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CREDO 1: Evaluation of the Effectiveness and Safety of Two Dosing Regimens of Olokizumab (OKZ), Compared to Placebo, in Subjects With Rheumatoid Arthritis (RA) Who Are Taking Methotrexate But Have Active Disease

Sponsor
R-Pharm International, LLC (Industry)
Overall Status
Completed
CT.gov ID
NCT02760368
Collaborator
Quintiles, Inc. (Industry), OCT Clinical Trials (Other), Mene Research (Other)
428
Enrollment
39
Locations
3
Arms
29
Duration (Months)
11
Patients Per Site
0.4
Patients Per Site Per Month

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 are already receiving, but not fully responding to, treatment with methotrexate (MTX).

The primary objective of this study was to evaluate the efficacy of olokizumab (OKZ) 64 mg administered subcutaneously (SC) once every 2 weeks (q2w) or once every 4 weeks (q4w) relative to placebo in subjects with moderately to severely active rheumatoid arthritis (RA) inadequately controlled by methotrexate (MTX) therapy.

Condition or Disease Intervention/Treatment Phase
Phase 3

Detailed Description

The goal of this Phase III study was to assess the efficacy, tolerability, and safety of OKZ in subjects with moderately to severely active RA who have responded inadequately to MTX. The primary endpoint of the trial was 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.

The CREDO 1 study included a 4-week Screening Period, a double-blind Treatment Period from Week 0 to Week 24, and a Safety Follow-Up Period from Week 24 to Week 44.

At randomization, a total of 420 eligible subjects were randomly assigned to 1 of 3 treatment groups in a 1:1:1 ratio:

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

  2. OKZ 64 mg q2w: SC injection of OKZ 64 mg q2w + MTX.

  3. Placebo: SC injection of placebo q2w + MTX

Throughout the double-blind Treatment Period, all subjects were required to remain on a stable dose of background MTX at 15 to 25 mg/week (or ≥ 10 mg/week if there was documented intolerance to higher doses) with a stable route of administration, and concomitant treatment with folic acid ≥5 mg per week or equivalent is required for all subjects. The last dose of study treatment (OKZ or placebo) was at Week 22 in all groups.

Following Visit 2 (randomization), subjects returned to the study site at least every other week through Week 24 for response and safety assessments as per the study Schedule of Events.

Subjects were classified in terms of their response to study treatment at Week 14, with nonresponders defined as subjects in any treatment group who do not improve by at least 20% in both swollen and tender joint counts (66-68 joint assessment). Starting at or as close as possible to Week 14, non-responders 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 the randomized treatment prematurely were required to come for the End of Treatment (EoT) Visit 2 weeks after the last study treatment administration and then continued with the scheduled study visits as per the Schedule of Events.

The study was conducted at approximately 50 sites across 4 countries globally, which included Russia, Belarus, Turkey, and Bulgaria.

Study Design

Study Type:
Interventional
Actual Enrollment :
428 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 Methotrexate Therapy
Study Start Date :
May 1, 2016
Actual Primary Completion Date :
Aug 1, 2018
Actual Study Completion Date :
Oct 1, 2018

Arms and Interventions

Arm Intervention/Treatment
Experimental: Arm 1: Olokizumab q4w

Olokizumab 64 mg Subcutaneous q4w +placebo+ Methotrexate (oral) in order to maintain the blind, subjects randomized to receive OKZ q4w will receive 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

Drug: Placebo
sodium chloride 0.9% solution supplied in polypropylene plastic ampoules of 10 mL cartons to contain 10 ampoules
Experimental: Arm 2: Olokizumab q2w

Olokizumab 64 mg Subcutaneous q2w + Methotrexate (oral)

Drug: Olokizumab
160 mg/mL sterile solution for SC injection in a 2 mL clear Type I glass vial
Placebo Comparator: Arm 3: Placebo

Placebo Subcutaneous q2w + Methotrexate (oral)

Drug: Placebo
sodium chloride 0.9% solution supplied in polypropylene plastic ampoules of 10 mL cartons to contain 10 ampoules

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 was defined as any subject satisfying ACR20 criteria and remaining on randomized treatment and in the study at Week 12)

Secondary Outcome Measures

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

    Defined as DAS28 (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]

    As measured by the Health Assessment Questionnaire Disability Index (HAQ DI) HAQ-DI provides an assessment of the impact of the disease and its treatment on physical function. 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 (activity) 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 (i.e., question in each category with the highest score for that category).

  3. ACR50 Response [at Week 24]

    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 24.

  4. Percentage of Subjects With Clinical Disease Activity Index (CDAI) ≤2.8 (Remission) [at Week 24]

    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 24

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 12 weeks prior to Screening.

  • Inadequate response to treatment with MTX for at least 12 weeks prior to Screening at a dose of 15 to 25 mg/week (or ≥10 mg/week if intolerant to higher doses).

  • The dose and means of administering MTX must have been stable for at least 6 weeks prior to Screening.

  • Subjects must be willing to take folic acid or equivalent throughout the study

  • Subjects must have moderately to severely active RA disease as defined by all of the following:

  • ≥6 tender joints (68 joint count) at Screening and baseline; and

  • ≥6 swollen joints (66 joint count) at Screening and baseline; and

  • CRP above ULN at Screening based on the central laboratory results.

Exclusion Criteria:

  • Diagnosis of any other inflammatory arthritis or systemic rheumatic disease (e.g., gout, psoriatic or reactive arthritis, Crohn's disease, Lyme disease, juvenile idiopathic arthritis, or systemic lupus erythematosus). However, subjects 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, with the following exception:

• Subjects who discontinued TNFi therapy due to a reason other than lack of efficacy are allowed to enter the study (TNFi therapy 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). The use of TNFi therapy within the following windows prior to baseline is exclusionary: i. 4 weeks for etanercept ii. 8 weeks for infliximab iii. 10 weeks for adalimumab, certolizumab, and golimumab

  • Use of parenteral and/or intra-articular glucocorticoids within 4 weeks prior to baseline

  • Use of oral glucocorticoids greater than 10 mg/day prednisone (or equivalent) or change in dosage within 2 weeks prior to baseline

  • Prior documented history of no response to hydroxychloroquine and sulfasalazine

  • Prior use of cDMARDs (other than MTX) within the following windows prior to baseline (cDMARDs 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 d oxycycline

  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 <100×109/L (<100,000/mm3)

  4. White blood cell count <3.5×10^9/L

  5. Neutrophil count <2000×106/L (<2000/mm3)

  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])
  1. Subjects who are positive for hepatitis B surface antibody (anti-HBs), but negative for HBsAg and anti-HBc, will be eligible.

