Background Glucocorticoids (GC) are associated with substantial treatment morbidity. New immunomodulatory agents offer the possibility of limiting GC exposure. To assess the comparative benefits of such agents, investigators must accurately measure their ability to prevent or reverse GC-related toxicity. No comprehensive instrument for measuring GC toxicity has previously been developed.
Objectives We aimed to develop a GC Toxicity Index (GTI) to assess GC-related morbidity and GC-sparing ability of new agents. Intermediate aims were to 1) define toxicity items for inclusion in the GTI 2) assign relative weights to items and 3) begin the validation process.
Methods 22 physician experts from 11 subspecialties with extensive experience in the clinical use, pharmacology, and toxicity of GCs were invited, and 19 participated. Ten investigators were from the United States and 9 were from Canada, Europe, or Australia. Group consensus methods and multi-criteria decision analysis using forced-choice technique (1000Minds platform) were utilized. The development process included ten 1-hour conference calls and a 12-hour face-to-face meeting.
GTI components: The GTI is composed of the Composite GTI (CGTI) and the Specific List. The CGTI reflects GC toxicity that is likely to change over the course of a trial and is designed to distinguish between low and high GC users. The toxicities included in the CGTI vary with GC exposure and are expected to occur in >5% of patients over the course of a clinical trial lasting 6 months to 3 years. The items in the CGTI are weighted and scored. The Specific List is designed to capture GC toxicity not included in the CGTI. Toxicities in the Specific List are comparatively less common and – although impactful for patients – are less likely to contribute to delineating between high and low dose GC regimens. Items of the Specific List are therefore tabulated but not weighted.
Results Item inclusion and definitions:
Thirty-one toxicity items derived from the literature and reviewed by the investigators were included in the CGTI, and 23 were included in the Specific List (Figure). The CGTI items reflect both improvement and worsening of GC toxicity and account for medication effects (e.g., anti-hypertensives) in scoring. The 31 mutually-exclusive CGTI items are organized in order of severity within nine domains. Only one item in each domain can be scored.
Weighting and evaluation of the CGTI: Relative weights for each item in the CGTI were derived at a face-to-face meeting utilizing multi-criteria decision analysis (Figure). In order to assess reliability, all participants assigned toxicity items on the CGTI to 15 paper cases. Inter-rater agreement was high (kappa 0.89). To assess the degree to which the CGTI corresponds to expert clinical judgement, participants ranked 15 cases by clinical judgement in order of highest to lowest GC toxicity. Expert rankings were then compared to case ranking by the CGTI, yielding excellent agreement (weighted kappa 0.87).
Conclusions We describe the development and initial evaluation of the GTI - a comprehensive instrument intended primarily for use in prospective, randomized clinical trials for the assessment of GC toxicity. The GTI can be used across clinical disciplines in trials that employ GCs to assess the comparative value of GC-sparing therapies, and to measure the impact of GC toxicity.
Acknowledgement This work was supported by Genentech
Disclosure of Interest E. Miloslavsky Grant/research support from: Genentech, R. Naden: None declared, J. Stone Grant/research support from: Genentech