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Center for Global Research Data

Predicting the Treatment Response of Biologics for Individual Patients with Rheumatoid Arthritis: An Individual Participant Data Meta-Analysis

Lead Investigator: Yan Luo, Kyoto University
Title of Proposal Research: Predicting the Treatment Response of Biologics for Individual Patients with Rheumatoid Arthritis: An Individual Participant Data Meta-Analysis
Vivli Data Request: 5990
Funding Source: None
Potential Conflicts of Interest: None

Summary of the Proposed Research:

Rheumatoid arthritis (RA) is a chronic inflammatory disease, for which currently we cannot expect complete cure. The drugs that can slow the disease progression are known as disease modifying anti-rheumatic drugs (DMARDs), which have many types. Most RA patients experience long-term treatment. According to the treat-to-target strategy proposed by the practice guideline, a physician should select an intervention for a patient, then re-evaluate after 3 to 6 months, based on which a next-step strategy is given. In order to improve long-term prognosis of RA (such as delaying the progression of bone fusion or functional deficiency), we should try to assure 3-6 months short-term clinical outcome to be good primarily. In other words, physicians should select an optimal intervention that would probably benefit the patient within the next 3 to 6 months treatment.

It is not an easy task for doctors to choose the right drug from so many alternatives. Especially evidence based on randomized controlled trials (RCTs) or their meta-analyses (MAs) at the aggregate level can only imply an average effect. But different patients would have different responses even if they are treated with the same drug. Thus it is necessary to identify subgroups of patients who show different responses. One way to achieve it is to build a prediction model of treatment response, taking account patients’ clinical and biological characteristics. We believe this prediction model would help physicians personalize treatment strategy.

For this purpose, we decide to develop a prediction model of treatment response using individual participant data meta-analysis (IPD-MA) of RCTs. It is regarded as a preferred approach, compared with usual observational study-based prediction models, since it has the following merits: (1) RCTs have more rigorously collected data; (2) RCTs are superior in computing relative treatment effects under alternative treatment conditions due to fewer confounders. In addition, IPD-MA, as a collection of multiple RCTs, can increase the statistical power in dealing with complex models.

Several promising modeling approaches of using IPD-MA to predict treatment response have been established and validated in some simulation studies, yet only one study has applied the method to real clinical settings (depression). The lead researcher of that study is also a co-researcher of our study. Besides, improving the modeling method is also one of our goal in this study. We will apply a new two-stage approach in developing this prediction model.

In summary, we are motivated to develop a prediction model via IPD-MA that can predict treatment effect for individual RA patients based on their baseline characteristics. Our final aim is to build a model that can predict treatment response for several key DMARDs, including adalimumab (ADA), a very important TNF-a inhibitors, tocilizumab (TCZ), an anti-IL6 antibody, and Rituximab (RTX), an anti-CD20 antibody, all with plenty of IPD.

The general study process is: (1) search/selection/risk of bias assessment of eligible studies; (2) applying for IPD; (3) conducting IPD-MA for average effect; (4) developing the prediction model using a two-stage approach: stage 1 – risk modeling; stage 2 – meta-regression.

Requested Studies:

A Phase 2b, Multicenter, Open-Label Study in Rheumatoid Arthritis Subjects Who Completed Preceding Study M13-390 With Adalimumab
Sponsor: AbbVie
Study ID: NCT01752855
Sponsor ID: M13-692

Study to Assess the Pharmacokinetic, Pharmacodynamic, Safety and Immunogenicity of a New Adalimumab Formulation in Subjects With Active Rheumatoid Arthritis
Sponsor: AbbVie
Study ID: NCT01712178
Sponsor ID: M13-390

A Multicenter, Randomized, Single-Blind Crossover Study of the Safety and Tolerability of Two Adalimumab Formulations in Adult Subjects With Rheumatoid Arthritis.
Sponsor: AbbVie
Study ID: NCT01561313
Sponsor ID: M12-783

