Agreement between local and central reading of endoscopic disease activity in ulcerative colitis: results from the tofacitinib OCTAVE trials

Abstract

Background: Endoscopy is routine in trials of ulcerative colitis therapies.

Aim: To investigate agreement between central and local Mayo endoscopic subscore (MES) reads in the OCTAVE programme METHODS: Flexible sigmoidoscopy was performed in tofacitinib induction (OCTAVE Induction 1&2, NCT01465763 and NCT01458951), maintenance (OCTAVE Sustain, NCT01458574) and open-label, long-term extension (OCTAVE Open, NCT01470612) studies. Kappa statistics and Bowker's tests evaluated agreement/disagreement between centrally and locally read MES, with potential determinants of differences analysed by logistic regression.

Results: Moderate-to-substantial agreement was observed between central and local reads at screening (77.1% agreement; kappa 0.62 [95% confidence interval 0.59-0.66]), OCTAVE Induction 1&2 week (Wk) 8 (63.8%; 0.62 [0.59-0.66]), OCTAVE Sustain Wk 52 (55.6%; 0.56 [0.50-0.62]) and for induction non-responders at OCTAVE Open month 2 (59.9%; 0.54 [0.48-0.60]). Where disagreements occurred, local reads were systematically lower than central reads at OCTAVE Induction 1&2 Wk 8, OCTAVE Sustain Wk 52 and OCTAVE Open month 2 (Bowker's P < 0.0001); this difference was not observed at screening (P = 0.0852). Using multivariable logistic regression, geographical region, C-reactive protein (Wk 8), partial Mayo score (Wk 8) and prior tumour necrosis factor antagonist failure were associated with disparity at OCTAVE Induction 1&2 Wk 8 (P < 0.05). In OCTAVE Induction 1&2 and OCTAVE Sustain, significantly higher proportions of patients endoscopic improvement, remission and endoscopic remission with tofacitinib vs placebo, using either central or local reads.

Conclusion: Moderate-to-substantial agreement was observed between central and local endoscopic reads. Where disagreements occurred, local reads were systematically lower than central reads at most timepoints, suggesting potential bias. ClinicalTrials.gov identifier: NCT01465763, NCT01458951, NCT01458574, NCT01470612.

Keywords: endoscopy; inflammatory bowel disease; symptom score or index; ulcerative colitis.

© 2021 Pfizer Inc. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.

Figures

FIGURE 1

Overview of the tofacitinib phase 3 OCTAVE clinical programme. b.d., twice daily; n, number of patients treated. †Final complete efficacy assessment at Week 8/52. Treatment continued up to Week 9/53. ‡Clinical response in OCTAVE Induction 1 and 2 was defined as a decrease from induction study baseline total Mayo score of ≥3 points and ≥30%, plus a decrease in rectal bleeding subscore of ≥1 point or an absolute rectal bleeding subscore of 0 or 1. §Study A3921139 (OCTAVE Open) was ongoing at the time of this interim analysis. ¶Remission was defined as a total Mayo score of ≤2 with no individual subscore >1, and a rectal bleeding subscore of 0. Adapted from Winthrop KL, et al. Inflamm Bowel Dis 2018;24:2258‐2265 (in accordance with the CC BY‐NC licence)

FIGURE 2

Distribution of local and central endoscopic reads and weighted kappa statistics at (A) screening in OCTAVE Induction 1 and 2, (B) Week 8 in OCTAVE Induction 1 and 2, (C) Week 52 of OCTAVE Sustain and (D) induction non‐responders at Month 2 of OCTAVE Open. CI, confidence interval; MES, Mayo endoscopic subscore; n, number of patients in each category. Data are full analysis set (observed cases), n (%). Agreement between central and local MES assignment: green, no difference; orange, 1‐point discrepancy; red, ≥2‐point discrepancy. The green boxes, therefore, show a “line” of agreement that runs diagonally across the figure. If a random error was responsible for all of the agreement, discordant scores would be distributed randomly around this “line of agreement.” However, if bias were present, discordant scores would be distributed unevenly to one side of the line or the other. The P‐values were based upon Bowker's test, which evaluates the distribution (cells that lay off the diagonal line of agreement) of disagreement within the agreement matrix. A P < 0.05 denotes significant asymmetry for exploratory purposes

FIGURE 3

(A) Endoscopic improvement,† (B) remission‡ and (C) endoscopic remission§ at Week 8 (OCTAVE Induction 1 and 2) and Week 52 (OCTAVE Sustain), based on centrally and locally read MES. b.d., twice daily; CI, confidence interval; MES, Mayo endoscopic subscore; TNF, tumour necrosis factor. Data are full analysis set with non‐responder imputation; treatment difference from placebo is presented with 95% CIs. *P < 0.01 vs placebo. **P < 0.001 vs placebo. For OCTAVE Induction 1 and 2, P‐values were based on the Cochran‐Mantel‐Haenszel chi‐squared test, stratified by study, prior TNF antagonist treatment, corticosteroid use at baseline and geographical region. For OCTAVE Sustain, P‐values were based on the Cochran‐Mantel‐Haenszel chi‐squared test stratified by treatment assignment in the induction study and remission at baseline. †Endoscopic improvement was defined by a MES ≤1. ‡Remission (primary endpoint) was defined as a total Mayo score ≤2 with no subscore >1, and a rectal bleeding subscore of 0. §Endoscopic remission was defined as a MES of 0