A Study of RoActemra/Actemra (Tocilizumab) in Patients With Moderate to Severe Rheumatoid Arthritis

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

This open-label study will evaluate the safety, tolerability and efficacy of RoActemra/Actemra (tocilizumab) in patients with moderate to severe active rheumatoid arthritis (RA) on background non-biologic DMARDs who have an inadequate response to current non-biologic DMARDs. Patients will receive 8 mg/kg RoActemra/Actemra as an intravenous infusion every 24 weeks for a total of 6 infusions. The anticipated time on study treatment is 24 weeks.

Study Overview

• Status: Completed
• Conditions: Rheumatoid Arthritis
• Intervention / Treatment: Drug: tocilizumab [RoActemra/Actemra]

• Study Type: Interventional
• Enrollment (Actual): 65
• Phase: Phase 3

Contacts and Locations

Study Locations

• Turkey
  • Adana, Turkey, 01330
  • Ankara, Turkey, 06100
  • Ankara, Turkey, 06500
  • Aydin, Turkey, 09100
  • Bursa, Turkey, 16059
  • Denizli, Turkey, 20020
  • Elaziğ, Turkey, 23119
  • Gaziantep, Turkey, 27310
  • Istanbul, Turkey, 34000
  • Izmir, Turkey, 35100
  • Izmir, Turkey, 35170
  • Izmir, Turkey, 54100
  • Izmit, Turkey, 41380
  • Konya, Turkey, 42080
  • Manisa, Turkey, 45200
  • Samsun, Turkey, 55139
  • Sivas, Turkey, 58140

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Adult patients, >/=18 years of age
• Moderate to severe active rheumatoid arthritis (DAS28>/=3.2) of >/=6 months duration
• Body weight </=150 kg
• Patients are on one or more non-biologic DMARDs at a stable dose for a period >/=8 weeks prior to study treatment
• Patients with inadequate clinical response to a stable dose of non-biologic DMARD

Exclusion Criteria:

• Major surgery (including joint surgery) within 8 weeks prior to screening or planned major surgery within 6 months following randomization
• Rheumatic autoimmune disease other than rheumatoid arthritis, including systemic lupus erythematosus, mixed connective tissue disease, scleroderma, polymyositis, or significant systemic involvement secondary to rheumatoid arthritis
• History of or current inflammatory joint disease other than rheumatoid arthritis

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1	Drug: tocilizumab [RoActemra/Actemra]; 8 mg/kg intravenous infusion every 4 weeks for a total of 6 infusions

