure Scale (SHAPS) will be administered (Week 0, Week 6, 
Week 12) 
 Digit Symbol Substitution Test (DSST) from the WAIS-III and the Rey Auditory Verbal 
Learning Test (RAVLT) will be administered at week 2. 
 The Perceived Deficits Questionnaire for Depression – 20 item will be administered at 
week 2. 
 Diet will be assessed using the Brief Diet Questionnaire (BDQ). 
 Spontaneously reported adverse events will be recorded. 
 Weight will be recorded. 
 Vital signs will be measured and recorded. 
 Changes to medicines will be assessed. 


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14
 Laboratory specimens will be collected (hematology and biochemistry at Week 2 and 
Week 6). 
 Changes in physical activity will be assessed using the International Physical Activity 
Questionnaire (IPAQ) (Screening, Week 6 and Week 12).  
 
 Stool sample will be collected at week 6 (optional participation). 
 
At a single time point during the study, the history of childhood and adolescent experience of 
neglect and abuse will be assessed using the Childhood Experience of Care and Abuse (CECA) 
Interview. The CECA interview will be conducted by telephone and audio-recorded. The 
interview and subsequent ratings will be made by highly trained and experienced research staff 
supervised by Dr. Kate Harkness.  
 
Laboratory Assessments 
Routine: The following laboratory tests will be completed: 
 CRP (at screening) 
 HIV testing (at screening) 
 Hep B, C testing (at screening) 
 hCG (at screening) 
 Hematology: hemoglobin, hematocrit, total and differential WBC count, platelet count 
 Chemistry: blood urea nitrogen/urea, creatinine, sodium, potassium, calcium, alkaline 
phosphatase, total protein, albumin, AST, ALT, total bilirubin 
 Lipid panel: triglycerides, HDL, LDL, total cholesterol 
 Insulin 
 Glucose 
 Lithium (if indicated) 
 Valproate (if indicated) 
 Urine drug screen (at screening) 
Biomarkers: Blood samples for biomarker analysis will be collected at baseline, week 2, week 
6, and week 12.. The samples will be collected after a 12 hour fast and centrifuged at 1000g for 
15 min at 4 oC; plasma will be stored at -80 oC. Ultrasensitive ELISA will be used to measure 
high-sensitivity CRP and TNF-α, TNF-R1 and TNF-R2.  For exploratory mechanistic analysis, 
inflammatory targets including inflammatory cytokines and receptors will be measured (e.g. 
IFN-γ, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13). Other exploratory targets include 
chemokines and receptors (e.g. MCP-1) as well as cell adhesion molecules (e.g., VCAM, 
NCAM, ICAM, e-selectin). Metabolic targets for evaluation include insulin, leptin, ghrelin, 
adiponectin and resistin levels. .  
 


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15
mRNA Analysis: Blood samples for mRNA analysis will be collected at baseline, week 2, week 
6, and week 12. Samples will be stored at -80 oC until analysis. 
 
Microbiome Analysis: Fecal samples will be collected from participants and controls and 
extracted DNA will be analyzed by PCR and next-generation sequencing. Microbial community 
profiles will be generated using Illumina sequencing and paired-end assembly of 16S rRNA gene 
reads (one lane; 1-2 million reads per sample). This method has been used multiple times in the 
Neufeld lab and has been published. Importantly, no human DNA will be amplified and 
sequenced with this approach. 
 
Other: Human anti-chimeric antibody (HACA) levels will also be measured at endpoint/early 
termination. 
 
 
COMPENSATION 
Subjects will receive financial compensation for participation in the study. Subjects will be 
reimbursed up to $50.00 per visit for travel expenses (e.g. parking, public transport) and food-
related expenses.  
 
Subjects who agree to provide stool samples will receive $10.00 at visits 2, 6, and 10. 
 
 
INVESTIGATOR PRODUCT AND ADMINISTRATION 
Investigational Product 
Infliximab is supplied as a sterile white lyophilized powder for intravenous infusion. Each vial 
contains 100 mg infliximab, 500 mg sucrose, 0.5 mg polysorbate 80, 2.2 mg monobasic sodium 
phosphate, monohydrate and 6.1 mg dibasic sodium phosphate, dehydrate. No preservative are 
present.  
 
Infliximab lyophilized concentrate for IV injection is supplied in individually-boxed single-use 
vials of 100 mg dosage strength. 
 
