Predictors of exposure, therapeutic and adverse effects of certolizumab pegol and baricitinib used in the treatment of rheumatoid arthritis

Lead Investigator: Ahmad Abuhelwa, University of South Australia
Title of Proposal Research: Predictors of exposure, therapeutic and adverse effects of certolizumab pegol and baricitinib used in the treatment of rheumatoid arthritis
Vivli Data Request: 5933, 5208
Funding Source: None
Potential Conflicts of Interest: None

Summary of the Proposed Research:

Rheumatoid arthritis (RA) is the most common auto-immune inflammatory disease in adults. The World Health Organization estimates more than 23 million people live with rheumatoid arthritis; this constitutes approximately 1% of the world population. There have been a number of important developments in the treatment of rheumatoid arthritis in the last decade including the introduction of certolizumab pegol, tocilizumab and baricitinib. However, response and toxicity to certolizumab pegol, baricitinib and tocilizumab can be unpredictable. For example, approximately 40% of the eligible patients who initiate certolizumab pegol, baricitinib or tocilizumab therapy for rheumatoid arthritis do not respond, while 40% may also experience some toxicity. Thus, more research is required to confirm and explore novel predictive markers of therapeutic and adverse effects of certolizumab pegol, baricitinib and tocilizumab in the treatment of rheumatoid arthritis.

Using the diverse range of data collected from clinical trials, it is possible to develop clinical tools that enable improved prediction of therapeutic and adverse outcomes of patients using certolizumab pegol, baricitinib or tocilizumab in the treatment of rheumatoid arthritis. Being able to identify the expected response and adverse effect profile may enable patients and clinicians to make better decisions regarding whether to commence, continue, discontinue or change dosing of certolizumab pegol, baricitinib and tocilizumab .

Available data from rheumatoid arthritis patients treated with certolizumab pegol, baricitinib and tocilizumab and relevant comparator arms (e.g. methotrexate or adalimumab) will be analysed to identify and validate predictors of the most important adverse effects, and clinical/biological/patient predictors of therapeutic outcomes such as response / progression, quality of life and survival.

Statistical Analysis Plan:

General model development:

Cox-proportional hazard / time-to-event models will be used to assess the association between potential predictors and the time to an adverse effect or response / progression / survival. Associations will be reported primarily as hazard ratios with 95% confidence intervals. The association of potential predictors with binary outcomes (e.g. yes / no) will be modelled using logistic regression and will be reported as odds ratios with 95% confidence intervals. Time-dependent analysis (e.g. linear and non-linear mixed effect modelling) will be used to assess the nature and patterns of longitudinal changes of key continuous variables (e.g. drug concentration, event outcomes, immune cell counts, number of swollen and tender joints).

Software:

The R Software (R Core Team) will be used for data preparation, modelling and graphical output.

Covariate analyses:

Potential predictors will be prioritised according to biological/clinical plausibility and prior evidence of association with the relevant outcome (adverse events, therapeutic response, drug exposure). Should multiple values of a covariate be recorded multiple times for a single visit (e.g. blood pressure) the mean of the multiple reads taken at each visit will be used. Crude associations will be reported based on univariate analysis (adjusting only for the clinical trial and where appropriate the medicines used), and adjusted associations based on a multivariable analysis. Continuous variables will be assessed for non-linearity of association with the outcome using restricted cubic splines. Clinical prediction models will be developed using multivariable analysis and will generally include all available known baseline predictors of the outcome of interest as well as covariates identified in univariate analysis. Penalised models will be used to minimse risk of overfitting. Early markers of exposure, response and toxicity will be primarily evaluated using a landmark approach where possible, with sensitivity analyses based on the use of time-dependent covariates. Landmark time will be dependent on the time points available in individual studies, and the time frame of changes in each specific predictor variable. As this analysis is primarily hypothesis generating and will require subsequent validation of any findings, no formal adjustment for multiple testing is intended. However, this limitation will be clearly stated in any publications of results. As it is expected that < 5% of data will be missing for any variable a complete case analysis is planned. Should variables with substantial missing data be present, the pattern and likely cause of the missing data will be evaluated and if missing at random is reasonable to assume then single regression imputation will be undertaken.