A Multicenter, Randomized, Single-Blind Crossover Study of the Safety and Tolerability of Two Adalimumab Formulations in Adult Subjects With Rheumatoid Arthritis
Sponsor: AbbVie
Study ID: NCT01502423
Sponsor ID: M11-964

A Double-Blind, Randomized, Parallel-Arm, Multicenter Study to Determine the Dose Response of Methotrexate (MTX) in Combination Therapy With Adalimumab in Subjects With Early Rheumatoid Arthritis (CONCERTO)
Sponsor: AbbVie
Study ID: NCT01185301
Sponsor ID: M12-073

A Multicenter, Double-Blind, Randomized, Parallel-Arm Study to Determine the Effect of Methotrexate Dose on Clinical Outcome and Ultrasonographic Signs in Subjects With Moderately to Severely Active Rheumatoid Arthritis Treated With Adalimumab (MUSICA)
Sponsor: AbbVie
Study ID: NCT01185288
Sponsor ID: M12-071

A Multicenter, Randomized, Open-Label Study of the Injection Time and Usability of the Physiolis Syringe and Autoinjector in Injection-Experienced Rheumatoid Arthritis Patients
Sponsor: AbbVie
Study ID: NCT01163617
Sponsor ID: M12-088

A Phase 3 Multi-Center, Randomized, Double-Blind, Parallel Group, Placebo-Controlled Study Comparing Adalimumab and Placebo in Adult Japanese Subjects With Rheumatoid Arthritis
Sponsor: AbbVie
Study ID: NCT00870467
Sponsor ID: M06-859

Open Label Study to Assess Efficacy and Safety of the Fully Human Anti-TNF-Alpha Monoclonal Antibody Adalimumab
Sponsor: AbbVie
Study ID: NCT00650390
Sponsor ID: M02-532

Multicenter Early Access Program of the Safety of Human Anti-TNF Monoclonal Antibody Adalimumab in Subjects With Active Rheumatoid Arthritis
Sponsor: AbbVie
Study ID: NCT00650026
Sponsor ID: M03-583

A Multi-Center Study of the Safety and Efficacy of Human Anti-TNF Monoclonal Antibody Adalimumab (D2E7) in Patients With Active Rheumatoid Arthritis
Sponsor: AbbVie
Study ID: NCT00649545
Sponsor ID: M02-574

Study of the Human Anti-TNF-Antibody Adalimumab
Sponsor: AbbVie
Study ID: NCT00647920
Sponsor ID: M02-573

A Study of Adalimumab in Adult Japanese Subjects With Rheumatoid Arthritis
Sponsor: AbbVie
Study ID: NCT00647491
Sponsor ID: M02-575

A Multi-center, Randomized, Double-blind,Placebo-controlled Study Comparing 80 mg of Adalimumab With Placebo, and Demonstrating the Non-inferiority of Monthly 80 mg Adalimumab Dosing Compared With 40 mg Adalimumab Every Other Week Dosing
Sponsor: AbbVie
Study ID: NCT00647270
Sponsor ID: M10-261

A Non-Randomized, Open-Label, Roll-Over Study With Self Injection of Adalimumab in Adult Japanese Subjects With Rheumatoid Arthritis
Sponsor: AbbVie
Study ID: NCT00603993
Sponsor ID: M05-775

A Multi-center Randomized, Phase 2/3, Double-blind, Parallel-group, Placebo-controlled Study to Assess the Safety and Efficacy of Adalimumab Administered as Subcutaneous Injections in Adult Chinese Rheumatoid Arthritis Subjects Treated With Methotrexate
Sponsor: AbbVie
Study ID: NCT00538902
Sponsor ID: M04-705