  • Subjects with HIV infection

  • Subjects with current active TB infection or a history of active TB infection

  • 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

  • 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

  • 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 (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] > 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

  • 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 a history of such predisposing conditions (e.g., diverticulitis, GI perforation, or ulcerative colitis)

  • Pre-existing central nervous system demyelinating disorders (e.g., multiple sclerosis and optic neuritis)

  • History of chronic alcohol or drug abuse as judged by the Investigator

  • Female subjects who are pregnant, currently lactating, have lactated within the last 12 weeks, or who 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 OR Male subjects with partners of childbearing potential not willing to use a highly effective method of contraception during the study and for at least 3 months after the last administration of study treatment

  • Subjects with a known hypersensitivity to any component of the OKZ drug product, or placebo

  • 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 City Clinical Hospital #1 Minsk Belarus 220013
2 Vitebsk Regional Clinical Hospital Vitebsk Belarus 210037
3 DCC 'Sv. Pantaleymon' OOD Pleven Bulgaria 5800
4 UMHAT "Kaspela", EOOD Plovdiv Bulgaria 4002
5 UMHAT "Sv. Ivan Rilski", EAD Sofia Bulgaria 1431
6 MC "Synexus - Sofia", EOOD Sofia Bulgaria 1784
7 Regional State Budgetary Healthcare Institution "Barnaul City Hospital #4" Barnaul Altai Region Russian Federation 656050
8 Medical Center LLC "Maksimum Zdoroviya" Kemerovo Kemerovo Oblast Russian Federation 650056
9 SAHI of Kemerovo region "Regional Clinical Hospital for War Veterans" Kemerovo Kemerovskaya Oblast Russian Federation 650000
10 Budgetary Healthcare Institution "Kursk Regional Clinical Hospital" of Healthcare Committee of Kursk region Kursk Kurskaya Oblast Russian Federation 305007
11 SPb SBHI "Clinical Rheumatological Hospital #25", Fourth Rheumatology Unit Saint Petersburg Leningradskaya Oblast Russian Federation 190068
12 State Budgetary Healthcare Institution of Moscow "City Clinical Hospital #1 n.a. Pirogov" Healthcare Departament of Moscow Moscow Moscovskaya Oblast Russian Federation 119094
13 FSBEI HE "First Moscow State Medical University n.a. I.M. Sechenov of MoH of Russian Federation", UCH #1 Moscow Moscovskaya Oblast Russian Federation 119991
14 FSBEI HE "FMSMU n.a. I.M. Sechenov of MoH of RF", University Hospital #2, Departament of New Drugs Introduction Moscow Moscovskaya Oblast Russian Federation 119991
15 SBEI HPE "First Moscow State Medical University n.a. I.M. Sechenov of MoH of Russian Federation" UCH #3 Moscow Moscovskaya Oblast Russian Federation 119991
16 State Budgetary Healthcare Institution "City Clinical Hospital # 15 n.a O.M. Filatov" of Moscow Healtheare Department Moscow Moscow Region Russian Federation 111539
17 SBHI of Moscow "City Clinical Hospital #4 of Moscow Healthcare Departament" Moscow Moskovskaya Oblast Russian Federation 115093
18 SBHI of Nizhny Novgorod Region "Nizhny Novgorod Regional Clinical Hospital n.a.Semashko" Nizhniy Novgorod Nizhegorodskaya Oblast Russian Federation 603126
19 State Autonomous Healthcare Institution of Novosibirsk region "City Polyclinic #1" Novosibirsk Novosibirsk Oblast Russian Federation 630099
20 LLC "Clinical Diagnostic Center "Ultramed" Omsk Omskaya Oblast Russian Federation 644024
21 Budgetary Healthcare Institution of Omsk Region "Regional Clinical Hospital" Omsk Omskaya Oblast Russian Federation 644111
22 SBHI of the Republic of Karelia "Republican Hospital named after V.A. Baranov" Petrozavodsk Republic Of Karelia Russian Federation 185019
23 State Budgetary Healthcare Institution "Republican Clinical Hospital n.a. G.G. Kuvatov" Ufa Respublic Of Bashkortostan Russian Federation 450005
24 SBEI HPE "Rostov State Medical University" of Ministry of Health of the Russian Federation Rostov Rostovskaya Oblast Russian Federation 344022
25 SBEI HPE "SSMU n.a. V.I. Razumovsky of MoH of RF", Clinical Hospital n.a. S.R. Mirotvorcev, Therapeutic Departament Saratov Saratovskaya Oblast Russian Federation 410012
26 State Healthcare Institution "Regional Clinical Hospital" Saratov Saratovskaya Oblast Russian Federation 410053
27 Non-governmental Healtheare Institution "Regional Clinical Hospital at Smolensk station of OJSC "Russian Railways" Smolensk Smolenskaya Oblast Russian Federation 214025
28 SBHI of Stavropol Region "Stavropol Regional Clinical Hospital" Stavropol' Stavropol Region Russian Federation 355017
29 State Budgetary Healthcare Institution of Sverdlovsk Region "Sverdlovsk Regional Clinical Hospital #1" Ekaterinburg Sverdlovskaya Oblast Russian Federation 620102
30 SBEI HPE "Ural State Medical University" of MoH of RF based MBI "Central City Clinical Hospital #6" Ekaterinburg Sverdlovskaya Oblast Russian Federation 620149
31 State Autonomous Healthcare Institution "Republican Clinical Hospital of Ministry of Health of Tatarstan Republic Kazan' The Republic Of Tatarstan Russian Federation 420064
32 State Healthcare Institution of Tula region "Tula Regional Clinical Hospital" Tula Tulskaya Oblast Russian Federation 300053
33 State Healthcare Institution "Ulyanovsk Regional Clinical Hospital" Ulyanovsk Ulyanovskaya Oblast Russian Federation 432063
34 SBHI of Vladimir Region "Regional Clinical Hospital", Rheumatology Departament Vladimir Vladimirskaya Oblast Russian Federation
35 State Autonomous Helthcare Institution of Yaroslavl region "Clinical Hospital of Emergency Care n.a. Solovyev" Yaroslavl' Yaroslavsakaya Oblast Russian Federation 150003
36 SBHI "Yaroslavl Regional Clinical Hospital", Rheumatology department Yaroslavl' Yaroslavskaya Oblast Russian Federation 150062
37 FSBSI "Scientific Research Institute of Rheumatology n.a. V.A. Nasonova" Moscow Russian Federation 115522
38 LLC "Tekhnologii Zdoroviya" Saint Petersburg Russian Federation 191144
39 SBHI "North-West Federat Medical Research Center n.a. V.A.Almazov" of the Ministry of Healthcare of the Russian Federation Saint Petersburg Russian Federation 197341

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)

More Information

Additional Information:

Publications

None provided.
Responsible Party:
R-Pharm International, LLC
ClinicalTrials.gov Identifier:
NCT02760368
Other Study ID Numbers:
  • CL04041022
  • 2014-004719-36
First Posted:
May 3, 2016
Last Update Posted:
Oct 30, 2020
Last Verified:
Oct 1, 2020
Keywords provided by R-Pharm International, LLC
moderate Rheumatoid Arthritis
severe Rheumatoid Arthritis
subcutaneous
Olokizumab
Additional relevant MeSH terms:
Arthritis
Arthritis, Rheumatoid

