Twitter Facebook LinkedIn
Center for Global Research Data

MIDRA: influence of demographic and environmental factors on anti-tumor necrosis factor efficacy in rheumatoid arthritis a systematic review and meta-analysis of randomized controlled trials

Lead Investigator: Marc-Antoine Sparfel, Tours Hospital
Title of Proposed Research: MIDRA: influence of demographic and environmental factors on anti-tumor necrosis factor efficacy in rheumatoid arthritis a systematic review and meta-analysis of randomized controlled trials
Vivli Data Request: 3288
Funding Source: None
Potential Conflicts of Interest: None. Thesis Project.

Summary of the Proposed Research:

Thesis project: meta-analysis on the influence of demographic and environmental factors on anti- tumor necrosis factor efficacy in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a relatively frequent immune mediated disease with a prevalence of 3 to 8/1,000 patients. RA alters quality of life and increases cardiovascular, infectious and other morbidity risks. Anti- tumor necrosis factor (anti-TNF) drugs are efficient, yet primary or secondary failure is still a problem for one patient out of 3, even if exposition to anti-TNF drugs is correct. Therefore, searching for determinants of treatment response is essential.

The aim of this study is to highlight factors which could have an impact on the therapeutical response.

The treat-to-target strategy in rheumatoid arthritis has been proposed to increase the therapeutic efficacy while minimizing the risk of adverse events. Therefore, it is important to assess if demographics and environmental factors could influence anti- tumor necrosis factor treatment effect and the direction of this influence. These factors could therefore be considered when initiating anti-TNF drugs in rheumatoid arthritis in order to increase response rate and anticipate and avoid failure.

Statistical Analysis Plan

Inclusion criteria: randomized controlled trials comparing an Anti- tumor necrosis factor (anti-TNF) drug (infliximab, adalimumab, golimumab, certolizumab pegol or etanercept) versus placebo or conventional Disease-modifying antirheumatic drugs (DMARDs), in rheumatoid arthritis (RA) patients and reported efficacy data by subgroups of demographic and disease related factors of interest.

The following factors of interest will be considered: age, gender, Body Mass Index (BMI), smoking status, disease duration, Disease Activity Score 28 (DAS28), C-reactive protein (CRP), anti-citrullinated protein antibodies (ACPA), Rheumatoid factor (RF), and physical activity.
– Exclusion criteria: non-randomized controlled trials, observational studies, randomized trials comparing 2 anti-TNF drugs without a control group.

Statistical analysis

A meta-analysis of aggregate data will be performed, following appropriate methods (relative risks or standardized mean difference) depending of the nature of the outcome considered (Mantel-Haenszel RR or Peto OR). A fixed effect model will be performed first, with addition of a random effect model in case of significant heterogeneity. Heterogeneity will be considered significant if the m-value of the heterogeneity test is <0.10 or I² is higher than 50%.

The null hypothesis is that there is no interaction between covariates of interest (age, gender…) and treatment effect. That is, the treatment effect is homogeneous in considered subgroups of patients. H1 the alternate hypothesis, is that the treatment effect varies significantly between subgroups.

No multiplicity adjustments are pre‐planned, since this is an exploratory analysis, the limits of which are well known

We will extract the following data: age, sex, Body Mass Index (BMI), physical activity, smoking status, disease duration, DAS28, CRP, ACPA status, RF status, author, year of publication, study acronym, journal, PubMed ID (PMID), NCT or clinical trial registry number, anti-TNF evaluated and type of control, number of patients included, main outcome, time for main outcome, duration, extension, sponsor.

Subgroups are pre-specified in the extraction sheet (Gender (Men/women), age (less than 50 years old /upper or equal to 50 years old), DAS28 (less than 5.1/upper or equal to 5.1), disease duration (less than 2 years/Between 2 and 10 years/upper to 10 years), Rheumatoid Factor (positive/negative), ACPA (Positive/Negative), BMI (less than 30/upper or equal to30), smoking status (Never/ever), physical activity (Yes/No)).

