Evaluation of the Efficacy and Safety of Two Dosing Regimens of Olokizumab (OKZ), Compared to Placebo and Adalimumab, in Subjects With Rheumatoid Arthritis (RA) Who Are Taking Methotrexate But Have Active Disease
Condition: Rheumatoid Arthritis
MeSH terms: Arthritis; Arthritis, Rheumatoid
Intervention: Olokizumab 64mg q4w; Olokizumab 64mg q2w; Adalimumab 40mg q2w; Placebo q2w
Intervention description: 160 mg/mL sterile solution for SC injection in a 2 mL clear Type I glass vial; 160 mg/mL sterile solution for SC injection in a 2 mL clear Type I glass vial; 0.4 or 0.8 mL prefilled, single-dose syringe; sodium chloride 0.9% solution supplied in either a 10 mL vial or ampoule, depending on market availability. Each placebo will be packed into a cardboard carton to contain 1 vial or ampoule
Intervention MeSH terms: Adalimumab
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 1648.0
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 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 RA inadequately controlled by MTX therapy.

      The secondary objective was to evaluate the efficacy of OKZ relative to adalimumab in
      subjects with moderately to severely active RA inadequately controlled by MTX therapy.
    

Eligibility criteria:

        Inclusion 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. (If the
             subject was diagnosed according to ACR 1987 criteria previously, the Investigator may
             classify the subject per ACR 2010 retrospectively, using available source data)

          -  Inadequate response to treatment with oral, SC, or intramuscular MTX (defined as a
             subject with at least 12 weeks of exposure prior to Screening and with either absence
             of any documented clinically significant response, or documented initial clinical
             response with subsequent loss of that response or partial response) 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 route of administering MTX had to have been stable for
             at least 6 weeks prior to Screening. A lower dose of MTX (≥7.5 mg/week) was permitted
             for subjects enrolled in the Republic of Korea, consistent with local clinical
             practice.

          -  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 the normal range (ULN) at Screening based on the central laboratory
                  results.

        Exclusion Criteria:

          -  Diagnosis of any other inflammatory arthritis or systemic rheumatic disease (eg, 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 are 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

          -  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 should not 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 concurrent 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]).
             Subjects who are are positive for hepatitis B surface antibodies (anti-HBs), but
             negative for HBsAg and anti-HBc, will be eligible

          -  Subjects with human immunodeficiency virus (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 of the cervix in situ 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 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 has 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 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 are 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 has 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 are 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,
             adalimumab, 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.