Back to resultsAn Efficacy and Safety Study of Subcutaneous Tocilizumab in Combination With Methotrexate (MTX) and as Monotherapy Versus MTX in Participants With Moderate to Severe Rheumatoid Arthritis With Inadequate Response to Current Disease-Modifying Antirheumatic Drug (DMARD) Therapy
Primary Purpose
Rheumatoid Arthritis
Status
Completed
Phase
Phase 3
Locations
China
Study Type
Interventional
Intervention
Tocilizumab
MTX
Placebo Matched to MTX
Placebo Matched to Tocilizumab
Sponsored by
About this trial
This is an interventional treatment trial for Rheumatoid Arthritis
Eligibility Criteria
Inclusion Criteria:
- Chinese participants who are located in mainland China with RA of greater than or equal to (>=) 6 months' duration from onset of the disease, diagnosed according to the revised 1987 ACR criteria and receiving treatment on an outpatient basis
- Participants must have discontinued etanercept (or YiSaiPu) for >= 2 weeks, infliximab, certolizumab, golimumab, abatacept or adalimumab for >= 8 weeks, anakinra for >= 1 week prior to randomization
- Have received oral MTX at a stable dose for at least 12 weeks prior to baseline (MTX dose 10 to 25 mg) and experience of failing at least one non-biologic DMARD including MTX
- All treatment with non-biological DMARDs except MTX should be withdrawn at least 2 weeks prior to baseline (leflunomide for >= 12 weeks or >= 14 days after standard cholestyramine or activated charcoal washout, azathioprine for >= 4 weeks)
- SJC >= 6 (on the basis of 66 joint counts) and TJC >= 8 (on the basis of 68 joint counts) at screening and baseline with at least 3 months of treatment with permitted DMARDs
- Participants must have either high sensitive CRP >= 10 milligrams per liter (mg/L) or ESR >=28 millimeters per hour (mm/hr) at screening
- Oral corticosteroids (<=10 mg/day prednisone or equivalent) and nonsteroidal anti-inflammatory drug (NSAIDs; up to the maximum recommended dose per local standard of care) are permitted if the dose has been stable for at least 4 weeks prior to baseline
- All treatment with Chinese traditional medicine and/or herb medicine for RA treatment should be withdrawn at least 2 weeks prior to baseline
- Females of childbearing potential and males with female partners of childbearing potential may participate only if using a reliable means of contraception as defined by the protocol
Exclusion Criteria:
- Participants with major surgery or planned major surgery, rheumatic autoimmune disease other than RA, and functional class IV (as defined by the ACR Classification of Functional Status in RA)
- Participants with unsuccessful treatment with an anti-tumor necrosis factor (anti-TNF) agent; previous treatment with any cell-depleting therapies including investigational agents and janus kinase (JAK) inhibitors or any other new agents which have DMARD/DMARD-like effect; treatment with intravenous (IV) gamma-globulin, plasmapheresis, or Prosorba column; treatment with alkylating agents
- Intra-articular or parenteral corticosteroids and/or immunization with a live/attenuated vaccine within 4 weeks prior to baseline
- History of severe allergic or anaphylactic reactions to human, humanized, or murine monoclonal antibodies
- Primary or secondary immunodeficiency (history of or currently active)
- Evidence of serious uncontrolled concomitant diseases and disease states; evidence of active malignant disease
- Participants with abnormal haematological parameters, abnormal renal and hepatic parameters
- Positive for either hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) and/or hepatitis C virus (HCV) antibody
Sites / Locations
- The First Affiliated Hospital of Baotou Medical College
- China-Japan Friendship Hospital
- Peking University First Hospital
- Peking University People's Hospital
- Beijing Union Hospital
- Affiliated Hospital of Bengbu Medical College
- the First Hospital of Jilin University
- West China Hospital, Sichuan University
- Guangdong General Hospital
- The 1st Affiliated Hospital of Harbin Medical University
- The First Affiliated Hospital of Anhui Medical University
- Affiliated Hospital of Inner Mongolia Medical College
- The First Hospital of Jiaxing
- Qilu Hospital of Shandong University
- The First Affilliated Hospital of Kunming Medical College
- Jiangsu Province Hospital
- Pingxiang People Hospital
- Shengjing Hospital of China Medical University
- The Second Hospital of Shanxi Medical University
- Tianjin Medical University General Hospital
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm Type
Experimental
Experimental
Active Comparator
Arm Label
Tocilizumab + MTX
Tocilizumab + Placebo Matched to MTX
Placebo Matched to Tocilizumab + MTX
Arm Description
Participants will receive tocilizumab SC injections Q2W along with MTX orally every week (QW) for 24-week double-blind treatment phase. Participants who complete the 24-week double-blind treatment phase may continue treatment until Week 48 in the extension phase, irrespective if they achieve or do not achieve DAS28 low activity (DAS28-ESR <= 3.2).