 
Storage 
The lyophilized product will be refrigerated at 2°C to 8°C (36°F to 46°F). Reconstitution and 
dilution of infliximab will take place in controlled, aseptic conditions. The infusion solution will 
be administered within 3 hours of reconstitution and dilution. If the diluted infliximab is not used 


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16
within 3 hours of preparation, the infusion solution may be stored for no longer than 24 hours at 
2°C to 8°C. 
 
Stool samples will be stored in a -80 ºC fridge at University of Toronto until transported in dry 
ice to the University of Waterloo for analysis. 
 
 
SAFETY MEASURES  
Tuberculin skin testing will be conducted at screening. All subjects will be screened for HIV, 
hepatitis B and C. Infusion will be delayed if any evidence of other infections is present at 
baseline until symptoms have resolved and/or appropriate treatment has been initiated. Treatment 
and safety at the time of infusion will be monitored by a trained Registered Nurse that has 
clinical trial experience with biologic agents. Safety measures will be evaluated at each visit and 
will include measurement of vital signs, assessment of mood symptoms and adverse event 
development; in addition, routine blood tests will be conducted at screening, week 2, 6, and 12. 
Adverse events will also be recorded at each visit by spontaneous report.  The YMRS will be 
administered at each visit to monitor induction of hypo/manic symptomatology. 
 
 
EFFICACY MEASURES 
 
Primary Endpoints 
Clinical outcome measures will be administered at baseline, week 1, 2, 3, 4, 6, 8, 10, and 12. The 
primary efficacy variable will be mean change from baseline to week 12 on the MADRS total 
score.  
 
Secondary Endpoints 
Secondary efficacy evaluations will be response (i.e. >50% reduction from baseline week 12 on 
the MADRS) and remission (i.e. MADRS <12) rates, as well as change in CGI Severity.  
STATISTICS 
Statistical Methods 
Separate randomization schedules will be prepared for each site.  
The intention-to-treat sample will include subjects who receive at least one infusion of 
infliximab or placebo and have at least one post-baseline assessment. Missing data will be 
estimated with the maximum likelihood method using a mixed model for repeated measures 
ANOVA. The mixed model repeated measures ANOVA will also be used to evaluate change 


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17
from baseline to endpoint as a function of treatment status. All tests will be two tailed with 
significance defined by <0.05. 
 
All data collected during this study will be uploaded to the National Institute for Mental Health 
data respiratory. 
Interim Analysis 
No interim analysis will be conducted. 
 
Sample Size Calculation and Statistical Analysis  
Using the published literature with infliximab in MDD (23), it is estimated that 30 evaluable 
subjects per treatment arm will have better than 80% power to detect a difference in depressive 
symptoms between infliximab-treated and placebo-treated subjects at level of 5% significance.  
 
ADVERSE EVENTS 
Definitions 
Adverse event 
An adverse event is the development of an undesirable medical condition or the deterioration of 
a pre-existing medical condition following or during exposure to a pharmaceutical product, 
whether or not considered causally related to the product.  An undesirable medical condition can 
be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the abnormal 
results of an investigation (e.g., laboratory findings, electrocardiogram).  In clinical studies, an 
AE can include an undesirable medical condition occurring at any time, including run-in or 
washout periods, even if no study treatment has been administered. 
Serious adverse event 
A serious adverse event is an AE occurring during any study phase (i.e., run-in, treatment, 
washout, follow-up), and at any dose of the investigational product, comparator or placebo, that 
fulfils one or more of the following criteria: 
 results in death 
 is immediately life-threatening 
 requires in-patient hospitalisation or prolongation of existing hospitalisation 
 results in persistent or significant disability or incapacity 
 is a congenital abnormality or birth defect 


