CREDO 3: Evaluation of the Efficacy and Safety of Two Dosing Regimens of Olokizumab (OKZ), Compared to Placebo, in Subjects With Rheumatoid Arthritis (RA) Who Were Taking an Existing Medication Called a Tumour Necrosis Factor Alpha Inhibitor But Had Active Disease

• Sponsor: R-Pharm International, LLC (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02760433
• Collaborator: Quintiles, Inc. (Industry), OCT Clinical Trials (Other), Mene Research (Other)
• Enrollment: 368
• Locations: 165
• Arms: 3
• Actual Duration (Months): 32.7
• Patients Per Site: 2.2
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this study was to determine how effective and safe the study drug Olokizumab is, in patients with Rheumatoid Arthritis (RA) who were already receiving, but not fully responding to treatment with an existing medication called a tumour necrosis factor alpha inhibitor

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 TNF-α inhibitor (TNFi) therapy.

Condition or Disease	Intervention/Treatment	Phase
Rheumatoid Arthritis	Drug: Olokizumab; Drug: Placebo	Phase 3

Detailed Description

The goal of this Phase III study was to assess the efficacy, safety and tolerability of OKZ in subjects with moderately to severely active RA who had responded inadequately to TNFi therapy. The primary endpoint of the trial was assessed at Week 12. Olokizumab was expected to reduce the disease activity and improve physical function. The study was expected to provide safety information in a large group of subjects over at least a 24 week period.

This was a randomized, double-blind, parallel-group, placebo-controlled, multicenter study. This study included a 4-week Screening Period, a double-blind Treatment Period from Week 0 to Week 24, and a Safety FollowUp Period from Week 24 to Week 44.

A total of 350 subjects were planned to be randomized.Subjects were assessed for eligibility to enter the study during a 4-week Screening Period. Eligible subjects were randomized at Visit 2 in a 2:2:1 ratio in one of 3 treatment groups (planned 140, 140, and 70 subjects per group, respectively) :

1. Olokizumab 64 mg q4w: SC injection of OKZ 64 mg q4w (alternating with SC injection of placebo OKZ q4w to maintain blinding) + MTX for 24 weeks,

2. Olokizumab 64 mg q2w: SC injection of OKZ 64 mg q2w + MTX for 24 weeks or

3. Placebo: SC injection of placebo q2w + MTX for 16 weeks.

Subjects who received placebo were re-randomized at Week 16 to receive 64 mg OKZ q4w + Methotrexate or 64 mg OKZ q2w +Methotrexate for 8 weeks.

Throughout the double-blind Treatment Period, all subjects were required to remain on a stable dose of background MTX with a stable route of administration. Concomitant treatment with folic acid was required for all subjects. The last dose of study treatment (OKZ) was at Week 22 in all groups.

Following Visit 2 (randomization; Week 0), subjects returned to the study site at least every 2 weeks through Week 24 for response and safety assessments.

At Week 14, subjects who did not improve by at least 20% in both swollen and tender joint counts were classified as nonresponders and were administered sulfasalazine and/or hydroxychloroquine as rescue medication in addition to the assigned treatment.

After completion of the 24-week double-blind Treatment Period, subjects either rolled over into the long-term open-label extension (OLE) study or entered the Safety Follow-Up Period. During the Safety Follow-Up Period, subjects returned for visits +4, +8, and +22 weeks after the last dose of study treatment.

Subjects who discontinued randomized treatment prematurely were required to come for the End of Treatment (EoT) Visit 2 weeks after the last study treatment administration and then continue with the scheduled study visits.

Adverse events (AEs) were assessed throughout the study (starting when the subject signed the informed consent form) and evaluated using the Common Terminology Criteria for Adverse Events Version 4.0. There was ongoing monitoring of safety events, including laboratory findings, by the Sponsor or the Sponsor's designee. In addition, safety was assessed throughout the study by an independent Data Safety Monitoring Board and potential major adverse cardiac events were evaluated by an independent Cardiovascular Adjudication Committee.

The study was conducted at 123 sites across 11 countries globally (in US,EU, Russian Federation, Asia, Latin America)

Study Design

• Study Type: Interventional
• Actual Enrollment: 368 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-blind, Parallel-group, Placebo-controlled, Multicenter Phase III Study of the Efficacy and Safety of Olokizumab in Subjects With Moderately to Severely Active Rheumatoid Arthritis Inadequately Controlled by Tumor Necrosis Factor Alpha (TNF-α) Inhibitor Therapy
• Actual Study Start Date: Jan 9, 2017
• Actual Primary Completion Date: Sep 12, 2019
• Actual Study Completion Date: Oct 1, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm 1: Olokizumab q4w Olokizumab 64mg subcutaneous q4w +placebo + Methotrexate Olokizumab 64 mg subcutaneous q4w + placebo+ concomitant background therapy (Methotrexate) at a stable dose with a stable route of administration (oral, subcutaneous, or intramuscular) in order to maintain the blind, subjects randomized to receive OKZ q4w received placebo injections at the alternate q4w interval (e.g., Week 2, Week 6, etc.)	Drug: Olokizumab; 160 mg/mL sterile solution for SC injection in a 2 mL clear Type I glass vial, containing a target fill volume of 1.1 mL (for withdrawal of not less than 0.8 mL) or a target fill volume of 0.5 mL (for withdrawal of not less than 0.4 mL); Drug: Placebo; sodium chloride 0.9% solution provided as 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
Experimental: Arm 2: Olokizumab q2w Olokizumab 64mg subcutaneous q2w + Methotrexate 64 mg Olokizumab administered subcutaneously once every 2 weeks + concomitant background therapy (Methotrexate) at a stable dose with a stable route of administration (oral, subcutaneous, or intramuscular)	Drug: Olokizumab; 160 mg/mL sterile solution for SC injection in a 2 mL clear Type I glass vial, containing a target fill volume of 1.1 mL (for withdrawal of not less than 0.8 mL) or a target fill volume of 0.5 mL (for withdrawal of not less than 0.4 mL)
Placebo Comparator: Arm 3: Placebo q2w Placebo q2w subcutaneous + Methotrexate Placebo administered subcutaneously once every 2 weeks + concomitant background therapy (Methotrexate) at a stable dose with a stable route of administration (oral, subcutaneous, or intramuscular) Starting at Week 16, all subjects in the placebo group were randomized in a blinded fashion to receive either OKZ 64 mg q2w or OKZ 64 mg q4w; equal numbers of subjects were planned to be assigned to each OKZ treatment group.	Drug: Placebo; sodium chloride 0.9% solution provided as 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

Outcome Measures

Primary Outcome Measures

1. ACR20 Response [at Week 12]

   The difference between OKZ and placebo in the percentage of subjects achieving an ACR20 response and remaining on randomized treatment and in the study at Week 12. A responder is defined as any subject satisfying ACR20 criteria and remaining on randomized treatment and in the study at Week 12. American College of Rheumatology 20 % response is a composite defined as a ≥ 20% improvement from baseline in the swollen joint counts assessed in 66 joints and in the tender joint count assessed in 68 joints; and a ≥20% improvement from baseline in at least 3 of the 5 remaining core set measures: Patient Global Assessment of Disease Activity (VAS) Patient Assessment of Pain (VAS) HAQ-DI Physician Global Assessment (VAS) Level of acute phase reactant (CRP)

Secondary Outcome Measures

1. Difference Between OKZ and Placebo in the Percentage of Subjects Achieving Low Disease Activity [at Week 12]

   Defined as Disease Activity Score 28-joint count (DAS28) C-reactive protein (CRP) <3.2, and remaining on randomized treatment and in the study at Week 12

2. Difference Between OKZ and Placebo in the Improvement of Physical Ability [Baseline to Week 12]

   Improvement of physical ability from baseline to week 12, as measured by HAQ-DI. The HAQ-DI assesses the degree of difficulty experienced in 8 domains of daily living activities using 20 questions. The domains are dressing and grooming, arising, eating, walking, hygiene, reach, grip and common daily activities, and each domain consists of 2 or 3 items. For each question, the level of difficulty is scored from 0 to 3 where 0 = without any difficulty (the best outcome), 1 = with some difficulty, 2 = much difficulty, and 3 = unable to do (the worst outcome). Each category is given a score by taking the maximum score of each question. A decrease from baseline indicates improvement for HAQ-DI. The HAQ-DI was calculated by dividing the sum of the category scores by the number of categories with at least 1 question answered. The HAQ-DI total score ranges from 0 to 3, with higher scores indicating greater disability.