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety: Percentage of Participants With Treatment Emergent Adverse /Serious Adverse Events	An adverse event (AE) was any untoward medical occurrence attributed to study drug in a participant who received study drug. A serious AE (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. An AE was considered treatment emergent if the date of onset of the AE was on or after the date of first dose of study medication. AEs of special interest included Major Adverse Cardiovascular Events (MACE) (including strokes), infections, and infusion reactions. An AE was considered an infection if the preferred term was in the predefined infection AE group term. A serious infection was an infection which was also considered as an AE. An AE was considered an infusion reaction if it occurred during or within 24 hours of an infusion.	24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With All-Cause Discontinuation	Participants who discontinued treatment due to any reason were included in this measure.	24 weeks
Number of Participants With Alanine Transaminase (ALT) and Asapartate Transaminase (AST) Elevations of Greater Than (>) 1.5 Upper Limit of Normal (ULN), >3 ULN and > 5 ULN	Elevations in ALT and AST could indicate hepatotoxicity.	Screening (Visit 1), Weeks 0 (Visit 2), 4 (Visit 3), 8 (Visit 4), 12 (Visit 5), 16 (Visit 6), 20 (Visit 7) and 24 (Visit 8)
Percentage of Participants With ALT and AST Elevations of >1.5 ULN, >3 ULN and > 5 ULN	Elevations in ALT and AST could indicate hepatotoxicity.	Screening (Visit 1), Weeks 0 (Visit 2), 4 (Visit 3), 8 (Visit 4), 12 (Visit 5), 16 (Visit 6), 20 (Visit 7) and 24 (Visit 8)
Percentage of Participants With Serious Infections	A serious infection was an infection which was also considered as an SAE. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly	Weeks 4 (Visit 3), 8 (Visit 4), and 16 (Visit 6)
Number of Participants With Serious Infections	A serious infection was an infection which was also considered as an SAE. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly	Weeks 4 (Visit 3), 8 (Visit 4), and 16 (Visit 6)
Change From Baseline to Highest Values for ALT and AST	Elevations in ALT and AST could indicate hepatotoxicity. These enzymes were measured as International Units per Liter (IU/L). The change from baseline was calculated as: baseline value minus the highest value observed post-baseline for each enzyme.	Baseline to Week 24
Change From Baseline to Highest Values for Low Density Lipoprotein (LDL) and Total Cholesterol	Elevations in LDL and total cholesterol could lead to heart disease. The change from baseline was calculated as: baseline value minus the highest value observed post-baseline and was measured as milligrams per deciliter (mg/dL).	Baseline to Week 24
Change From Baseline to Lowest Value for Absolute Neutrophil Count (ANC)	ANC is a measure of number of neutrophil granulocytes. An ANC less than 500 cells per microliter (cells/µL) is defined as neutropenia and significantly increases risk of infection. The change from baseline was calculated as: baseline value minus the highest value observed post-baseline. ANC was measured in cells/µL.	Baseline to Week 24
Number of Participants With Elevations in Lipids According to Adult Treatment Panel (ATP) III Guidelines	ATP III guidelines classify LDL cholesterol >160 mg/dL, Total cholesterol >240 mg/dL, High Density Lipoprotein (HDL) >60 mg/dL and Triglycerides (TG) >199 as elevated.	Screening (Visit 1), Weeks 0 (Visit 2), 4 (Visit 3), 8 (Visit 4),12 (Visit 5),16 (Visit 6), 20 (Visit 7) and 24 (Visit 8)
Percentage of Participants With Elevations in Lipids According to ATP III Guidelines	ATP III guidelines classify LDL cholesterol >160 mg/dL , Total cholesterol >240 mg/dL, HDL >60 mg/dL and TG >199 as elevated.	Screening (Visit 1), Weeks 0 (Visit 2), 4 (Visit 3), 8 (Visit 4), 12 (Visit 5), 16 (Visit 6), 20 (Visit 7) and 24 (Visit 8)