An Open-Label, Multi-Center Study to Assess the Safety and Efficacy of the Fully Human Anti-TNF-α Monoclonal Antibody Adalimumab (D2E7) When Added to Inadequate Standard Anti-Rheumatic Therapy in Patients With Active Rheumatoid Arthritis
Sponsor: AbbVie
Study ID: NCT00448383
Sponsor ID: M02-497

A Multicenter, Randomized, Double-Period, Double − Blind Study to Determine the Optimal Protocol for Treatment Initiation With Methotrexate and Adalimumab Combination Therapy in Patients With Early Rheumatoid Arthritis (OPTIMA)
Sponsor: AbbVie
Study ID: NCT00420927
Sponsor ID: M06-810

Open-Label Continuous Administration Study With Adalimumab (D2E7) in Subjects With Rheumatoid Arthritis
Sponsor: AbbVie
Study ID: NCT00235872
Sponsor ID: M03-651

A Randomized, Double-Blind, Placebo-Controlled, Phase III Study of the Human Anti-TNF Antibody Adalimumab Administered as Subcutaneous Injections in Korean Rheumatoid Arthritis Subjects Treated With Methotrexate
Sponsor: AbbVie
Study ID: NCT00235859
Sponsor ID: M02-556

Long-term Continuously Repeated Dose Study of Adalimumab (D2E7) in Patients With Rheumatoid Arthritis
Sponsor: AbbVie
Study ID: NCT00235833
Sponsor ID: M02-564

A Multi-Centre Randomized, Double-Blind Study Comparing Adalimumab (D2E7) Plus Methotrexate With Placebo Plus Methotrexate on Work Disability in Subjects With Early Rheumatoid Arthritis
Sponsor: AbbVie
Study ID: NCT00234845
Sponsor ID: M02-527

A Multi-Centre Open Label Continuation Study With Subcutaneous D2E7 (Adalimumab) for Patients With Rheumatoid Arthritis Who Completed a Preceding Clinical Study With D2E7 (Adalimumab)
Sponsor: AbbVie
Study ID: NCT00233571
Sponsor ID: DE018

A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study of the Human Anti-TNF Monoclonal Antibody Adalimumab in Rheumatoid Arthritis Patients Currently Receiving Treatment With Methotrexate
Sponsor: AbbVie
Study ID: NCT00195702
Sponsor ID: DE019

A Prospective Multi-Centre Randomised, Double-Blind, Active Comparator-Controlled, Parallel-Groups Study Comparing the Fully Human Monoclonal Anti-TNFα Antibody Adalimumab Given Every Second Week With Methotrexate Given Weekly and the Combination of Adalimumab and Methotrexate Administered Over 2 Years in Patients With Early Rheumatoid Arthritis (PREMIER).
Sponsor: AbbVie
Study ID: NCT00195663
Sponsor ID: DE013

A Multi-Center Continuation Study of the Human Anti-TNF Antibody D2E7 Administered as a Subcutaneous Injection in Patients With Rheumatoid Arthritis
Sponsor: AbbVie
Study ID: NCT00195650
Sponsor ID: DE020

A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study of the Safety of Human Anti-TNF Monoclonal Antibody D2E7 in Patients with Active Rheumatoid Arthritis
Sponsor: AbbVie
Sponsor ID: DE031

A Multicenter Randomized Placebo-Controlled Phase II Study of the Human Anti-TNF Antibody D2E7 Administered as Subcutenous Injections in Rheumatoid Arthritis Patients Treated with Methotrexate.
Sponsor: AbbVie
Sponsor ID: DE009

A multi-center randomized placebo-controlled phase II study of the human anti-TNF antibody D2E7 comparing three dose levels of D2E7 and placebo administered over 12 weeks as weekly subcutaneous injections in patients with rheumatoid arthritis followed by a continuation period with long term treatment with D2E7
Sponsor: AbbVie
Sponsor ID: DE007