Study Results

Participant Flow

Recruitment Details Enrollment was conducted at 42 clinical sites (in Belarus, Bulgaria, Russia,Turkey) between May 2016 and April 2018. 785 patients were included, 357 patients screen- failured, 428 patients were randomized (143 patients in OKZ q2w +MTX group, 142 patients in OKZ q4w +MTX group, 143 patients in Placebo q2w +MTX group). 427 patients were treated.
Pre-assignment Detail
Arm/Group Title Arm 2: Olokizumab q2w Arm 1: Olokizumab q4w Arm 3: Placebo
Arm/Group Description Olokizumab 64 mg Subcutaneous q2w + Methotrexate (oral) 64 mg Olokizumab administered subcutaneously once every 2 weeks + concomitant background therapy (Methotrexate) at a stable dose of 15 to 25 mg/week (or ≥10 mg/week if there is documented intolerance to higher doses) with a stable route of administration (oral, Subcutaneous, or intramuscular) Olokizumab 64 mg Subcutaneous q4w +placebo+ Methotrexate (oral) 64 mg Olokizumab administered subcutaneously once every 4 weeks + placebo in order to maintain the blind, subjects randomized to receive OKZ q4w will receive placebo injections at the alternate q4w interval (e.g., Week 2, Week 6, etc.)+concomitant background therapy (Methotrexate) at a stable dose of 15 to 25 mg/week (or ≥10 mg/week if there is documented intolerance to higher doses) with a stable route of administration (oral, Subcutaneous, or intramuscular) Placebo Subcutaneous q2w + Methotrexate (oral) Placebo administered subcutaneously once every 2 weeks + concomitant background therapy (Methotrexate) at a stable dose of 15 to 25 mg/week (or ≥10 mg/week if there is documented intolerance to higher doses) with a stable route of administration (oral, Subcutaneous, or intramuscular)
Period Title: Overall Study
STARTED 143 142 143
COMPLETED 130 134 132
NOT COMPLETED 13 8 11

Baseline Characteristics

Arm/Group Title Arm 1: Olokizumab q4w + Methotrexate Arm 2: Olokizumab q2w + Methotrexate Arm 3: Placebo q2w + Methotrexate Total
Arm/Group Description Olokizumab 64 mg Subcutaneous q4w +placebo q4w+ Methotrexate (oral) Olokizumab q4w: 160 mg/mL sterile solution for SC injection in a 2 mL clear Type I glass vial + placebo (sodium chloride 0.9% solution supplied in polypropylene plastic ampoules of 10 mL cartons to contain 10 ampoules) Olokizumab 64 mg Subcutaneous q2w + Methotrexate (oral) Olokizumab q2w: 160 mg/mL sterile solution for SC injection in a 2 mL clear Type I glass vial Placebo Subcutaneous q2w + Methotrexate (oral) Placebo q2w: sodium chloride 0.9% solution supplied in polypropylene plastic ampoules of 10 mL cartons to contain 10 ampoules Total of all reporting groups
Overall Participants 142 143 143 428
Age (Count of Participants)
<=18 years
0
0%
0
0%
0
0%
0
0%
Between 18 and 65 years
129
90.8%
125
87.4%
124
86.7%
378
88.3%
>=65 years
13
9.2%
18
12.6%
19
13.3%
50
11.7%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]
49.1
(12.07)
52.0
(11.77)
52.7
(11.29)
51.3
(11.79)
Sex: Female, Male (Count of Participants)
Female
118
83.1%
116
81.1%
120
83.9%
354
82.7%
Male
24
16.9%
27
18.9%
23
16.1%
74
17.3%
Race/Ethnicity, Customized (Count of Participants)
Asian
0
0%
0
0%
1
0.7%
1
0.2%
Black or African American
0
0%
0
0%
0
0%
0
0%
White
142
100%
143
100%
142
99.3%
427
99.8%
Other/Mixed
0
0%
0
0%
0
0%
0
0%
Region of Enrollment (participants) [Number]
Bulgaria
6
4.2%
12
8.4%
9
6.3%
27
6.3%
Russia
129
90.8%
124
86.7%
128
89.5%
381
89%
Belarus
7
4.9%
7
4.9%
6
4.2%
20
4.7%
Body Mass Index (BMI) (kg/m^2) [Mean (Full Range) ]
Mean (Full Range) [kg/m^2]
26.401
26.621
26.929
26.650
Baseline Disease Severity (Count of Participants)
Inactive (DAS28 (CRP) ≤ 3.2)
0
0%
0
0%
0
0%
0
0%
Moderately Active (DAS28 (CRP) > 3.2 to ≤ 5.1)
22
15.5%
19
13.3%
21
14.7%
62
14.5%
Very Active (DAS28 (CRP) > 5.1)
120
84.5%
122
85.3%
120
83.9%
362
84.6%

