A Long-Term Extension Study of WA22762 and NA25220 of Subcutaneous (SC) Tocilizumab (TCZ) in Moderate to Severe Rheumatoid Arthritis (RA)
- Registration Number
- NCT01662063
- Lead Sponsor
- Genentech, Inc.
- Brief Summary
This open-label extension study will evaluate the long-term safety and efficacy of SC TCZ in participants with moderate to severe RA who have completed the 97-week WA22762 (NCT01194414) or 96-week NA25220 (NCT01232569) core studies on SC or intravenous (IV) TCZ. Participants will receive TCZ 162 milligrams (mg) SC every week (QW) or every 2 weeks (Q2W) for up to 96 weeks.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 218
- Completed the 97-week WA22762 (NCT01194414) or 96-week NA25220 (NCT01232569) core study on SC or IV TCZ and, based on the Investigator's judgment, may continue to benefit from TCZ treatment in this study investigating the SC formulation
- Receiving treatment on an outpatient basis
- Females of childbearing potential and males with female partners of childbearing potential must agree to use reliable means of contraception as defined by protocol
- Premature withdrawal from WA22762 (NCT01194414) or NA25220 (NCT01232569) core studies for any reason
- History of severe allergic or anaphylactic reactions to human, humanized, or murine monoclonal antibodies
- Evidence of serious uncontrolled concomitant disease or disorder
- Known active current or history of recurrent bacterial, viral, fungal, mycobacterial, or other infections
- Any major episode of infection requiring hospitalization or treatment with IV antibiotics within 4 weeks of Screening or oral antibiotics within 2 weeks of Screening
- History of or currently active primary or secondary immunodeficiency
- Oral corticosteroids at greater than (>) 10 mg per day prednisone or equivalent, or non-steroidal anti-inflammatory drugs (NSAIDs) above the maximum recommended dose
- Intra-articular or parenteral corticosteroids within 4 weeks prior to Baseline
- Treatment with any investigational or commercially available biologic disease-modifying anti-rheumatic drug (DMARD) other than TCZ at any time between completion of the core study WA22762 (NCT01194414) or NA25220 (NCT01232569) and enrollment in the long-term extension study
- Pregnant or breastfeeding women
- History of alcohol, drug, or chemical abuse within 1 year prior to Screening
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description SC TCZ QW Tocilizumab Participants who received IV TCZ in the previous trial will be switched to SC TCZ 162 mg QW, and those who received SC TCZ will continue at their same dosage of SC TCZ 162 mg QW. Tocilizumab will be given for an additional 96 weeks in this open-label extension study. SC TCZ Q2W Tocilizumab Participants who received SC TCZ will continue at their same dosage of SC TCZ 162 mg Q2W. Tocilizumab will be given for an additional 96 weeks in this open-label extension study.
- Primary Outcome Measures
Name Time Method Number of Participants With at Least One Serious Adverse Event (SAE) From Baseline to 8 weeks after last dose; assessed continuously during treatment (up to 96 weeks) and up to 8 weeks after last dose (up to 2 years overall) Adverse events (AEs) were monitored throughout treatment. AEs were defined as any untoward medical occurrence in a participant who received study drug regardless of causality. SAEs were defined as AEs that were fatal or life-threatening, required hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, manifested as a congenital anomaly/birth defect, were medically significant, or required intervention to prevent any of the aforementioned outcomes. The number of participants with at least one SAE regardless of treatment relationship was reported.
Percentage of Participants With a Positive Anti-TCZ Antibody Assay at Baseline Baseline Blood samples were collected to test for the presence of antibodies to TCZ. The percentage of participants with a positive anti-TCZ antibody assay was calculated.
Percentage of Participants With a Positive Anti-TCZ Antibody Assay Post-Baseline From Week 12 up to 8 weeks after last dose; assessed at Weeks 12, 24, 36, 48, 60, 72, 84, 96; and up to 8 weeks after last dose (up to 2 years overall) Blood samples were collected to test for the presence of antibodies to TCZ. The percentage of participants with a positive anti-TCZ antibody assay was calculated. Positive assay results obtained post-Baseline were further investigated via confirmation assay and a neutralization assay.
