Disease‐modifying anti‐rheumatic drugs for rheumatoid arthritis: A network meta-analysis incorporating individual patient data

Lead Investigator: Glen Hazlewood, University of Calgary
Title of Proposal Research: Disease‐modifying anti‐rheumatic drugs for rheumatoid arthritis: A network meta-analysis incorporating individual patient data
Vivli Data Request: 5987, 8728
Funding Source: CIHR (pending review)
Potential Conflicts of Interest: None (following Conflict of Interest Policy for Cochrane Library Content).

Summary of the Proposed Research:

Rheumatoid arthritis (RA) is an autoimmune disease that affects between 0.2% to 0.4% of adults. People living with rheumatoid arthritis experience joint pain, stiffness, impaired function, fatigue and significantly decreased quality of life. While rheumatoid arthritis cannot be cured, there are now many effective medications available. These medications are referred to as disease-modifying antirheumatic drugs (DMARDS) and are the mainstay of RA treatment. They work to control the underlying inflammation that is responsible for peoples’ symptoms. In doing so, they also protect the joints from damage.

There are now over 20 different DMARDs available for RA. DMARDs can be divided into different categories, based on how they are made and what parts of the immune system they target. Conventional synthetic DMARDs and targeted synthetic DMARDs are both ‘traditional’ medications, in the sense that they are synthetically made. The difference is that the latter were developed with a specific target of the immune system (e.g. cell type or protein) in mind. These medications contrast with biologic DMARDs, which are made biologically (e.g. antibodies) and are much more complex in their structure. Given their complex structure, it is not possible to exactly reproduce biologics. As such, biologics are typically divided into biologic originator or biosimilar DMARDs, according to whether they were the first or subsequent manufacturers.

Given the many different choices of DMARDs available, we need high-quality evidence that compares the benefits and harms. Network meta-analysis is a method whereby every randomized trial that has been conducted on these treatments is analyzed together as a ‘network’. A main benefit of network meta-analysis is that it allows all treatments to be compared against one another. Our research group has published several Cochrane reviews of network meta-analyses comparing DMARD treatments in rheumatoid arthritis. Recently, we have transitioned these reviews to a ‘living’ mode, whereby the evidence will be updated continuously over time, to take into account new trials that are published.

While our network meta-analyses allow comparisons between treatments, the comparisons are made using average (group-level) data from the trials. In this study, we will conduct a network meta-analysis using the raw (individual level) data from the clinical trials, where this data is available. This has two main advantages. First, it will allow us to determine whether patients with certain characteristics may respond better to one drug or another. Second, it will allow us to ensure each trial is analyzed using similar approaches. Overall, this will allow us to more robust and personalized data to help patients and their physicians choose between all the DMARD options available.

Requested Studies:

A Golimumab Phase 3b, Multicenter, Assessment of Intravenous Efficacy in Rheumatoid Arthritis Subjects Who Have Diminished Disease Control Despite Treatment With Infliximab (REMICADE®)
Data Contributor: Johnson & Johnson
Study ID: NCT01962974
Sponsor ID: CR102117

A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study to Evaluate the Efficacy and Safety of Baricitinib (LY3009104) in Patients With Inadequate Response to Conventional Disease-Modifying Antirheumatic Drugs With Moderately to Severely Active Rheumatoid Arthritis
Data Contributor: Lilly
Study ID: NCT01721057
Sponsor ID: 14059

A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study Evaluating the Efficacy and Safety of Baricitinib (LY3009104) in Patients With Moderately to Severely Active Rheumatoid Arthritis Who Have Had an Inadequate Response to Tumor Necrosis Factor Inhibitors
Data Contributor: Lilly
Study ID: NCT01721044
Sponsor ID: 14058

A Multicenter, Single-blind, Randomized Parallel-group Study to Assess the Short- and Long-term Efficacy of Certolizumab Pegol Plus Methotrexate Compared to Adalimumab Plus Methotrexate in Subjects With Moderate to Severe Rheumatoid Arthritis Responding Inadequately to Methotrexate
Data Contributor: UCB
Study ID: NCT01500278
Sponsor ID: RA0077

A Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging, Parallel-Group, Phase 2 Study of Baricitinib (LY3009104) in Japanese Patients With Active Rheumatoid Arthritis on Background Methotrexate Therapy
Data Contributor: Lilly
Study ID: NCT01469013
Sponsor ID: 14116