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 was defined as any subject satisfying ACR20 criteria 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 2: Olokizumab q2w + Methotrexate Arm 1: Olokizumab q4w + Methotrexate Arm 3: Placebo q2w + Methotrexate
Arm/Group Description Olokizumab 64 mg Subcutaneous q2w + Methotrexate (oral) 64 mg Olokizumab administered subcutaneously once every 2 weeks + concomitant background therapy (Methotrexate) at a stable dose of 15 to 25 mg/week (or ≥10 mg/week if there is documented intolerance to higher doses) with a stable route of administration (oral, Subcutaneous, or intramuscular) Olokizumab 64 mg Subcutaneous q4w + Placebo + Methotrexate (oral) Olokizumab 64 mg Subcutaneous once every 4 weeks+placebo in order to maintain the blind, subjects randomized to receive OKZ q4w will receive placebo injections at the alternate q4w interval (e.g., Week 2, Week 6, etc.)+ concomitant background therapy (Methotrexate) at a stable dose of 15 to 25 mg/week (or ≥10 mg/week if there is documented intolerance to higher doses) with a stable route of administration (oral, Subcutaneous, or intramuscular) Placebo Subcutaneous q2w + Methotrexate (oral) Placebo administered subcutaneously once every 2 weeks + concomitant background therapy (Methotrexate) at a stable dose of 15 to 25 mg/week (or ≥10 mg/week if there is documented intolerance to higher doses) with a stable route of administration (oral, Subcutaneous, or intramuscular)
Measure Participants 143 142 143
Count of Participants [Participants]
91
64.1%
100
69.9%
37
25.9%
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Arm 2: Olokizumab q2w + Methotrexate, Arm 3: Placebo q2w + Methotrexate
Comments The OKZ ACR20 response rates for 64 q2w treatment group at Week 12 are expected to be at least 55%, resulting in an expected difference in ACR20 response rates of 30 percentage points between 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 <0.0001
Comments
Method Chi-squared
Comments 2x2 chi-square test
Method of Estimation Estimation Parameter Risk Difference (RD)
Estimated Value 0.378
Confidence Interval (2-Sided) 97.5%
0.248 to 0.489
Parameter Dispersion Type:
Value:
Estimation Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Arm 1: Olokizumab q4w + Methotrexate, Arm 3: Placebo q2w + Methotrexate
Comments The OKZ ACR20 response rates for 64 q4w treatment group at Week 12 are expected to be at least 50%, resulting in an expected difference in ACR20 response rates of 25 percentage points between 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 <0.0001
Comments
Method Chi-squared
Comments 2x2 chi-square test
Method of Estimation Estimation Parameter Risk Difference (RD)
Estimated Value 0.445
Confidence Interval (2-Sided) 97.5%
0.318 to 0.552
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 DAS28 (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 2: Olokizumab q2w + Methotrexate Arm 1: Olokizumab q4w + Methotrexate Arm 3: Placebo q2w + Methotrexate
Arm/Group Description Olokizumab 64 mg Subcutaneous q2w + Methotrexate (oral) 64 mg Olokizumab administered subcutaneously once every 2 weeks + concomitant background therapy (Methotrexate) at a stable dose of 15 to 25 mg/week (or ≥10 mg/week if there is documented intolerance to higher doses) with a stable route of administration (oral, Subcutaneous, or intramuscular) Olokizumab 64 mg Subcutaneous q4w + Placebo + Methotrexate (oral) Olokizumab 64 mg Subcutaneous once every 4 weeks+placebo in order to maintain the blind, subjects randomized to receive OKZ q4w will receive placebo injections at the alternate q4w interval (e.g., Week 2, Week 6, etc.)+ concomitant background therapy (Methotrexate) at a stable dose of 15 to 25 mg/week (or ≥10 mg/week if there is documented intolerance to higher doses) with a stable route of administration (oral, Subcutaneous, or intramuscular) Placebo Subcutaneous q2w + Methotrexate (oral) Placebo administered subcutaneously once every 2 weeks + concomitant background therapy (Methotrexate) at a stable dose of 15 to 25 mg/week (or ≥10 mg/week if there is documented intolerance to higher doses) with a stable route of administration (oral, Subcutaneous, or intramuscular)
Measure Participants 143 142 143
Count of Participants [Participants]
48
33.8%
55
38.5%
5
3.5%
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Arm 2: Olokizumab q2w + Methotrexate, Arm 3: Placebo q2w + Methotrexate
Comments DAS28 low disease activity (based on DAS28 [CRP] <3.2) response rate at Week 12 was estimated to be 10% in the placebo group and 30% in 64 q2w OKZ treatment groups respectively, resulting in an expected difference of 20 percentage points between OKZ q2w treatment group and placebo.
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesis p-Value <0.0001
Comments
Method Chi-squared
Comments 2x2 chi-square test
Method of Estimation Estimation Parameter Risk Difference (RD)
Estimated Value 0.301
Confidence Interval (2-Sided) 97.5%
0.203 to 0.396
Parameter Dispersion Type:
Value:
Estimation Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Arm 1: Olokizumab q4w + Methotrexate, Arm 3: Placebo q2w + Methotrexate
Comments DAS28 low disease activity (based on DAS28 [CRP] <3.2) response rate at Week 12 was estimated to be 10% in the placebo group and 22% in 64 mg q4w OKZ treatment group respectively, resulting in an expected difference of 12 percentage points between OKZ q4w treatment group and placebo.
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesis p-Value <0.0001
Comments
Method Chi-squared
Comments 2x2 chi-square test
Method of Estimation Estimation Parameter Risk Difference (RD)
Estimated Value 0.352
Confidence Interval (2-Sided) 97.5%
0.251 to 0.449
Parameter Dispersion Type:
Value:
Estimation Comments
3. Secondary Outcome
Title Difference Between OKZ and Placebo in the Improvement of Physical Ability
Description As measured by the Health Assessment Questionnaire Disability Index (HAQ DI) HAQ-DI provides an assessment of the impact of the disease and its treatment on physical function. 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 (activity) 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 (i.e., question in each category with the highest score for that category).
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 population.
Arm/Group Title Arm 2: Olokizumab q2w + Methotrexate Arm 1: Olokizumab q4w + Methotrexate Arm 3: Placebo q2w + Methotrexate
Arm/Group Description Olokizumab 64 mg Subcutaneous q2w + Methotrexate (oral) 64 mg Olokizumab administered subcutaneously once every 2 weeks + concomitant background therapy (Methotrexate) at a stable dose of 15 to 25 mg/week (or ≥10 mg/week if there is documented intolerance to higher doses) with a stable route of administration (oral, Subcutaneous, or intramuscular) Olokizumab 64 mg Subcutaneous q4w + Placebo + Methotrexate (oral) Olokizumab 64 mg Subcutaneous once every 4 weeks+placebo in order to maintain the blind, subjects randomized to receive OKZ q4w will receive placebo injections at the alternate q4w interval (e.g., Week 2, Week 6, etc.)+ concomitant background therapy (Methotrexate) at a stable dose of 15 to 25 mg/week (or ≥10 mg/week if there is documented intolerance to higher doses) with a stable route of administration (oral, Subcutaneous, or intramuscular) Placebo Subcutaneous q2w + Methotrexate (oral) Placebo administered subcutaneously once every 2 weeks + concomitant background therapy (Methotrexate) at a stable dose of 15 to 25 mg/week (or ≥10 mg/week if there is documented intolerance to higher doses) with a stable route of administration (oral, Subcutaneous, or intramuscular)
Measure Participants 143 142 143
Baseline
1.74
(0.471)
1.64
(0.499)
1.78
(0.493)
Week 12 (visit 9)
1.19
(0.540)
1.07
(0.512)
1.54
(0.536)
Change from baseline (obseved)
-0.55
(0.493)
-0.53
(0.542)
-0.22
(0.507)
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Arm 2: Olokizumab q2w + Methotrexate, Arm 3: Placebo q2w + Methotrexate
Comments
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesis p-Value <0.0001
Comments
Method ANCOVA
Comments
Method of Estimation Estimation Parameter Least Squares Mean Difference
Estimated Value -0.34
Confidence Interval (2-Sided) 97.5%
-0.47 to -0.21
Parameter Dispersion Type: Standard Error of the Mean
Value: 0.059
Estimation Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Arm 1: Olokizumab q4w + Methotrexate, Arm 3: Placebo q2w + Methotrexate
Comments
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesis p-Value <0.0001
Comments
Method ANCOVA
Comments
Method of Estimation Estimation Parameter Least Squares Mean Difference
Estimated Value -0.36
Confidence Interval (2-Sided) 97.5%
-0.49 to -0.23
Parameter Dispersion Type: Standard Error of the Mean
Value: 0.059
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 24.
Time Frame at Week 24

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 2: Olokizumab q2w + Methotrexate Arm 1: Olokizumab q4w + Methotrexate Arm 3: Placebo q2w + Methotrexate
Arm/Group Description Olokizumab 64 mg Subcutaneous q2w + Methotrexate (oral) 64 mg Olokizumab administered subcutaneously once every 2 weeks + concomitant background therapy (Methotrexate) at a stable dose of 15 to 25 mg/week (or ≥10 mg/week if there is documented intolerance to higher doses) with a stable route of administration (oral, Subcutaneous, or intramuscular) Olokizumab 64 mg Subcutaneous q4w + Placebo + Methotrexate (oral) Olokizumab 64 mg Subcutaneous once every 4 weeks+placebo in order to maintain the blind, subjects randomized to receive OKZ q4w will receive placebo injections at the alternate q4w interval (e.g., Week 2, Week 6, etc.)+ concomitant background therapy (Methotrexate) at a stable dose of 15 to 25 mg/week (or ≥10 mg/week if there is documented intolerance to higher doses) with a stable route of administration (oral, Subcutaneous, or intramuscular) Placebo Subcutaneous q2w + Methotrexate (oral) Placebo administered subcutaneously once every 2 weeks + concomitant background therapy (Methotrexate) at a stable dose of 15 to 25 mg/week (or ≥10 mg/week if there is documented intolerance to higher doses) with a stable route of administration (oral, Subcutaneous, or intramuscular)
Measure Participants 143 142 143
Count of Participants [Participants]
61
43%
69
48.3%
11
7.7%
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Arm 2: Olokizumab q2w + Methotrexate, Arm 3: Placebo q2w + Methotrexate
Comments
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesis p-Value <0.0001
Comments
Method Chi-squared
Comments 2x2 chi-square test
Method of Estimation Estimation Parameter Risk Difference (RD)
Estimated Value 0.350
Confidence Interval (2-Sided) 97.5%
0.239 to 0.450
Parameter Dispersion Type:
Value:
Estimation Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Arm 1: Olokizumab q4w + Methotrexate, Arm 3: Placebo q2w + Methotrexate
Comments
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesis p-Value <0.0001
Comments
Method Chi-squared
Comments 2x2 chi-square test
Method of Estimation Estimation Parameter Risk Difference (RD)
Estimated Value 0.409
Confidence Interval (2-Sided) 97.5%
0.296 to 0.509
Parameter Dispersion Type:
Value:
Estimation Comments
5. Secondary Outcome
Title Percentage of Subjects With 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 24
Time Frame at Week 24