Analyses will include evaluating predictors of toxicity incidence and response profiles for relevant comparator medicines. Analyses will also include evaluating the heterogeneity in toxicity incidence and response profiles according to model risk for certolizumab pegol, baricitinib and tocilizumab as compared to relevant comparator arms (e.g. methotrexate). Such analyses will allow a better understanding of the benefits of certolizumab pegol, baricitinib and tocilizumab , and whether the relationships identified are specific to certolizumab pegol, baricitinib and tocilizumab , the comparator medicine or are common across rheumatoid arthritis patients.

Power:

Predictors that have a clinically meaningful (e.g. double the risk) effect on mortality and adverse effects will be of primary interest. Based upon a 30% incidence of toxicity, a sample size of approximately 600 is required to detect a predictor (with a 10% frequency within the population) associated with a two-fold risk (α=0.05 with 80% power). Based upon an event rate of 40% during trial follow-up (e.g. for progression), approximately 450 participants are required for 80% power to detect a predictor (with a 10% frequency within the population) associated with a two-fold hazard of the event (α=0.05). Reference: Chow S, Shao J, Wang H. 2008. Sample Size Calculations in Clinical Research. 2nd Ed. Chapman & Hall/CRC Biostatistics Series. page 177. These samples sizes are well within scope for this study. These samples sizes are well within scope for this study. Sample sizes greater than this will allow the investigation of more complex relationships with greater predictive performance, which is a primary objective of this study.

Quality Control:

Data will be explored for inconsistencies in time recordings, physiologically unreasonable covariate values, and unit errors. Prior to beginning analyses, individual data values will be extracted/constructed based on the raw and analysis datasets provided. To ensure that each variable has been correctly extracted/constructed from the data provided, basic analyses and descriptive statistics will be reproduced to check for consistency with pertinent results in published manuscripts or CSRs relating to the specific trial. Where there are insufficient published results to confirm the proper extraction of the variable, the extracted values will be manually checked against a random sample of the original dataset values.

Requested Studies:

Efficacy and Safety of CDP870 400 mg in Combination With Methotrexate Compared to Methotrexate Alone in the Treatment of the Signs and Symptoms of Patients With Rheumatoid Arthritis Who Are Partial Responders to Methotrexate
Sponsor: UCB
Study ID: NCT00544154
Sponsor ID: C87014

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 III Multi-center, Open-label, Follow-up Study, to Assess the Safety and Efficacy of Liquid Certolizumab Pegol as Additional Medication to Methotrexate, in the Treatment of Signs and Symptoms and in the Prevention of Joint Damage in Patients With Active Rheumatoid Arthritis Who Participated in Study CDP870-050
Sponsor: UCB
Study ID: NCT00160641
Sponsor ID: C87051

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
Sponsor: UCB
Study ID: NCT01500278
Sponsor ID: RA0077

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 DMARDNaïve Adults With Early Active Rheumatoid Arthritis
Sponsor: UCB
Study ID: NCT01521923
Sponsor ID: RA0055 Period 2

A Phase III, Multicenter, Open-Label Long-Term Study to Assess the Safety and Tolerability of CDP870 400 mg Subcutaneously Every 4 Weeks, in Subjects With Rheumatoid Arthritis
Sponsor: UCB
Study ID: NCT00160693
Sponsor ID: C87015

Phase 4, Randomized, 52-Week Study To Evaluate Two Assessment Tools To Predict Treatment Success At 52 Weeks Based On A Treatment Decision At Week 12 In Subjects With Moderate To Severe Rheumatoid Arthritis Receiving Cimzia
Sponsor: UCB
Study ID: NCT01255761
Sponsor ID: RA0064

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
Sponsor: Eli Lilly and Company
Study ID: NCT01721044
Sponsor ID: 14058

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
Sponsor: Eli Lilly and Company
Study ID: NCT01721057
Sponsor ID: 14059