A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled Study Evaluating the Efficacy and Safety of Golimumab in the Treatment of Chinese Subjects With Active Rheumatoid Arthritis Despite Methotrexate Therapy
Data Contributor: Johnson & Johnson
Study ID: NCT01248780
Sponsor ID: CR015913

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
Data Contributor: 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
Data Contributor: Roche
Study ID: NCT01194414
Sponsor ID: WA22762

A Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging, Parallel-Group, Phase 2b Study of LY3009104 in Patients With Active Rheumatoid Arthritis on Background Methotrexate Therapy
Data Contributor: Lilly
Study ID: NCT01185353
Sponsor ID: 13854

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
Data Contributor: Roche
Study ID: NCT01119859
Sponsor ID: WA19924

A Multicenter, Randomized, Double-blind, Placebo-controlled Trial of Golimumab, an Anti-TNFalpha Monoclonal Antibody, Administered Intravenously, in Patients With Active Rheumatoid Arthritis Despite Methotrexate Therapy
Data Contributor: Johnson & Johnson
Study ID: NCT00973479
Sponsor ID: CR015784

Phase 3, Randomized, Double-Blind, Placebo-Controlled Study Of The Safety And Efficacy Of 2 Doses Of CP-690,550 In Patients With Active Rheumatoid Arthritis On Background Methotrexate With Inadequate Response To TNF Inhibitors
Data Contributor: Pfizer
Study ID: NCT00960440
Sponsor ID: A3921032

Phase 3 Randomized, Double Blind, Placebo Controlled Study Of The Efficacy And Safety Of 2 Doses Of CP-690,550 In Patients With Active Rheumatoid Arthritis On Background Methotrexate
Data Contributor: Pfizer
Study ID: NCT00847613
Sponsor ID: A3921044

Phase 3, Randomized, Double-Blind, Placebo-Controlled Study Of The Efficacy And Safety Of 2 Doses Of CP-690,550 Monotherapy In Patients With Active Rheumatoid Arthritis
Data Contributor: Pfizer
Study ID: NCT00814307
Sponsor ID: A3921045

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…
Data Contributor: Roche
Study ID: NCT00810199
Sponsor ID: MA21488

A Phase IIIb Multicenter Study With a 12-week Double-blind, Placebo-controlled, Randomized Period Followed by an Open-label, Extension Phase Evaluating Safety/Efficacy of Certolizumab Pegol Given to Patients With Active Rheumatoid Arthritis.
Data Contributor: UCB
Study ID: NCT00717236
Sponsor ID: C87094

A Phase IIIB, Multi-center, Double-blind, Placebo-controlled, Parallel Group, 52-week Study to Evaluate the Safety and Efficacy of Certolizumab Pegol, Administered With DMARDs, in Patients With Low to Moderate Disease Activity Rheumatoid Arthritis
Data Contributor: UCB
Study ID: NCT00674362
Sponsor ID: C87076

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

A Study of Adalimumab in Adult Japanese Subjects With Rheumatoid Arthritis
Data Contributor: 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
Data Contributor: AbbVie
Study ID: NCT00647270
Sponsor ID: M10-261

A Phase 2b, Randomized, Double Blind, Placebo Controlled Active Comparator, Multicenter Study To Compare 5 Dose Regimens Of CP- 690,550 And Adalimumab Versus Placebo, Administered For 6 Months In The Treatment Of Subjects With Active Rheumatoid Arthritis
Data Contributor: Pfizer
Study ID: NCT00550446
Sponsor ID: A3921035

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
Data Contributor: AbbVie
Study ID: NCT00538902
Sponsor ID: M04-705

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).
Data Contributor: 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)
Data Contributor: Roche
Study ID: NCT00531817
Sponsor ID: ML21136

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
Data Contributor: Roche
Study ID: NCT00468546
Sponsor ID: WA17042

A Phase 2B, Randomized, Double Blind, Placebo-Controlled, Multicenter Study To Compare 6 Dose Regimens Of CP-690,550 Vs. Placebo, Each Combined With Methotrexate, Administered For 6 Months In The Treatment Of Subjects With Active Rheumatoid Arthritis Who Have Had An Inadequate Response To Methotrexate Alone
Data Contributor: Pfizer
Study ID: NCT00413660
Sponsor ID: A3921025

A Multicenter, Randomized, Double-blind, Placebo-controlled Trial of Golimumab, a Fully Human Anti-TNFa Monoclonal Antibody, Administered Intravenously, in Subjects With Active Rheumatoid Arthritis Despite Methotrexate Therapy
Data Contributor: Johnson & Johnson
Study ID: NCT00361335
Sponsor ID: CR012781