3. ACR50 Response [at Week 12]

   Difference between OKZ and placebo in the percentage of subjects achieving an ACR50 response and remaining on randomized treatment and in the study at Week 12. American College of Rheumatology 50% Response is a composite defined as ≥50%, improvement from baseline in the swollen joint counts assessed in 66 joints and in the tender joint count assessed in 68 joints; and a ≥50%, improvement from baseline in at least 3 of the 5 remaining core set measures: Patient Global Assessment of Disease Activity (VAS) Patient Assessment of Pain (VAS) HAQ-DI Physician Global Assessment (VAS) Level of acute phase reactant (CRP)

4. Clinical Disease Activity Index (CDAI) ≤2.8 (Remission) [at Week 12]

   Difference between OKZ and placebo in the percentage of subjects with Clinical Disease Activity Index (CDAI) ≤2.8 (remission) and remaining on randomized treatment and in the study at Week 12

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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 24 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.)

• Treatment with oral, SC, or intramuscular (IM) MTX for at least 12 weeks prior to Screening at a dose of 15 to 25 mg/week (or ≥10 mg/week if there is documented intolerance 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.

• Subjects must have a documented inadequate response to treatment (i.e., TNFi failure) with ≥1 licensed TNFi following at least 12 weeks of therapy with that agent.

Inadequate response to treatment is classified as either:

• Primary failure: The absence of any documented clinically significant response; or

• Secondary failure: Documented initial response with subsequent loss of that response or partial response

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) with the exception of rituximab, which is allowed if it was discontinued at least 24 weeks prior to baseline (rituximab 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).

• Prior use of bDMARDs, within the following windows prior to baseline (bDMARDs 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 etanercept and anakinra

2. 8 weeks for infliximab

3. 10 weeks for adalimumab, certolizumab, and golimumab

4. 12 weeks for abatacept

• 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:

• Creatinine level ≥ 1.5 mg/dL (132 µmol/L) for females or ≥ 2.0 mg/dL (177 µmol/L) for males

• ALT or AST level ≥ 1.5 x ULN

• Platelets < 100 x 10^{9/L (<100,000/mm}3)

• White blood cell count < 3.5 x 10^9/L

• Neutrophil count <2000 x 10^{6/L (<2000/mm}3)

• Hemoglobin level ≤ 80 g/L

• 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])

1. subjects who 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

1. 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.

1. 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 and

3. The subject is willing to complete the entire course of recommended LTBI therapy

1. 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] >160 mm Hg and/or diastolic 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

• 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 the 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:

