A Randomized, Double-blind Study of Safety and Prevention of Structural Joint Damage During Treatment With Tocilizumab Versus Placebo, in Combination With Methotrexate, in Patients With Moderate to Severe Rheumatoid Arthritis
Overview
- Phase
- Phase 3
- Intervention
- tocilizumab [RoActemra/Actemra]
- Conditions
- Rheumatoid Arthritis
- Sponsor
- Hoffmann-La Roche
- Enrollment
- 1196
- Primary Endpoint
- Change in Physical Function as Measured by the Area Under the Curve (AUC) for the Change From Baseline in the Health Assessment Questionnaire (HAQ) Disability Index at Week 52
- Status
- Completed
- Last Updated
- 12 years ago
Overview
Brief Summary
This 3 arm study will compare the safety and efficacy, with respect to a reduction in signs and symptoms and prevention of joint damage, of tocilizumab versus placebo, both in combination with methotrexate (MTX) in patients with moderate to severe active rheumatoid arthritis. Patients will be randomized to receive tocilizumab 4 mg/kg IV, tocilizumab 8 mg/kg IV or placebo IV, every 4 weeks. All patients will also receive methotrexate, 10-25 mg/week. The anticipated time on study treatment is 1-2 years and the target sample size is 500+ individuals. After completion of the 2 year study participants could participate in the optional 3 year open label extension phase (year 3 to 5).
Investigators
Eligibility Criteria
Inclusion Criteria
- •adult patients at least 18 years of age with moderate to severe active RA for at least 6 months;
- •inadequate response to a stable dose of MTX;
- •patients of reproductive potential must be using reliable methods of contraception.
Exclusion Criteria
- •major surgery (including joint surgery) within 8 weeks before entering study, or planned surgery within 6 months after entering study;
- •prior treatment failure with an anti-tumor necrosis factor agent;
- •women who are pregnant or breast-feeding.
Arms & Interventions
Tocilizumab 4 mg/kg + Methotrexate
Tocilizumab 4 mg/kg IV every 4 weeks plus MTX 10-25 mg (oral or parenteral) weekly for 52 weeks. From Week 16 participants with \< 20% improvement in swollen and tender joints counts were eligible for escape therapy with tocilizumab. After Week 52 participants were able to switch to open label treatment with tocilizumab 8 mg/kg every 4 weeks for 12 months in year 2 (except patients who had a \>70% improvement in both swollen and tender joint counts who remained on blinded treatment). Participants who completed year 2 of the study were eligible to enter an optional open-label long-term extension period (Year 3 to 5) and received Tocilizumab 8 mg/kg every 4 weeks.
Intervention: tocilizumab [RoActemra/Actemra]
Tocilizumab 4 mg/kg + Methotrexate
Tocilizumab 4 mg/kg IV every 4 weeks plus MTX 10-25 mg (oral or parenteral) weekly for 52 weeks. From Week 16 participants with \< 20% improvement in swollen and tender joints counts were eligible for escape therapy with tocilizumab. After Week 52 participants were able to switch to open label treatment with tocilizumab 8 mg/kg every 4 weeks for 12 months in year 2 (except patients who had a \>70% improvement in both swollen and tender joint counts who remained on blinded treatment). Participants who completed year 2 of the study were eligible to enter an optional open-label long-term extension period (Year 3 to 5) and received Tocilizumab 8 mg/kg every 4 weeks.
Intervention: Methotrexate
Tocilizumab 8 mg/kg + Methotrexate
Tocilizumab 8 mg/kg IV every 4 weeks plus MTX 10-25 mg (oral or parenteral) weekly for 52 weeks. From Week 16 participants with \< 20% improvement in swollen and tender joints counts were eligible for escape therapy with tocilizumab. After Week 52 participants were able to switch to open label treatment with tocilizumab 8 mg/kg every 4 weeks for 12 months in year 2 (except patients who had a \>70% improvement in both swollen and tender joint counts who remained on blinded treatment). Participants who completed year 2 of the study were eligible to enter an optional open-label long-term extension period (Year 3 to 5) and received Tocilizumab 8 mg/kg every 4 weeks.