A Multicenter, Randomized, Double-blind, Placebo-controlled Trial of Golimumab, a Fully Human Anti-TNFa Monoclonal Antibody, Administered Subcutaneously in Subjects With Active Rheumatoid Arthritis and Previously Treated With Biologic Anti- TNFa Agent(s)
Data Contributor: Johnson & Johnson
Study ID: NCT00299546
Sponsor ID: CR006334

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
Data Contributor: Roche
Study ID: NCT00299130
Sponsor ID: U2973g

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
Data Contributor: Roche
Study ID: NCT00282308
Sponsor ID: U3374g

A Placebo-Controlled, Double-Blinded, Randomized Clinical Trial of Anti-TNF Chimeric Monoclonal Antibody (cA2) in Patients With Active Rheumatoid Arthritis Despite Methotrexate Treatment
Data Contributor: Johnson & Johnson
Study ID: NCT00269867
Sponsor ID: CR006259

A Multicenter, Randomized, Double-blind, Placebo-controlledTrial of Golimumab, a Fully Human Anti-TNFa MonoclonalAntibody, Administered Subcutaneously, in Subjects With ActiveRheumatoid Arthritis Despite Methotrexate Therapy
Data Contributor: Johnson & Johnson
Study ID: NCT00264550
Sponsor ID: CR006343

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
Data Contributor: AbbVie
Study ID: NCT00235859
Sponsor ID: M02-556

A Randomized, Double-blind, Dose-ranging Trial of CNTO 148 Subcutaneous Injection Compared With Placebo in Subjects With Active Rheumatoid Arthritis Despite Treatment With Methotrexate
Data Contributor: Johnson & Johnson
Study ID: NCT00207714
Sponsor ID: CR005263

A Placebo-Controlled, Double-Blinded, Randomized Clinical Trial of Anti-TNF Chimeric Monoclonal Antibody (cA2) in Korean Patients With Active Rheumatoid Arthritis Despite Methotrexate
Data Contributor: Johnson & Johnson
Study ID: NCT00202852
Sponsor ID: P04280

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
Data Contributor: AbbVie
Study ID: NCT00195702
Sponsor ID: DE019

A Phase III Multi-center, Double-blind, Placebo-controlled, Parallel Group 24-Week Study to Assess the Efficacy and Safety of Two Dose Regimens of Liquid Certolizumab Pegol as Additional Medication to Methotrexate in the Treatment of Signs and Symptoms of Rheumatoid Arthritis and in Prevention of Joint Damage in Patients With Active Rheumatoid Arthritis Who Have an Incomplete Response to Methotrexate.
Data Contributor: UCB
Study ID: NCT00160602
Sponsor ID: C87050

A Phase III Multicentre, Double Blind, Placebo-controlled, Parallel Group 52-week Study to Assess the Efficacy and Safety of 2 Dose Regimens of Lyophilised CDP870 as Additional Medication to Methotrexate in the Treatment of Signs and Symptoms and Preventing Structural Damage in Patients With Active Rheumatoid Arthritis Who Have an Incomplete Response to Methotrexate
Data Contributor: UCB
Study ID: NCT00152386
Sponsor ID: C87027

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
Data Contributor: 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
Data Contributor: 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
Data Contributor: 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
Data Contributor: Roche
Study ID: NCT00106522
Sponsor ID: WA18062

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
Data Contributor: Roche
Study ID: NCT00074438
Sponsor ID: WA17043/U2644g

A Randomized, Double-blind Trial of the Safety of Anti-TNF Chimeric Monoclonal Antibody (Infliximab) in Combination With Methotrexate Compared to Methotrexate Alone in Patients With Rheumatoid Arthritis on Standard Disease-modifying Anti-Rheumatic Drug Background Therapy.
Data Contributor: Johnson & Johnson
Study ID: NCT00036387
Sponsor ID: CR003133

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.
Data Contributor: Roche
Study ID: WA16291
Sponsor ID: WA16291

A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study of the Safety of Human Anti-TNF Monoclonal Antibody D2E7 in Patients with Active Rheumatoid Arthritis
Data Contributor: AbbVie
Study ID: DE031
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.
Data Contributor: AbbVie
Study ID: DE009
Sponsor ID: DE009

Therapeutic efficacy of multiple intravenous infusions of anti-tumor necrosis factor alpha monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis
Data Contributor: Johnson & Johnson
Study ID: C0168T14
Sponsor ID: C0168T14