A Randomized, Double-Blind, Active-Controlled, Phase 3 Study to Evaluate the Efficacy and Safety of Baricitinib (LY3009104) in Patients With Moderately to Severely Active Rheumatoid Arthritis Who Have Had Limited or No Treatment With Disease-Modifying Antirheumatic Drugs
Sponsor: Eli Lilly and Company
Study ID: NCT01711359
Sponsor ID: 14062

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
Sponsor: Eli Lilly and Company
Study ID: NCT01710358
Sponsor ID: 13978

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
Sponsor: Eli Lilly and Company
Study ID: NCT01469013
Sponsor ID: 14116

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
Sponsor: Eli Lilly and Company
Study ID: NCT01185353
Sponsor ID: 13854

(Note: Additional Studies added as part of Data Request 5933)

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: Hoffmann-La 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: Hoffmann-La Roche
Study ID: NCT00106535
Sponsor ID: WA17823

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: Hoffmann-La Roche
Study ID: NCT00109408
Sponsor ID: WA17824

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: Hoffmann-La Roche
Study ID: NCT00106522
Sponsor ID: WA18062

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: Hoffmann-La Roche
Study ID: NCT00106574
Sponsor ID: WA18063

Long-term Extension Study of Safety During Treatment With Tocilizumab (MRA) in Patients Completing Treatment in WA17822
Sponsor: Hoffmann-La 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: Hoffmann-La Roche
Study ID: NCT00720798
Sponsor ID: WA18696

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: Hoffmann-La Roche
Study ID: NCT01232569
Sponsor ID: NA25220

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: Hoffmann-La Roche
Study ID: NCT01007435
Sponsor ID: WA19926

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: Hoffmann-La 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: Hoffmann-La Roche
Study ID: NCT01119859
Sponsor ID: WA19924

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: Hoffmann-La Roche
Study ID: NCT00531817
Sponsor ID: ML21136

Public Disclosures:

Abuhelwa, A.Y., Hopkins, A.M., Sorich, M.J. et al. Association between obesity and remission in rheumatoid arthritis patients treated with disease-modifying anti-rheumatic drugs. Sci Rep 10, 18634 (2020). doi: 10.1038/s41598-020-75673-7
Abuhelwa AY, Foster DJR, Manning-Bennett A, et al. Concomitant beta-blocker use is associated with a reduced rate of remission in patients with rheumatoid arthritis treated with disease-modifying anti-rheumatic drugs: a post hoc multicohort analysis. Therapeutic Advances in Musculoskeletal Disease. January 2021. doi: 10.1177/1759720X211009020
Manning-Bennett, A. T., Hopkins, A. M., Sorich, M. J., Proudman, S. M., Foster, D. J. R., Abuhelwa, A. Y., & Wiese, M. D. (2022). The association of depression and anxiety with treatment outcomes in patients with rheumatoid arthritis – a pooled analysis of five randomised controlled trials. Therapeutic Advances in Musculoskeletal Disease. doi:10.1177/1759720X221111613
Daraghmeh DN, Hopkins AM, King C, Abuhelwa AY, Wechalekar MD, Proudman SM, Sorich MJ, Wiese MD. Female reproductive status and exogenous sex hormone use in rheumatoid arthritis patients treated with tocilizumab and csDMARDs. Rheumatology (Oxford). 2022 Jun 22:keac357. doi: 10.1093/rheumatology/keac357
Manning-Bennett A, Hopkins A, Sorich M, Proudman S, Foster D, Abuhelwa A, Wiese M. The Association of Cardiovascular Comorbidities with Remission in Rheumatoid Arthritis Patients Undergoing Treatment with Baricitinib and Conventional Synthetic DMARDs: A Post-Hoc Analysis [abstract]. Arthritis Rheumatol. 2022; 74 (suppl 9). https://acrabstracts.org/abstract/the-association-of-cardiovascular-comorbidities-with-remission-in-rheumatoid-arthritis-patients-undergoing-treatment-with-baricitinib-and-conventional-synthetic-dmards-a-post-hoc-analysis/