Participants will receive tocilizumab SC Q2W along with placebo matched to MTX for 24-week double-blind treatment phase. Participants who complete the 24-week double-blind treatment phase may continue treatment until Week 48 in the extension phase. In the extension phase up to Week 48, participants who achieve DAS28 low activity (DAS28-ESR <= 3.2) will remain on the same treatment they received in double-blind phase. Participants who do not achieve DAS28-ESR <= 3.2 will receive treatment with tocilizumab 162 mg SC Q2W + MTX from Week 26 to Week 48.
Participants will receive placebo matched to tocilizumab along with MTX orally QW for 24-week double-blind treatment phase. Participants who complete the 24-week double-blind treatment phase may continue treatment until Week 48 in the extension phase. In the extension phase up to Week 48, participants who achieve DAS28 low activity (DAS28-ESR <= 3.2) will remain on the same treatment they received in double-blind phase. Participants who do not achieve DAS28-ESR <= 3.2 will receive treatment with tocilizumab 162 mg SC Q2W + MTX from Week 26 to Week 48.
Outcomes
Primary Outcome Measures
Percentage of Participants With an American College of Rheumatology (ACR) 20 (ACR20) Response at Week 24
Secondary Outcome Measures
Percentage of Participants With Low Disease Activity at Week 24, Defined as Disease Activity Score 28-Erythrocyte Sedimentation Rate (DAS28-ESR) Score of Less Than or Equal to (<=) 3.2
Percentage of Participants With Remission at Week 24, Defined as DAS28-ESR Score of Less Than (<) 2.6
Change From Baseline in Tender Joint Count (TJC) at Week 24
Change From Baseline in Swollen Joint Count (SJC) at Week 24
Change From Baseline in C-reactive Protein (CRP) Levels at Week 24
Change From Baseline in Erythrocyte Sedimentation Rate (ESR) at Week 24
Change From Baseline in the Patient's Global Assessment of Disease Activity Visual Analog Scale (VAS) Score at Week 24
Change From Baseline in the Physician's Global Assessment of Disease Activity VAS Score at Week 24
Change From Baseline in the Health Assessment Questionnaire-Disability Index (HAQ-DI) Score at Week 24
Change From Baseline in the Patient's Pain VAS at Week 24
Change From Baseline in DAS28-ESR at Week 24
Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
Percentage of Participants With anti-Tocilizumab Antibody
Serum Interleukin-6 (IL-6) Levels
Serum Soluble Interleukin-6 Receptor (sIL-6R) Levels
Maximum Observed Plasma Concentration (Cmax) of Tocilizumab
Minimum Observed Plasma Concentration (Cmin) of Tocilizumab
Time to Reach Maximum Observed Plasma Concentration (Tmax) of Tocilizumab
Plasma Decay Half-Life (t1/2) of Tocilizumab
Area Under the Curve from Time Zero to end of dosing interval (AUCtau) of Tocilizumab
Accumulation Ratio for Area Under the Concentration Time Curve (Rac, AUC) of Tocilizumab
Accumulation Ratio for Maximum Observed Plasma Concentration (Rac, Cmax) of Tocilizumab
Accumulation Ratio for Minimum Observed Plasma Trough Concentration (Rac, Cmin) of Tocilizumab
Plasma Trough Concentration (Ctrough) of Tocilizumab
Percentage of Participants With ACR50 Responses at Week 24
Percentage of Participants With ACR70 Responses at Week 24
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT03155347
Brief Title
An Efficacy and Safety Study of Subcutaneous Tocilizumab in Combination With Methotrexate (MTX) and as Monotherapy Versus MTX in Participants With Moderate to Severe Rheumatoid Arthritis With Inadequate Response to Current Disease-Modifying Antirheumatic Drug (DMARD) Therapy
Official Title
A Randomized, Multi-Center, Double Blind, Parallel-Group Study to Evaluate the Efficacy and Safety of Subcutaneous (SC) Tocilizumab (TCZ) in Combination With Methotrexate (MTX) and as Monotherapy Versus MTX in Patients With Moderate to Severe Rheumatoid Arthritis With Inadequate Response to Current DMARD Therapy
Study Type
Interventional
2. Study Status
Record Verification Date
December 2022
Overall Recruitment Status
Completed
Study Start Date
August 2, 2017 (Actual)
Primary Completion Date
August 8, 2022 (Actual)
Study Completion Date
August 8, 2022 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Hoffmann-La Roche
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No
5. Study Description
Brief Summary
This is a randomized, double-blind, multi-center, parallel-group study to evaluate the efficacy and safety of subcutaneous (SC) tocilizumab (162 milligrams [mg] every 2 weeks [Q2W]) given as monotherapy and in combination with MTX versus MTX given as monotherapy, in participants with moderate to severe active rheumatoid arthritis (RA) who have inadequate response to current DMARD therapy. The study comprises a 24-week double-blind treatment phase, followed by a 24-week extension phase.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Rheumatoid Arthritis
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
340 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Tocilizumab + MTX
Arm Type
Experimental
Arm Description
Participants will receive tocilizumab SC injections Q2W along with MTX orally every week (QW) for 24-week double-blind treatment phase. Participants who complete the 24-week double-blind treatment phase may continue treatment until Week 48 in the extension phase, irrespective if they achieve or do not achieve DAS28 low activity (DAS28-ESR <= 3.2).