Requested Studies

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

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: Abbott
Study ID: NCT00420927
Sponsor ID: M06-810

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 (prior sponsor, Abbott)
Study ID: NCT00195663
Sponsor ID: DE013

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: Abbott
Study ID: NCT00195702
Sponsor ID: DE019

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: Abbott
Study ID: NCT00234845
Sponsor ID: M02-527

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: Abbott
Study ID: NCT00235859
Sponsor ID: M02-556

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

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: Abbott
Study ID: NCT00538902
Sponsor ID: M04-705

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: Abbott
Study ID: NCT00647270
Sponsor ID: M10-261

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: Abbott
Study ID: NCT00870467
Sponsor ID: M06-859

AbbVie study 3
Safety Trial of Adalimumab in Rheumatoid Arthritis (Abbott STAR trial)
Data Contributor: AbbVie
Study ID: DE031, PMID 14719195

AbbVie study 1
Data Contributor: AbbVie
Study ID: DE009, PMID 12528101

AbbVie study 2
Data Contributor: AbbVie
Study ID: DE007, PMID 14644854

Study Evaluating the Efficacy and Safety of Etanercept and Methotrexate in Japanese Subjects With Rheumatoid Arthritis
Data Contributor: Pfizer Inc.
Study ID: NCT00445770

Study Comparing Etanercept in Combination With Methotrexate in Subjects With Rheumatoid Arthritis (PRESERVE)
Data Contributor: Pfizer Inc.
Study ID: NCT00565409

Study Comparing The Effect On Disease Activity When Reducing Or Discontinuing Etanercept In Subjects With RA (DOSERA)
Data Contributor: Pfizer Inc.
Study ID: NCT00858780

Study Evaluating Etanercept Plus Methotrexate in Early Rheumatoid Arthritis
Data Contributor: Pfizer Inc.
Study ID: NCT00913458

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.
Sponsor: 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
Sponsor: UCB
Study ID: NCT00152386
Sponsor ID: C87027

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.
Sponsor: UCB
Study ID: NCT00717236
Sponsor ID: C87094

Efficacy and Safety of CDP870 400 mg Subcutaneously Versus Placebo in the Treatment of the Signs and Symptoms of Patients With Rheumatoid Arthritis Who Have Previously Failed at Least One DMARD
Sponsor: UCB
Study ID: NCT00548834
Sponsor ID: C87011

A Phase III Multi-centre, Open-label, follow-on Study to CDP870-027, to Assess the Efficacy and Safety of Lyophilized CDP870 an Engineered Human Anti-TNF PEG Conjugate, as Additional Medication to Methotrexate, in the Treatment of Signs and Symptoms and Preventing Structural Damage in Patients With Active Rheumatoid Arthritis
Sponsor: UCB
Study ID: NCT00175877
Sponsor ID: C87028

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
Sponsor: UCB
Study ID: NCT00674362
Sponsor ID: C87076

A Phase IIIb Open-label run-in Double-blind, Placebo Controlled, Randomized Study to Evaluate the Safety/Efficacy of Certolizumab Pegol Administered Concomitantly With Stable-dose Methotrexate in Patients With Active Rheumatoid Arthritis.
Sponsor: UCB
Study ID: NCT00580840
Sponsor ID: C87077

A 16-week Double-blind, Placebo-controlled (for Initial 2 Weeks) Randomized Period, Followed by a 24-week Open-label Extension to Assess Magnetic Resonance Image (MRI) – Verified Early Response to Certolizumab Pegol in Subjects With Active Rheumatoid Arthritis (RA)
Sponsor: UCB
Study ID: NCT01235598
Sponsor ID: RA0028

A Multi-center, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy and Safety of Certolizumab Pegol in Combination With Methotrexate for Inducing and Sustaining Clinical Response in the Treatment of DMARD-Naïve Adults With Early Active Rheumatoid Arthritis
Sponsor: UCB
Study ID: NCT01519791
Sponsor ID: RA0055 Period 1

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

Public Disclosure

Law-Wan J, Sparfel M, Derolez S, et al. Predictors of response to TNF inhibitors in rheumatoid arthritis: an individual patient data pooled analysis of randomised controlled trials. RMD Open 2021;7:e001882. doi: 10.1136/rmdopen-2021-001882