Intervention: tocilizumab [RoActemra/Actemra]
Tocilizumab 8 mg/kg + Methotrexate
Tocilizumab 8 mg/kg IV every 4 weeks plus MTX 10-25 mg (oral or parenteral) weekly for 52 weeks. From Week 16 participants with \< 20% improvement in swollen and tender joints counts were eligible for escape therapy with tocilizumab. After Week 52 participants were able to switch to open label treatment with tocilizumab 8 mg/kg every 4 weeks for 12 months in year 2 (except patients who had a \>70% improvement in both swollen and tender joint counts who remained on blinded treatment). Participants who completed year 2 of the study were eligible to enter an optional open-label long-term extension period (Year 3 to 5) and received Tocilizumab 8 mg/kg every 4 weeks.
Intervention: Methotrexate
Placebo + Methotrexate
Placebo intravenously (IV) every 4 weeks plus methotrexate (MTX) 10-25 mg (oral or parenteral) weekly for 52 weeks. From Week 16 participants with \< 20% improvement in swollen and tender joints counts were eligible for escape therapy with tocilizumab. After Week 52 participants were able to switch to open label treatment with tocilizumab 8 mg/kg every 4 weeks for 12 months in year 2 (except patients who had a \>70% improvement in both swollen and tender joint counts who remained on blinded treatment). Participants who completed year 2 of the study were eligible to enter an optional open-label long-term extension period (Year 3 to 5) and received Tocilizumab 8 mg/kg every 4 weeks.
Intervention: Placebo
Placebo + Methotrexate
Placebo intravenously (IV) every 4 weeks plus methotrexate (MTX) 10-25 mg (oral or parenteral) weekly for 52 weeks. From Week 16 participants with \< 20% improvement in swollen and tender joints counts were eligible for escape therapy with tocilizumab. After Week 52 participants were able to switch to open label treatment with tocilizumab 8 mg/kg every 4 weeks for 12 months in year 2 (except patients who had a \>70% improvement in both swollen and tender joint counts who remained on blinded treatment). Participants who completed year 2 of the study were eligible to enter an optional open-label long-term extension period (Year 3 to 5) and received Tocilizumab 8 mg/kg every 4 weeks.
Intervention: Methotrexate
Outcomes
Primary Outcomes
Change in Physical Function as Measured by the Area Under the Curve (AUC) for the Change From Baseline in the Health Assessment Questionnaire (HAQ) Disability Index at Week 52
Time Frame: Baseline to Week 52
HAQ-DI consisted of 20 questions in 8 domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip; common daily activities rated on a 4-point scale where 0=without any difficulty to 3=unable to do. The sum of scores was divided by the number of domains with a score for a total possible score of 0 (best) to 3 (worst). Functional disability was determined as a cumulative measure of HAQ-DI over 1 year by using the AUC of the change from baseline in HAQ-DI score through week 52. Decreases in AUC of change from baseline in HAQ-DI indicate a greater average improvement in physical function over time and represent a decrease in sustained impairment. For patients with missing week 52 HAQ-DI score, the AUC of the change from baseline was standardized to 52 weeks using the latest timepoint available for calculation of the AUC. The mean was adjusted for region. A negative change from baseline indicated improvement.
Percentage of Participants With American College of Rheumatology-ACR20 Response
Time Frame: Baseline, Week 24
ACR20 response is defined as a ≥ 20% improvement (reduction) compared with baseline for both total joint count-68 joints (TJC68) and swollen joint count-66 joints (SJC66), as well as for three of the additional five ACR core set variables: Patient's Assessment of Pain over the previous 24 hours: using a Visual Analog Scale (VAS) left end of the line 0=no pain to right end of the line 100=unbearable pain; Patient's Global Assessment of Disease Activity and Physician's Global Assessment of Disease Activity over the previous 24 hours using a VAS where left end of the line 0=no disease activity to right end of the line 100=maximum disease activity; Health Assessment Questionnaire: 20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip and activities, 0=without difficulty to 3=unable to do; and acute-phase reactant, either C-reactive protein or Erythrocyte Sedimentation Rate.