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 2: Olokizumab q2w + Methotrexate Arm 1: Olokizumab q4w + Methotrexate Arm 3: Placebo q2w + Methotrexate
Arm/Group Description Olokizumab 64 mg Subcutaneous q2w + Methotrexate (oral) 64 mg Olokizumab administered subcutaneously once every 2 weeks + concomitant background therapy (Methotrexate) at a stable dose of 15 to 25 mg/week (or ≥10 mg/week if there is documented intolerance to higher doses) with a stable route of administration (oral, Subcutaneous, or intramuscular) Olokizumab 64 mg Subcutaneous q4w + Placebo + Methotrexate (oral) Olokizumab 64 mg Subcutaneous once every 4 weeks+placebo in order to maintain the blind, subjects randomized to receive OKZ q4w will receive placebo injections at the alternate q4w interval (e.g., Week 2, Week 6, etc.)+ concomitant background therapy (Methotrexate) at a stable dose of 15 to 25 mg/week (or ≥10 mg/week if there is documented intolerance to higher doses) with a stable route of administration (oral, Subcutaneous, or intramuscular) Placebo Subcutaneous q2w + Methotrexate (oral) Placebo administered subcutaneously once every 2 weeks + concomitant background therapy (Methotrexate) at a stable dose of 15 to 25 mg/week (or ≥10 mg/week if there is documented intolerance to higher doses) with a stable route of administration (oral, Subcutaneous, or intramuscular)
Measure Participants 143 142 143
Count of Participants [Participants]
12
8.5%
11
7.7%
0
0%
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Arm 2: Olokizumab q2w + Methotrexate, Arm 3: Placebo q2w + Methotrexate
Comments
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesis p-Value <0.025
Comments 2x2 chi-square test.
Method Chi-squared
Comments
Method of Estimation Estimation Parameter Risk Difference (RD)
Estimated Value 0.084
Confidence Interval (2-Sided) 97.5%
0.032 to 0.151
Parameter Dispersion Type:
Value:
Estimation Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Arm 1: Olokizumab q4w + Methotrexate, Arm 3: Placebo q2w + Methotrexate
Comments
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesis p-Value <0.025
Comments 2x2 chi-square test
Method Chi-squared
Comments
Method of Estimation Estimation Parameter Risk Difference (RD)
Estimated Value 0.077
Confidence Interval (2-Sided) 97.5%
0.027 to 0.143
Parameter Dispersion Type:
Value:
Estimation Comments