Percentage of Participants With at Least One SAE From Baseline to 8 weeks after last dose; assessed continuously during treatment (up to 96 weeks) and up to 8 weeks after last dose (up to 2 years overall) AEs were monitored throughout treatment. AEs were defined as any untoward medical occurrence in a participant who received study drug regardless of causality. SAEs were defined as AEs that were fatal or life-threatening, required hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, manifested as a congenital anomaly/birth defect, were medically significant, or required intervention to prevent any of the aforementioned outcomes. The percentage of participants with at least one SAE regardless of treatment relationship was calculated.
Percentage of Participants With a Positive Anti-TCZ Antibody Assay at Any Timepoint From Baseline to 8 weeks after last dose; assessed at Baseline; Weeks 12, 24, 36, 48, 60, 72, 84, 96; and up to 8 weeks after last dose (up to 2 years overall) Blood samples were collected to test for the presence of antibodies to TCZ. The percentage of participants with a positive anti-TCZ antibody assay was calculated.
- Secondary Outcome Measures
Name Time Method Change From Baseline in DAS28 Score Baseline to Weeks 12, 24, 36, 48, 60, 72, 84 The DAS28 was calculated using the SJC, TJC, ESR, and Global Assessment of Disease Activity by the participant according to VAS score. For the DAS28 formula, the SJC and TJC values were based upon 28 joints, and VAS was transformed from a 100-mm scale to a 10-point score. The DAS28 was calculated as (0.56 × square root of TJC) + (0.28 × square root of SJC) + (0.7 × ln ESR) + (0.014 × VAS). Scores may range from 0 to 10, where higher scores indicate increased disease activity. The change from Baseline to each visit was calculated, where positive changes represent an increase or worsening in disease activity.
Clinical Disease Activity Index (CDAI) Score Baseline and Weeks 12, 24, 36, 48, 60, 72, 84 The CDAI was calculated using the SJC, TJC, and Global Assessment of Disease Activity by the patient and by the physician according to separate VAS scores. For the CDAI formula, the SJC and TJC values were based upon 28 joints, and VAS was transformed from a 100-mm scale to a 10-point score. The CDAI was calculated as the sum of the component scores, that is, SJC + TJC + VAS (participant) + VAS (physician). Scores may range from 0 to 76, where higher scores indicate increased disease activity.
Percentage of Participants Who Correctly Administered All SC TCZ Doses From Baseline to last dose; assessed every 4 weeks during treatment (up to 96 weeks overall) Compliance was assessed using drug dispensing logs, diary cards kept by the participant, and return records, as reviewed by the Investigator at regular visits. Total compliance up to the end of treatment was defined as the percentage of participants who correctly administered all scheduled doses of SC TCZ. Correct administration was defined as proper injection technique, injection of the correct amount (162 mg), device not left at room temperature for greater than (\>) 8 hours, and absence of other medication errors.
Disease Activity Score Based on 28 Joints (DAS28) Score Baseline and Weeks 12, 24, 36, 48, 60, 72, 84 The DAS28 was calculated using the Swollen Joint Count (SJC), Tender Joint Count (TJC), erythrocyte sedimentation rate (ESR), and Global Assessment of Disease Activity by the participant according to Visual Analog Scale (VAS) score. For the DAS28 formula, the SJC and TJC values were based upon 28 joints, and VAS was transformed from a 100-millimeter (mm) scale to a 10-point score. The DAS28 was calculated as (0.56 multiplied by \[×\] square root of TJC) + (0.28 × square root of SJC) + (0.7 × log natural \[ln\] ESR) + (0.014 × VAS). Scores may range from 0 to 10, where higher scores indicate increased disease activity.
Global Assessment of Disease Activity by the Participant According to Visual Analog Scale (VAS) Score Baseline and Weeks 12, 24, 36, 48, 60, 72, 84 The Global Assessment of Disease Activity was performed using a 100-mm horizontal VAS. Scores may range from 0 mm ("no disease activity") to 100 mm ("maximum disease activity"), with higher scores representing an increase in perceived symptoms.
