A Study of Subcutaneous (SC) Tocilizumab (RoActemra/Actemra) in Participants With Active Rheumatoid Arthritis (RA) and Inadequate Response to Disease-Modifying Anti-Rheumatic Drugs (DMARDs)

Study Overview
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Brief Summary
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This Phase IIIb, open-label, single-arm study will evaluate the safety, efficacy, and tolerability of SC tocilizumab (RoActemra/Actemra) in monotherapy or in combination with methotrexate or other non-biologic DMARDs in participants with active RA who are naive to tocilizumab. Participants will receive tocilizumab 162 milligrams (mg) subcutaneously weekly (QW) for 24 weeks.

Official Title
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Tocilizumab SC in Patients With Active Rheumatoid Arthritis and Inadequate Response to DMARDs. A Single-Arm, Open-Label Study to Evaluate Safety, Tolerability and Efficacy. In a Subgroup of Patients Inflammation Will Be Measured by Ultrasound.

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Drug: Tocilizumab
* Drug: Methotrexate
* Drug: Non-Biologic DMARDs


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Active RA according to the revised ACR (1987) criteria or EULAR/ACR (2010) criteria Moderate to severe RA with a DAS28-ESR score >3.2 points Inadequate response and/or intolerance to MTX or other non-biologic DMARDs and/or where MTX or other non-biologic DMARDs are inappropriate Oral corticosteroids (less than or equal to [</=] 10 mg per day prednisolone or equivalent) and nonsteroidal anti-inflammatory drugs (NSAIDs) permitted if on stable dose regimen for greater than or equal to [>/=] 4 weeks prior to baseline Permitted non-biologic DMARDs allowed if at stable dose for >/=4 weeks prior to baseline Receiving treatment on an outpatient basis, not including tocilizumab Agreement to use reliable means of contraception as defined by protocol, among females of childbearing potential and males with female partners of childbearing potential Exclusion Criteria: Major surgery (including joint surgery) within 8 weeks prior to screening or planned major surgery within 6 months following baseline Rheumatic autoimmune disease other than RA Functional Class IV as defined by the ACR Classification of Functional Status in Rheumatoid Arthritis Diagnosis of juvenile idiopathic arthritis or juvenile RA and/or RA before the age of 16 Prior history of or current inflammatory joint disease other than RA Exposure to tocilizumab or any other biologic DMARDs at any time prior to baseline Treatment with any investigational agent within 4 weeks (or 5 half-lives of the investigational drug, whichever is longer) of screening Intra-articular or parenteral corticosteroids within 4 weeks prior to baseline History of severe allergic or anaphylactic reactions to human, humanized, or murine monoclonal antibodies Evidence of serious concomitant disease or disorder Known active current or history of recurrent infection Any major episode of infection requiring hospitalization or treatment with intravenous (IV) antibiotics within 4 weeks of screening or oral antibiotics within 2 weeks of screening Active tuberculosis requiring treatment within the previous 3 years Positive for hepatitis B or hepatitis C History of or current active primary or secondary immunodeficiency Pregnant or lactating women Neuropathies or other conditions that might interfere with pain evaluation Inadequate hematologic, renal, or liver function