• 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

• 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

• 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

• 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Arizona Arthritis & Rheumatology Associates, P.C.	Glendale	Arizona	United States	85304
2	AZ Arthritis & Rheum Research	Mesa	Arizona	United States	85210
3	CHI St. Vincent Hot Springs	Hot Springs	Arkansas	United States	71913
4	Medvin Clinical Research	Covina	California	United States	91722
5	TriWest Research Associates, LLC	El Cajon	California	United States	92020-4124
6	Saint Jude Heritage Medical Grp	Fullerton	California	United States	92835
7	С V Mehta MD Med Corp.	Hemet	California	United States	92543
8	Advanced Medical Research, LLC	Lakewood	California	United States	90623
9	Riverside Medical Clinic	Riverside	California	United States	92506
10	East Bay Rheumatology Medical Group, Inc.	San Leandro	California	United States	94578
11	Pacific Arthritis Ctr Med Group	Santa Maria	California	United States	93454
12	Stanford University School of Medicine	Stanford	California	United States	94305
13	Inland Rheumatology Clinical Trials, Inc.	Upland	California	United States	91786
14	Denver Arthritis Clinic	Denver	Colorado	United States	80230
15	Javed Rheumatology Associates	Newark	Delaware	United States	19713
16	RASF - Clinical Research Center	Boca Raton	Florida	United States	33486
17	Suncoast Research Group LLC	Miami	Florida	United States	33135
18	Florida Medical center & Research Inc	Miami	Florida	United States	33142
19	Omega Research Consultants	Orlando	Florida	United States	32810
20	Family Clinical Trials, LLC.	Pembroke Pines	Florida	United States	33026
21	McIlwain Medical Group, PA	Tampa	Florida	United States	33613
22	AdventHealth Medical Group, PA	Tampa	Florida	United States	33614
23	Arthritis Center of North Georgia	Gainesville	Georgia	United States	30501
24	Institute of Arthritis Research	Idaho Falls	Idaho	United States	83404
25	Advanced Clinical Research	Meridian	Idaho	United States	83642
26	Graves Gilbert Clinic	Bowling Green	Kentucky	United States	42101
27	The Arthritis & Diabetes Clinic, Inc.	Monroe	Louisiana	United States	71203
28	Klein and Associates, M.D., P.A.	Cumberland	Maryland	United States	21502
29	Klein and Associates, M.D., P.A.	Hagerstown	Maryland	United States	21740
30	The Center for Rheumatology and Bone Research	Wheaton	Maryland	United States	20902
31	Clinical Pharmacology Study Group	Worcester	Massachusetts	United States	01605
32	Glacier View Research Instutute-Rheumatology	Kalispell	Montana	United States	59901
33	Arthritis & Osteoporosis Associates, PA	Freehold	New Jersey	United States	07728
34	Lovelace Scientific Resources, Inc.	Albuquerque	New Mexico	United States	87108
35	NYU Langone Ambulatory Care	New York	New York	United States	110201
36	Medication Management, LLC	Greensboro	North Carolina	United States	27408
37	Cape Fear Arthritis Care	Leland	North Carolina	United States	28451
38	Carolina Arthritis Associates	Wilmington	North Carolina	United States	28401
39	Trinity Medical Group	Minot	North Dakota	United States	58701
40	Cincinnati Rheumatic Disease Study Group	Cincinnati	Ohio	United States	45242
41	STAT Research, Inc.	Dayton	Ohio	United States	45417
42	Clinical Research Source, Inc.	Perrysburg	Ohio	United States	43606
43	Arthritis Group	Philadelphia	Pennsylvania	United States	19152
44	Low Country Research Center	Charleston	South Carolina	United States	29486
45	Center Inflammatory Disease	Nashville	Tennessee	United States	37203
46	Amarillo Center for Clinical Research	Amarillo	Texas	United States	79124
47	Austin Regional Clinic, P.A.	Austin	Texas	United States	78731
48	Accurate Clinical Research, Inc.	Baytown	Texas	United States	77521
49	Diagnostic Group of SE Texas	Beaumont	Texas	United States	77701
50	Precision Comprehensive Clinical Research Solutions	Grapevine	Texas	United States	76034
51	Therapeutic Concepts Rheumatology, LLC	Houston	Texas	United States	77004
52	Accurate Clinical Research, Inc.	Houston	Texas	United States	77034
53	Rheumatology Clinic of Houston, P.A.	Houston	Texas	United States	77065
54	Pioneer Research Solutions, Inc.	Houston	Texas	United States	77429
55	Endocrinology, Internal Medicine	Lubbock	Texas	United States	79410
56	Accurate Clinical Research, Inc.	Nassau Bay	Texas	United States	77058
57	Dr. Alex De Jesus Rheumatology, P.A.	San Antonio	Texas	United States	78229
58	Advanced Rheumatology of Houston	Woodville	Texas	United States	77382
59	West Virginia Research Institute	South Charleston	West Virginia	United States	25309
60	Hospital Italiano Regional del Sur	Bahia Blanca	Buenos Aires	Argentina	B8001HXM
61	Centro de Investigaciones Medicas Mar del Plata	Mar del Plata	Buenos Aires	Argentina	B7600FYK
62	Instituto de Investigaciones Clinicas-Mar del Plata	Mar del Plata	Buenos Aires	Argentina	B7600FZ
63	Instituto de Investigaciones Clinicas Quilmes	Quilmes	Buenos Aires	Argentina	B1878DVB
64	Sanatorio Delta	Rosario	Santa Fe	Argentina	S2000BIF
65	Clinica de Higado y Aparato Digestivo	Rosario	Santa Fe	Argentina	S2000
66	Sanatorio San Martin	Venado Tuerto	Santa Fe	Argentina	S2600KUE
67	Centro Medico Privado de Reumatologia	San Miguel de Tucuman	Tucuman	Argentina	T4000AXL
68	Centro de Investigaciones Reumatológicas	San Miguel de Tucuman	Tucuman	Argentina	T4000BRD
69	Instituto de Asistencia	Buenos Aires		Argentina	B1646DBM
70	Organizacion Medica de Investigacion (OMI)	Ciudad Autonoma Buenos Aires		Argentina	C1015ABO
71	APRILLUS	Ciudad Autonoma Buenos aires		Argentina	C1046AAQ
72	Instituto Centenario	Ciudad Autonoma Buenos Aires		Argentina	C1204AAD
73	Hospital General de Agudos Dr. J. M. Ramos Mejia	Ciudad Autonoma Buenos Aires		Argentina	C1221ADC
74	Atencion Integral en Reumatologia (AIR)	Ciudad Autonoma Buenos Aires		Argentina	C1426AAL
75	Instituto DAMIC Fundacion Rusculleda	Cordoba		Argentina	X5003DCE
76	Hospital Privado Centro Medico de Cordoba	Cordoba		Argentina	X5016KEH
77	Centro Polivalente de Asistencia e Inv. Clinica CER	San Juan		Argentina	5400
78	HUWC - UFC - Hospital Universitário Walter Cantídio - Universidade Federal do Ceará	Fortaleza	Ceará	Brazil	60430-370
79	CEDOES - Diagnóstico e Pesquisa	Vitória	Espírito Santo	Brazil	29055-450
80	CIP - Centro Internacional de Pesquisa	Goiânia	Goiás	Brazil	74110-120
81	CMiP - Centro Mineiro de Pesquisa	Juiz de Fora	Minas Gerais	Brazil	36010-570
82	CETI - Centro de Estudos em Terapias Inovadoras Ltda.	Curitiba	Paraná	Brazil	80030-110
83	Clinilive - Clínica do Idoso e Pesquisa Clínica	Maringá	Paraná	Brazil	87015-180
84	Hospital Bruno Born	Lajeado	Rio Grande Do Sul	Brazil	95900-010
85	LMK Serviços Médicos S/S Ltda	Porto Alegre	Rio Grande Do Sul	Brazil	90480-000
86	Faculdade de Medicina do ABC	Santo André	Sao Paulo	Brazil	09060-870
87	Hospital Estadual Mário Covas	Santo André	Sao Paulo	Brazil	9190510
88	HUCFF-UFRJ - Hospital Universitário Clementino Fraga Filho - Universidade Federal do Rio de Janeiro	Rio de Janeiro		Brazil	21941-913
89	Hospital São Vicente de Paulo	Rio Grande		Brazil	99010-080
90	Clínica de Neoplasias Litoral Ltda.	Santa Catarina		Brazil	88301-220
91	Hospital Abreu Sodré - AACD	Sao Paulo		Brazil	04023-000
92	CPCLIN - Centro de Pesquisas Clínicas Ltda.	São Paulo		Brazil	01228-200
93	Centro de Reumatologia y Ortopedia SAS	Barranquilla		Colombia	080020
94	Fundacion Hospital Universidad del Norte	Barranquilla		Colombia	111211
95	Fundacion Instituto de Reumatologia Fernando Chalem	Bogota		Colombia	00000
96	Centro de Investigacion en Reumatologia y Especialidades Medicas SAS. CIREEM	Bogotá		Colombia	110221
97	Medicity S.A.S.	Bucaramanga		Colombia	680003
98	Clinica de Artritis Temprana S.A.	Cali		Colombia	76001
99	Hospital Pablo Tobón Uribe	Medellín		Colombia	050034
100	CCR Brno S.R.O.	Brno		Czechia	602 00
101	Revmatologie MUDr. Klara Sirova s.r.o.	Ostrava - Moravska Ostrava		Czechia	70200
102	CCR Pardubice	Pardubice		Czechia	53002
103	MEDICAL PLUS s.r.o.	Uherske Hradiste		Czechia	68601
104	PV - Medical, s.r.o.	Zlin		Czechia	760 01
105	Kerckhoff-Klinik gGmbH	Bad Nauheim	Hessen	Germany	61231
106	CIRI - Centrum für Innovative Diagnostik und Therapie GmbH	Frankfurt	Hessen	Germany	60590
107	SMO.MD GmbH	Magdeburg	Sachsen Anhalt	Germany	39120
108	KH Dresden-Friedrichstadt	Dresden	Sachsen	Germany	01067
109	Rheumapraxis Dr. med. Reiner Kurthen	Aachen		Germany	52064
110	Charite Universitaetsmedizin Berlin - Campus Charite Mitte	Berlin		Germany	10117
111	Klin.Forsch. Berlin-Mitt GmbH	Berlin		Germany	13125
112	HRF Hamburger Rheuma Forschungszentrum	Hamburg		Germany	20095
113	Schoen Klinik Hamburg Eilbek	Hamburg		Germany	22081
114	Clinexpert Egeszsegugyi Szolg. es Ker. Kft.	Budapest		Hungary	1033
115	Obudai Egeszsegugyi Centrum	Budapest		Hungary	1036
116	MAV Korhaz és Rendelointezet	Szolnok		Hungary	5000
117	Vital Medical Center	Veszprem		Hungary	8200
118	Ajou University Hospital	Suwon-si	Gyeonggi-do	Korea, Republic of	16499
119	Chonbuk National University Hospital	Chungbuk		Korea, Republic of	54907
120	Chungnam National University Hospital	Daejeon		Korea, Republic of	35015
121	Eulji University Hospital	Daejeon		Korea, Republic of	35233
122	Chonnam National University Hospital	Gwangju		Korea, Republic of	61469
123	CHA Bundang Medical Center	Gyeonggi-do		Korea, Republic of	13496
124	Hallym University Sacred Heart Hospital	Gyeonggi-do		Korea, Republic of	431-796
125	Jeju National University Hospital	Jeju		Korea, Republic of	63241
126	The Catholic University of Korea, Seoul St. Mary's Hospital	Seoul		Korea, Republic of	06591
127	Severance Hospital, Yonsei University	Seoul		Korea, Republic of	3722
128	Centro de Investigacion Clínica GRAMEL S.C	Mexico	Distrito Federal	Mexico	03720
129	Clinstile, S.A. de C.V.	Mexico	Distrito Federal	Mexico	06700
130	Comop, A.C.	Mexico	Distrito Federal	Mexico	16100
131	Clinical Research Institute S.C.	Tlalnepantla	Estado De Mexico	Mexico	54055
132	Clinica de Investigacion en Reumatologia y Obesidad S.C.	Guadalajara	Jalisco	Mexico	44650
133	Centro de Estudios de Investigacion Basica y Clinica SC	Guadalajara	Jalisco	Mexico	44690
134	Accelerium S. de R.L. de C.V.	Monterrey	Nuevo León	Mexico	64000
135	Hospital y Clinica OCA SA de CV	Monterrey	Nuevo León	Mexico	64000
136	Universidad Autonoma de Nuevo Leon, Hospital Universitario Dr. Jose Eleuterio Gonzalez	Monterrey	Nuevo León	Mexico	64460
137	Centro de Alta Especialidad en Reumatología e Investigación del Potosí, S.C.	San Luis Potosi	San Luis Potos	Mexico	78213
138	Investigacion y Biomedicina de Chihuahua, S.C.	Chihuahua		Mexico	31000
139	Szpital Uniwersytecki nr 2 im.dr J. Biziela	Bydgoszcz		Poland	85-168
140	Szpital Specjalistyczny nr 1 w	Bytom		Poland	41902
141	McBk S.C.	Grodzisk Mazowiecki		Poland	05-825
142	Polimedica Centrum Badań, Profilaktyki I Leczenia	Kielce		Poland	25-355
143	Centrum Medyczne AMED	Lodz		Poland	91-363
144	Szpital Wojewodzki im. Prymasa Kardynala Stefana Wyszynskiego	Sieradz		Poland	98-200
145	Samodzielny Publiczny ZOZ Tomaszow Lubelski	Tomaszow Lubelski		Poland	22-600
146	McM Polimedica	Warszawa		Poland	02-777
147	Medical Center n a Almazov	Saint-Petersburg	Leningrad Oblast	Russian Federation	197341
148	State Budgetary Healthcare Institution of Moscow "City Clinical Hospital #1 n.a. Pirogov" Healthcare Departament of Moscow	Moscow	Moscovskaya Oblast	Russian Federation	119049
149	University hospital #3	Moscow	Moscow Oblast	Russian Federation	119991
150	Clinical Hospital #1	Moscow	Moscow Oblast	Russian Federation	119992
151	University n a Evdokimov	Moscow	Moscow Oblast	Russian Federation	121374
152	State Budgetary Healthcare Institution "City Clinical Hospital # 15 n.a O.M. Filatov" of Moscow Healtheare Department	Moscow	Moscow Region	Russian Federation	111539
153	City Clinical Hospital #1	Novosibirsk	Novosibirsk Oblast	Russian Federation	630099
154	Diagnostic Center Ultramed	Omsk	Omsk Oblast	Russian Federation	644024
155	SBHI of the Republic of Karelia "Republican Hospital named after V.A.Baranov"	Petrozavodsk	Republic Of Karelia	Russian Federation	185019
156	Rostov State Medical Unversity	Rostov-on-Don	Rostov Oblast	Russian Federation	344022
157	Regional Clinical Hospital	Saratov	Saratov Oblast	Russian Federation	410053
158	Clinical Hosp n a Mirotvorcev	Saratov	Saratov Oblast	Russian Federation	410054
159	SBHI of Stavropol Region "Stavropol Regional Clinical Hospital"	Stavropol'	Stavropol Region	Russian Federation	355000
160	State Autonomous Healthcare Institution "Republican Clinical Hospital of Ministry of Health of Tatarstan Republic	Kazan'	The Republic Of Tatarstan	Russian Federation	420064
161	Siberian Medical University	Tomsk	Tomsk Oblast	Russian Federation	634050
162	Regional Clinical Hospital	Vladimir	Vladimir Oblast	Russian Federation	600023
163	University n a Burdenko	Voronezh	Voronezh Oblast	Russian Federation	394066
164	Clinical Hospital 3	Yaroslavl	Yaroslavl Oblast	Russian Federation	150051
165	FSBSI "Scientific Research Institute of Rheumatology n.a. V.A. Nasonova"	Moscow		Russian Federation	115478

