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Abstract
Objectives Dryness, fatigue and joint/muscle pain are typically assessed in Sjögren’s trials using European Alliance of Associations for Rheumatology Sjögren’s Syndrome Patient Reported Index (ESSPRI). A Patient Acceptable Symptom State of <5 and a Minimal Clinically Important Improvement (MCII)/responder definition (RD) of ≥1 point or 15% on ESSPRI have previously been defined. This study explored alternative RDs to better discriminate between active treatment and placebo in trials.
Methods Anchor-based and distribution-based methods were used to derive RD thresholds in blinded phase IIb trial data (N=190) and confirm these in blinded data pooled from three early phase II trials (N=126). The populations consisted of individuals with moderate-to-severe systemic primary Sjögren’s. Anchors were prioritised by ESSPRI correlations and used in similar conditions. Triangulated estimates were discussed with experts (N=3). The revised RD was compared with the original using unblinded data to assess placebo and treatment responder rates.
Results Patients were predominantly female (>90%), white (90%), with mean age of 50 years. Receiver operating characteristic estimates supported an MCII threshold of 1.5–1.6 in the phase II data, whereas correlation-weighted mean change estimates supported a low/minimal symptom severity threshold of ≥2. A low/minimal symptom severity of ≤3 showed the greatest sensitivity/specificity balance. Analyses in the pooled data supported these thresholds (MCII: 1.5–2.1; low/minimal symptom severity: 2.7–3.7). Unblinded analyses confirmed the revised RD reduced placebo rates.
Conclusions Completing a trial with an improvement of ≥1.5 points compared with baseline and an ESSPRI score of ≤3 points is a relevant RD for moderate-to-severe systemic Sjögren’s and reduces placebo rates.
- Sjogren's Syndrome
- Patient Reported Outcome Measures
- Outcome Assessment, Health Care
Data availability statement
All data relevant to the study are included in the article or uploaded as supplemental information.
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Data availability statement
All data relevant to the study are included in the article or uploaded as supplemental information.
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Footnotes
Contributors SW contributed to the design of the study (including the statistical analysis plan) and interpretation of the results, was a major contributor to writing and revising the manuscript, and provided final approval of the manuscript. LA-W contributed to the design of the study (including the statistical analysis plan), interpretation of the results and revising the manuscript, and provided final approval of the manuscript. EA contributed to data analysis and interpretation of the results, and provided final approval of the manuscript. PGr contributed to the design of the study, data analysis, interpretation of the results and revising the manuscript, and provided final approval of the manuscript. SB made a substantial contribution to the interpretation of the results and revising the manuscript to ensure important intellectual content, and provided final approval of the manuscript. WH contributed to the design of the study, data analysis, interpretation of the results and revising the manuscript, and provided final approval of the manuscript. BN contributed to the design of the study, interpretation of the results and revising the manuscript, and provided final approval of the manuscript. DK contributed to the design of the study, data analysis, interpretation of the results and revising the manuscript, and provided final approval of the manuscript. PGo supervised the research and contributed to the design of the study, interpretation of the results and revising the manuscript, provided final approval of the manuscript and is responsible for the overall content as guarantor.
Funding This study was funded by Novartis.
Competing interests Authors on this manuscript are either employees of or consultants to Novartis, a pharmaceutical company developing products for patients with Sjogren’s. SB has consulted in the field of Sjogren’s in the past 3 years for AbbVie, AstraZeneca, BMS, Galapagos, Novartis and Resolve Pharmaceuticals.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.