Change From Baseline in the Modified Total Sharp-Genant Score at Week 104
Time Frame: Baseline, Week 104
Radiographs of each hand and foot were taken at Baseline and Week 104 and evaluated at a central reading service by two independent radiologists using the Genant modified method according to Sharp. Erosion Score: A total of 14 locations in each hand and wrist and 6 joints in the foot were evaluated for erosion using an 8-point scale where 0=Normal to 3.5=very severe erosion. Joint Narrowing Score: A total of 13 locations in each hand and wrist and 6 joints in the foot were evaluated for joint narrowing using a 9-point scale where 0=Normal to 4.0=definite ankylosis (stiffness or fixation of a joint). The maximum total erosion score in the hands is 100 and in the feet 42, the maximum scores for joint space narrowing in the hands is 100 and in the feet 48. The maximum modified Sharp score achievable is 290. A lower number change from Baseline indicated a better score.
Change From Baseline in Modified Total Sharp-Genant Score at Week 52
Time Frame: Baseline, Week 52
Radiographs were taken of each hand and foot at Baseline and Week 52 and evaluated at a central reading service by two independent radiologists using the Genant modified method according to Sharp. Erosion Score: A total of 14 locations in each hand and wrist and 6 joints in the foot were evaluated for erosion using an 8-point scale where 0=Normal to 3.5=very severe erosion. Joint Narrowing Score: A total of 13 locations in each hand and wrist and 6 joints in the foot were evaluated for joint narrowing score using a 9-point scale where 0=Normal to 4.0=definite ankylosis (stiffness or fixation of a joint). The maximum total erosion score in the hands is 100 (normalized from 98) and in the feet 42, the maximum scores for joint space narrowing in the hands is 100 (normalized from 104) and in the feet 48. The maximum modified Sharp score achievable is 290. A lower number change from Baseline indicated a better score.
Change in Physical Function as Measured by the Area Under the Curve for the Change From Baseline in the Health Assessment Questionnaire- Disability Index (HAQ-DI) at Week 104
Time Frame: Baseline to Week 104
HAQ-DI consisted of 20 questions in 8 domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip; common daily activities rated on a 4-point scale where 0=without any difficulty to 3=unable to do. The sum of scores was divided by the number of domains with a score for a total possible score of 0 (best) to 3 (worst). Functional disability was determined as a cumulative measure of HAQ-DI over 2 years by using the AUC of the change from baseline in HAQ-DI score through week 104. Decreases in AUC of change from baseline in HAQ-DI indicated a gr eater average improvement in physical function over time and represent a decrease in sustained impairment. For patients with missing week 104 HAQ-DI score, the AUC of the change from baseline was standardized to 104 weeks using the latest timepoint available for calculation of the AUC. A negative change from baseline indicated improvement.
Secondary Outcomes
- Percentage of Participants With ACR70 Response(Baseline,Week 24)
- Swollen Joint Count (66 Joint Count): Mean Change From Baseline at Week 24(Baseline, Week 24)
- Patient's Global Visual Analog Scale (VAS): Mean Change From Baseline at Week 24(Baseline, Week 24)
- Patient's Pain VAS: Mean Change From Baseline at Week 24(Baseline and Week 24)
- Change From Baseline in Swollen Joint Count at Week 52(Baseline, Week 52)
- Change From Baseline in Erythrocyte Sedimentation Rate (ESR) at Week 52(Baseline, Week 52)
- Change From Baseline in Swollen Joint Count at Week 104(Baseline, Week 104)
- Percentage of Participants With ACR50 Response(Baseline, Week 24)
- Tender Joint Count (68 Joint Count): Mean Change From Baseline at Week 24(Baseline, Week 24)
- Percentage of Participants With ACR70 Response at Week 104(Baseline, Week 104)
- Change From Baseline in the Patient's Pain VAS at Week 52(Baseline, Week 52)
- Change From Baseline in Physicians Global Assessment of Disease Activity at Week 104(Baseline, Week 104)