Sponsors and Collaborators

• R-Pharm International, LLC
• Quintiles, Inc.
• OCT Clinical Trials
• Mene Research

Investigators

• Study Director: Mikhail Samsonov, R-Pharm

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - May 28, 2018

More Information

Publications

None provided.

• Responsible Party: R-Pharm International, LLC
• ClinicalTrials.gov Identifier: NCT02760433
• Other Study ID Numbers: CL04041025; 2015-005308-27
• First Posted: May 3, 2016
• Last Update Posted: Jul 21, 2021
• Last Verified: Jun 1, 2021

• Keywords provided by R-Pharm International, LLC: moderate Rheumatoid Arthritis; severe Rheumatoid Arthritis; Olokizumab
• Additional relevant MeSH terms: Arthritis; Arthritis, Rheumatoid; Necrosis

Study Results

Participant Flow

Recruitment Details	Enrollment was conducted at 123 clinical sites across 11 countries (US,EU, Russian Federation, Asia, Latin America). 718 subjects were screened and 368 subjects were enrolled (randomized) and treated, 318 subjects completed the study. A total of 368 subjects were analyzed for efficacy in the ITT Population and 368 subjects were analyzed for safety in the Safety Population.

Arm/Group Title	Arm 1: Olokizumab q4w	Arm 2: Olokizumab q2w	Arm 4: Placebo-OKZ 64 mg q4w	Arm 5: Placebo-OKZ 64 mg q2w	Arm 6:Placebo Only
Arm/Group Description	Olokizumab 64mg subcutaneous q4w +placebo + Methotrexate Olokizumab 64 mg subcutaneous q4w + placebo+ concomitant background therapy (Methotrexate) at a stable dose with a stable route of administration (oral, subcutaneous, or intramuscular) in order to maintain the blind, subjects randomized to receive OKZ q4w received placebo injections at the alternate q4w interval (e.g., Week 2, Week 6, etc.) There was no re-randomization at week 16 for this arm	Olokizumab 64mg subcutaneous q2w + Methotrexate 64 mg Olokizumab administered subcutaneously once every 2 weeks + concomitant background therapy (Methotrexate) at a stable dose with a stable route of administration (oral, subcutaneous, or intramuscular) There was no re-randomization at week 16 for this arm	refers to subjects who initially received placebo q2w (Arm 3:Placebo administered subcutaneously once every 2 weeks + concomitant background therapy (Methotrexate)), but then were re-randomized at week 16 to receive OKZ 64 mg q4w. Arm 3 (placebo q2w) consisted of subjects from arms 4, 5 and 6.	refers to subjects who initially received placebo q2w (Arm 3:Placebo administered subcutaneously once every 2 weeks + concomitant background therapy (Methotrexate)), but then were re-randomized at week 16 to receive OKZ 64 mg q2w. Arm 3 (placebo q2w) consisted of subjects from arms 4, 5 and 6.	refers to subjects who were initially randomized to placebo q2w (Arm3:Placebo administered subcutaneously once every 2 weeks + concomitant background therapy (Methotrexate)), but who were not re-randomized to OKZ 64 mg q2w or OKZ 64 mg q4w. Arm 3 (placebo q2w) consisted of subjects from arms 4, 5 and 6.
Period Title: Overall Study
STARTED	161	138	26	32	11
COMPLETED	134	128	25	30	1
NOT COMPLETED	27	10	1	2	10