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18
 is an important medical event that may jeopardise the patient or may require medical 
intervention to prevent one of the outcomes listed above. 
The causality of SAEs (i.e., their relationship to study treatment) will be assessed by the 
investigator(s).  Note that SAEs that could be associated with any study procedure should also be 
reported. For such events the casual relationship is implied as "yes". 
Recording of adverse events 
AEs will be collected from baseline visit to until the end of the study. At each visit, subjects will 
be asked if they have had any health problems since the previous visit.  All AEs will be recorded 
appropriately, whether or not considered related to the investigational product. This will include 
AEs spontaneously reported by the patient and/or observed by the staff as well as AEs reported 
in response to a direct question e.g. “Have you had any health problems since your last visit?”  
For each AE, the following parameters be described: 
 start and stop date 
 action taken with regards to investigational product 
 outcome 
 if the AE caused the patient to discontinue 
 a statement if the AE fulfils the criteria for a SAE or not 
 the investigator’s assessment of the causal relationship between the event and the 
investigational product 
 intensity of the AE 
o mild (awareness of sign or symptom, but easily tolerated) 
o moderate (discomfort sufficient to cause interference with normal activities) 
o severe (incapacitating, with inability to perform normal activities) 
It is important to distinguish between serious and severe AEs.  Severity is a measure of intensity 
whereas seriousness is defined by the criteria in Section.  An AE of severe intensity need not 
necessarily be considered serious.  For example, nausea that persists for several hours may be 
considered severe nausea, but not an SAE.  On the other hand, a stroke that results in only a 
limited degree of disability may be considered a mild stroke but would be an SAE.  
Symptoms associated with overdose should be reported as AEs. For further information 
regarding overdose, see section. 
Pregnancy in itself is not regarded as an AE unless there is a suspicion that an investigational 
product may have interfered with the effectiveness of a contraceptive medication.  
Follow-up of adverse events should be based upon the clinical judgement of the investigator. 
Reporting of serious adverse events 


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19
Reporting of SAEs to regulatory authorities will be done by the investigator in accordance with 
local regulations. A copy of the report will also be sent to the manufacturer of the investigational 
product. 
 
 
Reference List 
 
 
(1)  McIntyre RS, Soczynska JK, Beyer JL, Woldeyohannes HO, Law CW, Miranda A, 
Konarski JZ, Kennedy SH. Medical comorbidity in bipolar disorder: re-prioritizing unmet 
needs. Curr Opin Psychiatry 2007 July;20(4):406-16. 
 
(2)  Genome-wide association study of 14,000 cases of seven common diseases and 3,000 
shared controls. Nature 2007 June 7;447(7145):661-78. 
 
(3)  Kauer-Sant'anna M, Kapczinski F, Andreazza AC, Bond DJ, Lam RW, Trevor YL, 
Yatham LN. Brain-derived neurotrophic factor and inflammatory markers in patients 
with early- vs. late-stage bipolar disorder. Int J Neuropsychopharmacol 2008 September 
4;1-12. 
 
(4)  Bob P, Raboch J, Maes M, Susta M, Pavlat J, Jasova D, Vevera J, Uhrova J, Benakova H, 
Zima T. Depression, traumatic stress and interleukin-6. J Affect Disord 2010 
January;120(1-3):231-4. 
 
(5)  Padmos RC, Hillegers MH, Knijff EM, Vonk R, Bouvy A, Staal FJ, de RD, Kupka RW, 
Nolen WA, Drexhage HA. A discriminating messenger RNA signature for bipolar 
disorder formed by an aberrant expression of inflammatory genes in monocytes. Arch 
Gen Psychiatry 2008 April;65(4):395-407. 
 
(6)  Pae CU, Lee KU, Han H, Serretti A, Jun TY. Tumor necrosis factor alpha gene-G308A 
polymorphism associated with bipolar I disorder in the Korean population. Psychiatry 
Res 2004 January 30;125(1):65-8. 
 
(7)  Pollmacher T, Haack M, Schuld A, Kraus T, Hinze-Selch D. Effects of antipsychotic 
drugs on cytokine networks. J Psychiatr Res 2000 November;34(6):369-82. 
 
(8)  Akhondzadeh S, Jafari S, Raisi F, Nasehi AA, Ghoreishi A, Salehi B, Mohebbi-Rasa S, 
Raznahan M, Kamalipour A. Clinical trial of adjunctive celecoxib treatment in patients 
with major depression: a double blind and placebo controlled trial. Depress Anxiety 
2009;26(7):607-11. 
 
(9)  Nery FG, Monkul ES, Hatch JP, Fonseca M, Zunta-Soares GB, Frey BN, Bowden CL, 
Soares JC. Celecoxib as an adjunct in the treatment of depressive or mixed episodes of 
bipolar disorder: a double-blind, randomized, placebo-controlled study. Hum 
Psychopharmacol 2008 March;23(2):87-94. 
 (10)  Muller N, Schwarz MJ, Dehning S, Douhe A, Cerovecki A, Goldstein-Muller B, 
Spellmann I, Hetzel G, Maino K, Kleindienst N, Moller HJ, Arolt V, Riedel M. The 


