A Study Of Tocilizumab in Patients With Moderate to Severe Active Rheumatoid Arthritis Who Have an Inadequate Response to or Are Unable to Tolerate Biologic and Non-Biologic Disease-modifying Antirheumatic Drugs (DMARDs)

Study Overview
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Brief Summary
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This 3 arm randomized open label study will evaluate the safety, tolerability and efficacy of tocilizumab in patients with moderate to severe active rheumatoid arthritis, who have had inadequate response to or are unable to tolerate DMARDs. The protocol incorporates risk mitigation strategies developed in partnership with the FDA to manage known and potential risks associated with the treatment of tocilizumab. Patients will be randomized to receive tocilizumab either 4 mg/kg intravenous (iv) or 8 mg/kg iv with concomitant non-biologic DMARDs, or 8 mg/kg iv without concomitant non-biologic DMARDs, every 4 weeks, for a total of 6 infusions. The anticipated time on study treatment is 3-12 months, and the target sample size is 500-1000 individuals.

Official Title
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Open-Label Study to Evaluate the Safety, Tolerability and Efficacy of Tocilizumab in Patients With Active Rheumatoid Arthritis on Background Non-biologic DMARDs and Monotherapy Who Have an Inadequate Response to Current Non-Biologic or Biologic DMARDs

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Drug: tocilizumab [RoActemra/Actemra]
* Drug: tocilizumab [RoActemra/Actemra]
* Drug: Nonbiologic DMARDs of investigator's choice


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: adult patients, >=18 years of age; moderate to severe active rheumatoid arthritis for >6 months; inadequate clinical response or unable to tolerate current or prior biologic or non-biologic Disease-modifying antirheumatic drug (DMARD) therapy; Swollen joint count (SJC) >/=4 and Tender joint count (TJC) >/=4 body weight </=150kg current permitted non-biologic DMARDs must be on stable dose for >/= 7 weeks prior to baseline; Exclusion Criteria: history of autoimmune disease or inflammatory joint disease other than rheumatoid arthritis; functional class IV as defined by the American College of Rheumatology (ACR) Classification of Functional Status in rheumatoid arthritis; treatment with rituximab within 6 months before screening; intraarticular corticosteroids within 8 weeks or intramuscular (im)/ intravenous (iv) corticosteroids within 12 weeks prior to screening; known active current or history of recurrent infections, or any major episode of infection requiring hospitalization or treatment with iv antibiotics within 4 weeks of screening, or oral antibiotics within 2 weeks prior to screening.

