Evaluation of the Effectiveness and Safety of Two Dosing Regimens of Olokizumab (OKZ), Compared to Placebo, in Subjects With Rheumatoid Arthritis (RA) Who Are Taking Methotrexate But Have Active Disease
Condition: Rheumatoid Arthritis
MeSH terms: Arthritis; Arthritis, Rheumatoid
Intervention: Olokizumab; Placebo
Intervention description: 160 mg/mL sterile solution for SC injection in a 2 mL clear Type I glass vial; sodium chloride 0.9% solution supplied in polypropylene plastic ampoules of 10 mL cartons to contain 10 ampoules
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 428.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: moderate Rheumatoid Arthritis; severe Rheumatoid Arthritis; subcutaneous; Olokizumab

Summary:

      The purpose of this study was to determine how effective and safe the study drug Olokizumab
      was in patients with Rheumatoid Arthritis (RA) who had been already receiving, but not fully
      responding to treatment with methotrexate (MTX).

      The primary objective of this study was to evaluate the efficacy of olokizumab (OKZ) 64 mg
      administered subcutaneously (SC) once every 2 weeks (q2w) or once every 4 weeks (q4w)
      relative to placebo in subjects with moderately to severely active rheumatoid arthritis (RA)
      inadequately controlled by methotrexate (MTX) therapy.
    

Eligibility criteria:

        Inclusion Criteria:

        Subjects may be enrolled in the study only if they meet all of the following criteria:

          -  Subjects willing and able to sign informed consent

          -  Subjects must have a diagnosis of adult onset RA classified by ACR/EULAR 2010 revised
             classification criteria for RA for at least 12 weeks prior to Screening.

          -  Inadequate response to treatment with MTX for at least 12 weeks prior to Screening at
             a dose of 15 to 25 mg/week (or ≥10 mg/week if intolerant to higher doses).

               -  The dose and means of administering MTX must have been stable for at least 6
                  weeks prior to Screening.

          -  Subjects must be willing to take folic acid or equivalent throughout the study

          -  Subjects must have moderately to severely active RA disease as defined by all of the
             following:

               -  ≥6 tender joints (68 joint count) at Screening and baseline; and

               -  ≥6 swollen joints (66 joint count) at Screening and baseline; and

               -  CRP above ULN at Screening based on the central laboratory results.

        Exclusion Criteria:

          -  Diagnosis of any other inflammatory arthritis or systemic rheumatic disease (e.g.,
             gout, psoriatic or reactive arthritis, Crohn's disease, Lyme disease, juvenile
             idiopathic arthritis, or systemic lupus erythematosus). However, subjects could have
             secondary Sjogren's syndrome or hypothyroidism

          -  Subjects who were Steinbrocker class IV functional capacity (incapacitated, largely or
             wholly bed-ridden or confined to a wheelchair, with little or no self-care)

          -  Prior exposure to any licensed or investigational compound directly or indirectly
             targeting IL-6 or IL-6R (including tofacitinib or other Janus kinases and spleen
             tyrosine kinase [SYK] inhibitors)

          -  Prior treatment with cell-depleting therapies, including anti-CD20 or investigational
             agents (e.g., CAMPATH, anti-CD4, anti-CD5, anti-CD3, and anti-CD19)

          -  Prior use of bDMARDs, with the following exception:

             • Subjects who discontinued TNFi therapy due to a reason other than lack of efficacy
             were allowed to enter the study (TNFi therapy was not to be discontinued to facilitate
             a subject's participation in the study but should instead have been previously
             discontinued as part of a subject's medical management of RA). The use of TNFi therapy
             within the following windows prior to baseline was exclusionary:

               1. 4 weeks for etanercept

               2. 8 weeks for infliximab

               3. 10 weeks for adalimumab, certolizumab, and golimumab

          -  Use of parenteral and/or intra-articular glucocorticoids within 4 weeks prior to
             baseline

          -  Use of oral glucocorticoids greater than 10 mg/day prednisone (or equivalent), or
             change in dosage within 2 weeks prior to baseline

          -  Prior documented history of no response to hydroxychloroquine and sulfasalazine

          -  Prior use of cDMARDs (other than MTX) within the following windows prior to baseline
             (cDMARDs were not to be discontinued to facilitate a subject's participation in the
             study, but should instead have been previously discontinued as part of a subject's
             medical management of RA):

