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 (CREDO 1)
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| ClinicalTrials.gov Identifier: NCT02760368 |
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Recruitment Status :
Completed
First Posted : May 3, 2016
Results First Posted : October 30, 2020
Last Update Posted : October 30, 2020
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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 |
|---|---|---|
| Rheumatoid Arthritis | Drug: Olokizumab Drug: Placebo | Phase 3 |
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:
- OKZ 64 mg q4w: SC injection of OKZ 64 mg q4w (alternating with SC injection of placebo OKZ q4w to maintain blinding) + MTX.
- OKZ 64 mg q2w: SC injection of OKZ 64 mg q2w + MTX.
- 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 Type : | Interventional (Clinical Trial) |
| 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 2016 |
| Actual Primary Completion Date : | August 2018 |
| Actual Study Completion Date : | October 2018 |
| Arm | Intervention/treatment |
|---|---|
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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.)
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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 |
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Experimental: Arm 2: Olokizumab q2w
Olokizumab 64 mg Subcutaneous q2w + Methotrexate (oral)
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Drug: Olokizumab
160 mg/mL sterile solution for SC injection in a 2 mL clear Type I glass vial |
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Placebo Comparator: Arm 3: Placebo
Placebo Subcutaneous q2w + Methotrexate (oral)
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Drug: Placebo
sodium chloride 0.9% solution supplied in polypropylene plastic ampoules of 10 mL cartons to contain 10 ampoules |
- ACR20 Response [ Time Frame: 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)
- Difference Between OKZ and Placebo in the Percentage of Subjects Achieving Low Disease Activity [ Time Frame: at Week 12 ]Defined as DAS28 (CRP) <3.2, and remaining on randomized treatment and in the study at Week 12.
- Difference Between OKZ and Placebo in the Improvement of Physical Ability [ Time Frame: 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).
- ACR50 Response [ Time Frame: 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.
- Percentage of Subjects With Clinical Disease Activity Index (CDAI) ≤2.8 (Remission) [ Time Frame: 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
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| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| 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.
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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
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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)
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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
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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):
- 4 weeks for sulfasalazine, azathioprine, cyclosporine, hydroxychloroquine, chloroquine, gold, penicillamine, minocycline, or d oxycycline
- 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
- 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
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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× ULN
- Platelets <100×10^9/L (<100,000/mm^3)
- White blood cell count <3.5×10^9/L
- Neutrophil count <2000×10^6/L (<2000/mm^3)
- Hemoglobin level ≤ 80 g/L
- Glycosylated hemoglobin (HbA1c) level ≥ 8%
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Subjects with concurrent acute or chronic viral hepatitis B or C infection as detected by blood tests at Screening (e.g., positive for hepatitis B surface antigen [HBsAg], total hepatitis B core antibody [anti-HBc], or hepatitis C virus antibody [HCV Ab])
a) Subjects who are 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
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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:
- 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);
- 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
- The subject is willing to complete the entire course of recommended LTBI therapy
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Positive interferon-gamma release assay (IGRA) result at Screening. If indeterminate, the IGRA can be repeated once during the Screening Period. If there is a second indeterminate result, the subject will be excluded.
i. Subjects with a positive IGRA result at Screening may be re-screened and enrolled if they fulfill all 3 of the following criteria:
- 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);
- 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
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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])
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Subjects with any of the following CV conditions:
- 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)
- Untreated or resistant arterial hypertension Grade II-III (systolic blood pressure [BP] > 160 mm Hg and/or diastolic BP >100 mm Hg)
- 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
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02760368
Show 39 study locations
| Study Director: | Mikhail Samsonov | R-Pharm |
Documents provided by R-Pharm ( R-Pharm International, LLC ):
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
| Responsible Party: | R-Pharm International, LLC |
| ClinicalTrials.gov Identifier: | NCT02760368 |
| Other Study ID Numbers: |
CL04041022 2014-004719-36 ( EudraCT Number ) |
| First Posted: | May 3, 2016 Key Record Dates |
| Results First Posted: | October 30, 2020 |
| Last Update Posted: | October 30, 2020 |
| Last Verified: | October 2020 |
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moderate Rheumatoid Arthritis severe Rheumatoid Arthritis subcutaneous Olokizumab |
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Arthritis Arthritis, Rheumatoid Joint Diseases Musculoskeletal Diseases |
Rheumatic Diseases Connective Tissue Diseases Autoimmune Diseases Immune System Diseases |