Rheumatoid Arthritis

The primary objective of this study is 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.

Olokizumab

Olokizumab

sterile solution for SC injection

160

The primary efficacy endpoint is the American College of Rheumatology 20% (ACR20) response at Week 14, where a responder is defined as any subject satisfying ACR20 criteria and remaining on randomized treatment and in the study at Week 14. This endpoint will serve to demonstrate that the efficacy of OKZ is superior to placebo.
Secondary Efficacy Endpoints:
The following secondary efficacy endpoints will be evaluated:
For EU submission: ACR20 response at Week 14, where a responder is defined as any subject satisfying ACR20 criteria and remaining on randomized treatment and in the study at Week 14. This endpoint will serve to demonstrate that the efficacy of OKZ is non-inferior to adalimumab, provided that superiority of adalimumab to placebo (assay sensitivity) is demonstrated concurrently based on the same endpoint
Difference between OKZ and placebo in the percentage of subjects achieving low disease activity,defined as Disease Activity Score 28-joint count (DAS28) C-reactive protein (CRP) <3.2, andremaining on randomized treatment and in the study at Week 14
 Difference between OKZ and placebo in the improvement of physical ability from baseline to
Week 14, as measured by the Health Assessment Questionnaire-Disability Index (HAQ-DI)
Difference between OKZ and placebo in the percentage of subjects achieving an American College of Rheumatology 50% (ACR50) response and remaining on randomized treatment and in the study at Week 24
Difference between OKZ and placebo in the percentage of subjects with Simplified Disease Activity Index (SDAI) ≤3.3 (remission) and remaining on randomized treatment and in the study at Week 24

Subjects may be enrolled in the study only if they meet all of the following criteria:
1. Male or female subjects ≥18 years of age
2. Subjects willing and able to sign informed consent
3. Subjects must have a diagnosis of adult-onset RA classified by
ACR/EULAR 2010 revised classification criteria for RA (Aletaha et al, 2010) 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.
4. Inadequate response to treatment with oral, SC, or intramuscular (IM) MTX (see
Section 5.1 for definition of inadequate response to MTX treatment) 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.
5. Subjects must have moderately to severely active RA disease as defined by all of the
following:
a. ≥6 tender joints (68-joint count) at Screening and baseline; and
b. ≥6 swollen joints (66-joint count) at Screening and baseline; and
c. CRP above ULN at Screening based on the central laboratory results

Subjects who meet any of the following criteria will not be eligible for the study:
1. 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.
2. 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) (see Appendix 1 [Section 13.1])
3. Prior exposure to any licensed or investigational compound directly or indirectly
targeting IL-6 or IL-6R (including Janus kinases and spleen tyrosine kinase [SYK]
inhibitors)
4. Treatment with any cell-depleting therapies including anti-CD20 or investigational
agents (e.g., CAMPATH, anti-CD4, anti-CD5, anti-CD3, and anti-CD19)
5. Past history of exposure to TNFi therapy
6. Use of parenteral and/or intra-articular glucocorticoids within 4 weeks prior to
baseline
7. Use of oral glucocorticoids greater than 10 mg/day prednisone (or equivalent) or change in dosage within 2 weeks prior to baseline
8. Prior history of no response to hydroxychloroquine and sulfasalazine
9. Prior use of DMARDs other than MTX is allowed with the following washout periods to be completed prior to baseline:
a. 4 weeks for sulfasalazine, azathioprine, cyclosporine, hydroxychloroquine,
chloroquine, gold, penicillamine, minocycline, or doxycycline
b. 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 a day for at least 24 hours
c. 24 weeks for cyclophosphamide
10. Vaccination with live vaccines in the 6 weeks prior to baseline or planned vaccination
with live vaccines during the study
11. 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
12. Use of anakinra within 30 days or abatacept within 12 weeks prior to baseline
13. Other treatments for RA (e.g., Prosorba Device/Column) within 6 months prior to
baseline
14. Use of intra-articular hyaluronic acid injections within 4 weeks prior to baseline
15. Use of non-steroidal anti-inflammatory drugs (NSAIDs) on unstable dose or
switching of NSAIDs within 2 weeks prior to baseline
16. Previous participation in this study (randomized) or another study of OKZ
17. Abnormal laboratory values as defined below.
a. Creatinine level ≥1.5 mg/dL (132 µmol/L) for females or ≥2.0 mg/(177 µmol for males
b. ALT or AST level ≥1.5 times ULNc. Platelets <100×109<100,000/mm3)d. White blood cell count <3.5×109
e. Neutrophil count <2000×106(<2000/mm3)
f. Hemoglobin level ≤80 g/L
g. Glycosylated hemoglobin (HbA1c) level ≥8%
18. Subjects with concurrent acute or chronic viral hepatitis B or C infection as detected
by blood tests at Screening(e.g., positive for HBsAg, anti-HBc, or HCV Ab)
a. Subjects who are are positive for hepatitis B surface antibodies (anti-HBs), but
negative for hepatitis B surface antigen (HBsAg) and total hepatitis B core
antibody (anti-HBc), will be eligible.
19. Subjects with HIV infection
20. Subjects with:
a. Suspected or confirmed current active TB infection or a history of active TB
infection
b. Experience in close contact (i.e., sharing the same household or other enclosed
environment) with an individual with active TB within 1.5 years prior to
Screening.
c. Positive interferon-gamma release assay (IGRA) result or repeated indeterminate
IGRA results at Screening.
i. If positive the subjects will be excluded. If indeterminate, the IGRA test
can be repeated once during the Screening Period. If there is a second
indeterminate result, the subject will be considered not eligible for the
study.
d. Radiographic evidence of TB
21. 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])
22. Subjects with a history or presence of CV (such as acute coronary syndrome or
stroke/transient ischemic attack in the previous 6 months before Screening), respiratory, hepatic, renal, GI, endocrinological, dermatological, neurological, psychiatric, hematological (including bleeding disorder), or immunologic/immunodeficiency disorder(s) or any other concurrent severe and/or uncontrolled medical condition 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 investigational
medicinal product (IMP), or constitute a possible confounding factor for assessment
of efficacy or safety of the IMP
23. 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) as noted in Appendix 2 (see Section 13.2)
24. Untreated or resistant arterial hypertension Grade II-III (systolic blood pressure [BP]
>160 mm Hg and/or diastolic BP >100 mm Hg)
25. Uncontrolled diabetes mellitus
26. 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
27. 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
28. 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
29. Subjects with active diverticular disease or other symptomatic GI conditions that
might predispose the subject to perforations, including subjects with history of
diverticulitis or GI perforation
30. Pre-existing central nervous system demyelinating disorders (e.g., multiple sclerosis
and optic neuritis)
31. History of chronic alcohol or drug abuse as judged by the Investigator
32. 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 drug
33. 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 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 drug 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 drug Highly effective contraception is defined as:
 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 drug
 In the case of oophorectomy alone, only when the reproductive status of the
woman has been confirmed by documented follow-up hormone level
assessment
 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.
 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.
 Placement of established intrauterine device (IUD): IUD copper or IUD with
progesterone
 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
34. Subjects with a known hypersensitivity to any component of the OKZ drug product,
adalimumab, or placebo
35. Subjects with a known hypersensitivity to any component of the rescue therapy (see
Section 6.13.3)
36. History of severe allergic or anaphylactic reactions to human, humanized, or mural
monoclonal antibodies
37. Subject's unwillingness or inability to follow the procedures outlined in the protocol
38. 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