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cyclooxygenase-2 inhibitor celecoxib has therapeutic effects in major depression: results 
of a double-blind, randomized, placebo controlled, add-on pilot study to reboxetine. Mol 
Psychiatry 2006 July;11(7):680-4. 
 (11)  Brietzke E, Kapczinski F. TNF-alpha as a molecular target in bipolar disorder. Prog 
Neuropsychopharmacol Biol Psychiatry 2008 August 1;32(6):1355-61. 
 (12)  Tracey D, Klareskog L, Sasso EH, Salfeld JG, Tak PP. Tumor necrosis factor antagonist 
mechanisms of action: a comprehensive review. Pharmacol Ther 2008 
February;117(2):244-79. 
 (13)  Visvanathan S, Wagner C, Marini JC, Baker D, Gathany T, Han J, van der HD, Braun J. 
Inflammatory biomarkers, disease activity and spinal disease measures in patients with 
ankylosing spondylitis after treatment with infliximab. Ann Rheum Dis 2008 
April;67(4):511-7. 
 (14)  Uguz F, Akman C, Kucuksarac S, Tufekci O. Anti-tumor necrosis factor-alpha therapy is 
associated with less frequent mood and anxiety disorders in patients with rheumatoid 
arthritis. Psychiatry Clin Neurosci 2009 February;63(1):50-5. 
 (15)  Ertenli I, Ozer S, Kiraz S, Apras SB, Akdogan A, Karadag O, Calguneri M, Kalyoncu U. 
Infliximab, a TNF-alpha antagonist treatment in patients with ankylosing spondylitis: the 
impact on depression, anxiety and quality of life level. Rheumatol Int 2012 
February;32(2):323-30. 
 (16)  Persoons P, Vermeire S, Demyttenaere K, Fischler B, Vandenberghe J, Van OL, Pierik 
M, Hlavaty T, Van AG, Noman M, Rutgeerts P. The impact of major depressive disorder 
on the short- and long-term outcome of Crohn's disease treatment with infliximab. 
Aliment Pharmacol Ther 2005 July 15;22(2):101-10. 
 (17)  Minderhoud IM, Samsom M, Oldenburg B. Crohn's disease, fatigue, and infliximab: is 
there a role for cytokines in the pathogenesis of fatigue? World J Gastroenterol 2007 
April 14;13(14):2089-93. 
 (18)  Tookman AJ, Jones CL, Dewitte M, Lodge PJ. Fatigue in patients with advanced cancer: 
a pilot study of an intervention with infliximab. Support Care Cancer 2008 May 21. 
 (19)  Krugel U, Fischer J, Radicke S, Sack U, Himmerich H. Antidepressant effects of TNF-
alpha blockade in an animal model of depression. J Psychiatr Res 2013 May;47(5):611-6. 
 (20)  Tyring S, Gottlieb A, Papp K, Gordon K, Leonardi C, Wang A, Lalla D, Woolley M, 
Jahreis A, Zitnik R, Cella D, Krishnan R. Etanercept and clinical outcomes, fatigue, and 
depression in psoriasis: double-blind placebo-controlled randomised phase III trial. 
Lancet 2006 January 7;367(9504):29-35. 
 (21)  Gelfand JM, Kimball AB, Mostow EN, Chiou CF, Patel V, Xia HA, Freundlich B, 
Stevens SR. Patient-reported outcomes and health-care resource utilization in patients 


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with psoriasis treated with etanercept: continuous versus interrupted treatment. Value 
Health 2008 May;11(3):400-7. 
 (22)  Loftus EV, Feagan BG, Colombel JF, Rubin DT, Wu EQ, Yu AP, Pollack PF, Chao J, 
Mulani P. Effects of adalimumab maintenance therapy on health-related quality of life of 
patients with Crohn's disease: patient-reported outcomes of the CHARM trial. Am J 
Gastroenterol 2008 December;103(12):3132-41. 
 (23)  Raison CL, Rutherford RE, Woolwine BJ, Shuo C, Schettler P, Drake DF, Haroon E, 
Miller AH. A randomized controlled trial of the tumor necrosis factor antagonist 
infliximab for treatment-resistant depression: the role of baseline inflammatory 
biomarkers. JAMA Psychiatry 2013 January;70(1):31-41. 
 
(24)     Karabulut KU, Egercioglu TU, Uyar M, Ucar Y. The change of neutrophils/lymphocytes 
ratio in migraine attacks: A case-controlled study. Annals of Medicine and Surgery. 2016 
Sep 30;10:52-6. 
 