Adverse Events

Time Frame All Adverse Events (AE) 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. 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 2: Olokizumab q2w + Methotrexate Arm 1: Olokizumab q4w + Methotrexate Arm 3: Placebo q2w + Methotrexate
Arm/Group Description Olokizumab 64 mg Subcutaneous q2w + Methotrexate (oral) 64 mg Olokizumab administered subcutaneously once every 2 weeks + concomitant background therapy (Methotrexate) at a stable dose of 15 to 25 mg/week (or ≥10 mg/week if there is documented intolerance to higher doses) with a stable route of administration (oral, Subcutaneous, or intramuscular) Olokizumab 64 mg Subcutaneous q4w + Placebo + Methotrexate (oral) Olokizumab 64 mg Subcutaneous once every 4 weeks + placebo in order to maintain the blind, subjects randomized to receive OKZ q4w will receive placebo injections at the alternate q4w interval (e.g., Week 2, Week 6, etc.) + concomitant background therapy (Methotrexate) at a stable dose of 15 to 25 mg/week (or ≥10 mg/week if there is documented intolerance to higher doses) with a stable route of administration (oral, Subcutaneous, or intramuscular) Placebo Subcutaneous q2w + Methotrexate (oral) Placebo administered subcutaneously once every 2 weeks + concomitant background therapy (Methotrexate) at a stable dose of 15 to 25 mg/week (or ≥10 mg/week if there is documented intolerance to higher doses) with a stable route of administration (oral, Subcutaneous, or intramuscular)
All Cause Mortality
Arm 2: Olokizumab q2w + Methotrexate Arm 1: Olokizumab q4w + Methotrexate Arm 3: Placebo q2w + Methotrexate
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 1/143 (0.7%) 0/142 (0%) 0/142 (0%)
Serious Adverse Events
Arm 2: Olokizumab q2w + Methotrexate Arm 1: Olokizumab q4w + Methotrexate Arm 3: Placebo q2w + Methotrexate
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 8/143 (5.6%) 8/142 (5.6%) 4/142 (2.8%)
Gastrointestinal disorders
Obstructive pancreatitis 0/143 (0%) 0 1/142 (0.7%) 1 0/142 (0%) 0
Hepatobiliary disorders
Drug-induced liver injury 0/143 (0%) 0 1/142 (0.7%) 1 0/142 (0%) 0
Infections and infestations
Subcutaneous abscess 2/143 (1.4%) 2 0/142 (0%) 0 0/142 (0%) 0
Gastroenteritis 0/143 (0%) 0 0/142 (0%) 0 1/142 (0.7%) 1
Pneumonia 0/143 (0%) 0 0/142 (0%) 0 1/142 (0.7%) 1
Pulmonary tuberculosis 1/143 (0.7%) 1 0/142 (0%) 0 0/142 (0%) 0
Staphylococcal sepsis 1/143 (0.7%) 1 0/142 (0%) 0 0/142 (0%) 0
Toxic shock syndrome 1/143 (0.7%) 1 0/142 (0%) 0 0/142 (0%) 0
Investigations
Alanine aminotransferase increased 2/143 (1.4%) 2 4/142 (2.8%) 4 1/142 (0.7%) 1
Aspartate aminotransferase increased 0/143 (0%) 0 3/142 (2.1%) 3 0/142 (0%) 0
Musculoskeletal and connective tissue disorders
Rheumatoid arthritis 2/143 (1.4%) 2 0/142 (0%) 0 1/142 (0.7%) 1
Fistula 0/143 (0%) 0 1/142 (0.7%) 1 0/142 (0%) 0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cervix carcinoma stage II 0/143 (0%) 0 1/142 (0.7%) 1 0/142 (0%) 0
Nervous system disorders
Vertebrobasilar insufficiency 0/143 (0%) 0 1/142 (0.7%) 1 0/142 (0%) 0
Renal and urinary disorders
Renal cyst 1/143 (0.7%) 1 0/142 (0%) 0 0/142 (0%) 0
Vascular disorders
Diabetic vascular disorder 1/143 (0.7%) 1 0/142 (0%) 0 0/142 (0%) 0
Other (Not Including Serious) Adverse Events
Arm 2: Olokizumab q2w + Methotrexate Arm 1: Olokizumab q4w + Methotrexate Arm 3: Placebo q2w + Methotrexate
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 83/143 (58%) 81/142 (57%) 62/142 (43.7%)
Blood and lymphatic system disorders
Leukopenia 8/143 (5.6%) 8 7/142 (4.9%) 7 4/142 (2.8%) 4
Neutropenia 5/143 (3.5%) 5 9/142 (6.3%) 9 2/142 (1.4%) 2
Anaemia 4/143 (2.8%) 4 3/142 (2.1%) 3 6/142 (4.2%) 6
Lymphopenia 2/143 (1.4%) 2 1/142 (0.7%) 1 3/142 (2.1%) 3
Iron deficiency anaemia 0/143 (0%) 0 1/142 (0.7%) 1 1/142 (0.7%) 1
Monocytopenia 2/143 (1.4%) 2 0/142 (0%) 0 0/142 (0%) 0
Eosinophilia 0/143 (0%) 0 0/142 (0%) 0 1/142 (0.7%) 1
Leukocytosis 1/143 (0.7%) 1 0/142 (0%) 0 0/142 (0%) 0
Lymphadenopathy 0/143 (0%) 0 1/142 (0.7%) 1 0/142 (0%) 0
Lymphocytosis 0/143 (0%) 0 1/142 (0.7%) 1 0/142 (0%) 0
Cardiac disorders
Extrasystoles 0/143 (0%) 0 1/142 (0.7%) 1 1/142 (0.7%) 1
Aortic valve calcification 0/143 (0%) 0 0/142 (0%) 0 1/142 (0.7%) 1
Atrial flutter 1/143 (0.7%) 1 0/142 (0%) 0 0/142 (0%) 0
Atrial tachycardia 0/143 (0%) 0 1/142 (0.7%) 1 0/142 (0%) 0
Cardiomyopathy 0/143 (0%) 0 0/142 (0%) 0 1/142 (0.7%) 1
Supraventricular tachycardia 0/143 (0%) 0 0/142 (0%) 0 1/142 (0.7%) 1
Ventricular extrasystoles 1/143 (0.7%) 1 0/142 (0%) 0 0/142 (0%) 0
Ear and labyrinth disorders
Vertigo 0/143 (0%) 0 1/142 (0.7%) 1 0/142 (0%) 0
Endocrine disorders
Autoimmune thyroiditis 0/143 (0%) 0 1/142 (0.7%) 1 0/142 (0%) 0
Goitre 0/143 (0%) 0 1/142 (0.7%) 1 0/142 (0%) 0
Premature menarche 1/143 (0.7%) 1 0/142 (0%) 0 0/142 (0%) 0
Eye disorders
Cataract 0/143 (0%) 0 1/142 (0.7%) 1 0/142 (0%) 0
Chalazion 1/143 (0.7%) 1 0/142 (0%) 0 0/142 (0%) 0
Retinal degeneration 0/143 (0%) 0 1/142 (0.7%) 1 0/142 (0%) 0
Visual impairment 1/143 (0.7%) 1 0/142 (0%) 0 0/142 (0%) 0
Gastrointestinal disorders
Chronic gastritis 1/143 (0.7%) 1 0/142 (0%) 0 1/142 (0.7%) 1
