Is radiographic progression in modern rheumatoid arthritis trials still a robust outcome? Experience from tofacitinib clinical trials

Abstract

BackgroundThe detection of statistically significant reductions in radiographic progression during clinical studies in patients with rheumatoid arthritis (RA) has become increasingly difficult over the past decade due to early-escape study designs and declining rates of progression in control-group patients. We investigated the impact of extremes of radiographic data (outliers) and baseline prognostic factors on detection of treatment effects, to provide guidance on future analysis of joint structural data in RA clinical trials.MethodsData were from two, phase 3, randomized, double-blind, placebo-controlled trials of tofacitinib in adult patients with moderate to severe RA: ORAL Scan (NCT00847613) and ORAL Start (NCT01039688). These studies detected significant reductions in radiographic progression with tofacitinib 10 mg twice daily (BID) plus background methotrexate (ORAL Scan), and with tofacitinib 5 or 10 mg BID as monotherapy (ORAL Start). We evaluated mean changes from baseline in van der Heijde modified total Sharp score (mTSS) at month 6 and month 12, using analysis of covariance (ANCOVA). A trimmed analysis was used to deal with extremes of data. The impact of baseline prognostic factors on radiographic progression was evaluated using ANCOVA to analyze the mean change from baseline in mTSS for each factor in turn.ResultsThe analysis included data from 720 patients from ORAL Scan and 880 patients from ORAL Start. Trimmed analyses were unbiased for the true mean estimate and enabled us to remove the effect of influential extreme observations in the data set. Almost all patients had at least one poor prognostic factor at baseline (e.g., high level of disease activity, or positive for rheumatoid factor). The strongest predictor of treatment effect was the severity of radiographic damage at baseline.ConclusionsA trimmed analysis can establish whether any significant inhibition of structural damage is being driven by extremes of data, and should be one of the sensitivity analyses of choice for structural data in RA clinical trials. Furthermore, analysis of radiographic data based on baseline prognostic factors may reveal increased treatment effects. Application of these methods to analysis of radiographic data from clinical trials in patients with RA, allows a more complete interpretation of data.Trial registrationClinicaltrials.gov NCT00847613 (registered 17 February 2009) and NCT01039688 (registered 23 December 2009)Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-016-1106-y) contains supplementary material, which is available to authorized users.

Radiographic remission in rheumatoid arthritis quantified by computer-aided joint space analysis (CASJA): a post hoc analysis of the RAPID 1 trial

“…Consequently, the non-significant change of JSD-MCP is a surrogate marker for structural integrity, defined by zero radiographic progression [3,14,19]. With the introduction of biological and targeted synthetic DMARDs, the conventional radiographic scoring systems seem to be impaired in detecting radiographic changes and structural preservation [3,19,20].…”

Assessing structural damage progression in psoriatic arthritis and its role as an outcome in research

“…A main challenge in assessing radiographic progression is detecting a treatment effect [39,40]. Ethical considerations in clinical trials limit the duration of placebo treatment, impacting the ability to detect radiographic progression in this group.…”

“…Additionally, patients randomized to placebo are allowed to switch to active treatment due to lack of efficacy or to discontinue the study before radiographic progression is assessed or discernable. These low rates of radiographic progression in the control group and incomplete radiographic data may impact the statistical power of these trials to detect a treatment effect [39].…”

“…In addition to imputation methodologies, enriching for patients who are at high risk of radiographic progression may increase the power of a study to detect treatment effects [39]. This could be achieved by increasing the number of patients who present with predictive factors for radiographic progression or by indirectly enriching the data through post hoc analyses.…”

Röntgendiagnostik in der Rheumatologie im Jahr 2020

“…Durch die van der Heijde-Mo-difikation des Sharp-Scores werden Hände und Vorfüße bezüglich Erosionen (44 Gelenkregionen) und einer Gelenkspaltverschmälerung (42 Gelenkregionen) beurteilt [21]. Durch die Entwicklung neuer Disease Modifying Antirheumatic Drugs als auch den Einsatz effektiver Behandlungsschemata als Kontrollgruppe ist eine deutliche Abnahme der radiologischen Progression in klinischen Studien zu verzeichnen [22], sodass hier teilweise keine Gruppenunterschiede bezüglich der radiologischen Progression zwischen den Behandlungsarmen mehr nachweisbar sind [23]. Weiterführend ist das Scoring von Röntgenaufnahmen als sehr zeitaufwendig einzustufen (bis zu 22 Minuten) [20], sodass in der klinischen Praxis routinemäßig kein Scoring durchgeführt wird.…”