A Randomized, Double-Blind, Placebo- and Active-Controlled, Phase 3 Study Evaluating the Efficacy and Safety of Baricitinib in Patients With Moderately to Severely Active Rheumatoid Arthritis Who Have Had an Inadequate Response to Methotrexate Therapy
Data Contributor: Lilly
Study ID: NCT01710358
Sponsor ID: 13978

For other trials, the published group-level data (i.e.- publicly available data, not individual data) will be brought into Vivli’s platform to allow the NMA analyses, which combine IPD and group-level data. The dataset will be generated as an Excel sheet or .csv file from our ongoing Cochrane review that this project is linked with. The dataset will include a row for each arm of each trial. The columns will include a study id, intervention, extracted outcome data from our Cochrane review (e.g. mean (SD) for continuous outcomes; n/X for dichotomous outcomes), and extracted group-level baseline variables, also from our Cochrane review, which are needed for the met-regression models. This data is necessary to complete our NMA analyses. The validity will be ensured, as the dataset will be generated using standard Cochrane approaches to ensure the validity of extracted data. The final dataset is not yet available as the Cochrane review is ongoing, but it is anticipated to be small in size (<1 MB)
Data Contributor: I WILL BRING MY OWN
Sponsor ID: Other trials

(Note: Additional studies added as part of Data Request 8728)

A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Study to Investigate the Safety and Efficacy of ABT-494 Given With Methotrexate (MTX) in Subjects With Moderately to Severely Active Rheumatoid Arthritis (RA) Who Have Had an Inadequate Response or Intolerance to Anti-TNF Biologic Therapy
Data Contributor: AbbVie
Study ID: NCT01960855
Sponsor ID: M13-550

A Golimumab Phase 3b, Multicenter, Switch Assessment of Subcutaneous and Intravenous Efficacy in Rheumatoid Arthritis Patients Who Have Inadequate Disease Control Despite Treatment With Etanercept (ENBREL) or Adalimumab (HUMIRA)
Data Contributor: Johnson & Johnson
Study ID: NCT01004432
Sponsor ID: CR016663

Open-label, Pilot Protocol of Patients With Rheumatoid Arthritis Who Switch to Infliximab After Incomplete Response to Etanercept
Data Contributor: Johnson & Johnson
Study ID: NCT00317538
Sponsor ID: CR003136

ASCERTAIN Study – A Randomized, Double-Blind, Double-Dummy Study Assessing The Safety and Tolerability of Sarilumab and Tocilizumab In Patients With Rheumatoid Arthritis Who Are Inadequate Responders to or Intolerant of TNF Antagonists
Data Contributor: Sanofi
Study ID: NCT01768572
Sponsor ID: NCT01768572

TARGET Study – A Randomized, Double-blind, Parallel, Placebo-controlled Study Assessing the Efficacy and Safety of Sarilumab Added to Non-biologic DMARD Therapy in Patients With Rheumatoid Arthritis Who Are Inadequate Responders to or Intolerant of TNF-α Antagonists
Data Contributor: Sanofi
Study ID: NCT01709578
Sponsor ID: NCT01709578

A Randomized, Double-blind, Placebo-controlled, Multicenter, Two-part, Dose Ranging and Confirmatory Study With an Operationally Seamless Design, Evaluating Efficacy and Safety of SAR153191 on Top of Methotrexate (MTX) in Patients With Active Rheumatoid Arthritis Who Are Inadequate Responders to MTX Therapy
Data Contributor: Sanofi
Study ID: NCT01061736
Sponsor ID: NCT01061736

SWITCH Clinical Trial for Patients With Rheumatoid Arthritis Who Have Failed an Initial TNF-blocking Drug
Data Contributor: I WILL BRING MY OWN
Study ID: NCT01295151
Sponsor ID: N/A

CERT-001: Can TNF-Alpha Incomplete Secondary Responders Attain a Safe and Efficacious Response Switching to Cimzia
Data Contributor: I WILL BRING MY OWN
Study ID: NCT01147341
Sponsor ID: N/A

Rotation or Change of Biotherapy After First Anti-TNF Treatment Failure for Rheumatoid Arthritis (ROC)
Data Contributor: I WILL BRING MY OWN
Study ID: NCT01000441
Sponsor ID: N/A

Cost-effectiveness of abatacept, rituximab, and TNFi treatment after previous failure with TNFi treatment in rheumatoid arthritis: a pragmatic multi-centre randomised trial
Data Contributor: I WILL BRING MY OWN
Study ID: N/A
Sponsor ID: DREAM-TIME (NL1535 (NTR1605))