Change From Baseline in CDAI Score Baseline to Weeks 12, 24, 36, 48, 60, 72, 84 The CDAI was calculated using the SJC, TJC, and Global Assessment of Disease Activity by the patient and by the physician according to separate VAS scores. For the CDAI formula, the SJC and TJC values were based upon 28 joints, and VAS was transformed from a 100-mm scale to a 10-point score. The CDAI was calculated as the sum of the component scores, that is, SJC + TJC + VAS (participant) + VAS (physician). Scores may range from 0 to 76, where higher scores indicate increased disease activity. The change from Baseline to each visit was calculated, where positive changes represent an increase or worsening in disease activity.
Simplified Disease Activity Index (SDAI) Score Baseline and Weeks 12, 24, 36, 48, 60, 72, 84 The SDAI was calculated using the SJC, TJC, Global Assessment of Disease Activity by the patient and by the physician according to separate VAS scores, and high-sensitivity C-reactive protein (hsCRP) level. For the SDAI formula, the SJC and TJC values were based upon 28 joints, and VAS was transformed from a 100-mm scale to a 10-point score. The SDAI was calculated as the sum of the component scores, that is, SJC + TJC + VAS (participant) + VAS (physician) + hsCRP. Because the formula includes hsCRP, scores may theoretically range from 0 to infinity, where higher scores indicate increased disease activity. However, based upon normal hsCRP level within 1 milligram per deciliter (mg/dL), scores would be expected to fall within less than or equal to (≤) 77 points.
Change From Baseline in SDAI Score Baseline to Weeks 12, 24, 36, 48, 60, 72, 84 The SDAI was calculated using the SJC, TJC, Global Assessment of Disease Activity by the patient and by the physician according to separate VAS scores, and hsCRP level. For the SDAI formula, the SJC and TJC values were based upon 28 joints, and VAS was transformed from a 100-mm scale to a 10-point score. The SDAI was calculated as the sum of the component scores, that is, SJC + TJC + VAS (participant) + VAS (physician) + hsCRP. Because the formula includes hsCRP, scores may theoretically range from 0 to infinity, where higher scores indicate increased disease activity. However, based upon normal hsCRP level within 1 mg/dL, scores would be expected to fall within ≤77 points. The change from Baseline to each visit was calculated, where positive changes represent an increase or worsening in disease activity.
Tender Joint Count (TJC) Score Baseline and Weeks 12, 24, 36, 48, 60, 72, 84 Sixty-eight joints were assessed and classified as tender/not tender by pressure and joint manipulation on physical examination. The number of tender joints was taken as the TJC score, where values may range from 0 to 68.
Change From Baseline in TJC Score Baseline to Weeks 12, 24, 36, 48, 60, 72, 84 Sixty-eight joints were assessed and classified as tender/not tender by pressure and joint manipulation on physical examination. The number of tender joints was taken as the TJC score, where values may range from 0 to 68. The change from Baseline to each visit was calculated, where positive changes represent an increase in number of tender joints.
Change From Baseline in SJC Score Baseline to Weeks 12, 24, 36, 48, 60, 72, 84 Sixty-six joints were assessed and classified as swollen/not swollen by pressure and joint manipulation on physical examination. The number of swollen joints was taken as the SJC score, where values may range from 0 to 66. The change from Baseline to each visit was calculated, where positive changes represent an increase in number of swollen joints.
Percentage of Reasons Given for DMARD Discontinuation From Baseline to last dose; assessed every 4 weeks during treatment (up to 96 weeks overall) Use of concomitant medications, including non-biologic DMARDs, was recorded throughout the study. Any change in DMARD therapy was documented and reported among those participants receiving at least one DMARD at Baseline. The reasons for any DMARD discontinuation were reported. More than one reason could be given for a single change in DMARD therapy, and each participant could also change DMARD therapy more than once. Therefore, the number of reasons could exceed the number of participants analyzed.