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tocilizumab Alone or Combined with Methotrexate or Other DMARD<br>All participants will receive tocilizumab as a single fixed dose (monotherapy) or in combination with methotrexate or other non-biologic DMARDs, irrespective of body weight, for 24 weeks. | Drug: Tocilizumab<br>* Tocilizumab 162 mg will be administered subcutaneously QW.<br>* Other names: RoActemra, Actemra;Drug: Methotrexate<br>* Methotrexate dosing is not specified by the protocol and will be given as per standard practice. Participants must be at a stable dose that was initiated at least 4 weeks prior to baseline.<br>Drug: Non-Biologic DMARDs<br>* Participants will receive non-biologic DMARDs (same non-biologic DMARD that participant was receiving at time of study entry). Dosing is not specified by the protocol and will be given as per standard practice. Participants must be at a stable dose that was initiated at least 4 weeks prior to baseline.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Clinical Disease Activity Index (CDAI) at Week 12 | CDAI was derived as the sum of the following: tender joint count (TJC), swollen joint count (SJC), participant global assessment (PGA) of disease activity, and physician assessment of disease activity. TJC and SJC were taken as the number of tender and swollen joints, respectively, out of 28 assessed joints. PGA and physician assessment of disease activity were scored 0-100 millimeters (mm) and rounded to the nearest centimeter (cm) on a visual analog scale (VAS), where higher scores indicate greater perceived disease activity. The total CDAI score range was 0-76, where higher scores indicate increased disease activity. Change from baseline was averaged among all participants. Negative values indicate improvement/reduction in RA disease activity. | Baseline, Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Disease Activity Score 28 (DAS28)-Erythrocyte Sedimentation Rate (ESR) Score | DAS28-ESR was based on TJC, SJC, PGA of disease activity, and laboratory-derived ESR. TJC and SJC were taken as the number of tender and swollen joints, respectively, out of 28 assessed joints. PGA of disease activity was scored 0-100 mm on a VAS, where higher scores indicate greater perceived disease activity. The total DAS28-ESR score was transformed to a single score range of 0-10, where higher scores indicate increased disease activity. Change from baseline was averaged among all participants. Negative values indicate improvement/reduction in RA disease activity. | Baseline and Weeks 2, 4, 8, 12, 16, 20, 24 | 
| Percentage of Participants With American College of Rheumatology (ACR) Response | ACR response was assessed on the basis of percent improvement (20% for ACR20, 50% for ACR50, 70% for ACR70) in both TJC and SJC as well as at least three of the following: physician assessment of disease activity, PGA of disease activity, PGA of pain, Health Assessment Questionnaire-Disability Index (HAQ-DI), and either ESR or C-reactive protein level. TJC and SJC were taken as the number of tender and swollen joints, out of 68 and 66 assessed joints, respectively. PGA and physician assessments were scored 0-100 mm on a VAS, where higher scores indicate greater perceived disease activity or pain. HAQ-DI was scored using participant responses to 20 questions assessing activities of daily living (ADLs), with total score scale of 0-3, where higher scores indicate increased functional disability. The percentage of participants meeting criteria for each level of ACR response was reported. | Weeks 2, 4, 8, 12, 16, 20, 24 | 
| Percentage of Participants With European League Against Rheumatism (EULAR) Response | EULAR response was assessed by change from baseline and absolute DAS28-ESR score. EULAR response classification was as follows: Good (change >1.2 with absolute score </=3.2), Moderate (change >1.2 with absolute score >3.2 or change >0.6 with absolute score </=5.1), None (change </=0.6 or absolute score >5.1). DAS28-ESR was based on TJC, SJC, and PGA of disease activity, and laboratory-derived ESR. TJC and SJC were taken as the number of tender and swollen joints, respectively, out of 28 assessed joints. PGA of disease activity was scored 0-100 mm on a VAS, where higher scores indicate greater perceived disease activity. The total DAS28-ESR score was transformed to a single score range of 0-10, where higher scores indicate increased disease activity. The percentage of participants meeting criteria for each level of EULAR response was reported. | Weeks 2, 4, 8, 12, 16, 20, 24 | 
| Change From Baseline in CDAI at Weeks 2, 4, 8, 16, 20, and 24 | CDAI was derived as the sum of the following: TJC, SJC, PGA of disease activity, and physician assessment of disease activity. TJC and SJC were taken as the number of tender and swollen joints, respectively, out of 28 assessed joints. PGA and physician assessment of disease activity were scored 0-100 mm and rounded to the nearest cm on a VAS, where higher scores indicate greater perceived disease activity. The total CDAI score range was 0-76, where higher scores indicate increased disease activity. Change from baseline was averaged among all participants. Negative values indicate improvement/reduction in RA disease activity. | Baseline and Weeks 2, 4, 8, 16, 20, 24 | 