Number of Participants Who Achieved Clinically Meaningful Improvement in Disease Activity Score 28 (DAS28) At Every Visit	The DAS28 is a combined index for measuring disease activity in Rheumatoid Arthritis (RA). The index includes swollen and tender joint counts, acute phase response, and general health status. The DAS28, which uses a 28 joint count, is derived from the original DAS. The index is calculated using the following formula: DAS28 = 0.56 x (TJC28)^0.5 + 0.28 x (SJC28)^0.5 + 0.70 x In(ESR) + 0.014 x GH Where TJC28 = tender joint count on 28 joints, SJCz8 = swollen joint count on 28 joints, ın = natural log, ESR = erythrocyte sedimentation rate and GH = general health (participant's global assessment of disease activity). DAS28 scale ranges from 0 to 10, where higher scores represent higher disease activity. A score of less than (<) 2.6 represents clinical remission, a score of: <3.2 represents low disease activity (LDA), and a score of > 5.1 represents severe disease. A reduction from previous visit of at least 1.2 units in DAS28 is considered to be a clinically meaningful improvement.	Screening (Visit 1), Weeks 0 (Visit 2), 4 (Visit 3), 8 (Visit 4), 12 (Visit 5), 16 (Visit 6), 20 (Visit 7) and 24 (Visit 8)
Percentage of Participants Who Achieved Clinically Meaningful Improvement in DAS28 At Every Visit	The DAS28 is a combined index for measuring disease activity in RA. The index includes swollen and tender joint counts, acute phase response, and general health status. The DAS28, which uses a 28 joint count, is derived from the original DAS. The index is calculated using the following formula: DAS28 = 0.56 x (TJC28)^0.5 + 0.28 x (SJC28)^0.5 + 0.70 x In(ESR) + 0.014 x GH Where TJC28 = tender joint count on 28 joints, SJCz8 = swollen joint count on 28 joints, ın = natural log, ESR = erythrocyte sedimentation rate and GH = general health (participant's global assessment of disease activity). 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 LDA, and a score of > 5.1 represents severe disease. A reduction of at least 1.2 units from previous visit in DAS28 is considered to be a clinically meaningful improvement.	Screening (Visit 1), Weeks 0 (Visit 2), 4 (Visit 3), 8 (Visit 4),12 (Visit 5),16 (Visit 6), 20 (Visit 7) and 24 (Visit 8)
Number of Participants Who Achieved LDA By Visit	The DAS28 is a combined index for measuring disease activity in RA. The index includes swollen and tender joint counts, acute phase response, and general health status. The DAS28, which uses a 28 joint count, is derived from the original DAS. The index is calculated using the following formula: DAS28 = 0.56 x (TJC28)^0.5 + 0.28 x (SJC28)^0.5 + 0.70 x In(ESR) + 0.014 x GH Where TJC28 = tender joint count on 28 joints, SJCz8 = swollen joint count on 28 joints, ın = natural log, ESR = erythrocyte sedimentation rate and GH = general health (participant's global assessment of disease activity). 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 LDA, and a score of > 5.1 represents severe disease. A reduction of at least 1.2 units from previous visit in DAS28 is considered to be a clinically meaningful improvement.	Screening (Visit 1), Weeks 0 (Visit 2), 4 (Visit 3), 8 (Visit 4), 12 (Visit 5), 16 (Visit 6), 20 (Visit 7) and 24 (Visit 8)
Percentage of Participants Who Achieved LDA By Visit	TThe DAS28 is a combined index for measuring disease activity in RA. The index includes swollen and tender joint counts, acute phase response, and general health status. The DAS28, which uses a 28 joint count, is derived from the original DAS. The index is calculated using the following formula: DAS28 = 0.56 x (TJC28)^0.5 + 0.28 x (SJC28)^0.5 + 0.70 x In(ESR) + 0.014 x GH Where TJC28 = tender joint count on 28 joints, SJCz8 = swollen joint count on 28 joints, ın = natural log, ESR = erythrocyte sedimentation rate and GH = general health (participant's global assessment of disease activity). 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 LDA, and a score of > 5.1 represents severe disease. A reduction of at least 1.2 units from previous visit in DAS28 is considered to be a clinically meaningful improvement.	Screening (Visit 1), Weeks 0 (Visit 2), 4 (Visit 3), 8 (Visit 4), 12 (Visit 5), 16 (Visit 6), 20 (Visit 7) and 24 (Visit 8)
Time to LDA (DAS28 ) Based on First Visit When LDA Was Observed	The DAS28 is a combined index for measuring disease activity in RA. The index includes swollen and tender joint counts, acute phase response, and general health status. The DAS28, which uses a 28 joint count, is derived from the original DAS. The index is calculated using the following formula: DAS28 = 0.56 x (TJC28)^0.5 + 0.28 x (SJC28)^0.5 + 0.70 x In(ESR) + 0.014 x GH Where TJC28 = tender joint count on 28 joints, SJCz8 = swollen joint count on 28 joints, ın = natural log, ESR = erythrocyte sedimentation rate and GH = general health (participant's global assessment of disease activity). 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 LDA, and a score of > 5.1 represents severe disease. A reduction of at least 1.2 units from previous visit in DAS28 is considered to be a clinically meaningful improvement.	Screening (Visit 1), Weeks 0 (Visit 2), 4 (Visit 3), 8 (Visit 4), 12 (Visit 5), 16 (Visit 6), 20 (Visit 7) and 24 (Visit 8)