(25)     Sarchielli P, Alberti A, Baldi A, Coppola F, Rossi C, Pierguidi L, Floridi A, Calabresi P. 
Proinflammatory cytokines, adhesion molecules, and lymphocyte integrin expression in 
the internal jugular blood of migraine patients without aura assessed ictally. Headache: 
The Journal of Head and Face Pain. 2006 Feb 1;46(2):200-7. 
 
  
 

ICF_001.pdf: 
 
 
 
 
 
Infliximab in the treatment of Bipolar Depression 
 
                        
April 3, 2017 
1 of 9 
 
 
 
 
 
     
 
 
 
  
 
 
 
CONSENT TO PARTICIPATE IN A RESEARCH STUDY 
 
 
 
TITLE: 
A Multisite, 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 
 
PRINCIPAL INVESTIGATOR:  Dr. Roger S. McIntyre  
(416) 603-5279 
 
Study Contact Number:  
 
(416)-603-5133 
 
Introduction 
 
You are being asked to take part in a research study. Before agreeing to participate in this study, 
it is important that you read and understand the following explanation of the proposed study 
procedures. The following information describes the purpose, procedures, benefits, discomforts, 
risks and precautions associated with this study. It also describes your right to refuse to 
participate or withdraw from the study at any time. In order to decide whether you wish to 
participate in this research study, you should understand enough about its risks and benefits to be 
able to make an informed decision. This is known as the informed consent process.  
 
Please ask the study doctor or study team to explain any words you do not understand before 
signing this consent form. Make sure all your questions have been answered to your satisfaction 
before signing this document.  
 
Background 
 
You have been asked to take part in this research study because you are currently suffering form 
depression and have been diagnosed with bipolar disorder by a health care professional.  
 
Bipolar disorder is usually treated with mood stabilizers and/or antipsychotics. There are many 
medications that have been shown to help hypo/manic symptoms in individuals with bipolar 
disorder. The treatment of depression in individuals with bipolar disorder is more difficult and 
very few medications have proven to be helpful. 
 
This study aims to evaluate the study drug called infliximab as a new treatment option for bipolar 
depression. Infliximab is currently approved by Health Canada for the treatment of rheumatoid 
arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, psoriatic arthritis, and plaque 
psoriasis. In this study, infliximab is an investigational medication. Investigational in this study 
means that infliximab has not been approved by Health Canada as treatment for bipolar 
depression. There is evidence that some people with bipolar depression have more inflammation 


 
 
 
 
 
Infliximab in the treatment of Bipolar Depression 
 
                        
April 3, 2017 
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in the body and this study aims to improve depressive symptoms by reducing inflammation with 
infliximab.  
 
As part of a sub-study, you will be asked to provide stool samples to examine changes in the 
bacteria that normally reside in the gut after treatment with infliximab for bipolar depression. 
The gut is inhabited by millions of bacteria that normally reside in harmony with us and 
contribute to our health. However, changes  that occur amongst the bacteria are now thought to 
be associated with or even contribute to chronic illnesses. While evidence is still limited in 
psychiatric illnesses, the available data suggests that this may happen in psychiatric illness as 
well. Participation in the sub-study is optional and does not affect participation in the main study. 
You will be asked to indicate your decision at the end of this consent form. 
 
A total of 60 participants will be enrolled in this study; approximately 55 participants will be 
enrolled from the Mood Disorders Psychopharmacology Unit (MDPU), University Health 
Network (UHN), at the Toronto Western Hospital. 
 
Purpose 
 
This study is designed to investigate if treatment with intravenous infliximab in addition to your 
usual treatment will help your mood, your cognition and your quality of life.  If it is found that 
the treatment helps, then it could be a new treatment for bipolar depression.  
 
You should not be enrolled in this study if you have a history of severe infections including 
severe sepsis, abscesses, tuberculosis, viral hepatitis and HIV because the study drug may 
activate these infection. 
 
As part of a sub-study, you will be asked to provide stool samples for the investigation of 
changes in gut bacteria after treatment with infliximab for bipolar depression.  
 
Study Design 
 
This study compares the study drug infliximab with a placebo. A placebo looks just like 
infliximab but contains no active medication. Whether you get the study drug or the placebo will 
be decided randomly (by chance) like flipping a coin or rolling dice. The number of people 
getting infliximab will be 15 and the number getting placebo will be 15, approximately. This 
study will be double-blinded. This means that neither you nor the study team will know whether 
you are on infliximab or on placebo until the study is finished. This information can be found out 
in case of emergency. You will receive infliximab at 3 time points during the study. You will be 
in this study for 12 weeks after the initiation of treatment. There will be 10 visits during the 
study. There may be instances when additional visits are required to complete study procedures. 
Most visits will last for 1.5 hours, though some last longer (please refer to Calendar of Visits). 
 
