A Long-term Extension Study of Tocilizumab (Myeloma Receptor Antibody [MRA]) in Patients With Rheumatoid Arthritis

Study Overview
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Brief Summary
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This open-label, international multi-center extension study WA18695 was designed to assess the long term safety of tocilizumab in patients who had moderate to severe active rheumatoid arthritis (RA). Patients enrolled in the WA18695 study had previously received treatment in the 24-week, placebo-controlled, Phase III Study WA17822. Eligible patients were assigned to treatment with 8 mg/kg tocilizumab every 4 weeks for a maximum of 5 years.

Detailed Description
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The primary objective of this extension study was to assess the long-term safety of 8 mg/kg tocilizumab with regard to adverse events (AEs) and laboratory result abnormalities. The secondary objectives were as follows: To explore the possibility of reducing concomitant steroid treatment To determine the long-term efficacy of 8 mg/kg tocilizumab with regard to reduction in signs and symptoms To better understand and predict tocilizumab efficacy, response, safety, and progression of rheumatoid arthritis (RA) and associated diseases with regard to its effect on biomarkers No viable biomarkers for TCZ treatment effects were identified from the controlled studies. There were, therefore, no biomarkers that warranted further investigation in long-term studies, so no biomarker data are reported. The extension study WA18695 was an open-label, international multi-center study in patients with moderate to severe active rheumatoid arthritis (RA) who had completed treatment in the 24 weeks placebo-controlled Phase III study WA17822. Patients entering WA17822 had an inadequate response to methotrexate (MTX), and, during WA17822, patients had received treatment with intravenous infusions of tocilizumab 4 mg/kg, 8 mg/kg, or placebo every 4 weeks with background MTX therapy. All patients who completed the planned course of treatment or escape therapy in the WA17822 study were eligible to enter the WA18695 long-term extension study, where they were assigned to treatment with 8 mg/kg RoActemra/Actemra plus MTX. The dose of RA medications such as MTX and nonsteroidal anti-inflammatory drugs (NSAIDs), but excluding corticosteroids, was to be kept stable for the first 48 weeks of the WA18695 study. During this time dose reductions in these treatments were only allowed as clinically required for safety reasons. After week 48, the administration of disease-modifying antirheumatic drugs (DMARDs) and NSAIDs could be changed, according to the investigator's practice and as tolerated by the patient.

Official Title
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Long-term Extension Study of Safety During Treatment With Tocilizumab (MRA) in Patients Completing Treatment in WA17822

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Drug: Tocilizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients who have completed participation in the Phase III study WA17822 (NCT00106548) in adult rheumatoid arthritis. Exclusion Criteria: Treatment with any investigational agent since the last administration of study drug in WA17822. Treatment with intravenous (IV) gammaglobulin, plasmapheresis, or Prosorba column since the last administration of study drug in WA17822. Treatment with an anti-tumor necrosis factor or anti-interleukin-1 agent, or a T cell costimulation modulator since the last administration of study drug in WA17822. Previous treatment with any cell-depleting therapies. Parenteral, intramuscular, or intra-articular corticosteroids within 6 weeks prior to baseline.