A Randomized, Double-blind, Parallel Group Study of Safety and the Effect on Clinical Outcome of Tocilizumab Subcutaneous (sc) Versus Placebo sc in Combination With Traditional Disease Modifying Anti-rheumatic Drugs (DMARDs) in Patients With Moderate to Severe Active Rheumatoid Arthritis
Sponsor: Roche
Study ID: NCT01232569
Sponsor ID: NA25220

A Randomized, Double-blind, Parallel Group Study of the Safety and Effect on Clinical Outcome of Tocilizumab SC Versus Tocilizumab IV, in Combination With Traditional Disease Modifying Anti-rheumatic Drugs (DMARDs), in Patients With Moderate to Severe Active Rheumatoid Arthritis
Sponsor: Roche
Study ID: NCT01194414
Sponsor ID: WA22762

A Multi-center, Randomized, Blinded, Parallel-group Study of the Reduction of Signs and Symptoms During Monotherapy Treatment With Tocilizumab 8 mg/kg Intravenously Versus Adalimumab 40 mg Subcutaneously in Patients With Rheumatoid Arthritis
Sponsor: Roche
Study ID: NCT01119859
Sponsor ID: WA19924

A Multi-center, Randomized, Double-blind, Parallel Group Study of the Safety, Disease Remission and Prevention of Structural Joint Damage During Treatment With Tocilizumab (TCZ), as a Monotherapy and in Combination With Methotrexate (MTX), Versus Methotrexate in Patients With Early, Moderate to Severe Rheumatoid Arthritis
Sponsor: Roche
Study ID: NCT01007435
Sponsor ID: WA19926

Randomized Placebo-controlled Study of Two Treatment Strategies Based on Tocilizumab (TCZ) With or Without Methotrexate (MTX) and Possible Addition of Other Disease-modifying Anti-rheumatic Drugs (DMARDs) in Patients…
Sponsor: Roche
Study ID: NCT00810199
Sponsor ID: MA21488

Long-term Extension Study of Safety During Treatment With Tocilizumab (MRA) in Patients Completing Treatment in WA17822
Sponsor: Roche
Study ID: NCT00721123
Sponsor ID: WA18695

Long-term Extension Study of Safety During Treatment With Tocilizumab (MRA) in Patients Completing Treatment in MRA Core Studies
Sponsor: Roche
Study ID: NCT00720798
Sponsor ID: WA18696

A Mechanism of Action Study to Evaluate the Effects of IL-6 Receptor Blockade With Tocilizumab (TCZ) on Lipids, Arterial Stiffness, and Markers of Atherogenic Risk in Patients With Moderate to Severe Active Rheumatoid Arthritis (RA).
Sponsor: Roche
Study ID: NCT00535782
Sponsor ID: WA19923

A Randomized, Double-blind, Parallel-group Study to Evaluate the Safety and Efficacy of Tocilizumab (TCZ) Versus Placebo in Combination With Disease Modifying Antirheumatic Drugs (DMARDs) in Patients With Moderate to Severe Active Rheumatoid Arthritis (RA)
Sponsor: Roche
Study ID: NCT00531817
Sponsor ID: ML21136

A Randomized, Double-blind Study of Safety and Reduction in Signs and Symptoms During Treatment With Tocilizumab Monotherapy Versus Methotrexate Monotherapy in Patients With Moderate to Severe Active Rheumatoid Arthritis
Sponsor: Roche
Study ID: NCT00109408
Sponsor ID: WA17824

A Randomized, Double-blind Study of the Effect of Tocilizumab on Reduction in Signs and Symptoms in Patients With Moderate to Severe Active Rheumatoid Arthritis and Inadequate Response to DMARD Therapy
Sponsor: Roche
Study ID: NCT00106574
Sponsor ID: WA18063

A Randomized, Double-blind Study of Safety and Reduction in Signs and Symptoms During Treatment With Tocilizumab Versus Placebo, in Combination With Methotrexate, in Patients With Moderate to Severe Rheumatoid Arthritis
Sponsor: Roche
Study ID: NCT00106548
Sponsor ID: WA17822