Study Visits and Procedures 
 
All Visits (Screening Visits to Visit 10) 
The following procedures will be performed at all study visits: 


 
 
 
 
 
Infliximab in the treatment of Bipolar Depression 
 
                        
April 3, 2017 
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- 
You will be asked about any prescription or non-prescription drugs, herbal or nutritional 
supplements that you are taking or planning to take. You will also be asked if there have 
been any changes to your drugs and/or supplements. 
- 
You will be asked about how you have been feeling. 
- 
Your weight and waist circumference will be measured 
- 
Your blood pressure and pulse rate will be measured. 
- 
You will be asked if you have noticed any medical changes. 
 
Visit 1 (Screening Visit) 
In addition to the procedures performed for all visits and blood tests, the following will be 
completed during this visit: 
- 
Your demographic information will be recorded, , including current physical activity 
levels 
- 
The study team will carry out an interview to confirm your diagnosis of bipolar disorder 
and your suitability for the study. 
- 
A physical exam will be completed.  
- 
Your height will be measured. 
- 
A pregnancy test (if female) and drug screen will be completed. 
- 
You will be screened for hepatitis and HIV. 
- 
You will also be asked to complete a TB skin test. 
- 
We may contact your doctor for your medical records that are pertinent to your study 
participation. Your consent will be obtained prior to such contact. 
 
Visits 2, 4, 7 
In addition to the procedures performed for all visits and blood tests, the following will be 
complete during this visit: 
- 
You will receive treatment with either infliximab or placebo. Treatment is administered 
through infusion into a vein. Infusions will take place at the Toronto Western Hospital. A 
healthcare professional will oversee the procedure and monitor you for any infusion-
related reactions. 
- 
You will provide stool samples (optional). 
 
Visits 2, 4, 10 
- 
Cognitive tests will be completed. 
 
Visits 2-10 
–Self-report questionnaires will be completed.  
 
Visits 1, 2, 4, 7, 10 
- 
Blood test may be repeated after visit 1 and before visit 2 upon the doctor’s discretion. 
- 
Blood samples will be collected for a routine evaluation (except on visit 2). 
- 
Blood samples will also be collected and stored for the assessment of biomarkers 
(including on visit 2). Biomarkers are biological markers that may reflect the presence of 
an illness and/or the severity of the illness. 
 


 
 
 
 
 
Infliximab in the treatment of Bipolar Depression 
 
                        
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These are fasting visits. This means that you will be asked to not have food after midnight the 
night before. This is important to ensure that your blood test results are reflective of your health 
status. Blood samples will be stored for biomarker analysis. Biomarkers of interest consist of 
various proteins and mRNA (blueprints that carry instructions for building proteins). 
 
Visits 2, 10 
- 
Two types of medical imaging (i.e., MRI and MRS) will be completed. The MRI will be 
used to assess the structure and function of your brain whereas the MRS will be used to 
measure the presence and concentration of various substances that are produced during 
metabolism in your brain. 
 
 
At a single time point during the study, a telephone interview will be conducted by highly trained 
and experienced research staff with the aim to evaluate your history of childhood and adolescent 
experience. This interview will be audio-recorded. You are not required to answer any question 
that you are not comfortable answering. 
 
Reminders: 
 
- 
Please fast for 12 hours before visits 1, 2, 4, 7, and 10. 
- 
Please do not exercise for 48 hours before visits 1, 2, 4, 7, and 10. 
- 
The following medications are prohibited for the duration of your study participation: 
anakinra, abatacept, other biologics, non-steroidal and steroidal anti-inflammatory 
medications (Note: prescribed treatment with 81 mg aspirin is permitted). 
- 
Medications that are taken irregularly are restricted. Please consult study doctor and 
follow advice. 
 