- Erythrocyte Sedimentation Rate: Mean Change From Baseline at Week 24(Baseline, Week 24)
- Percentage of Participants With ACR50 Response at Week 104(Baseline, Week 104)
- Percentage of Participants With ACR70 Response at Week 52(Baseline, Week 52)
- Percentage of Participants With ACR70 Response Maintained for 6 Consecutive Months(104 Weeks)
- Physician's Global VAS: Mean Change From Baseline at Week 24(Baseline, Week 24)
- Percentage of Participants With ACR50 Response at Week 52(Baseline, Week 52)
- Change From Baseline in Physicians Global Assessment of Disease Activity at Week 52(Baseline, Week 52)
- Change From Baseline in Patient's Global Assessment of Disease Activity at Week 104(Baseline, Week 104)
- Change From Baseline in Erythrocyte Sedimentation Rate (ESR) at Week 104(Baseline, Week 104)
- Percentage of Participants Who Achieve an Improvement of at Least 0.3 Units From Baseline in the HAQ Disability Index at Week 52(Baseline, Week 52)
- Area Under Curve (AUC) of the ACRn to Week 52(52 Weeks)
- Change From Baseline in Modified Total Sharp-Genant Score at Week 24(Baseline, Week 24)
- C-Reactive Protein (CRP): Mean Change From Baseline at Week 24(Baseline, Week 24)
- Health Assessment Questionnaire Disability Index (HAQ-DI): Mean Change From Baseline at Week 24(Baseline, Week 24)
- Percentage of Participants With American College of Rheumatology (ACR20) Response at Week 52(Baseline, Week 52)
- Percentage of Participants With ACR20 Response at Week 104(Baseline, Week 104)
- Change From Baseline in Patient's Global Assessment of Disease Activity at Week 52(Baseline, Week 52)
- Change From Baseline in Tender Joint Count at Week 52(Baseline, Week 52)
- Change From Baseline in C-Reactive Protein (CRP) at Week 52(Baseline, Week 52)
- Change From Baseline in Tender Joint Count at Week 104(Baseline, Week 104)
- Percentage of Participants Who Achieve an Improvement of at Least 0.3 Units From Baseline in the HAQ Disability Index at Week 104(Baseline, Week 104)
- Change From Baseline in Disease Activity Score (DAS28) at Week 24(Baseline, Week 24)
- Change From Baseline in Disease Activity Score (DAS28) at Week 104(Baseline, Week 104)
- Percentage of Participants With DAS28 Good or Moderate EULAR Response at Week 104(Baseline, Week 104)
- Area Under Curve (AUC) of Disease Activity Score (DAS28) at Week 104(104 Weeks)
- Change From Baseline in the Patient's Pain VAS at Week 104(Baseline, Week 104)
- Area Under Curve (AUC) of the ACRn Score at Week 104(104 Weeks)
- Change From Baseline in Disease Activity Score (DAS28) at Week 52(Baseline, Week 52)
- Percentage of Participants With DAS28 Good or Moderate EULAR Response at Week 52(Baseline, Week 52)
- Area Under Curve (AUC) of Disease Activity Score (DAS28) at Week 24(24 Weeks)
- Change From Baseline in Erosion Score at Week 104(Baseline, Week 104)
- Change From Baseline in Functional Assessment of Chronic Illness Therapy Fatigue (FACIT-F) Score at Week 24(Baseline, Week 24)
- Change From Baseline in Rheumatoid Factor (RF) at Week 104 in Those Patients With Positive RF(Baseline, Week 104)
- Change From Baseline in C-Reactive Protein (CRP) at Week 104(Baseline, Week 104)
- Percentage of Participants With DAS28 Remission at Week 24(Week 24)
- Area Under Curve (AUC) of Disease Activity Score (DAS28) at Week 52(52 Weeks)
- Change From Baseline in Modified Total Sharp-Genant Score at Week 80(Baseline, Week 80)
- Change From Baseline in Erosion Score at Week 52(Baseline, Week 52)
- Percentage of Participants With no Progression of Joint Space Narrowing at Week 104(Baseline, Week 104)
- Change From Baseline in HAQ Disability Index at Week 104(Baseline, Week 104)
- Area Under Curve (AUC) of the ACRn to Week 24(24 Weeks)
- Percentage of Participants With DAS28 Good or Moderate EULAR Response at Week 24(Baseline, Week 24)
- Percentage of Participants With DAS28 Remission at Week 52(Week 52)
- Percentage of Participants With DAS28 Remission at Week 104(Week 104)
- Change From Baseline in Erosion Score at Week 24(Baseline, Week 24)