| Change From Baseline in Simplified Disease Activity Index (SDAI) | SDAI was derived as the sum of the following: TJC, SJC, PGA of disease activity, physician assessment of disease activity, and laboratory-derived C-reactive protein level. TJC and SJC were taken as the number of tender and swollen joints, respectively, out of 28 assessed joints. PGA and physician assessment of disease activity were scored 0-100 mm and rounded to the nearest cm on a VAS, where higher scores indicate greater perceived disease activity. The total SDAI score range was 0-86, where higher scores indicate increased disease activity. Change from baseline was averaged among all participants. Negative values indicate improvement/reduction in RA disease activity. | Baseline and Weeks 2, 4, 8, 12, 16, 20, 24 | 
| Change From Baseline in TJC | TJC was taken as the number of tender joints out of 28 assessed joints. | Baseline and Weeks 2, 4, 8, 12, 16, 20, 24 | 
| Change From Baseline in SJC | SJC was taken as the number of swollen joints out of 28 assessed joints. | Baseline and Weeks 2, 4, 8, 12, 16, 20, 24 | 
| Percentage of Participants With At Least One Adverse Event Leading to Dosage Modification | The percentage of participants with at least one adverse event leading to dose/frequency reduction or temporary dose hold was reported. | Baseline up to Week 24 | 
| Number of Participants With Neutralizing Anti-Tocilizumab Antibodies | Participants were evaluated for the presence of anti-tocilizumab antibodies. Confirmatory assays were performed in the case of a positive screen assay result. | Baseline to FU Week 8 (up to 32 weeks overall) | 
| Tocilizumab Concentration | Tocilizumab concentration was determined, averaged among all participants, and expressed in micrograms per milliliter (mcg/mL). | Predose (30 minutes) at baseline; Weeks 12, 24; and FU Week 8 (up to 32 weeks overall) | 
| Soluble Interleukin-6 Receptor (sIL-6R) Concentration | sIL-6R concentration was determined, averaged among all participants, and expressed in nanograms per milliliter (ng/mL). | Predose (30 minutes) at baseline; Weeks 12, 24; and FU Week 8 (up to 32 weeks overall) | 
| Change From Baseline in Patient Global Assessment of Disease Activity According to VAS | PGA of disease activity was scored 0-100 mm on a VAS, where higher scores indicate greater perceived disease activity. Change from baseline was averaged among all participants. Negative values indicate improvement/reduction in RA disease activity. | Baseline and Weeks 2, 4, 8, 12, 16, 20, 24 | 
| Change From Baseline in Patient Global Assessment of RA-Related Pain According to VAS | PGA of RA-related pain was scored 0-100 mm on a VAS, where higher scores indicate greater perceived pain. Change from baseline was averaged among all participants. Negative values indicate improvement/reduction in RA-related pain. | Baseline and Weeks 2, 4, 8, 12, 16, 20, 24 | 
| Change From Baseline in HAQ-DI Score | HAQ-DI consisted of 20 questions assessing ADLs in 8 domains (dress/groom, arise, eat, walk, reach, grip, hygiene) with each item rated 0 (no difficulty) to 3 (unable to do). The highest score recorded for any question in a domain determined the score for that domain, unless assistance was required. The total HAQ-DI score was the sum of domain scores divided by the number of domains answered/scored, for a single score range of 0-3, where higher scores indicate increased functional disability. Change from baseline was averaged among all participants. Negative values indicate improvement in ability to perform ADLs. | Baseline and Weeks 2, 4, 8, 12, 16, 20, 24 | 
| Compliance With Treatment According to Percentage of Injections Administered | Participants were provided with diary cards to record home injections. Compliance with treatment was calculated individually for each participant as the actual number of injections as a percentage of the planned number of injections (up to the point of discontinuation for those who discontinued study treatment prematurely) and then averaged among all participants. | Baseline up to Week 24 | 
| Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Score | FACIT-F consisted of 40 questions/statements assessing chronic illness therapy with special emphasis on fatigue over the past 7 days, with each item rated 0 (not at all) to 4 (very much). During score calculations, negatively-worded item scales (e.g., I have a lack of energy) were reversed so that higher scores indicated more favorable conditions. The total FACIT-F score was the sum of all item scores and ranged 0-160, and the brief FACIT-F score was the sum of 13 item scores and ranged 0-52, where higher scores indicate greater well-being. Change from baseline was averaged among all participants. Positive values indicate improvement in well-being. | Baseline and Weeks 2, 4, 8, 12, 16, 20, 24 |