Arm Title
Tocilizumab + Placebo Matched to MTX
Arm Type
Experimental
Arm Description
Participants will receive tocilizumab SC Q2W along with placebo matched to MTX for 24-week double-blind treatment phase. Participants who complete the 24-week double-blind treatment phase may continue treatment until Week 48 in the extension phase. In the extension phase up to Week 48, participants who achieve DAS28 low activity (DAS28-ESR <= 3.2) will remain on the same treatment they received in double-blind phase. Participants who do not achieve DAS28-ESR <= 3.2 will receive treatment with tocilizumab 162 mg SC Q2W + MTX from Week 26 to Week 48.
Arm Title
Placebo Matched to Tocilizumab + MTX
Arm Type
Active Comparator
Arm Description
Participants will receive placebo matched to tocilizumab along with MTX orally QW for 24-week double-blind treatment phase. Participants who complete the 24-week double-blind treatment phase may continue treatment until Week 48 in the extension phase. In the extension phase up to Week 48, participants who achieve DAS28 low activity (DAS28-ESR <= 3.2) will remain on the same treatment they received in double-blind phase. Participants who do not achieve DAS28-ESR <= 3.2 will receive treatment with tocilizumab 162 mg SC Q2W + MTX from Week 26 to Week 48.
Intervention Type
Drug
Intervention Name(s)
Tocilizumab
Other Intervention Name(s)
RO4877533
Intervention Description
Participants will receive tocilizumab 162 mg given as 0.9 milliliter (mL) of a 180 mg/mL solution in a prefilled syringe, administered by SC injection Q2W.
Intervention Type
Drug
Intervention Name(s)
MTX
Intervention Description
Participants will receive MTX stable doses at 10 to 25 mg orally.
Intervention Type
Drug
Intervention Name(s)
Placebo Matched to MTX
Intervention Description
Placebo matched to MTX.
Intervention Type
Drug
Intervention Name(s)
Placebo Matched to Tocilizumab
Intervention Description
Placebo matched to tocilizumab.
Primary Outcome Measure Information:
Title
Percentage of Participants With an American College of Rheumatology (ACR) 20 (ACR20) Response at Week 24
Time Frame
Week 24
Secondary Outcome Measure Information:
Title
Percentage of Participants With Low Disease Activity at Week 24, Defined as Disease Activity Score 28-Erythrocyte Sedimentation Rate (DAS28-ESR) Score of Less Than or Equal to (<=) 3.2
Time Frame
Week 24
Title
Percentage of Participants With Remission at Week 24, Defined as DAS28-ESR Score of Less Than (<) 2.6
Time Frame
Week 24
Title
Change From Baseline in Tender Joint Count (TJC) at Week 24
Time Frame
Baseline, Week 24
Title
Change From Baseline in Swollen Joint Count (SJC) at Week 24
Time Frame
Baseline, Week 24
Title
Change From Baseline in C-reactive Protein (CRP) Levels at Week 24
Time Frame
Baseline, Week 24
Title
Change From Baseline in Erythrocyte Sedimentation Rate (ESR) at Week 24
Time Frame
Baseline, Week 24
Title
Change From Baseline in the Patient's Global Assessment of Disease Activity Visual Analog Scale (VAS) Score at Week 24
Time Frame
Baseline, Week 24
Title
Change From Baseline in the Physician's Global Assessment of Disease Activity VAS Score at Week 24
Time Frame
Baseline, Week 24
Title
Change From Baseline in the Health Assessment Questionnaire-Disability Index (HAQ-DI) Score at Week 24
Time Frame
Baseline, Week 24
Title
Change From Baseline in the Patient's Pain VAS at Week 24
Time Frame
Baseline, Week 24
Title
Change From Baseline in DAS28-ESR at Week 24
Time Frame
Baseline, Week 24
Title
Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
Time Frame
56 weeks
Title
Percentage of Participants With anti-Tocilizumab Antibody
Time Frame
Baseline, Week 12, Week 24, Week 48, at the time of withdrawal up to approximately 48 weeks
Title
Serum Interleukin-6 (IL-6) Levels
Time Frame
Baseline, predose (Hour 0) on Weeks 2, 4, 8, 12, 16, 24, 48