Swollen Joint Count (SJC) Score Baseline and Weeks 12, 24, 36, 48, 60, 72, 84 Sixty-six joints were assessed and classified as swollen/not swollen by pressure and joint manipulation on physical examination. The number of swollen joints was taken as the SJC score, where values may range from 0 to 66.
Number of Participants With a Disease-Modifying Anti-Rheumatic Drug (DMARD) Dose Reduction, Interruption, or Discontinuation From Baseline to last dose; assessed every 4 weeks during treatment (up to 96 weeks overall) Use of concomitant medications, including non-biologic DMARDs, was recorded throughout the study. Any change in DMARD therapy was documented and reported among those participants receiving at least one DMARD at Baseline.
Percentage of Participants With a DMARD Dose Reduction, Interruption, or Discontinuation From Baseline to last dose; assessed every 4 weeks during treatment (up to 96 weeks overall) Use of concomitant medications, including non-biologic DMARDs, was recorded throughout the study. Any change in DMARD therapy was documented and reported among those participants receiving at least one DMARD at Baseline.
Percentage of Reasons Given for DMARD Dose Reduction or Interruption From Baseline to last dose; assessed every 4 weeks during treatment (up to 96 weeks overall) Use of concomitant medications, including non-biologic DMARDs, was recorded throughout the study. Any change in DMARD therapy was documented and reported among those participants receiving at least one DMARD at Baseline. The reasons for any DMARD dose reduction/interruption ≤60 days were reported. More than one reason could be given for a single change in DMARD therapy, and each participant could also change DMARD therapy more than once. Therefore, the number of reasons could exceed the number of participants analyzed.
Number of Participants With a Corticosteroid (CCS) Dose Reduction, Interruption, or Discontinuation From Baseline to last dose; assessed every 4 weeks during treatment (up to 96 weeks overall) Use of concomitant medications, including CCS treatment, was recorded throughout the study. Any change in CCS therapy was documented and reported among those participants who received at least one CCS before the last dose of SC TCZ.
Percentage of Participants With a CCS Dose Reduction, Interruption, or Discontinuation From Baseline to last dose; assessed every 4 weeks during treatment (up to 96 weeks overall) Use of concomitant medications, including CCS treatment, was recorded throughout the study. Any change in CCS therapy was documented and reported among those participants who received at least one CCS before the last dose of SC TCZ.
Percentage of Reasons Given for CCS Dose Reduction From Baseline to last dose; assessed every 4 weeks during treatment (up to 96 weeks overall) Use of concomitant medications, including CCS treatment, was recorded throughout the study. Any change in CCS therapy was documented and reported among those participants who received at least one CCS before the last dose of SC TCZ. The reasons for any CCS dose reduction were reported. More than one reason could be given for a single change in CCS therapy, and each participant could also change CCS therapy more than once. Therefore, the number of reasons could exceed the number of participants analyzed.
Percentage of Reasons Given for CCS Dose Interruption From Baseline to last dose; assessed every 4 weeks during treatment (up to 96 weeks overall) Use of concomitant medications, including CCS treatment, was recorded throughout the study. Any change in CCS therapy was documented and reported among those participants who received at least one CCS before the last dose of SC TCZ. The reasons for any CCS dose interruption ≤14 days were reported. More than one reason could be given for a single change in CCS therapy, and each participant could also change CCS therapy more than once. Therefore, the number of reasons could exceed the number of participants analyzed.
Number of Participants Who Returned to the QW Regimen After Switching to the Q2W Regimen From Baseline to last dose; assessed every 4 weeks during treatment (up to 96 weeks overall) Participants could switch between regimens at the Investigator's judgment based upon safety, efficacy, and pharmacokinetic/pharmacodynamic data. The number of participants who switched from the QW to the Q2W regimen and thereafter returned to the QW regimen was reported with the reason for returning to the QW regimen.
Change From Baseline in Global Assessment of Pain by the Participant According to VAS Score Baseline to Weeks 12, 24, 36, 48, 60, 72, 84 The Global Assessment of Pain was performed using a 100-mm horizontal VAS. Scores may range from 0 mm ("no pain") to 100 mm ("unbearable pain"), with higher scores representing an increase in pain. The change from Baseline to each visit was calculated, where positive changes represent an increase or worsening in pain.
