A Study in Patients With Moderate to Severe Active Rheumatoid Arthritis Comparing Different Infusion Durations of RoActemra/Actemra (Tocilizumab) Treatment

Study Overview
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Brief Summary
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This multi-center, randomized, parallel-group, active-controlled, open-label study will evaluate the safety and efficacy of a shortened RoActemra/Actemra (tocilizumab) infusion time compared to the normal infusion time. Patients will be randomized to 8 mg/kg RoActemra/Actemra infusion of 31 minutes every 4 weeks or to RoActemra/Actemra 8 mg/kg infusion of 60 minutes every 4 weeks. The anticipated time on study treatment is 24 weeks.

Official Title
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Multicenter, Randomized, Parallel Group Study to Compare the Incidence of Tocilizumab Related Infusion Reactions in Patients With Moderate to Severe Active RA, When Infusion is Given Over 31 Minutes Compared to 1 Hour

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: Adult patients, at least 18 years of age, inclusive Diagnosis of rheumatoid arthritis of at least 6 months duration Moderate to severe active rheumatoid arthritis (DAS28 >/=3.2) Patients received at least 1 disease-modifying anti-rheumatic drug (DMARD) and/or 1 or more TNFalfa-inhibitors over a period of at least 8 weeks Exclusion Criteria: Major surgery (including joint surgery) within 8 weeks prior to screening or planned surgery within 6 months following randomization Rheumatic autoimmune disease other than rheumatoid arthritis Prior history of or current inflammatory joint disease other than rheumatoid arthritis Functional class IV (ACR criteria) History of severe allergic reaction to human, humanized or murine monoclonal antibodies Known active current or history of recurrent infection (including tuberculosis) Primary or secondary immunodeficiency (history of or currently active) Body weight >150 kg Previous treatment with any cell-depleting therapies Previous treatment with tocilizumab