Title
Serum Soluble Interleukin-6 Receptor (sIL-6R) Levels
Time Frame
Baseline, predose (Hour 0) on Weeks 2, 4, 8, 12, 16, 24, 48
Title
Maximum Observed Plasma Concentration (Cmax) of Tocilizumab
Time Frame
predose (Hour 0) and 6-hours postdose on Day 0, Day 84; predose (Hour 0) on Day 14 and 98; on Day 1, 2, 3, 5, 7, 10, 85, 86, 87, 89, 91, and 94
Title
Minimum Observed Plasma Concentration (Cmin) of Tocilizumab
Time Frame
predose (Hour 0) on Day 0, 14, 84, and 98; on Day 1, 2, 3, 5, 7, 10, 85, 86, 87, 89, 91, and 94
Title
Time to Reach Maximum Observed Plasma Concentration (Tmax) of Tocilizumab
Time Frame
predose (Hour 0) and 6-hours postdose on Day 0, Day 84; predose (Hour 0) on Day 14 and 98; on Day 1, 2, 3, 5, 7, 10, 85, 86, 87, 89, 91, and 94
Title
Plasma Decay Half-Life (t1/2) of Tocilizumab
Time Frame
predose (Hour 0) and 6-hours postdose on Day 0, Day 84; predose (Hour 0) on Day 14 and 98; on Day 1, 2, 3, 5, 7, 10, 85, 86, 87, 89, 91, and 94
Title
Area Under the Curve from Time Zero to end of dosing interval (AUCtau) of Tocilizumab
Time Frame
predose (Hour 0) and 6-hours postdose on Day 0, Day 84; predose (Hour 0) on Day 14 and 98; on Day 1, 2, 3, 5, 7, 10, 85, 86, 87, 89, 91, and 94
Title
Accumulation Ratio for Area Under the Concentration Time Curve (Rac, AUC) of Tocilizumab
Time Frame
predose (Hour 0) and 6-hours postdose on Day 0, Day 84; predose (Hour 0) on Day 14 and 98; on Day 1, 2, 3, 5, 7, 10, 85, 86, 87, 89, 91, and 94
Title
Accumulation Ratio for Maximum Observed Plasma Concentration (Rac, Cmax) of Tocilizumab
Time Frame
predose (Hour 0) and 6-hours postdose on Day 0, Day 84; predose (Hour 0) on Day 14 and 98; on Day 1, 2, 3, 5, 7, 10, 85, 86, 87, 89, 91, and 94
Title
Accumulation Ratio for Minimum Observed Plasma Trough Concentration (Rac, Cmin) of Tocilizumab
Time Frame
predose (Hour 0) on Day 14, 84
Title
Plasma Trough Concentration (Ctrough) of Tocilizumab
Time Frame
predose (Hour 0) on Day 0, 14, 28, 56, 84, 98, 112, 140, 168, and 336
Title
Percentage of Participants With ACR50 Responses at Week 24
Time Frame
Week 24
Title
Percentage of Participants With ACR70 Responses at Week 24
Time Frame
Week 24
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Chinese participants who are located in mainland China with RA of greater than or equal to (>=) 6 months' duration from onset of the disease, diagnosed according to the revised 1987 ACR criteria and receiving treatment on an outpatient basis
Participants must have discontinued etanercept (or YiSaiPu) for >= 2 weeks, infliximab, certolizumab, golimumab, abatacept or adalimumab for >= 8 weeks, anakinra for >= 1 week prior to randomization
Have received oral MTX at a stable dose for at least 12 weeks prior to baseline (MTX dose 10 to 25 mg) and experience of failing at least one non-biologic DMARD including MTX
All treatment with non-biological DMARDs except MTX should be withdrawn at least 2 weeks prior to baseline (leflunomide for >= 12 weeks or >= 14 days after standard cholestyramine or activated charcoal washout, azathioprine for >= 4 weeks)
SJC >= 6 (on the basis of 66 joint counts) and TJC >= 8 (on the basis of 68 joint counts) at screening and baseline with at least 3 months of treatment with permitted DMARDs
Participants must have either high sensitive CRP >= 10 milligrams per liter (mg/L) or ESR >=28 millimeters per hour (mm/hr) at screening
Oral corticosteroids (<=10 mg/day prednisone or equivalent) and nonsteroidal anti-inflammatory drug (NSAIDs; up to the maximum recommended dose per local standard of care) are permitted if the dose has been stable for at least 4 weeks prior to baseline
All treatment with Chinese traditional medicine and/or herb medicine for RA treatment should be withdrawn at least 2 weeks prior to baseline