Number of Participants Who Achieved Remission (DAS28) By Visit	The DAS28 is a combined index for measuring disease activity in RA. The index includes swollen and tender joint counts, acute phase response, and general health status. The DAS28, which uses a 28 joint count, is derived from the original DAS. The index is calculated using the following formula: DAS28 = 0.56 x (TJC28)^0.5 + 0.28 x (SJC28)^0.5 + 0.70 x In(ESR) + 0.014 x GH Where TJC28 = tender joint count on 28 joints, SJCz8 = swollen joint count on 28 joints, ın = natural log, ESR = erythrocyte sedimentation rate and GH = general health (participant's global assessment of disease activity). 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 LDA, and a score of > 5.1 represents severe disease. A reduction of at least 1.2 units in DAS28 is considered to be a clinically meaningful improvement.	Screening (Visit 1), Weeks 0 (Visit 2), 4 (Visit 3), 8 (Visit 4), 12 (Visit 5), 16 (Visit 6), 20 (Visit 7) and 24 (Visit 8)
Percentage of Participants Who Achieved Remission (DAS28) At Every Visit	The DAS28 is a combined index for measuring disease activity in RA. The index includes swollen and tender joint counts, acute phase response, and general health status. The DAS28, which uses a 28 joint count, is derived from the original DAS. The index is calculated using the following formula: DAS28 = 0.56 x (TJC28)^0.5 + 0.28 x (SJC28)^0.5 + 0.70 x In(ESR) + 0.014 x GH Where TJC28 = tender joint count on 28 joints, SJCz8 = swollen joint count on 28 joints, ın = natural log, ESR = erythrocyte sedimentation rate and GH = general health (participant's global assessment of disease activity). 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 LDA, and a score of > 5.1 represents severe disease. A reduction of at least 1.2 units in DAS28 is considered to be a clinically meaningful improvement.	Screening (Visit 1), Weeks 0 (Visit 2), 4 (Visit 3), 8 (Visit 4), 12 (Visit 5), 16 (Visit 6), 20 (Visit 7) and 24 (Visit 8)
Percentage of Participants Achieving Their First Remission Status By Visit	The DAS28 is a combined index for measuring disease activity in RA. The index includes swollen and tender joint counts, acute phase response, and general health status. The DAS28, which uses a 28 joint count, is derived from the original DAS. The index is calculated using the following formula: DAS28 = 0.56 x (TJC28)^0.5 + 0.28 x (SJC28)^0.5 + 0.70 x In(ESR) + 0.014 x GH Where TJC28 = tender joint count on 28 joints, SJCz8 = swollen joint count on 28 joints, ın = natural log, ESR = erythrocyte sedimentation rate and GH = general health (participant's global assessment of disease activity). 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 LDA, and a score of > 5.1 represents severe disease. A reduction of at least 1.2 units in DAS28 is considered to be a clinically meaningful improvement.	Weeks 4 (Visit 3), 8 (Visit 4), 12 (Visit 5), 16 (Visit 6), 20 (Visit 7) and 24 (Visit 8)
Disease Activity Score as Measured By DAS28 at Each Visit	The DAS28 is a combined index for measuring disease activity in RA. The index includes swollen and tender joint counts, acute phase response, and general health status. The DAS28, which uses a 28 joint count, is derived from the original DAS. The index is calculated using the following formula: DAS28 = 0.56 x (TJC28)^0.5 + 0.28 x (SJC28)^0.5 + 0.70 x In(ESR) + 0.014 x GH Where TJC28 = tender joint count on 28 joints, SJCz8 = swollen joint count on 28 joints, ın = natural log, ESR = erythrocyte sedimentation rate and GH = general health (participant's global assessment of disease activity). 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 LDA, and a score of > 5.1 represents severe disease. A reduction of at least 1.2 units in DAS28 is considered to be a clinically meaningful improvement.	Screening (Visit 1), Weeks 0 (Visit 2), 4 (Visit 3), 8 (Visit 4), 12 (Visit 5), 16 (Visit 6), 20 (Visit 7) and 24 (Visit 8)