Calendar of Visits 
 
Visit 
Interview Blood 
Test 
Medical 
Imaging 
Treatment Stool 
Sample 
Time 
Visit 1 
(Screening) 
X 
X 
 
 
 
3 hours 
Visit 2 
(Baseline)  
X 
X 
X 
X 
X 
6 hours 
Visit 3  
(Week 1) 
X 
 
 
 
 
1.5 hours 
Visit 4  
(Week 2) 
X 
X 
 
X 
 
5 hours 
Visit 5  
(Week 3) 
X 
 
 
 
 
1.5 hours 
Visit 6  
(Week 4) 
X 
 
 
 
 
1.5 hours 
Visit 7  
(Week 6) 
X 
X 
 
X 
X 
4 hours 
Visit 8  
X 
 
 
 
 
1.5 hours 


 
 
 
 
 
Infliximab in the treatment of Bipolar Depression 
 
                        
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(Week 8) 
Visit 9  
(Week 10) 
X 
 
 
 
 
1.5 hours 
Visit 10  
(Week 12) 
X 
X 
X 
 
X 
3.5 hours 
 
Risks Related to Being in the Study 
 
Taking part in this study has risks. Some of these risks we know about. There is also a possibility 
of risks that we do not know about and have not been seen in humans to date. Please call the 
study doctor if you have any side effects even if you do not think it has anything to do with this 
study.  
 
The known risks associated with infliximab infusions are: 
 
Common (20 – 49%): 
- 
Upper respiratory tract infection 
- 
Inflammation of the back throat 
- 
Irritation and inflammation of nasal membrane 
- 
Nausea 
- 
Abdominal pain 
- 
Diarrhea 
- 
Pain 
- 
Headache 
 
Less Common: (1 – 19%) 
- 
Coughing 
- 
Sinusitis 
- 
Bronchitis 
- 
Vomiting 
- 
Indigestion 
- 
Rash 
- 
Itchiness 
- 
Fatigue 
- 
Joint pain 
- 
Back pain 
- 
Muscle pain 
- 
Dizziness 
- 
Fever 
- 
Allergic reactions (immediate or delayed) 
- 
Serious infections including tuberculosis, pneumonia and other infections 
- 
Opportunistic infections such as systemic fungal, viral and bacterial infections 
 
Rare (< 1%): 
- 
Liver injury 
- 
Heart failure 


 
 
 
 
 
Infliximab in the treatment of Bipolar Depression 
 
                        
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- 
Low blood counts 
- 
Nervous system disorders 
- 
Tumor, unregulated cell growth or other cancers 
- 
lupus 
- 
psychosis 
Treatment with infliximab may also result in reactivation of hepatitis B virus in people who carry 
this virus. 
 
It is not known if infliximab interferes with vaccinations. 
 
The known risks associated with blood draws/infusions include a slight pain, bruising, and/or 
inflammation at the insertion site of the needle. Rarely, scarring may occur at the site. 
 
There may be some degree of distress associated with providing stool samples. 
 
There are no known problems associated with the magnetic field used for medical imaging (i.e., 
MRI and MRS). However, there is a risk if there is any foreign metal object is in your body 
including a pacemaker, steel plate etc. Please notify the study doctor/study coordinator if this is 
the case. 
 
Some of the questions asked as part of the study may cause distress or discomfort. You are not 
required to answer any question that you are not comfortable answering. 
 
Risks Related to Pregnancy  
 
It is not known if the drugs used in this study affect an unborn baby or sperm. You should not 
become pregnant or father a child while in this study. Men and women who agree to take part in 
the study must use effective method of birth control during and for 6 months after last study drug 
infusion.  
If you do get pregnant, you should tell the study doctor.  
 
Benefits to Being in the Study 
 
You may or may not receive direct benefit from being in this study. Information learned from 
this study may help other people with bipolar depression in the future. The research may lead to 
new advances in understanding, treating, and preventing mood disorders. 
 
Voluntary Participation 
 
Your participation in this study is voluntary.  You may decide not to be in this study, or to be in 
the study now and then change your mind later. You may leave the study at any time without 
affecting your care.  
 
We will give you new information that is learned during the study that might affect your decision 
to stay in the study.   


 
 
 
 
 
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Alternatives to Being in the Study Treatments 
 
You do not have to participate to receive treatment for bipolar disorder. You may consider other 
treatment options including mood stabilizers and/or antipsychotics. There may also be other 
research studies looking at different treatment for your condition. You may also choose not to 
have any treatment for your condition. The study doctor will discuss these and other options with 
you.  
 
Confidentiality 
 
Personal Health Information 
 
If you agree to join this study, the study doctor and his study team will look at your personal 
health information and collect only the information they need for the study. Personal health 
information is any information that could be used to identify you and includes your: 
 Name  
 Address 
 Date of Birth  
 New or existing medical records, which includes types, dates and results of medical tests 
or procedures.   
 
The information that is collected for the study will be kept in a locked and secure area by the 
study doctor for 25 years. Only the study team or the people or groups listed below will be 
allowed to look at your records. Your participation in this study may also be recorded in your 
medical record at this hospital. 
 