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tocilizumab, Normal Administration<br>Tocilizumab 8 mg/kg infusion of 60 minutes duration every 4 weeks for 6 infusions (up to 24 weeks) | Drug: Tocilizumab<br>* 8 mg/kg infusion<br>* Other names: Actemra;|
| Experimental: Tocilizumab, Fast Administration<br>Tocilizumab 8 mg/kg infusion of 31 minutes duration every 4 weeks for 6 infusions (up to 24 weeks). The first infusion was 1 hour. If an infusion reaction occurred during any treatment, 1 hour infusions were used for all subsequent infusions | Drug: Tocilizumab<br>* 8 mg/kg infusion<br>* Other names: Actemra;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Any Infusion Reaction | An infusion reaction was defined as any adverse event (AE) that occurred during the infusion or during the 24 hours following the infusion and deemed possibly or probably related to tocilizumab. | Baseline (Day 1), and Weeks 4, 8, 12, 16, and 20 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Discontinuing Tocilizumab in Response to an AE or a Serious Adverse Event (SAE) | All occurrences of participants who received at least 1 infusion of tocilizumab and then stopped tocilizumab infusions due to an AE or SAE were analyzed. | Baseline (Day 1) and Weeks 4, 8, 12, 16, 20, and 24 | 
| Percentage of Participants Discontinuing Tocilizumab for Other Reasons | Participants that stopped the administration of tocilizumab and discontinued the study prematurely due to reasons other than an AE or SAE were analyzed. | Baseline and Weeks, 4, 8, 12, 16, 20, and 24 | 
| Percentage of Participants With Increased Liver Enzyme Values of Greater Than (>)1.5 Times, or >3 Times, or >5 Times Over the Upper Limit of Normal (ULN) by Visit Among Participants Who Completed All Visits | Increased liver enzyme values defined as Alanine Aminotransferase (ALT) and/or Aspartate Aminotransferase (AST) values of >1.5 times, or >3 times, or >5 times over the ULN. Almost none of the participants had increased measurements of AST, thus only values of ALT were presented. None of the participants presented with increased values of ALT above 3 or 5 ULN at any of the visits. ITT Completers is defined as a subset of the participants in the ITT population who completed all study visits. | Baseline and Weeks 4, 8, 12, 16, 20, and 24 | 
| Percentage of Participants With Increased Lipid Values by Visit Among Participants Who Completed All Visits | Increased levels of high density lipoproteins (HDL) equal to or greater than (≥)1.5 millimoles per liter (mmol/L), and low density lipoproteins (LDL) ≥4.1 mmol/L, and total cholesterol ≥5.1 mmol/L, are defined according to the Adult Treatment Panel III (ATP-III) guidelines. | Screening and Weeks 4, 8, 12, 16, 20, and 24 | 
| Percentage of Participants With a Reduction of at Least 1.2 Points in Disease Activity Score Based on 28-Joint Count (DAS28) by Visit Among Participants Who Completed All Visits | Improvement in Rheumatoid Arthritis (RA) disease activity was measured by the DAS28 score, which is an index combining measurements of swollen and tender joints, acute phase response High sensitivity C-Reactive Protein (hsCRP), and global assessment of disease activity by the participant. A clinically meaningful improvement was defined as a reduction of at least 1.2 units in the DAS28 score during the study period. A low disease activity was defined as a DAS28 score less than (<)3.2, and remission was defined as a DAS28 score <2.6. | Weeks 4, 8, 12, 16, 20, and 24 | 
| Percentage of Participants Achieving a DAS28 Score Below 3.2 (Low Disease Activity) by Visit Among Participants Who Completed All Visits | Improvement in RA disease activity was measured by the DAS28 score, which is an index combining measurements of swollen and tender joints, acute phase response hsCRP, and global assessment of disease activity by the participant. A clinically meaningful improvement was defined as a reduction of at least 1.2 units in the DAS28 score during the study period. A low disease activity was defined as a DAS28 score <3.2, and remission was defined as a DAS28 score <2.6. | Weeks 4, 8, 12, 16, 20, and 24 | 
| Percentage of Participants Achieving a DAS28 Score Below 2.6 (Remission) by Visit Among Participants Who Completed All Visits | Improvement in RA disease activity was measured by the DAS28 score, which is an index combining measurements of swollen and tender joints, acute phase response hsCRP, and global assessment of disease activity by the participant. A clinically meaningful improvement was defined as a reduction of at least 1.2 units in the DAS28 score during the study period. A low disease activity was defined as a DAS28 score <3.2, and remission was defined as a DAS28 score <2.6. | Weeks 4, 8, 12, 16, 20, and 24 | 
| DAS28 Score by Visit Among Participants Who Completed All Visits | Improvement in RA disease activity was measured by the DAS28 score, which is an index combining measurements of swollen and tender joints, acute phase response hsCRP, and global assessment of disease activity by the participant. A clinically meaningful improvement was defined as a reduction of at least 1.2 units in the DAS28 score during the study period. A low disease activity was defined as a DAS28 score <3.2, and remission was defined as a DAS28 score <2.6. | Baseline, Weeks, 4, 8, 12, 16, 20, and 24 | 
| Percentage of Participants Achieving American College of Rheumatology 20 Percent (%) Improvement (ACR20 Response) by Visit Among Participants Who Completed All Visits | ACR20 response is defined as an improvement of ≥20% in swollen joint count (SJC; 66 joints) and tender joint count (TJC; 68 joints) as well as ≥20% improvement in at least 3 of the following 5 remaining ACR assessments: Patient Global Assessment of Pain; Patient Global Assessment of Disease Activity; Physician Global Assessment of Disease Activity; Health Assessment Questionnaire - Disability Index (HAQ-DI); and acute phase reactive factors (Erythrocyte Sedimentation Rate [ESR] or C-Reactive Protein [CRP]). | Weeks 4, 8, 12, 16, 20, and 24 | 
| Percentage of Participants Achieving ACR 50% Improvement (ACR50 Response) by Visit Among Participants Who Completed All Visits | ACR50 response is defined as an improvement of ≥50% in SJC (66 joints) and TJC (68 joints) as well as ≥50% improvement in at least 3 of the following 5 remaining ACR assessments: Patient Global Assessment of Pain; Patient Global Assessment of Disease Activity; Physician Global Assessment of Disease Activity; HAQ-DI; and acute phase reactive factors (ESR or CRP). | Weeks, 4, 8, 12, 16, 20, and 24 | 
| Percentage of Participants Achieving ACR 70% Improvement (ACR70 Response) by Visit, Among Participants Who Completed All Visits | ACR70 response is defined as an improvement of ≥70% in SJC (66 joints) and TJC (68 joints) as well as ≥70% improvement in at least 3 of the following 5 remaining ACR assessments: Patient Global Assessment of Pain; Patient Global Assessment of Disease Activity; Physician Global Assessment of Disease Activity; HAQ-DI; and acute phase reactive factors (ESR or CRP). | Weeks 4, 8, 12, 16, 20 and 24 | 
| Percentage of Participants Achieving ACR 90% Improvement (ACR90 Response) by Visit Among Participants Who Completed All Visits | ACR90 response is defined as an improvement of ≥90% in SJC (66 joints) and TJC (68 joints) as well as ≥90% improvement in at least 3 of the following 5 remaining ACR assessments: Patient Global Assessment of Pain; Patient Global Assessment of Disease Activity; Physician Global Assessment of Disease Activity; HAQ-DI; and acute phase reactive factors (ESR or CRP). | Weeks 4, 8, 12, 16, 20 and 24 | 
| High Sensitivity C-Reactive Protein (hsCRP) Levels by Visit Among Participants Who Completed All Visits | hsCRP is a marker for inflammation and is measured in milligrams per liter (mg/L). High levels of this protein indicate inflammation in diseases such as RA. | Screening, Baseline, Weeks 4, 8, 12, 16, 20, and 24 | 
| Modified Health Assessment Questionnaire (M-HAQ) Score by Visit Among Participants Who Completed All Visits | M-HAQ is a self-reported, valid assessment of functional disability in RA. Assessment based on ability of participants to perform daily activities in 8 categories: dressing, arising, eating, walking, reaching, gripping, hygiene, and carrying out daily activities. Scores range 0 to 3; without any difficulty=0, with some difficulty=1, with much difficulty=2, unable to do=3. | Baseline, Weeks 4, 8, 12, 20, and 24 | 
| Percentage of Participants With Improvement of at Least 0.22 Units in M-HAQ Compared to Baseline Per Visit Among Participants Who Completed All Visits | M-HAQ is a self-reported, valid assessment of functional disability in RA. Assessment based on ability of participants to perform daily activities in 8 categories: dressing, arising, eating, walking, reaching, gripping, hygiene, and carrying out daily activities. Scores range 0 to 3; without any difficulty=0, with some difficulty=1, with much difficulty=2, unable to do=3. | Weeks 4, 8. 12, 20, and 24 |