Females of childbearing potential and males with female partners of childbearing potential may participate only if using a reliable means of contraception as defined by the protocol
Exclusion Criteria:
Participants with major surgery or planned major surgery, rheumatic autoimmune disease other than RA, and functional class IV (as defined by the ACR Classification of Functional Status in RA)
Participants with unsuccessful treatment with an anti-tumor necrosis factor (anti-TNF) agent; previous treatment with any cell-depleting therapies including investigational agents and janus kinase (JAK) inhibitors or any other new agents which have DMARD/DMARD-like effect; treatment with intravenous (IV) gamma-globulin, plasmapheresis, or Prosorba column; treatment with alkylating agents
Intra-articular or parenteral corticosteroids and/or immunization with a live/attenuated vaccine within 4 weeks prior to baseline
History of severe allergic or anaphylactic reactions to human, humanized, or murine monoclonal antibodies
Primary or secondary immunodeficiency (history of or currently active)
Evidence of serious uncontrolled concomitant diseases and disease states; evidence of active malignant disease
Participants with abnormal haematological parameters, abnormal renal and hepatic parameters
Positive for either hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) and/or hepatitis C virus (HCV) antibody
Facility Information:
Facility Name
The First Affiliated Hospital of Baotou Medical College
City
Baotou
ZIP/Postal Code
014010
Country
China
Facility Name
China-Japan Friendship Hospital
City
Beijing City
ZIP/Postal Code
100029
Country
China
Facility Name
Peking University First Hospital
City
Beijing City
ZIP/Postal Code
100034
Country
China
Facility Name
Peking University People's Hospital
City
Beijing
ZIP/Postal Code
100044
Country
China
Facility Name
Beijing Union Hospital
City
Beijing
ZIP/Postal Code
100730
Country
China
Facility Name
Affiliated Hospital of Bengbu Medical College
City
Bengbu
ZIP/Postal Code
233004
Country
China
Facility Name
the First Hospital of Jilin University
City
Changchun
ZIP/Postal Code
130021
Country
China
Facility Name
West China Hospital, Sichuan University
City
Chengdu
ZIP/Postal Code
610041
Country
China
Facility Name
Guangdong General Hospital
City
Guangzhou
ZIP/Postal Code
510080
Country
China
Facility Name
The 1st Affiliated Hospital of Harbin Medical University
City
Harbin
ZIP/Postal Code
150001
Country
China
Facility Name
The First Affiliated Hospital of Anhui Medical University
City
Hefei
ZIP/Postal Code
230022
Country
China
Facility Name
Affiliated Hospital of Inner Mongolia Medical College
City
Hohhot
ZIP/Postal Code
010050
Country
China
Facility Name
The First Hospital of Jiaxing
City
Jiaxing
ZIP/Postal Code
314001
Country
China
Facility Name
Qilu Hospital of Shandong University
City
Jinan
ZIP/Postal Code
250012
Country
China
Facility Name
The First Affilliated Hospital of Kunming Medical College
City
Kunming
ZIP/Postal Code
650032
Country
China
Facility Name
Jiangsu Province Hospital
City
Nanjing
ZIP/Postal Code
210008
Country
China
Facility Name
Pingxiang People Hospital
City
Pingxiang City
ZIP/Postal Code
337000
Country
China
Facility Name
Shengjing Hospital of China Medical University
City
ShenYang
ZIP/Postal Code
110004
Country
China
Facility Name
The Second Hospital of Shanxi Medical University
City
Taiyuan
Country
China
Facility Name
Tianjin Medical University General Hospital
City
Tianjin
ZIP/Postal Code
300052
Country
China
12. IPD Sharing Statement
Plan to Share IPD
No
Learn more about this trial
An Efficacy and Safety Study of Subcutaneous Tocilizumab in Combination With Methotrexate (MTX) and as Monotherapy Versus MTX in Participants With Moderate to Severe Rheumatoid Arthritis With Inadequate Response to Current Disease-Modifying Antirheumatic Drug (DMARD) Therapy
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