Baseline Characteristics

Arm/Group Title	Arm 1: Olokizumab q4w	Arm 2: Olokizumab q2w	Arm 4: Placebo-OKZ 64 mg q4w	Arm 5: Placebo-OKZ 64 mg q2w	Arm 6:Placebo Only	Total
Arm/Group Description	Olokizumab 64mg subcutaneous q4w +placebo + Methotrexate Olokizumab 64 mg subcutaneous q4w + placebo+ concomitant background therapy (Methotrexate) at a stable dose with a stable route of administration (oral, subcutaneous, or intramuscular) in order to maintain the blind, subjects randomized to receive OKZ q4w received placebo injections at the alternate q4w interval (e.g., Week 2, Week 6, etc.)	Olokizumab 64mg subcutaneous q2w + Methotrexate 64 mg Olokizumab administered subcutaneously once every 2 weeks + concomitant background therapy (Methotrexate) at a stable dose with a stable route of administration (oral, subcutaneous, or intramuscular)	refers to subjects who initially received placebo q2w, but then were re-randomized at week 16 to receive OKZ 64 mg q4w	refers to subjects who initially received placebo q2w, but then were re-randomized at week 16 to receive OKZ 64 mg q2w	refers to subjects who were initially randomized to placebo, but who were not re-randomized to OKZ 64 mg q2w or OKZ 64 mg q4w	Total of all reporting groups
Overall Participants	161	138	26	32	11	368
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	132 82%	114 82.6%	20 76.9%	27 84.4%	7 63.6%	300 81.5%
>=65 years	29 18%	24 17.4%	6 23.1%	5 15.6%	4 36.4%	68 18.5%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	53.9 (11.68)	53.4 (12.68)	53.5 (14.13)	53.9 (11.67)	48.9 (18.28)	53.5 (12.43)
Sex: Female, Male (Count of Participants)
Female	130 80.7%	122 88.4%	20 76.9%	27 84.4%	8 72.7%	307 83.4%
Male	31 19.3%	16 11.6%	6 23.1%	5 15.6%	3 27.3%	61 16.6%
Race/Ethnicity, Customized (Count of Participants)
Asian	3 1.9%	6 4.3%	1 3.8%	1 3.1%	0 0%	11 3%
Black of African American	11 6.8%	11 8%	0 0%	1 3.1%	0 0%	23 6.3%
White	139 86.3%	110 79.7%	19 73.1%	24 75%	10 90.9%	302 82.1%
Other/Mixed	8 5%	11 8%	6 23.1%	6 18.8%	1 9.1%	32 8.7%
Region of Enrollment (participants) [Number]
Colombia	3 1.9%	5 3.6%	2 7.7%	3 9.4%	0 0%	13 3.5%
Argentina	14 8.7%	11 8%	1 3.8%	2 6.3%	0 0%	28 7.6%
South Korea	1 0.6%	2 1.4%	0 0%	1 3.1%	0 0%	4 1.1%
Hungary	8 5%	10 7.2%	2 7.7%	3 9.4%	1 9.1%	24 6.5%
United States	63 39.1%	44 31.9%	10 38.5%	8 25%	3 27.3%	128 34.8%
Czechia	17 10.6%	13 9.4%	2 7.7%	2 6.3%	2 18.2%	36 9.8%
Brazil	8 5%	11 8%	1 3.8%	3 9.4%	1 9.1%	24 6.5%
Poland	5 3.1%	5 3.6%	0 0%	2 6.3%	1 9.1%	13 3.5%
Mexico	27 16.8%	28 20.3%	8 30.8%	8 25%	2 18.2%	73 19.8%
Germany	3 1.9%	1 0.7%	0 0%	0 0%	0 0%	4 1.1%
Russia	12 7.5%	8 5.8%	0 0%	0 0%	1 9.1%	21 5.7%
Body Mass Index (BMI),Continuous (kg/m^2) [Mean (Full Range) ]
Mean (Full Range) [kg/m^2]	29.218	28.755	28.895	28.467	26.976	28.888

Outcome Measures

1. Primary Outcome

Title	ACR20 Response
Description	The difference between OKZ and placebo in the percentage of subjects achieving an ACR20 response and remaining on randomized treatment and in the study at Week 12. A responder is defined as any subject satisfying ACR20 criteria and remaining on randomized treatment and in the study at Week 12. American College of Rheumatology 20 % response is a composite defined as a ≥ 20% improvement from baseline in the swollen joint counts assessed in 66 joints and in the tender joint count assessed in 68 joints; and a ≥20% improvement from baseline in at least 3 of the 5 remaining core set measures: Patient Global Assessment of Disease Activity (VAS) Patient Assessment of Pain (VAS) HAQ-DI Physician Global Assessment (VAS) Level of acute phase reactant (CRP)
Time Frame	at Week 12

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population: The ITT population includes all randomized subjects. Subjects were analyzed according to the treatment group to which they were randomized. The ITT population is the primary analysis population.

Arm/Group Title	Arm 1: Olokizumab 64 mg q4w	Arm 2: Olokizumab 64 mg q2w	Arm 3: Placebo q2w
Arm/Group Description	Olokizumab 64mg subcutaneous q4w +placebo + Methotrexate Olokizumab 64 mg subcutaneous q4w + placebo+ concomitant background therapy (Methotrexate) at a stable dose with a stable route of administration (oral, subcutaneous, or intramuscular) in order to maintain the blind, subjects randomized to receive OKZ q4w received placebo injections at the alternate q4w interval (e.g., Week 2, Week 6, etc.)	Olokizumab 64mg subcutaneous q2w + Methotrexate 64 mg Olokizumab administered subcutaneously once every 2 weeks + concomitant background therapy (Methotrexate) at a stable dose with a stable route of administration (oral, subcutaneous, or intramuscular)	Placebo q2w subcutaneous + Methotrexate Placebo administered subcutaneously once every 2 weeks + concomitant background therapy (Methotrexate) at a stable dose with a stable route of administration (oral, subcutaneous, or intramuscular) Starting at Week 16, all subjects in the placebo group were randomized in a blinded fashion to receive either OKZ 64 mg q2w or OKZ 64 mg q4w; Arm 3 (placebo q2w) consisted of subjects from arms 4, 5 and 6 reported previously
Measure Participants	161	138	69
Count of Participants [Participants]	96 59.6%	84 60.9%	28 107.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm 1: Olokizumab 64 mg q4w, Arm 3: Placebo q2w
	Comments	The ACR20 response rate at Week 12 for the placebo group is estimated to be 20% in this study population. The OKZ ACR20 response rate for 64 mg q4w treatment group at Week 12 are expected to be at least 45%, resulting in an expected difference in ACR20 response rates of 25 percentage points between the respective OKZ treatment group and placebo. Sample size yield 100% disjunctive power for testing the primary hypothesis
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0125
	Comments
	Method	Chi-squared
	Comments	2x2 chi-square test
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	0.190
	Confidence Interval	(2-Sided) 97.5%; 0.030 to 0.337
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Arm 2: Olokizumab 64 mg q2w, Arm 3: Placebo q2w
	Comments	The ACR20 response rate at Week 12 for the placebo group is estimated to be 20% in this study population .The OKZ ACR20 response rate for 64 mg q2w treatment group at Week 12 is expected to be at least 50%, resulting in an expected difference in ACR20 response rates of 30 percentage points between the respective OKZ treatment group and placebo. Sample size yield 100% disjunctive power for testing the primary hypothesis
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0125
	Comments
	Method	Chi-squared
	Comments	2x2 chi-square test
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	0.203
	Confidence Interval	(2-Sided) 97.5%; 0.038 to 0.353
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Difference Between OKZ and Placebo in the Percentage of Subjects Achieving Low Disease Activity
Description	Defined as Disease Activity Score 28-joint count (DAS28) C-reactive protein (CRP) <3.2, and remaining on randomized treatment and in the study at Week 12
Time Frame	at Week 12

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population: The ITT population includes all randomized subjects. Subjects were analyzed according to the treatment group to which they were randomized. The ITT population is the primary analysis population.