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
Sponsor: Roche
Study ID: NCT00106535
Sponsor ID: WA17823

A Randomized, Double-blind Study of Safety and Reduction in Signs and Symptoms During Treatment With Tocilizumab Versus Placebo, in Combination With Methotrexate, in Patients With Moderate to Severe Active Rheumatoid Arthritis and Inadequate Response to Anti-TNF Therapy
Sponsor: Roche
Study ID: NCT00106522
Sponsor ID: WA18062

An Open Label Study of the Efficacy and Safety of Re-treatments With Rituximab (MabThera/Rituxan) in Patients With Active Rheumatoid Arthritis Who Have Had an Inadequate Response to Anti-TNFa Therapies
Sponsor: Roche
Study ID: NCT02097745
Sponsor ID: WA17531

An Open-label Study of the Efficacy and Safety of Re-treatments With Rituximab (MabThera®/Rituxan®) in Patients With Active Rheumatoid Arthritis
Sponsor: Roche
Study ID: NCT02093026
Sponsor ID: WA16855

A Randomized, Placebo-controlled, Double-blind, Multicenter Study to Evaluate the Safety and Efficacy of Rituximab in Combination With Methotrexate in Patients With Active Rheumatoid Arthritis Who Have Had an Inadequate Response to Anti-TNF Alpha Therapies
Sponsor: Roche
Study ID: NCT00468546
Sponsor ID: WA17042

An Open-Label, Prospective Study of the Safety of Rituximab in Combination With Other Disease-Modifying Anti-Rheumatic Drugs in Subjects With Active Rheumatoid Arthritis
Sponsor: Roche
Study ID: NCT00443651
Sponsor ID: U3924g

A Randomized, Double-blind Study to Evaluate the Effect of Various Re-treatment Regimens of MabThera in Combination With Methotrexate on Treatment Response in Rheumatoid Arthritis Patients With an Inadequate Response to Methotrexate.
Sponsor: Roche
Study ID: NCT00422383
Sponsor ID: WA17044

A Randomized, Placebo Controlled, Double-blind, Parallel Group, International Study to Evaluate the Safety and Efficacy of Rituximab in Combination With Methotrexate, Compared to Methotrexate Monotherapy, in Patients With Active Rheumatoid Arthritis
Sponsor: Roche
Study ID: NCT00299130
Sponsor ID: U2973g

A Randomized, Phase 3, Controlled, Double-Blind, Parallel-Group, Multicenter Study to Evaluate the Safety and Efficacy of Rituximab in Combination With Methotrexate (MTX) Compared to MTX Alone, in Methotrexate-Naive Patients With Active Rheumatoid Arthritis
Sponsor: Roche
Study ID: NCT00299104
Sponsor ID: U3373g

A Phase II, Randomized, Parallel-group, Open-label, Multicenter Study to Evaluate the Effects of Rituximab on Immune Responses in Subjects With Active Rheumatoid Arthritis Receiving Background Methotrexate
Sponsor: Roche
Study ID: NCT00282308
Sponsor ID: U3374g

A Phase III, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study of Retreatment With Rituximab in Subjects With Rheumatoid Arthritis Receiving Background Methotrexate
Sponsor: Roche
Study ID: NCT00266227
Sponsor ID: U3384g

Randomized, Multifactorial, Double-blind, Parallel-group, Dose-ranging Study of the Efficacy and Safety of Rituximab (MabThera®/Rituxan®) in Combination With Methotrexate in Patients With Active Rheumatoid Arthritis
Sponsor: Roche
Study ID: NCT00074438
Sponsor ID: WA17043/U2644g

A randomised, double dummy controlled, parallel group study of the efficacy and safety of Mabthera (rituximab) alone or in combination with either cyclophosphamide or methotrexate, in patients with rheumatoid arthritis.
Sponsor: Roche
Sponsor ID: WA16291