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
Phase 3
Completed
- Conditions
- Rheumatoid Arthritis
- Interventions
- Registration Number
- NCT03155347
- Lead Sponsor
- Hoffmann-La Roche
- 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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 340
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- All treatment with non-biological DMARDs except MTX should be withdrawn at least 2 weeks prior to baseline (leflunomide for 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Tocilizumab + Placebo Matched to MTX Placebo Matched to MTX 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. Placebo Matched to Tocilizumab + MTX MTX 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. Placebo Matched to Tocilizumab + MTX Placebo Matched to Tocilizumab 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. Tocilizumab + MTX Tocilizumab 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). Tocilizumab + Placebo Matched to MTX Tocilizumab 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. Tocilizumab + MTX MTX 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). Tocilizumab + Placebo Matched to MTX MTX 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. Placebo Matched to Tocilizumab + MTX Tocilizumab 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.
- Primary Outcome Measures
Name Time Method Percentage of Participants With an American College of Rheumatology (ACR) 20 (ACR20) Response at Week 24 Week 24
- Secondary Outcome Measures
Name Time Method Serum Interleukin-6 (IL-6) Levels Baseline, predose (Hour 0) on Weeks 2, 4, 8, 12, 16, 24, 48 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 Week 24 Percentage of Participants With Remission at Week 24, Defined as DAS28-ESR Score of Less Than (<) 2.6 Week 24 Change From Baseline in C-reactive Protein (CRP) Levels at Week 24 Baseline, Week 24 Minimum Observed Plasma Concentration (Cmin) of Tocilizumab 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 Change From Baseline in the Patient's Global Assessment of Disease Activity Visual Analog Scale (VAS) Score at Week 24 Baseline, Week 24 Change From Baseline in the Physician's Global Assessment of Disease Activity VAS Score at Week 24 Baseline, Week 24 Change From Baseline in the Health Assessment Questionnaire-Disability Index (HAQ-DI) Score at Week 24 Baseline, Week 24 Change From Baseline in the Patient's Pain VAS at Week 24 Baseline, Week 24 Change From Baseline in Swollen Joint Count (SJC) at Week 24 Baseline, Week 24 Change From Baseline in DAS28-ESR at Week 24 Baseline, Week 24 Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) 56 weeks Change From Baseline in Tender Joint Count (TJC) at Week 24 Baseline, Week 24 Change From Baseline in Erythrocyte Sedimentation Rate (ESR) at Week 24 Baseline, Week 24 Percentage of Participants With anti-Tocilizumab Antibody Baseline, Week 12, Week 24, Week 48, at the time of withdrawal up to approximately 48 weeks Serum Soluble Interleukin-6 Receptor (sIL-6R) Levels Baseline, predose (Hour 0) on Weeks 2, 4, 8, 12, 16, 24, 48 Accumulation Ratio for Minimum Observed Plasma Trough Concentration (Rac, Cmin) of Tocilizumab predose (Hour 0) on Day 14, 84 Maximum Observed Plasma Concentration (Cmax) of Tocilizumab 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 Time to Reach Maximum Observed Plasma Concentration (Tmax) of Tocilizumab 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 Plasma Decay Half-Life (t1/2) of Tocilizumab 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 Area Under the Curve from Time Zero to end of dosing interval (AUCtau) of Tocilizumab 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 Accumulation Ratio for Area Under the Concentration Time Curve (Rac, AUC) of Tocilizumab 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 Accumulation Ratio for Maximum Observed Plasma Concentration (Rac, Cmax) of Tocilizumab 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 Plasma Trough Concentration (Ctrough) of Tocilizumab predose (Hour 0) on Day 0, 14, 28, 56, 84, 98, 112, 140, 168, and 336 Percentage of Participants With ACR50 Responses at Week 24 Week 24 Percentage of Participants With ACR70 Responses at Week 24 Week 24
Trial Locations
- Locations (20)
Peking University People's Hospital
🇨🇳Beijing, China
Peking University First Hospital
🇨🇳Beijing City, China
The First Affilliated Hospital of Kunming Medical College
🇨🇳Kunming, China
Shengjing Hospital of China Medical University
🇨🇳ShenYang, China
Pingxiang People Hospital
🇨🇳Pingxiang City, China
Affiliated Hospital of Bengbu Medical College
🇨🇳Bengbu, China
The 1st Affiliated Hospital of Harbin Medical University
🇨🇳Harbin, China
Tianjin Medical University General Hospital
🇨🇳Tianjin, China
Guangdong General Hospital
🇨🇳Guangzhou, China
Affiliated Hospital of Inner Mongolia Medical College
🇨🇳Hohhot, China
China-Japan Friendship Hospital
🇨🇳Beijing City, China
The First Affiliated Hospital of Anhui Medical University
🇨🇳Hefei, China
Beijing Union Hospital
🇨🇳Beijing, China
The Second Hospital of Shanxi Medical University
🇨🇳Taiyuan, China
The First Affiliated Hospital of Baotou Medical College
🇨🇳Baotou, China
the First Hospital of Jilin University
🇨🇳Changchun, China
West China Hospital, Sichuan University
🇨🇳Chengdu, China
The First Hospital of Jiaxing
🇨🇳Jiaxing, China
Qilu Hospital of Shandong University
🇨🇳Jinan, China
Jiangsu Province Hospital
🇨🇳Nanjing, China