Arm/Group Title	Arm 1: Olokizumab q4w	Arm 2: Olokizumab q2w	Arm 3: Placebo q2w
Arm/Group Description	Olokizumab 64mg subcutaneous q4w +placebo + Methotrexate Olokizumab 64 mg subcutaneous q4w + placebo+ concomitant background therapy (Methotrexate) at a stable dose with a stable route of administration (oral, subcutaneous, or intramuscular) in order to maintain the blind, subjects randomized to receive OKZ q4w received placebo injections at the alternate q4w interval (e.g., Week 2, Week 6, etc.)	Olokizumab 64mg subcutaneous q2w + Methotrexate 64 mg Olokizumab administered subcutaneously once every 2 weeks + concomitant background therapy (Methotrexate) at a stable dose with a stable route of administration (oral, subcutaneous, or intramuscular)	Placebo q2w subcutaneous + Methotrexate Placebo administered subcutaneously once every 2 weeks + concomitant background therapy (Methotrexate) at a stable dose with a stable route of administration (oral, subcutaneous, or intramuscular) Starting at Week 16, all subjects in the placebo group were randomized in a blinded fashion to receive either OKZ 64 mg q2w or OKZ 64 mg q4w; Arm 3 (placebo q2w) consisted of subjects from arms 4, 5 and 6 reported previously
Measure Participants	161	138	69
Count of Participants [Participants]	45 28%	55 39.9%	8 30.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm 1: Olokizumab 64 mg q4w, Arm 3: Placebo q2w
	Comments	The DAS28 low disease activity (based on DAS28 [CRP] <3.2) response rate at Week 12 was estimated to be 5% in the placebo group and 18% and 21% in 64 mg q4w and q2w OKZ groups, respectively, resulting in an expected difference of 13 and 16 percentage points between respective OKZ groups and placebo.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0125
	Comments
	Method	Chi-squared
	Comments	2x2 chi-square test
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	0.164
	Confidence Interval	(2-Sided) 97.5%; 0.029 to 0.268
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Arm 2: Olokizumab 64 mg q2w, Arm 3: Placebo q2w
	Comments	The DAS28 low disease activity (based on DAS28 [CRP] <3.2) response rate at Week 12 was estimated to be 5% in the placebo group and 18% and 21% in 64 mg q4w and q2w OKZ groups, respectively, resulting in an expected difference of 13 and 16 percentage points between respective OKZ groups and placebo.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0125
	Comments
	Method	Chi-squared
	Comments	2x2 chi-square test
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	0.283
	Confidence Interval	(2-Sided) 97.5%; 0.139 to 0.396
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Difference Between OKZ and Placebo in the Improvement of Physical Ability
Description	Improvement of physical ability from baseline to week 12, as measured by HAQ-DI. The HAQ-DI assesses the degree of difficulty experienced in 8 domains of daily living activities using 20 questions. The domains are dressing and grooming, arising, eating, walking, hygiene, reach, grip and common daily activities, and each domain consists of 2 or 3 items. For each question, the level of difficulty is scored from 0 to 3 where 0 = without any difficulty (the best outcome), 1 = with some difficulty, 2 = much difficulty, and 3 = unable to do (the worst outcome). Each category is given a score by taking the maximum score of each question. A decrease from baseline indicates improvement for HAQ-DI. The HAQ-DI was calculated by dividing the sum of the category scores by the number of categories with at least 1 question answered. The HAQ-DI total score ranges from 0 to 3, with higher scores indicating greater disability.
Time Frame	Baseline to Week 12

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population: The ITT population includes all randomized subjects. Subjects were analyzed according to the treatment group to which they were randomized. The ITT population is the primary analysis

Arm/Group Title	Arm 1: Olokizumab q4w	Arm 2: Olokizumab q2w	Arm 3: Placebo q2w + Methotrexate
Arm/Group Description	Olokizumab 64mg subcutaneous q4w +placebo + Methotrexate Olokizumab 64 mg subcutaneous q4w + placebo+ concomitant background therapy (Methotrexate) at a stable dose with a stable route of administration (oral, subcutaneous, or intramuscular) in order to maintain the blind, subjects randomized to receive OKZ q4w received placebo injections at the alternate q4w interval (e.g., Week 2, Week 6, etc.)	Olokizumab 64mg subcutaneous q2w + Methotrexate 64 mg Olokizumab administered subcutaneously once every 2 weeks + concomitant background therapy (Methotrexate) at a stable dose with a stable route of administration (oral, subcutaneous, or intramuscular)	Placebo q2w subcutaneous + Methotrexate Placebo administered subcutaneously once every 2 weeks + concomitant background therapy (Methotrexate) at a stable dose with a stable route of administration (oral, subcutaneous, or intramuscular) Starting at Week 16, all subjects in the placebo group were randomized in a blinded fashion to receive either OKZ 64 mg q2w or OKZ 64 mg q4w; Arm 3 (placebo q2w) consisted of subjects from arms 4, 5 and 6 reported previously
Measure Participants	161	138	69
Baseline	1.78 (0.558)	1.79 (0.533)	1.78 (0.639)
Week 12 (visit 9)	1.37 (0.613)	1.30 (0.626)	1.49 (0.642)
Change from Baseline (Observed and Imputed)	-0.39 (0.048)	-0.49 (0.056)	-0.32 (0.063)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm 1: Olokizumab 64 mg q4w, Arm 3: Placebo q2w
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.1814
	Comments	p-value was greater than the threshold p-value of 0.0125
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.07
	Confidence Interval	(2-Sided) 97.5%; -0.26 to 0.11
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.081
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Arm 2: Olokizumab 64 mg q2w, Arm 3: Placebo q2w
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.0227
	Comments	p-value was greater than the threshold p-value of 0.0125
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.17
	Confidence Interval	(2-Sided) 97.5%; -0.35 to 0.02
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.083
	Estimation Comments

4. Secondary Outcome

Title	ACR50 Response
Description	Difference between OKZ and placebo in the percentage of subjects achieving an ACR50 response and remaining on randomized treatment and in the study at Week 12. American College of Rheumatology 50% Response is a composite defined as ≥50%, improvement from baseline in the swollen joint counts assessed in 66 joints and in the tender joint count assessed in 68 joints; and a ≥50%, improvement from baseline in at least 3 of the 5 remaining core set measures: Patient Global Assessment of Disease Activity (VAS) Patient Assessment of Pain (VAS) HAQ-DI Physician Global Assessment (VAS) Level of acute phase reactant (CRP)
Time Frame	at Week 12

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population: The ITT population includes all randomized subjects. Subjects were analyzed according to the treatment group to which they were randomized. The ITT population is the primary analysis population.

