Andecaliximab as Add-On Therapy to a Tumor Necrosis Factor Inhibitor and Methotrexate Regimen in Adults With Moderately to Severely Active Rheumatoid Arthritis

Key Inclusion Criteria:

* Diagnosis of RA (according to the 2010 American College of Rheumatology and European League Against Rheumatism (ACR/EULAR) classification criteria) confirmed at screening
* Must have taken oral or parenteral methotrexate (MTX) dosed from 7.5 to 25 mg/week continuously for at least 12 weeks and tolerated this medication, with at least 6 weeks of stable dose (defined as no change in prescription) prior to first dose of study drug
* Individuals on MTX may also be on concurrent chloroquine or hydroxychloroquine at a stable dose (defined as no change in prescription) for at least 4 week prior to Baseline; if so, they should plan to continue this medication for the duration of the study
* Must have an inadequate response to ≥ 12 weeks of ongoing treatment with an approved, stable subcutaneous (SC) formulation of TNF inhibitor (adalimumab, certolizumab pegol, etanercept, or golimumab), or marketed SC biosimilar TNF inhibitor with at least 6 weeks of stable dose (defined as no change in prescription), defined as: must have a DAS28(CRP) \> 3.2 at screening AND must have ≥ 3 swollen and ≥ 3 tender joints (using the DAS28 joint counts) at screening and at baseline (do not need to be the same joints)
* Non-steroidal anti-inflammatory drugs (NSAIDs) and/or oral corticosteroids (≤ 10 mg prednisone/day or equivalent) at a stable dose (defined as no change in prescription) for ≥ 4 weeks prior to baseline are allowed and throughout the blinded period of the study. PRN NSAID for indications other than RA are also allowed. (PRN means "pro re nata" or when necessary)
* Tuberculosis (TB) Screening: Must meet either a. or b.:

  1. A negative history of TB infection and a negative QuantiFERON® TB-Gold In-Tube test and chest x-ray results. (QuantiFERON® tests with inconclusive results may be repeated one time. If the repeat result is also inconclusive, the individual will be excluded from the study).

     OR,
  2. Individuals with a history of latent TB treated with a full course of prophylaxis as per local guidelines are allowed per investigator judgment. It is the responsibility of the investigator to verify the adequacy of previous treatment and to provide appropriate documentation. In these cases, no QuantiFERON® test need be obtained. In addition, these cases must be approved by the medical monitor prior to enrollment. (Any new diagnosis of latent TB or prior untreated /partially treated latent TB in NOT allowed (ie, individuals who require prophylactic therapy for TB during the study). Any prior history of active TB \[regardless of treatment\] is exclusionary).
* A negative chest x-ray (views per local guidelines) for active TB or other lung disease at screening; or a chest x-ray within 90 days of screening if films or report are available for investigator review

Key Exclusion Criteria:

* Current treatment with any other disease modifying anti-rheumatic drug (DMARD) other than MTX, chloroquine or hydroxychloroquine, OR current treatment with other immune modulating/suppressive non-biologic and biologic medications as described in the study protocol
* Intraarticular corticosteroid injection of any joint within 4 weeks of baseline
* Any infection requiring oral antimicrobial therapy within 2 weeks prior to baseline
* Current inflammatory joint disease, other than RA, such as gout, reactive arthritis, psoriatic arthritis, seronegative spondylarthritis, or Lyme disease, OR other current autoimmune diseases such as: systemic lupus erythematosus (SLE), inflammatory bowel disease, fibromyalgia, polymyalgia rheumatica, scleroderma, inflammatory myopathy, mixed connective tissue disease, or other overlap syndrome that would interfere with the evaluation of RA or require protocol prohibited medication (individuals with Sjogren's syndrome or controlled thyroiditis as defined by the investigator are not excluded)
* Active systemic involvement secondary to RA such as vasculitis or Felty's syndrome
* History of any of the following within 12 months of baseline:

  * infection requiring parenteral antibiotics or hospitalization
  * any life-threatening infection
  * sepsis
* The results of the following laboratory tests performed at the central laboratory at screening meet any of the criteria below:

  * Hemoglobin \< 8.0 g/dL (International System of Units (SI): \< 80 g/L)
  * White blood cells \< 3.0 x 10\^3 cells/mm\^3 (SI: \< 3.0 x 10\^9 cells/L)
  * Neutrophils \< 1.5 x 10\^3 cells/mm\^3 (SI: \< 1.5 x 10\^9 cells/L)
  * Lymphocytes \< 0.5 x 10\^3 cells/mm\^3 (SI: \< 0.5 x 10\^9 cells/L)
  * Platelets \< 100 x 10\^3 cells/mm\^3 (SI: \< 100 x 10\^9 cells/L)
  * Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥ 2 x upper limit of normal (ULN)
  * Total bilirubin level ≥ 2 x ULN unless the individual has been diagnosed with Gilbert's disease and this is clearly documented
  * Estimated glomerular filtration rate \< 40 mL/min/1.73 m\^2 based on the Modification of Diet in Renal Disease (MDRD) formula
  * Positive HIV serology during screening
  * Evidence of active Hepatitis B Virus (HBV) infection
  * Evidence of active Hepatitis C Virus (HCV) infection
* Any uncontrolled clinically significant laboratory abnormality that would affect interpretation of study data or the individual's participation in the study
* Malignancy or a history of malignancy or lymphoproliferative disorder within 10 years of screening with the following exceptions:

  * Carcinoma in situ of the cervix that has been successfully treated
  * Adequately treated basal or squamous cell cancer that has been successfully treated

Note: Other protocol defined inclusion/exclusion criteria may apply.