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 (CREDO 2)

This is an interventional treatment trial for Rheumatoid Arthritis focused on measuring moderate Rheumatoid Arthritis, severe Rheumatoid Arthritis, subcutaneous, Olokizumab Read More

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 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 may 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

• Abnormal laboratory values as defined below:

  1. Creatinine level ≥ 1.5 mg/dL (132 µmol/L) for females or ≥ 2.0 mg/dL (177 µmol/L) for males
  2. ALT or AST level ≥ 1.5× ULN
  3. Platelets <100×10^9/L (<100,000/mm^3)
  4. White blood cell count <3.5×10^9/L
  5. Neutrophil count <2000×10^6/L (<2000/mm^3)
  6. Hemoglobin level ≤ 80 g/L
  7. Glycosylated hemoglobin (HbA1c) level ≥ 8%

• 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])

  a) Subjects who are are positive for hepatitis B surface antibodies (anti-HBs), but negative for HBsAg and anti-HBc, will be 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
  3. History of untreated latent TB infection (LTBI), regardless of IGRA result at Screening

  i. Subjects with a history of untreated LTBI may be re-screened and enrolled if they fulfill all 3 of the following criteria:

  1. Active TB is ruled out by a certified TB specialist or pulmonologist who is familiar with diagnosing and treating TB (as acceptable per local practice);
  2. The subject has completed at least 30 days of LTBI-appropriate prophylaxis prior to baseline with agents recommended as preventative therapy for LTBI according to country-specific/Centers for Disease Control and Prevention (CDC) guidelines (treatment with isoniazid for 6 months is not an appropriate prophylactic regime for this study and it should not be used); and
  3. The subject is willing to complete the entire course of recommended LTBI therapy d. Positive interferon-gamma release assay (IGRA) result at Screening. If indeterminate, the IGRA can be repeated once during the Screening Period. If there is a second indeterminate result, the subject will be excluded i. Subjects with a positive IGRA result at Screening may be re-screened and enrolled if they fulfill all 3 of the following criteria
  1. Active TB is ruled out by a certified TB specialist or pulmonologist who is familiar with diagnosing and treating TB (as acceptable per local practice);
  2. The subject has completed at least 30 days of LTBI-appropriate prophylaxis prior to baseline with agents recommended as preventative therapy for LTBI according to country-specific/CDC guidelines (treatment with isoniazid for 6 months is not an appropriate prophylactic regime for this study and it should not be used); and
  3. The subject is willing to complete the entire course of recommended LTBI therapy ii. If a subject with a positive IGRA result at Screening has documented evidence of completing treatment for LTBI with a treatment regime and treatment duration that are appropriate for this study, the subject may be enrolled without further prophylaxis if recommended by a certified TB specialist or pulmonologist who is familiar with diagnosing and treating TB (as acceptable per local practice) and no new exposure in close contact with an individual with active TB after completing the prophylactic treatment is suspected
• 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 of the following CV conditions:

  1. Uncompensated congestive heart failure, or class III or IV heart failure defined by the New York Heart Association classification (The Criteria Committee of the New York Heart Association, 1994)
  2. Untreated or resistant arterial hypertension Grade II-III (systolic blood pressure (BP) >100 mm Hg)
  3. History or presence of concurrent severe and/or uncontrolled CV disorder (including but not limited to acute coronary syndrome or stroke/transient ischemic attack in the previous 3 months before Screening) that would, in the Investigator's judgment, contraindicate subject participation in the clinical study, or clinically significant enough in the opinion of the Investigator to alter the disposition of the study treatment, or constitute a possible confounding factor for assessment of efficacy or safety of the study treatment
• Subjects with a history or presence of any concurrent severe and/or uncontrolled medical condition (including but not limited to respiratory, hepatic, renal, GI, endocrinological, dermatological, neurological, psychiatric, hematological (including bleeding disorder), or immunologic/immunodeficiency disorder(s) ) that would, in the Investigator's judgment, contraindicate subject participation in the clinical study, or clinically significant enough in the opinion of the Investigator to alter the disposition of the study treatment, or constitute a possible confounding factor for assessment of efficacy or safety of the study treatment
• Uncontrolled diabetes mellitus
• 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

Highly effective contraception is defined as:

1. Female sterilization surgery: hysterectomy, surgical bilateral oophorectomy (with or without hysterectomy), or tubal ligation at least 6 weeks prior to the first dose of study treatment

   • In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by documented follow-up hormone level assessment
2. Total abstinence if it is the preferred and constant lifestyle of the subject. Thus, periodic abstinence such as ovulation, symptothermal, postovulation, calendar methods, and withdrawal are not acceptable methods of contraception
3. Male sterilization surgery: at least 6 months prior to Screening (with the appropriate postvasectomy documentation of the absence of sperm in the ejaculate). For female subjects, the vasectomized male should be the only partner.
4. Placement of established intrauterine device (IUD): IUD copper or IUD with progesterone

5. Barrier method (condom and intravaginal spermicide, cervical caps with spermicide, diaphragma with spermicide) in combination with the following: established oral, injected, or implanted hormone methods of contraception or contraceptive patch

   • 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
   • Subject's unwillingness or inability to follow the procedures outlined in the protocol
   • Other medical or psychiatric conditions or laboratory abnormalities that may increase potential risk associated with study participation and administration of investigational products, or that may affect study results interpretation and, as per the Investigator's judgment, make the subject ineligible