               1. 4 weeks for sulfasalazine, azathioprine, cyclosporine, hydroxychloroquine,
                  chloroquine, gold, penicillamine, minocycline, or doxycycline

               2. 12 weeks for leflunomide unless the subject has completed the following
                  elimination procedure at least 4 weeks prior to baseline: Cholestyramine at a
                  dosage of 8 grams 3 times daily for at least 24 hours, or activated charcoal at a
                  dosage of 50 grams 4 times daily for at least 24 hours

               3. 24 weeks for cyclophosphamide

          -  Vaccination with live vaccines in the 6 weeks prior to baseline or planned vaccination
             with live vaccines during the study

          -  Participation in any other investigational drug study within 30 days or 5 times the
             terminal half-life of the investigational drug, whichever is longer, prior to baseline

          -  Other treatments for RA (e.g., Prosorba Device/Column) within 6 months prior to
             baseline

          -  Use of intra-articular hyaluronic acid injections within 4 weeks prior to baseline

          -  Use of non-steroidal anti-inflammatory drugs (NSAIDs) on unstable dose or switching of
             NSAIDs within 2 weeks prior to baseline

          -  Previous participation in this study (randomized) or another study of OKZ

          -  Subjects with acute or chronic viral hepatitis B or C infection as detected by blood
             tests at Screening (e.g., positive for hepatitis B surface antigen [HBsAg], total
             hepatitis B core antibody [anti-HBc], or hepatitis C virus antibody [HCV Ab])

             a. Subjects who were positive for hepatitis B surface antibody (anti-HBs), but
             negative for HBsAg and anti-HBc, were eligible

          -  Subjects with HIV infection

          -  Subjects with:

               1. Suspected or confirmed current active TB disease or a history of active TB
                  disease

               2. Close contact (i.e., sharing the same household or other enclosed environment,
                  such as a social gathering place, workplace, or facility, for extended periods
                  during the day) with an individual with active TB within 1.5 years prior to
                  Screening.

          -  Concurrent malignancy or a history of malignancy within the last 5 years (with the
             exception of successfully treated carcinoma in situ of the cervix and successfully
             treated basal cell carcinoma and squamous cell carcinoma not less than 1 year prior to
             Screening [and no more than 3 excised skin cancers within the last 5 years prior to
             Screening])

          -  Subjects with any infection requiring oral antibiotic or antiviral therapy in the 2
             weeks prior to Screening or at baseline, injectable anti-infective therapy in the last
             4 weeks prior to baseline, or serious or recurrent infection with a history of
             hospitalization in the 6 months prior to baseline

          -  Subjects with evidence of disseminated herpes zoster infection, zoster encephalitis,
             meningitis, or other non-self-limited herpes zoster infections in the 6 months prior
             to baseline

          -  Subjects with planned surgery during the study or surgery ≤4 weeks prior to Screening
             and from which the subject had not fully recovered, as judged by the Investigator

          -  Subjects with diverticulitis or other symptomatic GI conditions that might predispose
             the subject to perforations, including subjects with a history of such predisposing
             conditions (e.g., diverticulitis, GI perforation, or ulcerative colitis)

          -  Pre-existing central nervous system demyelinating disorders (e.g., multiple sclerosis
             and optic neuritis)

          -  History of chronic alcohol or drug abuse as judged by the Investigator

          -  Female subjects who are pregnant, currently lactating, have lactated within the last
             12 weeks, or who were planning to become pregnant during the study or within 6 months
             of last dose of study treatment

          -  Female subjects of childbearing potential (unless permanent cessation of menstrual
             periods, determined retrospectively after a woman had experienced 12 months of natural
             amenorrhea as defined by the amenorrhea with underlying status [e.g., correlative age]
             or 6 months of natural amenorrhea with documented serum follicle-stimulating hormone
             levels >40 mIU/mL and estradiol <20 pg/mL) who were not willing to use a highly
             effective method of contraception during the study and for at least 6 months after the
             last administration of study treatment OR Male subjects with partners of childbearing
             potential not willing to use a highly effective method of contraception during the
             study and for at least 3 months after the last administration of study treatment;

          -  Subjects with a known hypersensitivity to any component of the OKZ drug product, or
             placebo

          -  Subjects with a known hypersensitivity or contraindication to any component of the
             rescue medication

          -  History of severe allergic or anaphylactic reactions to human, humanized, or murine
             monoclonal antibodies

        The above information was not intended to contain all considerations relevant to a
        participant's potential participation in a clinical trial.