Number of Participants Who Achieved American College of Rheumatology (ACR) 20, ACR 50, ACR 70 and ACR 90 Response	ACR20/50/70/90 response: greater than or equal to (≥) 20/50/70/90 percent (%) improvement in TJC; ≥20/50/70/90% improvement in SJC; and ≥20/50/70/90% improvement in at least 3 of 5 remaining ACR core measures: participant assessment of pain; participant global assessment of disease activity; physician global assessment of disease activity; self-assessed disability (disability index of the Health Assessment Questionnaire [HAQ]); and C-Reactive Protein (CRP). Improvements were assessed on the basis of prior visit.	Weeks 0 (Visit 2), 4 (Visit 3), 8 (Visit 4),12 (Visit 5),16 (Visit 6), 20 (Visit 7) and 24 (Visit 8)
Percentage of Participants Who Achieved ACR 20, ACR 50, ACR 70 and ACR 90 Response	ACR20/50/70/90 response: ≥ 20/50/70/90 % improvement in TJC; ≥20/50/70/90% improvement in SJC; and ≥20/50/70/90% improvement in at least 3 of 5 remaining ACR core measures: participant assessment of pain; participant global assessment of disease activity; physician global assessment of disease activity; self-assessed disability (disability index of the Health Assessment Questionnaire [HAQ]); and C-Reactive Protein (CRP). Improvements were assessed on the basis of prior visit. .	Weeks 0 (Visit 2), 4 (Visit 3), 8 (Visit 4),12 (Visit 5),16 (Visit 6), 20 (Visit 7) and 24 (Visit 8)
C-Reactive Protein Levels	CRP is an inflammatory marker used to measure inflammation in RA and is measured as mg/dL.	Screening (Visit 1), Weeks 0 (Visit 2), 4 (Visit 3), 8 (Visit 4), 12 (Visit 5), 16 (Visit 6), 20 (Visit 7) and 24 (Visit 8)
Erythrocyte Sedimentation Rate	ESR is an inflammatory marker used to measure inflammation in RA and is measured as millimeters per hour (mm/hr).	Screening (Visit 1), Weeks 0 (Visit 2), 4 (Visit 3), 8 (Visit 4), 12 (Visit 5), 16 (Visit 6), 20 (Visit 7) and 24 (Visit 8)
Mean Number of Tender and Swollen Joints	Participants were asked to classify 28 joints as tender or not tender and swollen or not swollen to count the total number of tender and swollen joints by visit.	Screening (Visit 1), Weeks 0 (Visit 2), 4 (Visit 3), 8 (Visit 4), 12 (Visit 5), 16 (Visit 6), 20 (Visit 7) and 24 (Visit 8)
Participant's (PT) and Investigator's (IN) Assessment of Disease Activity	VAS is a visual scale of 100 mm for the assessment of disease activity by participants or investigator. Disease activity/pain increases while approaching 100 mm. For the screening visit (baseline visit) there's only investigator assessment data, for other visits participant's pain assessment, participant's disease activity assessment and investigator's disease activity assessment parameters were collected.	Screening (Visit 1), Weeks 0 (Visit 2), 4 (Visit 3), 8 (Visit 4), 12 (Visit 5), 16 (Visit 6), 20 (Visit 7) and 24 (Visit 8)
Participant's Assessment of Pain	VAS is a visual scale of 100 mm for the assessment of disease activity by participants or investigator. Disease activity/pain increases while approaching 100 mm. For the screening visit (baseline visit) there's only investigator assessment data, for other visits participant's pain assessment, participant's disease activity assessment and investigator's disease activity assessment parameters were collected.	Weeks 0 (Visit 2), 4 (Visit 3), 8 (Visit 4), 12 (Visit 5), 16 (Visit 6), 20 (Visit 7) and 24 (Visit 8)
Health Assessment Questionnaire Score (General Score)	The Stanford HAQ disability index is a participant completed questionnaire specific for RA. It consists of 20 questions referring to 8 component sections: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities. The questionnaire was provided in validated translation into the local languages at the participating sites and was scored. Every question in each section was scored at a scale from 0 to 3 by the participant where 0 = able to perform the activity without any difficulty and 3 = unable to perform the activity. General score was calculated as an average of the 8 sections.	Weeks 0 (Visit 2), 4 (Visit 3), 8 (Visit 4), 12 (Visit 5), 16 (Visit 6), 20 (Visit 7) and 24 (Visit 8)

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche

Study record dates

Study Major Dates

• Study Start: September 1, 2011
• Primary Completion (Actual): August 1, 2014
• Study Completion (Actual): August 1, 2014

Study Registration Dates

• First Submitted: November 17, 2010
• First Submitted That Met QC Criteria: November 19, 2010
• First Posted (Estimate): November 22, 2010

Study Record Updates

• Last Update Posted (Estimate): November 3, 2015
• Last Update Submitted That Met QC Criteria: October 5, 2015
• Last Verified: October 1, 2015

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Arthritis; Arthritis, Rheumatoid
• Other Study ID Numbers: ML25095

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No