Number of Participants With Low Disease Activity According to DAS28, SDAI, and CDAI Criteria Baseline and Weeks 12, 24, 36, 48, 60, 72, 84 Low disease activity was defined as DAS28 ≤3.2, SDAI ≤11, or CDAI ≤10. For each formula, the SJC and TJC values were based upon 28 joints, and VAS was transformed from a 100-mm scale to a 10-point score. The DAS28 was calculated as (0.56 × square root of TJC) + (0.28 × square root of SJC) + (0.7 × ln ESR) + (0.014 × VAS), with potential scores from 0 to 10. The SDAI was calculated as SJC + TJC + VAS (participant) + VAS (physician) + hsCRP, with potential scores from 0 to infinity. However, based upon normal hsCRP level within 1 mg/dL, scores would be expected to fall within ≤77 points. The CDAI was calculated as SJC + TJC + VAS (participant) + VAS (physician), with potential scores from 0 to 76. For all instruments, higher scores indicate increased disease activity. The number of participants who met criteria for low disease activity was reported at each visit.
Percentage of Reasons Given for CCS Discontinuation From Baseline to last dose; assessed every 4 weeks during treatment (up to 96 weeks overall) Use of concomitant medications, including CCS treatment, was recorded throughout the study. Any change in CCS therapy was documented and reported among those participants who received at least one CCS before the last dose of SC TCZ. The reasons for any CCS discontinuation \>14 days were reported. More than one reason could be given for a single change in CCS therapy, and each participant could also change CCS therapy more than once. Therefore, the number of reasons could exceed the number of participants analyzed.
Number of Participants Who Switched From the QW Regimen and Remained on the Q2W Regimen From Baseline to last dose; assessed every 4 weeks during treatment (up to 96 weeks overall) Participants could switch between regimens at the Investigator's judgment based upon safety, efficacy, and pharmacokinetic/pharmacodynamic data. The number of participants who switched from the QW to the Q2W regimen and did not return to the QW regimen was reported.
Percentage of Participants Who Switched From the QW Regimen and Remained on the Q2W Regimen From Baseline to last dose; assessed every 4 weeks during treatment (up to 96 weeks overall) Participants could switch between regimens at the Investigator's judgment based upon safety, efficacy, and pharmacokinetic/pharmacodynamic data. The percentage of participants who switched from the QW to the Q2W regimen and did not return to the QW regimen was calculated.
Time to Return to the QW Regimen After Switching to the Q2W Regimen From Baseline to last dose; assessed every 4 weeks during treatment (up to 96 weeks overall) Participants could switch between regimens at the Investigator's judgment based upon safety, efficacy, and pharmacokinetic/pharmacodynamic data. Time to return was defined as the time between switching to the Q2W regimen and returning to the previous QW regimen.
Change From Baseline in Global Assessment of Disease Activity by the Participant According to VAS Score Baseline to Weeks 12, 24, 36, 48, 60, 72, 84 The Global Assessment of Disease Activity was performed using a 100-mm horizontal VAS. Scores may range from 0 mm ("no disease activity") to 100 mm ("maximum disease activity"), with higher scores representing an increase in perceived symptoms. The change from Baseline to each visit was calculated, where positive changes represent an increase or worsening in perceived disease activity.
Percentage of Participants With HAQ-DI Score <0.5 Baseline and Weeks 12, 24, 36, 48, 60, 72, 84 The Stanford HAQ-DI was calculated as the average of 20 questions, each scored from 0 (no difficulty) to 3 (unable to do). The questionnaire included 8 component sets: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and common activities. Overall scores may range from 0 to 3, with higher scores representing increased disability. The percentage of participants achieving a score \<0.5 was calculated at each visit.
Global Assessment of Pain by the Participant According to VAS Score Baseline and Weeks 12, 24, 36, 48, 60, 72, 84 The Global Assessment of Pain was performed using a 100-mm horizontal VAS. Scores may range from 0 mm ("no pain") to 100 mm ("unbearable pain"), with higher scores representing an increase in pain.