Diarrhoea 0/143 (0%) 0 1/142 (0.7%) 1 1/142 (0.7%) 1
Nausea 1/143 (0.7%) 1 1/142 (0.7%) 1 0/142 (0%) 0
Abdominal pain upper 0/143 (0%) 0 1/142 (0.7%) 1 0/142 (0%) 0
Dental cyst 1/143 (0.7%) 1 0/142 (0%) 0 0/142 (0%) 0
Duodenitis 0/143 (0%) 0 0/142 (0%) 0 1/142 (0.7%) 1
Dyspepsia 0/143 (0%) 0 0/142 (0%) 0 1/142 (0.7%) 1
Haemorrhoids 0/143 (0%) 0 1/142 (0.7%) 1 0/142 (0%) 0
Obstructive pancreatitis 0/143 (0%) 0 1/142 (0.7%) 1 0/142 (0%) 0
Oesophagitis 0/143 (0%) 0 0/142 (0%) 0 1/142 (0.7%) 1
Pancreatitis 1/143 (0.7%) 1 0/142 (0%) 0 0/142 (0%) 0
Vomiting 0/143 (0%) 0 0/142 (0%) 0 1/142 (0.7%) 1
General disorders
Injection site pain 1/143 (0.7%) 1 1/142 (0.7%) 1 0/142 (0%) 0
Fatigue 0/143 (0%) 0 1/142 (0.7%) 1 0/142 (0%) 0
Hyperthermia 1/143 (0.7%) 1 0/142 (0%) 0 0/142 (0%) 0
Oedema peripheral 0/143 (0%) 0 1/142 (0.7%) 1 0/142 (0%) 0
Hepatobiliary disorders
Cholecystitis chronic 0/143 (0%) 0 0/142 (0%) 0 1/142 (0.7%) 1
Drug-induced liver injury 0/143 (0%) 0 1/142 (0.7%) 1 0/142 (0%) 0
Gallbladder disorder 0/143 (0%) 0 1/142 (0.7%) 1 0/142 (0%) 0
Hepatic cyst 0/143 (0%) 0 1/142 (0.7%) 1 0/142 (0%) 0
Hyperbilirubinaemia 1/143 (0.7%) 1 0/142 (0%) 0 0/142 (0%) 0
Adrenal atrophy 1/143 (0.7%) 1 0/142 (0%) 0 0/142 (0%) 0
Immune system disorders
Allergy to plants 0/143 (0%) 0 1/142 (0.7%) 1 0/142 (0%) 0
Seasonal allergy 1/143 (0.7%) 1 0/142 (0%) 0 0/142 (0%) 0
Infections and infestations
Nasopharyngitis 4/143 (2.8%) 4 3/142 (2.1%) 3 6/142 (4.2%) 6
Upper respiratory tract infection 2/143 (1.4%) 2 6/142 (4.2%) 6 4/142 (2.8%) 4
Oral herpes 3/143 (2.1%) 3 1/142 (0.7%) 1 5/142 (3.5%) 5
Respiratory tract infection viral 0/143 (0%) 0 3/142 (2.1%) 3 5/142 (3.5%) 5
Bronchitis 4/143 (2.8%) 4 0/142 (0%) 0 1/142 (0.7%) 1
Latent tuberculosis 3/143 (2.1%) 3 0/142 (0%) 0 2/142 (1.4%) 2
Rhinitis 2/143 (1.4%) 2 1/142 (0.7%) 1 1/142 (0.7%) 1
Pharyngitis 1/143 (0.7%) 1 2/142 (1.4%) 2 0/142 (0%) 0
Paronychia 0/143 (0%) 0 2/142 (1.4%) 2 0/142 (0%) 0
Subcutaneous abscess 2/143 (1.4%) 2 0/142 (0%) 0 0/142 (0%) 0
Tonsillitis 0/143 (0%) 0 2/142 (1.4%) 2 0/142 (0%) 0
Viral upper respiratory tract infection 0/143 (0%) 0 1/142 (0.7%) 1 1/142 (0.7%) 1
Acute sinusitis 0/143 (0%) 0 0/142 (0%) 0 1/142 (0.7%) 1
Conjunctivitis 1/143 (0.7%) 1 0/142 (0%) 0 0/142 (0%) 0
Cystitis 0/143 (0%) 0 1/142 (0.7%) 1 0/142 (0%) 0
Epstein-Barr virus infection 1/143 (0.7%) 1 0/142 (0%) 0 0/142 (0%) 0
Erysipelas 1/143 (0.7%) 1 0/142 (0%) 0 0/142 (0%) 0
Gastroenteritis 0/143 (0%) 0 0/142 (0%) 0 1/142 (0.7%) 1
Herpes zoster 0/143 (0%) 0 0/142 (0%) 0 1/142 (0.7%) 1
Laryngitis 1/143 (0.7%) 1 0/142 (0%) 0 0/142 (0%) 0
Pneumonia 0/143 (0%) 0 0/142 (0%) 0 1/142 (0.7%) 1
Pulmonary tuberculosis 1/143 (0.7%) 1 0/142 (0%) 0 0/142 (0%) 0
Skin candida 1/143 (0.7%) 1 0/142 (0%) 0 0/142 (0%) 0
Staphylococcal sepsis 1/143 (0.7%) 1 0/142 (0%) 0 0/142 (0%) 0
Tinea versicolour 0/143 (0%) 0 1/142 (0.7%) 1 0/142 (0%) 0
Toxic shock syndrome 1/143 (0.7%) 1 0/142 (0%) 0 0/142 (0%) 0
Tracheitis 0/143 (0%) 0 0/142 (0%) 0 1/142 (0.7%) 1
Urinary tract infection 0/143 (0%) 0 0/142 (0%) 0 1/142 (0.7%) 1
Vulvovaginal candidiasis 1/143 (0.7%) 1 0/142 (0%) 0 0/142 (0%) 0
Injury, poisoning and procedural complications
Arthropod bite 0/143 (0%) 0 2/142 (1.4%) 2 0/142 (0%) 0
Contusion 0/143 (0%) 0 0/142 (0%) 0 1/142 (0.7%) 1
Foreign body in eye 1/143 (0.7%) 1 0/142 (0%) 0 0/142 (0%) 0
Radius fracture 0/143 (0%) 0 0/142 (0%) 0 1/142 (0.7%) 1
Rib fracture 1/143 (0.7%) 1 0/142 (0%) 0 0/142 (0%) 0
Scratch 0/143 (0%) 0 1/142 (0.7%) 1 0/142 (0%) 0
Skin laceration 0/143 (0%) 0 0/142 (0%) 0 1/142 (0.7%) 1
Thermal burn 0/143 (0%) 0 0/142 (0%) 0 1/142 (0.7%) 1
Wound 0/143 (0%) 0 1/142 (0.7%) 1 0/142 (0%) 0
Investigations
Alanine aminotransferase increased 25/143 (17.5%) 25 33/142 (23.2%) 33 11/142 (7.7%) 11
Aspartate aminotransferase increased 16/143 (11.2%) 16 22/142 (15.5%) 22 10/142 (7%) 10
White blood cell count decreased 7/143 (4.9%) 7 6/142 (4.2%) 6 4/142 (2.8%) 4
Neutrophil count decreased 6/143 (4.2%) 6 7/142 (4.9%) 7 3/142 (2.1%) 3
Blood cholesterol increased 6/143 (4.2%) 6 4/142 (2.8%) 4 3/142 (2.1%) 3
Gamma-glutamyltransferase increased 3/143 (2.1%) 3 6/142 (4.2%) 6 4/142 (2.8%) 4
Blood bilirubin increased 5/143 (3.5%) 5 3/142 (2.1%) 3 1/142 (0.7%) 1
Activated partial thromboplastin time prolonged 1/143 (0.7%) 1 5/142 (3.5%) 5 2/142 (1.4%) 2
Low density lipoprotein increased 4/143 (2.8%) 4 1/142 (0.7%) 1 3/142 (2.1%) 3
Blood triglycerides increased 2/143 (1.4%) 2 2/142 (1.4%) 2 1/142 (0.7%) 1
Lymphocyte count decreased 2/143 (1.4%) 2 1/142 (0.7%) 1 2/142 (1.4%) 2
Eosinophil count increased 1/143 (0.7%) 1 3/142 (2.1%) 3 0/142 (0%) 0
Haemoglobin decreased 0/143 (0%) 0 1/142 (0.7%) 1 3/142 (2.1%) 3
Mycobacterium tuberculosis complex test positive 2/143 (1.4%) 2 2/142 (1.4%) 2 0/142 (0%) 0
Blood alkaline phosphatase increased 1/143 (0.7%) 1 1/142 (0.7%) 1 1/142 (0.7%) 1
Blood potassium increased 0/143 (0%) 0 3/142 (2.1%) 3 0/142 (0%) 0
Haematocrit decreased 2/143 (1.4%) 2 1/142 (0.7%) 1 0/142 (0%) 0
N-terminal prohormone brain natriuretic peptide increased 1/143 (0.7%) 1 0/142 (0%) 0 2/142 (1.4%) 2