- Change From Baseline in Erosion Score at Week 80(Baseline, Week 80)
- Change From Baseline in Joint Space Narrowing Score at Week 80(Baseline, Week 80)
- Percentage of Participants With no Progression of Erosion at Week 24(Baseline, Week 24)
- Percentage of Participants With no Progression of Erosion at Week 52(Baseline, Week 52)
- Percentage of Participants With no Progression of Erosion at Week 104(Baseline, Week 104)
- Change From Baseline in Joint Space Narrowing Score at Week 24(Baseline, Week 24)
- Change From Baseline in Joint Space Narrowing Score at Week 52(Baseline, Week 52)
- Change From Baseline in Joint Space Narrowing Score at Week 104(Baseline, Week 104)
- Percentage of Participants With no Progression of Joint Space Narrowing at Week 24(Baseline, Week 24)
- Time to Onset of ACR70 by Treatment Group(6 months)
- Percentage of Participants in Each Treatment Group Who Receive Escape Therapy(104 Weeks)
- End of Study: Change From Baseline in Swollen Joint Count at Week 260(Baseline, Week 260)
- End of Study: Change From Baseline in the Patient's Pain VAS at Week 260(Baseline, Week 260)
- Percentage of Participants With no Progression of Joint Space Narrowing at Week 52(Baseline, Week 52)
- Change From Baseline in SF-36 Score at Week 104(Baseline, Week 104)
- Change From Baseline in FACIT-F Score at Week 52(Baseline, Week 52)
- Change From Baseline in Rheumatoid Factor (RF) at Week 24 in Those Patients With Positive RF(Baseline, Week 24)
- Percentage of Participants Who Withdraw Due to Lack of Sufficient Therapeutic Response(104 Weeks)
- Percentage of Participants Who Achieved Remission According to the ACR Remission Criteria by Week 52(52 Weeks)
- Percentage of Participants Who Achieved Remission According to the ACR Remission Criteria by Week 104(104 Weeks)
- End of Study: Change From Baseline in Tender Joint Count at Week 260(Baseline, Week 260)
- End of Study: Change From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) at Week 260(Baseline, Week 260)
- End of Study: Percentage of Participants With Clinical Relevant Improvement in the SF-36 Score at Week 260(Baseline, Week 260)
- Change From Baseline in HAQ Disability Index (HAQ-DI) at Week 52(Baseline, Week 52)
- Change From Baseline in Quality Life Short Form-36 (SF-36) Score at Week 24(Baseline, Week 24)
- Change From Baseline in SF-36 Score at Week 52(Baseline, Week 52)
- Change From Baseline in FACIT-F Score at Week 104(Baseline, Week 104)
- Change From Baseline in Rheumatoid Factor (RF) at Week 52 in Those Patients With Positive RF(Baseline, Week 52)
- Time to Onset of ACR20 by Treatment Group(6 months)
- Time to Onset of ACR50 by Treatment Group(6 months)
- Percentage of Participants Who Achieved Complete Clinical Response at Week 52(52 Weeks)
- End of Study: Percentage of Participants With DAS28 European League Against Rheumatism (EULAR) Good or Moderate Response at Week 260(Baseline, Week 260)
- Percentage of Participants Who Achieved Remission According to the ACR Remission Criteria by Week 24(24 Weeks)
- Percentage of Participants Who Achieved Complete Clinical Response at Week 104(104 Weeks)
- End of Study: Percentage of Participants With ACR Response at Week 260(Baseline, Week 260)
- End of Study: Percentage of Participants With DAS28 Remission at Week 260(Week 260)
- End of Study: Percentage of Participants With DAS28 Low Disease Activity (LDA) at Week 260(Week 260)
- End of Study: Change From Baseline in the Patient's Global Assessment of Disease Activity Visual Analog Scale (VAS) at Week 260(Baseline, Week 260)
- End of Study: Change From Baseline in Total Sharp-Genant Score at Week 260(Baseline, Week 260)
- End of Study: Change From Baseline in Erosion Score at Week 260(Baseline, Week 260)
- End of Study: Change From Baseline in the Physician's Global Assessment of Disease Activity VAS at Week 260(Baseline, Week 260)
- End of Study: Percentage of Participants With Clinical Improvement in the FACIT-Fatigue Score at Week 260(Baseline, Week 260)
- End of Study: Change From Baseline in Joint Space Narrowing Score at Week 260(Baseline, Week 260)