Arm/Group Title	Arm 1: Olokizumab q4w	Arm 2: Olokizumab q2w	Arm 3: Placebo q2w
Arm/Group Description	Olokizumab 64mg subcutaneous q4w +placebo + Methotrexate Olokizumab 64 mg subcutaneous q4w + placebo+ concomitant background therapy (Methotrexate) at a stable dose with a stable route of administration (oral, subcutaneous, or intramuscular) in order to maintain the blind, subjects randomized to receive OKZ q4w received placebo injections at the alternate q4w interval (e.g., Week 2, Week 6, etc.)	Olokizumab 64mg subcutaneous q2w + Methotrexate 64 mg Olokizumab administered subcutaneously once every 2 weeks + concomitant background therapy (Methotrexate) at a stable dose with a stable route of administration (oral, subcutaneous, or intramuscular)	Placebo q2w subcutaneous + Methotrexate Placebo q2w subcutaneous + Methotrexate Placebo administered subcutaneously once every 2 weeks + concomitant background therapy (Methotrexate) at a stable dose with a stable route of administration (oral, subcutaneous, or intramuscular) Arm 3 (placebo q2w) consisted of subjects from arms 4, 5 and 6 reported previously Starting at Week 16, all subjects in the placebo group were randomized in a blinded fashion to receive either OKZ 64 mg q2w or OKZ 64 mg q4w;
Measure Participants	161	138	69
Count of Participants [Participants]	52 32.3%	46 33.3%	11 42.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm 1: Olokizumab 64 mg q4w, Arm 3: Placebo q2w
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	0.164
	Confidence Interval	(2-Sided) 97.5%; 0.020 to 0.278
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Arm 2: Olokizumab 64 mg q2w, Arm 3: Placebo q2w
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	0.174
	Confidence Interval	(2-Sided) 97.5%; 0.027 to 0.294
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Clinical Disease Activity Index (CDAI) ≤2.8 (Remission)
Description	Difference between OKZ and placebo in the percentage of subjects with Clinical Disease Activity Index (CDAI) ≤2.8 (remission) and remaining on randomized treatment and in the study at Week 12
Time Frame	at Week 12

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population: The ITT population includes all randomized subjects. Subjects were analyzed according to the treatment group to which they were randomized. The ITT population is the primary analysis population.

