An Efficacy and Safety Study of Sirukumab in Participants With Major Depressive Disorder

The purpose of this study is to evaluate the efficacy of sirukumab as adjunctive treatment to antidepressant therapy (monoaminergic antidepressant) where sirukumab (administered as a 50 milligram (mg) subcutaneous (SC) injection at Day 1, Day 28 and Day 56 during the 12- week double-blind treatment period) is compared to adjunctive placebo based on the change from baseline to 12-week endpoint in depressive symptoms as measured by the total score on the Hamilton Depression Rating Scale (HDRS), in participants diagnosed with Major Depressive Disorder (MDD) who have had a suboptimal response to the current standard oral antidepressant therapy and have a screening high sensitivity C-Reactive Protein (hsCRP) \>=0.300 milligram per deciliters (mg/dL) (International System of Units (SI) 3.00 mg/L). A cohort of subjects with hsCRP \<0.300 milligram per deciliter will also be enrolled to allow a better understanding of the relationship between CRP and clinical changes.

A double-blind, placebo-controlled, multicenter study of sirukumab as adjunctive treatment to a monoaminergic antidepressant in adults with major depressive disorder. Participants will be randomly assigned to receive either placebo or sirukumab 50 milligram (mg) at a ratio of 1:1 at Day 1, 28 and 56. Participants will primarily be assessed for change from baseline in Hamilton Depression Rating Scale (HDRS17) score at Week 12. Safety will be monitored throughout the study.

Eligibility Criteria:
Inclusion Criteria:

* Participants must have a primary DSM-5 diagnosis of MDD
* Must have a HDRS total score greater than or equal to (\>=) 18 at screening and predose at Day 1, as recorded by the remote independent rater and must not demonstrate an improvement of \> 25 percent (%) on their HDRS total score from the screening to baseline visit
* Must be medically stable on the basis of physical examination, medical history, vital signs, clinical laboratory tests and 12-lead ECG performed at screening. If there are abnormalities, the participant may be included only if the investigator judges the abnormalities or deviations from normal to be not clinically significant. This determination must be recorded in the subject's source documents and initialed by the investigator
* Participants with hypothyroidism who are on stable treatment for 3 months prior to screening are required to have thyroid stimulating hormone (TSH) and free thyroxine (FT4) obtained. If the TSH value is out of range, but FT4 is normal, such cases should be discussed directly with the medical monitor before the subject is enrolled. If the FT4 value is out of range, the participant is not eligible

Exclusion Criteria:

* Any other current Axis one psychiatric condition, including, but not limited to, MDD with current psychotic features, bipolar disorder (including lifetime diagnosis), obsessive-compulsive disorder, borderline personality disorder, eating disorder (eg, bulimia, anorexia nervosa), or schizophrenia (lifetime). The MINI will be used to screen for comorbid psychiatric diagnoses. As noted above, subjects with a diagnosis of comorbid GAD, Post-Traumatic Stress Disorder, Persistent Depressive Disorder, ADHD, Social Anxiety Disorder, Panic Disorder with or without agoraphobia or Nicotine/Caffeine Dependence may be included, if the investigator considers MDD to be the primary diagnosis
* A history of alcohol or substance use disorder (abuse/dependence) within 6 months prior to screening (nicotine and caffeine dependence are not exclusionary)
* A current or recent (within the past year) history of clinically significant suicidal ideation (corresponding to a score of \>= 3 for ideation) or any suicidal behavior within the past year, as validated on the C-SSRS at screening or baseline. Subjects with a prior suicide attempt of any sort, or history of prior serious suicidal ideation/plan should be carefully screened for current suicidal ideation and only included at the discretion of the investigator
* More than 3 failed antidepressant treatments (of adequate dose and duration) in the current episode of depression (verified by the MGH-ATRQ)
* Length of current major depressive episode \> 60 months