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 8 mg/kg<br>All participants received tocilizumab 8 mg/kg to a maximum of 800 mg, administered by intravenous (IV) infusion over one hour, every 4 weeks. Concomitant therapies were limited to dosage and administration constraints detailed in the protocol. | Drug: Tocilizumab<br>* Tocilizumab (myeloma receptor antibody [MRA]) was supplied in sterile solution of 20 mg TCZ/mL for aseptic preparation of infusion bags for IV administration.<br>* Other names: TCZ;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Event (AE) Summary Over Time | The number of participants experiencing at least one adverse event (AE) is recorded for each 12-month time period, with multiple occurrences in a single individual counted. Because months were calculated as 28 days, the periods actually equate to 48 weeks. | through 264 Weeks | 
| Summary Adverse Event Rates Over Time | Patient year (PY) refers to duration in study, calculated from first active drug intake to last safety assessment available + 1. Patient year rates with confidence interval were calculated for adverse events of interest in evaluating the long-term safety of the product being studied. Abbreviations include the following: adverse event (AE), adverse event of special interest (AESI), gastrointestinal (GI), serious adverse event (SAE), and investigational product (IP). Hypersensitivity events were defined as AEs that occurred during or within 24 hours of IP infusion and were not deemed unrelated to trial treatment by the investigator. This definition includes all types of AEs, regardless of whether or not they were consistent with hypersensitivity. Medical confirmation of the AESI GI perforation was based on medical adjudication of events captured by the GI Perforation Standardised MedDRA Queries (SMQs). | through 264 Weeks | 
| Overall Death Rate Over Time | Patient year (PY) refers to duration in study, calculated from first active drug intake to last safety assessment available + 1. To calculate the death rate, the total cumulative number of years that all participants were exposed to the drug, from first active drug intake to last safety assessment available + 1, was calculated as 2461.94. Since 10 participants died during that time, the death rate per year was not informative (0.00). Therefore, the overall death rate was calculated with the confidence interval based on events per 100 patient years exposure. | through 264 Weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Participants Showing Improvement in Rheumatoid Arthritis Symptoms Over Time, Through 264 Weeks | The American College of Rheumatology (ACR) established certain criteria to measure improvement in rheumatoid arthritis symptoms that include tender or swollen joint counts and five other criteria, including acute phase reactant, patient assessment, physician assessment, pain scale, and disability/functional questionnaire. Clinical trials use the ACR Score, based on those criteria, as a standard for reporting different degrees of improvement in rheumatoid arthritis symptoms. Scores on the ACR scale may be up to ACR100 because the number after ACR is the percent of improvement in tender or swollen joint counts as well as in three of the other five criteria. Clinical trials determine the percentage of participants who achieve that score - that percentage of improvement. | through 264 Weeks | 
| Percentage of Participants Classified as Responders by Disease Activity Scores Over Time, Through 264 Weeks | The disease activity score 28 (DAS28) is a combined index for measuring disease activity in rheumatic arthritis (RA) that includes swollen and tender joint counts, erythrocyte sedimentation rate (ESR), and general health (GH) status. The DAS28 scale ranges from 0 to 10, where lower scores represent less disease activity. Participants with DAS28 scores less than 2.6 were categorized as responders with remission and those with DAS 28 scores of 3.2 or less were categorized as responders with low disease activity (LDA). The percentage of participants classified as responders in each category was recorded over time. | through 264 Weeks | 
| Percentage of Participants Classified as Responders by EULAR Response Over Time, Through 264 Weeks | Participants were classified as responders based on a European League Against Rheumatism (EULAR) response of Good or Moderate. Comparing the DAS28 from one patient on two different time points, it is possible to define improvement or response. The EULAR response criteria take into consideration both the first score and the change in score in order to classify them as good response, moderate response or no response. The percentage of participants who were classified as responders was recorded, as posted below. | through 264 Weeks | 
| Change From Baseline in Scores for Swollen and Tender Joint Counts Over Time, Through 264 Weeks | Swollen joint count (SJC) includes an assessment of 66 joints, and tender joint count (TJC) include an assessment of 68 joints. Joint prosthesis, arthrodesis or fused joints were not considered. Joints were assessed and classified as swollen/not swollen, and tender/not tender, by pressure and joint manipulation on physical examination. Change from Baseline in the SJC and TJC were calculated at given time points, and a negative change indicates improvement. A small proportion of participants in the all-exposure population reduced or stopped their oral corticosteroid use due to sustained efficacy (defined as at least a 50% improvement in both swollen joint count (SJC) and tender joint count (TJC). | through 264 Weeks | 
| Change From Baseline in Scores for Health Assessment Questionnaire - Disability Index Over Time, Through 264 Weeks | The Stanford Health Assessment Questionnaire - Disability Index (HAQ-DI) is a questionnaire specific for rheumatoid arthritis with 8 component sets (domains): dressing/grooming, arising, eating, walking, hygiene, reach, grip, and common daily activities. Each domain has 2-3 questions (for a total of 20) that participants answer with categorical answers enumerated as a scale of 0-3, where 0=without any difficulty, 1=with some difficulty, 2=with much difficulty, and 3=unable to do. To calculate the HAQ-DI the patient must have a domain score for at least 6 of the eight domains. The HAQ-DI is the sum of the domain scores, divided by the number of domains that have a score (in range 6-8). The resulting HAQ-DI scores are on a scale that ranges from 0 to 3, where 0=lowest level of difficulty and 3=highest level of difficulty. A negative change from baseline indicates improvement. | through 264 Weeks | 
| Change From Baseline in Scores for Patient's Global Assessment of Disease Activity Over Time, Through 264 Weeks | Patient's global assessment of disease activity is the patient's overall assessment of their disease activity during specified time periods on a 100 mm horizontal visual analogue scale (VAS). The left-hand extreme of the line was described as no disease activity (symptom-free and no arthritis symptoms) and the right-hand extreme as maximum disease activity (maximum arthritis disease activity). Change from baseline was calculated for given periods, and a negative change indicates improvement. | through 264 Weeks | 
| Change From Baseline in Scores for Physician's Global Assessment of Disease Activity Over Time, Through 264 Weeks | Physician's global assessment of disease activity is the treating physician's assessment of the patient's current disease activity on a 100 mm horizontal visual analogue scale (VAS). The extreme left end of the line was described as no disease activity (symptom-free and no arthritis symptoms) and the extreme right end as maximum disease activity. Change from baseline was calculated for given periods, and a negative change indicates improvement. | through 264 Weeks | 
| Change From Baseline in Scores for Patient's Level of Pain Over Time, Through 264 Weeks | The patient's assessment of the patient's current level of pain on a 100 mm horizontal VAS was recorded. The extreme left end of the line was described as no pain and the extreme right end as unbearable pain. Change from baseline was calculated for given periods, and a negative change indicates improvement. | through 264 Weeks | 
| Percentage of Participants With at Least a 5-point Improvement From Baseline in Quality of Life Measure for Fatigue Over Time, Through 264 Weeks | Quality of life is measured using the sub-scale for Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F). The assessment was originally developed for chronic illnesses and is now widely used for patients with rheumatoid arthritis. FACIT-F is a 13-item questionnaire. Participants score each item on a 5-point scale: 0 (Not at all) to 4 (Very much), for a highest possible score of 52. The responses are transformed into a FACIT-F score, where a higher score reflects an improvement. The percentage of participants with at least a 5-point improvement from baseline in the Facit-F score is shown at categorical time points. | through 264 Weeks | 
| Percentage of Participants With at Least a 5-point Improvement From Baseline in Quality of Life Using the 36-Item Short-Form Health Survey (SF-36) Over Time, Through 264 Weeks | The SF-36 Health Survey is a standardized questionnaire consisting of 36 questions that measures patient-reported symptoms on 8 dimensions; it is used to assess health-related quality of life (HRQoL). The Physical Component Summary (PCS) score summarizes the subscales Physical Functioning, Role-Physical, Bodily Pain, and General Health. The Mental Component Summary (MCS) score summarizes the subscales Vitality, Social Functioning, Role-Emotional, and Mental Health. Each score was scaled from 0 to 100. A positive change score indicates better HRQoL. The percentage of participants with at least a 5-point improvement from baseline is presented for each subscale. | through 264 Weeks |