Arm/Group Title	Arm 1: Olokizumab q4w	Arm 2: Olokizumab q2w	Arm 3: Placebo q2w
Arm/Group Description	Olokizumab 64mg subcutaneous q4w +placebo + Methotrexate Olokizumab 64 mg subcutaneous q4w + placebo+ concomitant background therapy (Methotrexate) at a stable dose with a stable route of administration (oral, subcutaneous, or intramuscular) in order to maintain the blind, subjects randomized to receive OKZ q4w received placebo injections at the alternate q4w interval (e.g., Week 2, Week 6, etc.)	Olokizumab 64mg subcutaneous q2w + Methotrexate 64 mg Olokizumab administered subcutaneously once every 2 weeks + concomitant background therapy (Methotrexate) at a stable dose with a stable route of administration (oral, subcutaneous, or intramuscular)	Placebo q2w subcutaneous + Methotrexate Placebo administered subcutaneously once every 2 weeks + concomitant background therapy (Methotrexate) at a stable dose with a stable route of administration (oral, subcutaneous, or intramuscular) Starting at Week 16, all subjects in the placebo group were randomized in a blinded fashion to receive either OKZ 64 mg q2w or OKZ 64 mg q4w; Arm 3 (placebo q2w) consisted of subjects from arms 4, 5 and 6 reported previously
Measure Participants	161	138	69
Count of Participants [Participants]	5 3.1%	9 6.5%	0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm 1: Olokizumab 64 mg q4w, Arm 3: Placebo q2w
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	0.031
	Confidence Interval	(2-Sided) 97.5%; -0.052 to 0.083
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Arm 2: Olokizumab 64 mg q2w, Arm 3: Placebo q2w
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	0.065
	Confidence Interval	(2-Sided) 97.5%; -0.023 to 0.134
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	All AEs were collected from the signature of the informed consent form until the last visit of the subject in the study (up to 22 weeks after the final dose of study treatment) regardless of relationship to study treatment, up to approximately 44 weeks. Any SAE with a start date after the Safety Follow-Up Period was not required to be reported unless the Investigator thought that the event might be related to either the study treatment, study treatment administration, or a protocol procedure
Adverse Event Reporting Description	All AEs and SAEs reported below are related to the Safety Population (safety population included all subjects who receive at least 1 dose of study treatment). Data for TEAEs were reported below. A Treatment Emergent Adverse Event (TEAE) is defined as an AE that first occurred or worsened in severity after the first dose of the study treatment.
Arm/Group Title	Arm 1: OKZ 64 mg q4w		Arm 2: OKZ 64 mg q2w		Arm 3: Placebo q2w		Arm 4: Placebo-OKZ 64 mg q4w		Arm 5: Placebo-OKZ 64 mg q2w		Arm 6: Any OKZ 64 mg q4w		Arm 7: Any OKZ 64 mg q2w		Arm 8:Total
Arm/Group Description	refers to subjects initially randomized to receive OKZ q4w and relates to AEs reported for this group during the total 24-week study treatment period		refers to subjects initially randomized to receive OKZ q2w and relates to AEs reported for this group during the total 24-week study treatment period		refers to subjects initially randomized to receive placebo and relates only to AEs reported for this group during the 16-week treatment period up to re-randomization		refers to subjects re-randomized to receive OKZ q4w and relates only to AEs reported for this group during the treatment period after re-randomization from Week 16 to Week 24		refers to subjects re-randomized to receive OKZ q2w and relates only to AEs reported for this group during the treatment period after re-randomization from Week 16 to Week 24		refers to a combination of the AEs reported for the OKZ 64 mg q4w group and the Placebo-OKZ 64 mg q4w group		refers to a combination of the AEs reported for the OKZ 64 mg q2w group and the Placebo-OKZ 64 mg q2w group		refers to AEs reported for all subjects at all visits
All Cause Mortality
	Arm 1: OKZ 64 mg q4w		Arm 2: OKZ 64 mg q2w		Arm 3: Placebo q2w		Arm 4: Placebo-OKZ 64 mg q4w		Arm 5: Placebo-OKZ 64 mg q2w		Arm 6: Any OKZ 64 mg q4w		Arm 7: Any OKZ 64 mg q2w		Arm 8:Total
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/160 (0%)		0/139 (0%)		0/69 (0%)		0/26 (0%)		0/32 (0%)		0/186 (0%)		0/171 (0%)		0/368 (0%)
Serious Adverse Events
	Arm 1: OKZ 64 mg q4w		Arm 2: OKZ 64 mg q2w		Arm 3: Placebo q2w		Arm 4: Placebo-OKZ 64 mg q4w		Arm 5: Placebo-OKZ 64 mg q2w		Arm 6: Any OKZ 64 mg q4w		Arm 7: Any OKZ 64 mg q2w		Arm 8:Total
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/160 (3.8%)		12/139 (8.6%)		0/69 (0%)		0/26 (0%)		0/32 (0%)		6/186 (3.2%)		12/171 (7%)		18/368 (4.9%)
Cardiac disorders
Sinus bradycardia	1/160 (0.6%)	1	0/139 (0%)	0	0/69 (0%)	0	0/26 (0%)	0	0/32 (0%)	0	1/186 (0.5%)	1	0/171 (0%)	0	1/368 (0.3%)	1
Gastrointestinal disorders
Gastrointestinal disorder	1/160 (0.6%)	1	0/139 (0%)	0	0/69 (0%)	0	0/26 (0%)	0	0/32 (0%)	0	1/186 (0.5%)	1	0/171 (0%)	0	1/368 (0.3%)	1
Hepatobiliary disorders
Cholecystitis	0/160 (0%)	0	1/139 (0.7%)	1	0/69 (0%)	0	0/26 (0%)	0	0/32 (0%)	0	0/186 (0%)	0	1/171 (0.6%)	1	1/368 (0.3%)	1
Immune system disorders
Anaphylactic reaction	1/160 (0.6%)	1	0/139 (0%)	0	0/69 (0%)	0	0/26 (0%)	0	0/32 (0%)	0	1/186 (0.5%)	1	0/171 (0%)	0	1/368 (0.3%)	1
Infections and infestations
Cellulitis	1/160 (0.6%)	1	1/139 (0.7%)	1	0/69 (0%)	0	0/26 (0%)	0	0/32 (0%)	0	1/186 (0.5%)	1	1/171 (0.6%)	1	2/368 (0.5%)	2
Pilonidal cyst	0/160 (0%)	0	1/139 (0.7%)	1	0/69 (0%)	0	0/26 (0%)	0	0/32 (0%)	0	0/186 (0%)	0	1/171 (0.6%)	1	1/368 (0.3%)	1
Pneumonia	1/160 (0.6%)	1	0/139 (0%)	0	0/69 (0%)	0	0/26 (0%)	0	0/32 (0%)	0	1/186 (0.5%)	1	0/171 (0%)	0	1/368 (0.3%)	1
Sepsis	0/160 (0%)	0	1/139 (0.7%)	1	0/69 (0%)	0	0/26 (0%)	0	0/32 (0%)	0	0/186 (0%)	0	1/171 (0.6%)	1	1/368 (0.3%)	1
Injury, poisoning and procedural complications
Hip fracture	0/160 (0%)	0	1/139 (0.7%)	1	0/69 (0%)	0	0/26 (0%)	0	0/32 (0%)	0	0/186 (0%)	0	1/171 (0.6%)	1	1/368 (0.3%)	1
Ulna fracture	0/160 (0%)	0	1/139 (0.7%)	1	0/69 (0%)	0	0/26 (0%)	0	0/32 (0%)	0	0/186 (0%)	0	1/171 (0.6%)	1	1/368 (0.3%)	1
Investigations
Alanine aminotransferase increased	1/160 (0.6%)	1	0/139 (0%)	0	0/69 (0%)	0	0/26 (0%)	0	0/32 (0%)	0	1/186 (0.5%)	1	0/171 (0%)	0	1/368 (0.3%)	1
Aspartate aminotransferase increased	0/160 (0%)	0	1/139 (0.7%)	1	0/69 (0%)	0	0/26 (0%)	0	0/32 (0%)	0	0/186 (0%)	0	1/171 (0.6%)	1	1/368 (0.3%)	1
Transaminases increased	0/160 (0%)	0	1/139 (0.7%)	1	0/69 (0%)	0	0/26 (0%)	0	0/32 (0%)	0	0/186 (0%)	0	1/171 (0.6%)	1	1/368 (0.3%)	1
Musculoskeletal and connective tissue disorders
Intervertebral disc protrusion	0/160 (0%)	0	1/139 (0.7%)	1	0/69 (0%)	0	0/26 (0%)	0	0/32 (0%)	0	0/186 (0%)	0	1/171 (0.6%)	1	1/368 (0.3%)	1
Musculoskeletal chest pain	0/160 (0%)	0	1/139 (0.7%)	1	0/69 (0%)	0	0/26 (0%)	0	0/32 (0%)	0	0/186 (0%)	0	1/171 (0.6%)	1	1/368 (0.3%)	1
Osteoarthritis	0/160 (0%)	0	1/139 (0.7%)	1	0/69 (0%)	0	0/26 (0%)	0	0/32 (0%)	0	0/186 (0%)	0	1/171 (0.6%)	1	1/368 (0.3%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Invasive ductal breast carcinoma	0/160 (0%)	0	1/139 (0.7%)	1	0/69 (0%)	0	0/26 (0%)	0	0/32 (0%)	0	0/186 (0%)	0	1/171 (0.6%)	1	1/368 (0.3%)	1
Psychiatric disorders
Anxiety	0/160 (0%)	0	1/139 (0.7%)	1	0/69 (0%)	0	0/26 (0%)	0	0/32 (0%)	0	0/186 (0%)	0	1/171 (0.6%)	1	1/368 (0.3%)	1
Renal and urinary disorders
Renal failure	1/160 (0.6%)	1	0/139 (0%)	0	0/69 (0%)	0	0/26 (0%)	0	0/32 (0%)	0	1/186 (0.5%)	1	0/171 (0%)	0	1/368 (0.3%)	1
Vascular disorders
Hypertensive crisis	0/160 (0%)	0	1/139 (0.7%)	1	0/69 (0%)	0	0/26 (0%)	0	0/32 (0%)	0	0/186 (0%)	0	1/171 (0.6%)	1	1/368 (0.3%)	1
Other (Not Including Serious) Adverse Events
	Arm 1: OKZ 64 mg q4w		Arm 2: OKZ 64 mg q2w		Arm 3: Placebo q2w		Arm 4: Placebo-OKZ 64 mg q4w		Arm 5: Placebo-OKZ 64 mg q2w		Arm 6: Any OKZ 64 mg q4w		Arm 7: Any OKZ 64 mg q2w		Arm 8:Total
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	38/160 (23.8%)		38/139 (27.3%)		16/69 (23.2%)		2/26 (7.7%)		8/32 (25%)		40/186 (21.5%)		46/171 (26.9%)		98/368 (26.6%)
Blood and lymphatic system disorders
Anaemia	1/160 (0.6%)	1	1/139 (0.7%)	1	4/69 (5.8%)	4	0/26 (0%)	0	2/32 (6.3%)	2	1/186 (0.5%)	1	3/171 (1.8%)	3	8/368 (2.2%)	8
Gastrointestinal disorders
Diarrhoea	3/160 (1.9%)	3	6/139 (4.3%)	6	0/69 (0%)	0	0/26 (0%)	0	2/32 (6.3%)	2	3/186 (1.6%)	3	8/171 (4.7%)	8	11/368 (3%)	11
General disorders
Injection site erythema	7/160 (4.4%)	7	1/139 (0.7%)	1	0/69 (0%)	0	0/26 (0%)	0	0/32 (0%)	0	7/186 (3.8%)	7	1/171 (0.6%)	1	8/368 (2.2%)	8
Infections and infestations
Nasopharyngitis	7/160 (4.4%)	7	9/139 (6.5%)	9	1/69 (1.4%)	1	0/26 (0%)	0	1/32 (3.1%)	1	7/186 (3.8%)	7	10/171 (5.8%)	10	18/368 (4.9%)	18
Upper respiratory tract infection	6/160 (3.8%)	6	5/139 (3.6%)	5	4/69 (5.8%)	4	0/26 (0%)	0	1/32 (3.1%)	1	6/186 (3.2%)	6	6/171 (3.5%)	6	16/368 (4.3%)	16
Latent tuberculosis	6/160 (3.8%)	6	4/139 (2.9%)	4	0/69 (0%)	0	1/26 (3.8%)	1	2/32 (6.3%)	2	7/186 (3.8%)	7	6/171 (3.5%)	6	13/368 (3.5%)	13
Influenza	0/160 (0%)	0	5/139 (3.6%)	5	4/69 (5.8%)	4	0/26 (0%)	0	1/32 (3.1%)	1	0/186 (0%)	0	6/171 (3.5%)	6	10/368 (2.7%)	10
Investigations
Alanine aminotransferase increased	13/160 (8.1%)	13	10/139 (7.2%)	10	0/69 (0%)	0	0/26 (0%)	0	1/32 (3.1%)	1	13/186 (7%)	13	11/171 (6.4%)	11	24/368 (6.5%)	24
Aspartate aminotransferase increased	8/160 (5%)	8	9/139 (6.5%)	9	1/69 (1.4%)	1	0/26 (0%)	0	1/32 (3.1%)	1	8/186 (4.3%)	8	10/171 (5.8%)	10	19/368 (5.2%)	19
Vascular disorders
Hypertension	1/160 (0.6%)	1	4/139 (2.9%)	4	3/69 (4.3%)	3	1/26 (3.8%)	1	0/32 (0%)	0	2/186 (1.1%)	2	4/171 (2.3%)	4	9/368 (2.4%)	9

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Any study related information could be made public available only after Sponsors written permission.