Patient-Centered Outcomes, Adelphi Values, Bollington, UK.
Rheumatology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.
RMD Open. 2023 Mar;9(1). doi: 10.1136/rmdopen-2022-002721.
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.
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.
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.
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.
干燥、疲劳和关节/肌肉疼痛通常在干燥综合征试验中使用欧洲风湿病联盟干燥综合征患者报告指数（ESSPRI）进行评估。先前已经定义了<5 的患者可接受症状状态和≥1 点或 ESSPRI 上 15%的最小临床重要改善（MCII）/应答者定义（RD）。本研究旨在探索替代 RD，以便在试验中更好地区分活性治疗与安慰剂。
使用基于锚定和基于分布的方法从盲法 IIb 期试验数据（N=190）中得出 RD 阈值，并在从三项早期 II 期试验中汇集的盲法数据中对这些阈值进行确认（N=126）。这些人群由中重度系统性原发性干燥综合征患者组成。根据 ESSPRI 相关性对锚定进行优先级排序，并在相似条件下使用。与专家（N=3）讨论了三角估计。使用未盲数据比较修订后的 RD，以评估安慰剂和治疗应答者的比率。
患者主要为女性（>90%），白人（90%），平均年龄为 50 岁。受试者工作特征估计值支持 II 期数据中 MCII 阈值为 1.5-1.6，而相关加权平均变化估计值支持低/最小症状严重程度阈值为≥2。低/最小症状严重程度≤3 显示出最大的敏感性/特异性平衡。汇总数据的分析支持这些阈值（MCII：1.5-2.1；低/最小症状严重程度：2.7-3.7）。未盲分析证实修订后的 RD 降低了安慰剂的比率。
与基线相比，改善≥1.5 分且 ESSPRI 评分≤3 分完成试验是中重度系统性干燥综合征的一个相关 RD，可降低安慰剂的比率。