Blood creatinine increased 2/143 (1.4%) 2 0/142 (0%) 0 0/142 (0%) 0
Blood glucose decreased 0/143 (0%) 0 2/142 (1.4%) 2 0/142 (0%) 0
Blood urea increased 2/143 (1.4%) 2 0/142 (0%) 0 0/142 (0%) 0
Brain natriuretic peptide increased 1/143 (0.7%) 1 0/142 (0%) 0 1/142 (0.7%) 1
Platelet count increased 0/143 (0%) 0 2/142 (1.4%) 2 0/142 (0%) 0
Adiponectin increased 1/143 (0.7%) 1 0/142 (0%) 0 0/142 (0%) 0
Blood glucose increased 0/143 (0%) 0 1/142 (0.7%) 1 0/142 (0%) 0
Blood homocysteine increased 0/143 (0%) 0 0/142 (0%) 0 1/142 (0.7%) 1
Blood pressure increased 1/143 (0.7%) 1 0/142 (0%) 0 0/142 (0%) 0
Haematocrit increased 0/143 (0%) 0 1/142 (0.7%) 1 0/142 (0%) 0
Haemoglobin increased 0/143 (0%) 0 1/142 (0.7%) 1 0/142 (0%) 0
Interferon gamma release assay positive 0/143 (0%) 0 1/142 (0.7%) 1 0/142 (0%) 0
Lymphocyte count increased 0/143 (0%) 0 1/142 (0.7%) 1 0/142 (0%) 0
Monocyte count increased 0/143 (0%) 0 0/142 (0%) 0 1/142 (0.7%) 1
Neutrophil count increased 0/143 (0%) 0 1/142 (0.7%) 1 0/142 (0%) 0
Platelet count decreased 0/143 (0%) 0 1/142 (0.7%) 1 0/142 (0%) 0
Protein total increased 1/143 (0.7%) 1 0/142 (0%) 0 0/142 (0%) 0
Red blood cell count decreased 1/143 (0.7%) 1 0/142 (0%) 0 0/142 (0%) 0
Red blood cell count increased 0/143 (0%) 0 1/142 (0.7%) 1 0/142 (0%) 0
White blood cell count increased 0/143 (0%) 0 1/142 (0.7%) 1 0/142 (0%) 0
Metabolism and nutrition disorders
Hypercholesterolaemia 4/143 (2.8%) 4 2/142 (1.4%) 2 0/142 (0%) 0
Dyslipidaemia 1/143 (0.7%) 1 3/142 (2.1%) 3 1/142 (0.7%) 1
Hyperglycaemia 2/143 (1.4%) 2 0/142 (0%) 0 1/142 (0.7%) 1
Hyperkalaemia 1/143 (0.7%) 1 1/142 (0.7%) 1 0/142 (0%) 0
Hypertriglyceridaemia 1/143 (0.7%) 1 1/142 (0.7%) 1 0/142 (0%) 0
Diabetes mellitus 1/143 (0.7%) 1 0/142 (0%) 0 0/142 (0%) 0
Hypoglycaemia 0/143 (0%) 0 0/142 (0%) 0 1/142 (0.7%) 1
Obesity 0/143 (0%) 0 1/142 (0.7%) 1 0/142 (0%) 0
Musculoskeletal and connective tissue disorders
Rheumatoid arthritis 3/143 (2.1%) 3 4/142 (2.8%) 4 3/142 (2.1%) 3
Arthralgia 1/143 (0.7%) 1 0/142 (0%) 0 1/142 (0.7%) 1
Fistula 0/143 (0%) 0 1/142 (0.7%) 1 0/142 (0%) 0
Joint swelling 0/143 (0%) 0 0/142 (0%) 0 1/142 (0.7%) 1
Muscle spasms 0/143 (0%) 0 1/142 (0.7%) 1 0/142 (0%) 0
Osteochondrosis 1/143 (0.7%) 1 0/142 (0%) 0 0/142 (0%) 0
Periarthritis 0/143 (0%) 0 0/142 (0%) 0 1/142 (0.7%) 1
Periostitis 1/143 (0.7%) 1 0/142 (0%) 0 0/142 (0%) 0
Rotator cuff syndrome 0/143 (0%) 0 1/142 (0.7%) 1 0/142 (0%) 0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cervix carcinoma stage II 0/143 (0%) 0 1/142 (0.7%) 1 0/142 (0%) 0
Nervous system disorders
Headache 2/143 (1.4%) 2 3/142 (2.1%) 3 2/142 (1.4%) 2
Dizziness 0/143 (0%) 0 0/142 (0%) 0 1/142 (0.7%) 1
Hypoaesthesia 0/143 (0%) 0 0/142 (0%) 0 1/142 (0.7%) 1
Polyneuropathy 1/143 (0.7%) 1 0/142 (0%) 0 0/142 (0%) 0
Vertebrobasilar insufficiency 0/143 (0%) 0 1/142 (0.7%) 1 0/142 (0%) 0
Psychiatric disorders
Apathy 0/143 (0%) 0 1/142 (0.7%) 1 0/142 (0%) 0
Insomnia 0/143 (0%) 0 1/142 (0.7%) 1 0/142 (0%) 0
Renal and urinary disorders
Dysuria 0/143 (0%) 0 1/142 (0.7%) 1 1/142 (0.7%) 1
Nephropathy 2/143 (1.4%) 2 0/142 (0%) 0 0/142 (0%) 0
Renal cyst 1/143 (0.7%) 1 0/142 (0%) 0 0/142 (0%) 0
Chronic kidney disease 0/143 (0%) 0 1/142 (0.7%) 1 0/142 (0%) 0
Renal colic 0/143 (0%) 0 1/142 (0.7%) 1 0/142 (0%) 0
Ureterolithiasis 0/143 (0%) 0 1/142 (0.7%) 1 0/142 (0%) 0
Reproductive system and breast disorders
Dysmenorrhoea 1/143 (0.7%) 1 0/142 (0%) 0 0/142 (0%) 0
Respiratory, thoracic and mediastinal disorders
Pulmonary fibrosis 2/143 (1.4%) 2 0/142 (0%) 0 0/142 (0%) 0
Rhinitis allergic 0/143 (0%) 0 1/142 (0.7%) 1 0/142 (0%) 0
Skin and subcutaneous tissue disorders
Pruritus 3/143 (2.1%) 3 0/142 (0%) 0 1/142 (0.7%) 1
Erythema 1/143 (0.7%) 1 1/142 (0.7%) 1 0/142 (0%) 0
Rash 1/143 (0.7%) 1 1/142 (0.7%) 1 0/142 (0%) 0
Alopecia 1/143 (0.7%) 1 0/142 (0%) 0 0/142 (0%) 0
Dermatitis 0/143 (0%) 0 0/142 (0%) 0 1/142 (0.7%) 1
Dermatitis allergic 1/143 (0.7%) 1 0/142 (0%) 0 0/142 (0%) 0
Ecchymosis 1/143 (0.7%) 1 0/142 (0%) 0 0/142 (0%) 0
Rash pruritic 1/143 (0.7%) 1 0/142 (0%) 0 0/142 (0%) 0
Sweat discolouration 0/143 (0%) 0 1/142 (0.7%) 1 0/142 (0%) 0
Vascular disorders
Hypertension 1/143 (0.7%) 1 2/142 (1.4%) 2 2/142 (1.4%) 2
Diabetic vascular disorder 1/143 (0.7%) 1 1/142 (0.7%) 1 0/142 (0%) 0
Haematoma 1/143 (0.7%) 1 0/142 (0%) 0 1/142 (0.7%) 1
Arterial insufficiency 0/143 (0%) 0 1/142 (0.7%) 1 0/142 (0%) 0
Essential hypertension 0/143 (0%) 0 0/142 (0%) 0 1/142 (0.7%) 1
Hypotension 0/143 (0%) 0 0/142 (0%) 0 1/142 (0.7%) 1
Peripheral arterial occlusive disease 1/143 (0.7%) 1 0/142 (0%) 0 0/142 (0%) 0
Varicose vein 0/143 (0%) 0 1/142 (0.7%) 1 0/142 (0%) 0

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.

Results Point of Contact

Name/Title Elena Korneva, Senior Scientific Advisor
Organization R-Pharm
Phone 0074959567937 ext 3819
Email korneva@rpharm.ru
Responsible Party:
R-Pharm International, LLC
ClinicalTrials.gov Identifier:
NCT02760368
Other Study ID Numbers:
  • CL04041022
  • 2014-004719-36
First Posted:
May 3, 2016
Last Update Posted:
Oct 30, 2020
Last Verified:
Oct 1, 2020