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 8 mg/kg Monotherapy<br>Participants received Tocilizumab 8 mg/kg as a 60 minute intravenous infusion every 4 weeks for a total of 6 infusions for 24 weeks. Participants who completed the 24 week treatment period were offered the option of entering a long-term extension phase at the investigator's discretion. | Drug: tocilizumab [RoActemra/Actemra]<br>* 8 mg/kg intravenous every 4 weeks for 24 weeks<br>|
| Experimental: Tocilizumab 4 mg/kg + DMARD<br>Participants received Tocilizumab (TCZ) 4 mg/kg as a 60 minute intravenous infusion every 4 weeks for a total of 6 infusions plus non-biologic disease-modifying antirheumatic drug (DMARD) of the investigator's choice for 24 weeks. Participants not achieving a 20% improvement from baseline in tender and swollen joint counts at Week 8 were to have their dosage increased to 8 mg/kg, per protocol. Beginning at Week 12 dosage increase to 8 mg/kg was at the discretion of the investigator. Participants who completed the 24 week treatment period were offered the option of entering a long-term extension phase at the investigator's discretion. | Drug: tocilizumab [RoActemra/Actemra]<br>* 8 mg/kg intravenous every 4 weeks for 24 weeks<br>Drug: tocilizumab [RoActemra/Actemra]<br>* 4 mg/kg every 4 weeks for 24 weeks<br>Drug: Nonbiologic DMARDs of investigator's choice<br>* Nonbiologic disease-modifying antirheumatic drugs (DMARDs) As prescribed<br>|
| Experimental: Tocilizumab 8 mg/kg + DMARD<br>Participants received Tocilizumab (TCZ) 8 mg/kg as a 60 minute intravenous infusion every 4 weeks for a total of 6 infusions plus non-biologic disease-modifying antirheumatic drug (DMARD) of the investigator's choice for 24 weeks. Participants who completed the 24 week treatment period were offered the option of entering a long-term extension phase at the investigator's discretion. | Drug: tocilizumab [RoActemra/Actemra]<br>* 8 mg/kg intravenous every 4 weeks for 24 weeks<br>Drug: Nonbiologic DMARDs of investigator's choice<br>* Nonbiologic disease-modifying antirheumatic drugs (DMARDs) As prescribed<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Experiencing at Least One Serious Adverse Event (SAE) During the 24 Week Treatment Period | An SAE was any adverse event that at any dose fulfilled at least one of the following criteria: Was fatal (results in death) Was life-threatening Required in-patient hospitalization or prolongation of existing hospitalization Resulted in persistent or significant disability/incapacity Was a congenital anomaly/birth defect Was medically significant or required intervention to prevent one or other of the outcomes listed above. | 24 Weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Experiencing Serious Adverse Events of Special Interest | Serious Adverse Events of Special interest include: Serious infections including opportunistic infections Complications of diverticulitis (including lower gastrointestinal [GI] perforations) Myocardial infarction/acute coronary syndrome Stroke Spontaneous or serious bleeding Malignant neoplasms | 24 Weeks | 
| Percentage of Participants Experiencing Non-serious Adverse Events of Special Interest | Non-serious adverse Events of Special interest include: Serious/Medically Significant Hepatic Events Spontaneous /Serious Bleeding Malignant Neoplasms | 24 Weeks | 
| Percentage of Participants Achieving Clinical Remission at Weeks 8, 16, and 24 | Clinical Remission is defined as a Disease Activity Score 28 [DAS28] < 2.6. The DAS28 is a combined index for measuring disease activity in RA. The index includes tender joint count (TJC) -28 joints and swollen joint count (SJC)-28 joints, acute phase response (CRP) and general health status. The DAS28 scale ranges from 0 to 10, where higher scores represent higher disease activity. | Weeks 8,16,24 | 
| Change From Baseline in DAS28 Score at Weeks 8, 16 and 24 | The DAS28 is a combined index for measuring disease activity in rheumatoid arthritis (RA). The index includes tender joint count (TJC) -28 joints and swollen joint count (SJC)-28 joints, acute phase response C-reactive protein (CRP) and general health status. The DAS28 scale ranges from 0 to 10, where higher scores represent higher disease activity. A score of < 2.6 represents clinical remission, a score of ≤ 3.2 represents low disease activity, and a score of > 5.1 represents high disease activity. The Change from Baseline to Weeks 8, 16 and 24 is reported. | Baseline, Weeks 8,16,24 | 
| Percentage of Participants Achieving American College of Rheumatology (ACR) (ACR20/50/70) Responses at Weeks 8, 16, and 24 | The ACR response rates ACR20, ACR50, and ACR70 are defined as ≥20%, ≥50%, and ≥70% improvement from baseline, respectively, in: Swollen Joint Count (66 joints) and Tender Joint Count (68 joints) and At least 3 of the following 5 assessments: Patient's global assessment of pain-Visual Analog Scale (VAS) Patient global assessment of disease activity-(VAS) Physician global assessment of disease activity-(VAS) Patient assessment of disability (physical function scale of the Multidimensional Health Assessment Questionnaire) Acute phase response C-Reactive Protein (CRP) | Baseline, Weeks 8,16,24 | 
| Percentage of Participants With Tocilizumab Dose Increased From 4 mg/kg to 8 mg/kg at Week 8 | Dosage could be increased from 4 mg/kg Tocilizumab to 8 mg/kg due to failure to achieve 20% improvement from baseline in swollen and tender joint counts. | Baseline, Week 8 | 
| Number of Participants Having Their Tocilizumab Dose Increased From 4 mg/kg to 8 mg/kg at Weeks 12, 16, and 20 | Dosage of Tocilizumab 4 mg/kg could be increased to 8 mg/kg at the discretion of the investigator based on assessment of the patient's benefit-risk after Week 12. | Weeks 12,16, 20 | 
| Change From Baseline in Routine Assessment Patient Index Data (RAPID3) Score at Weeks 8, 16, and 24 | The RAPID3 is a combined index derived from the Multidimensional Health Assessment Questionnaire that includes physical function score, pain Visual Analog Scale (VAS), and global assessment of disease activity VAS. The total RAPID3 score ranges from 0 to 10 where higher scores represent worse outcomes. A negative change from baseline indicates improvement. | Baseline, Weeks 8,16,24 | 
| Change From Baseline in Fatigue Visual Analogue Scale (VAS) at Weeks 8, 16, and 24 | The fatigue VAS is a single-item, patient-reported outcome that measures the severity of the fatigue over the past week. Patients rate their fatigue on a scale of 0 (fatigue is no problem) to 100 (fatigue is a major problem). Higher scores represent higher disease activity and a negative change from baseline indicates improvement. | Baseline, Weeks 8,16,24 |