If you participate in this study, information about you from this research project may be stored in 
your hospital file and in the UHN computer system.  The UHN shares the patient information 
stored on its computers with other hospitals and health care providers in Ontario so they can 
access the information if it is needed for your clinical care.  The study team can tell you what 
information about you will be stored electronically and may be shared outside of the UHN.  If 
you have any concerns about this, or have any questions, please contact the UHN Privacy Office 
at 416-340-4800, x6937 (or by email at privacy@uhn.ca). 
 
All non-identifiable data that is collected as part of this study will be added to the National 
Institute for Mental Health data repository. The data will be stored in this database indefinitely. 
This is a requirement by our funding agency (The Stanley Medical Research Institute). Your 
health information from this research project will be sent to other countries but your identifiers 
will be removed. They will not be able to identify you. 
 
The following people may come to the hospital to look at the study records and at your personal 
health information to check that the information collected for the study is correct and to make 
sure the study followed proper laws and guidelines: 
 The study sponsor or its representatives/partner companies. 
 Representatives of the University Health Network Research Ethics Board. 


 
 
 
 
 
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 Representatives of Health Canada, or other regulatory bodies (groups of people who 
oversee research studies), outside of Canada, such as the United States Food and Drug 
Administration 
 
 
Study Information That Does Not Identify You 
Some study information will be sent outside of the hospital to the granting agency. Any 
information about you that is sent out of the hospital will have a code and will not show your 
name or address, or any information that directly identifies you.  
 
The Sponsor may use the study information and share it with its partner companies or with 
national and international regulatory agencies to help answer the study question, to get approval 
to sell intravenous infliximab, to develop future studies on this product or for research related to 
this study.   
 
All information collected during this study, including your personal health information, will be 
kept confidential and will not be shared with anyone outside the study unless required by law.  
You will not be named in any reports, publications, or presentations that may come from this 
study.  
 
If you decide to leave the study, the information about you that was collected before you left the 
study will still be used. No new information will be collected without your permission. 
 
Rights as a Participant 
 
If you are harmed as a direct result of taking part in this study, all necessary medical treatment 
will be made available to you at no cost. 
 
By signing this form, you do not give up any of your legal rights against the investigators, 
sponsor or involved institutions for compensation, nor does this form relieve the investigators, 
sponsor or involved institutions of their legal and professional responsibilities. 
 
Costs and Reimbursement 
 
Reimbursement of up to $50 per visit will be offered for food and travel related expenses i.e. 
parking and public transportation. Receipts are required in order to receive refund.  
 
If you decide to participate in the sub-study, you will receive an additional $10.00 for each visit 
that requires a stool sample (Visits 2, 4, and 7).  
 
Questions About the Study 
 
If you have any questions, concerns or would like to speak to the study team for any reason, 
please call: Dr. Roger McIntyre at 416-603-5279 or Mehala Subramaniapillai at 416-603-5133 
(office) or mehala.subram@uhn.ca. You can also call the 24-Hour emergency study number at 
(647) 780-9533.  


 
 
 
 
 
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If you have any questions about your rights as a research participant or have concerns about this 
study, please call the Chair of the University Health Network Research Ethics Board (REB) or 
the Research Ethics office number at 416-581-7849. The REB is a group of people who oversee 
the ethical conduct of research studies. The UHN REB is not part of the study team. Everything 
that you discuss will be kept confidential. 
 
You will be given a signed copy of this consent form. 
 
Consent 
 
This study has been explained to me and any questions I had have been answered. I know that I 
may leave the study at any time. I agree to the use of my information as described in this form. I 
agree to take part in this study.  
 
 
 Yes         No  
 I would also like to participate in the optional sub-study 
 
We would like your permission to contact your family physician to obtain additional medical 
information or to let them know you are participating in this research study.  Please check off the 
appropriate box below indicating your choice to allow us to communicate with your physician or 
primary care provider. 
  
The study doctor may tell my regular family doctor about my being in this study: 
 
 YES          NO 
 
 
 
_______________________________          ______________________    ____________ 
Study Participant’s Name  
            Study Participant’s Signature   Date  
 
My signature means that I have explained the study to the participant named above.  I have 
answered all questions.    
 
 
 
_________________________ 
      ______________________ 
  _____________ 
Name of Person  
                        Signature   
 
              Date 
Obtaining Consent 
 
 
 
_________________________                ________________________        ____________ 
Name of Principal Investigator 
      Signature 
           Date