Percentage of Participants With Low Disease Activity According to DAS28, SDAI, and CDAI Criteria Baseline and Weeks 12, 24, 36, 48, 60, 72, 84 Low disease activity was defined as DAS28 ≤3.2, SDAI ≤11, or CDAI ≤10. For each formula, the SJC and TJC values were based upon 28 joints, and VAS was transformed from a 100-mm scale to a 10-point score. The DAS28 was calculated as (0.56 × square root of TJC) + (0.28 × square root of SJC) + (0.7 × ln ESR) + (0.014 × VAS), with potential scores from 0 to 10. The SDAI was calculated as SJC + TJC + VAS (participant) + VAS (physician) + hsCRP, with potential scores from 0 to infinity. However, based upon normal hsCRP level within 1 mg/dL, scores would be expected to fall within ≤77 points. The CDAI was calculated as SJC + TJC + VAS (participant) + VAS (physician), with potential scores from 0 to 76. For all instruments, higher scores indicate increased disease activity. The percentage of participants who met criteria for low disease activity was calculated at each visit.
Percentage of Participants With Remission According to DAS28, SDAI, and Boolean Criteria Baseline and Weeks 12, 24, 36, 48, 60, 72, 84 Remission was defined as DAS28 \<2.6, SDAI ≤3.3, or meeting all Boolean criteria (28-count SJC and TJC ≤1, VAS ≤10 mm, and hsCRP ≤1 mg/dL). For DAS28 and SDAI formulas, the SJC and TJC values were based upon 28 joints, and VAS was transformed from a 100-mm scale to a 10-point score. The DAS28 was calculated as (0.56 × square root of TJC) + (0.28 × square root of SJC) + (0.7 × ln ESR) + (0.014 × VAS), with potential scores from 0 to 10. The SDAI was calculated as SJC + TJC + VAS (participant) + VAS (physician) + hsCRP, with potential scores from 0 to infinity. However, based upon normal hsCRP level within 1 mg/dL, scores would be expected to fall within ≤77 points. For these instruments, higher scores indicate increased disease activity. The percentage of participants who met criteria for remission was calculated at each visit.
Heath Assessment Questionnaire-Disability Index (HAQ-DI) Score Baseline and Weeks 12, 24, 36, 48, 60, 72, 84 The Stanford HAQ-DI was calculated as the average of 20 questions, each scored from 0 (no difficulty) to 3 (unable to do). The questionnaire included 8 component sets: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and common activities. Overall scores may range from 0 to 3, with higher scores representing increased disability.
Change From Baseline in HAQ-DI Score Baseline to Weeks 12, 24, 36, 48, 60, 72, 84 The Stanford HAQ-DI was calculated as the average of 20 questions, each scored from 0 (no difficulty) to 3 (unable to do). The questionnaire included 8 component sets: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and common activities. Overall scores may range from 0 to 3, with higher scores representing increased disability. The change from Baseline to each visit was calculated, where positive changes represent an increased need for assistance with daily activities.
Number of Participants With Remission According to DAS28, SDAI, and Boolean Criteria Baseline and Weeks 12, 24, 36, 48, 60, 72, 84 Remission was defined as DAS28 \<2.6, SDAI ≤3.3, or meeting all Boolean criteria (28-count SJC and TJC ≤1, VAS ≤10 mm, and hsCRP ≤1 mg/dL). For DAS28 and SDAI formulas, the SJC and TJC values were based upon 28 joints, and VAS was transformed from a 100-mm scale to a 10-point score. The DAS28 was calculated as (0.56 × square root of TJC) + (0.28 × square root of SJC) + (0.7 × ln ESR) + (0.014 × VAS), with potential scores from 0 to 10. The SDAI was calculated as SJC + TJC + VAS (participant) + VAS (physician) + hsCRP, with potential scores from 0 to infinity. However, based upon normal hsCRP level within 1 mg/dL, scores would be expected to fall within ≤77 points. For these instruments, higher scores indicate increased disease activity. The number of participants who met criteria for remission was reported at each visit.