The Glucocorticoid Toxicity Index-Metabolic Domains, an abridged version of the Glucocorticoid Toxicity Index: post-hoc analysis of data from the ADVOCATE trial.

Background: Quantifying glucocorticoid toxicity is crucial to efforts to reduce it. The Glucocorticoid Toxicity Index (GTI) measures toxicity effectively in clinical trials by calculating two scores: the cumulative worsening score (CWS) and the aggregate improvement score (AIS). However, in clinical practice, high patient volumes limit the time available for standardised assessments. We aimed to compare the GTI with an abbreviated version of the GTI, the GTI-Metabolic Domains (GTI-MD), which could help to address this issue by using data that are collected easily at routine visits and do not require additional effort from clinicians.
Methods: We did a post-hoc analysis of data from ADVOCATE, a randomised, double-blind, double-dummy, phase 3 trial in which avacopan replaced a standard prednisone taper in patients with antineutrophil cytoplasmic antibody-associated vasculitis. We calculated the cumulative worsening score (CWS) and aggregate improvement score (AIS) for each domain of the GTI-MD-comprising the BMI, glucose tolerance, blood pressure, and lipid metabolism domains of the GTI-to test its ability to differentiate the avacopan and prednisone groups by glucocorticoid toxicity. Data from two additional disease cohorts, one comprising patients with asthma and the other comprising patients with autoimmune blistering disease, constituted the validation set.
Findings: Complete data were available for 321 (97%) of the 330 participants comprising the intention-to-treat population in the ADVOCATE trial at week 13, and 307 (93%) at week 26; data from these individuals were included in our post-hoc analysis. In ADVOCATE, 98 (59%) of 166 participants in the avacopan group were men and 68 (41%) were women, 88 (54%) of 164 in the prednisone group were men and 76 (46%) were women; the mean age of participants was 61·2 years [SD 14·6] in the avacopan group and 60·5 years [14·5] in the prednisone group. The validation cohort included 159 patients (89 with glucocorticoid-dependent asthma, of whom 40 [45%] were men and 49 [55%] were women, and 70 with autoimmune blistering disease of the skin, of whom 30 [43%] were men and 40 [57%] were women). The Spearman's rank correlation coefficient in ADVOCATE for the GTI-MD CWS with the GTI CWS for the treatment groups combined was 0·78 (95% CI 0·75-0·81; p<0·0001). The corresponding correlation for the AIS was 0·73 (0·69-0·77, p<0·0001). The GTI-MD distinguished the groups by glucocorticoid toxicity at both 13 weeks and 26 weeks. The mean GTI-MD CWS was lower in the avacopan group than in the prednisone group, consistent with less toxicity (15·9 vs 23·0 at 13 weeks [p=0·0010]; 26·7 vs 31·7 at 26 weeks [p=0·0092]). The GTI-MD AIS values were also consistent with less toxicity in the avacopan group (2·5 vs 13·0 at 13 weeks [p=0·0003], 4·4 vs 10·1 at 26 weeks [p=0·027]). A GTI-MD score of 0 corresponded to a low likelihood of toxicity in the other GTI domains. In the validation set, the Spearman's rank correlation coefficient for the GTI-MD CWS with the GTI CWS was 0·61 (95% CI 0·50-0·70; p<0·0001) and the corresponding correlation for the AIS was 0·58 (0·47-0·68; p<0·0001).
Interpretation: The GTI-MD correlates well with the full GTI and could be incorporated readily into routine clinic workflows without additional input from the clinician. Using the GTI-MD on the background of electronic medical records systems could help clinicians to monitor glucocorticoid toxicity longitudinally, with the goals of preventing the burden of chronic, treatment-related harms and reducing long-term costs to health systems.
Funding: ChemoCentryx.
Competing Interests: Declaration of interests NJP reports consulting fees from FVC Health and Alosa Health, unrelated to the current work. DRWJ reports consultancy fees from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, ChemoCentryx (now Amgen), GSK, NICE, Novartis, Otsuka, Roche/Genentech, Takeda, UCB, Vifor Pharma, Catalyst Pharmaceuticals, Medscape, and Chinook Therapeutics; lecture fees from Amgen, Vifor Pharma, and Medscape; board member fees from and stock options in Aurinia Pharmaceuticals; commercial research grants from GSK and Roche/Genentech; and non-commercial research grants from the EU, the Medical Research Council, the National Institute for Health and Care Research, and Versus Arthritis. PAM reports consulting with AbbVie, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, ChemoCentryx (now Amgen), CSL Behring, Dynacure, EMD Serono, Forbius, Genentech/Roche, Genzyme/Sanofi, GlaxoSmithKline, Immagene, InflaRx, Janssen Pharmaceuticals, Kiniksa Pharmaceuticals, Kyverna Therapeutics, Magenta Therapeutics, MiroBio, Neutrolis, Novartis, Pfizer, Regeneron, Sparrow Pharmaceuticals, Takeda, and Talaris Therapeutics; research support from AbbVie, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, ChemoCentryx (now Amgen), Eicos Sciences, Forbius, Genentech/Roche, Genzyme/Sanofi, GSK, InflaRx, Sanofi, and Takeda; and royalties from UpToDate. PB reports consulting fees from ChemoCentryx (now Amgen) and owns stock and stock options in ChemoCentryx (now Amgen). PJM reports honoraria from GSK. LGH reports sponsorship for attending international scientific meetings from AstraZeneca, Boehringer Ingelheim, Chiesi Farmaceutici, GSK, and Napp Pharmaceuticals; advisory board fees from Novartis, Hoffman la Roche/Genentech, Sanofi, GSK, AstraZeneca, Teva Pharmaceuticals, Theravance Biopharma, and Circassia Group; institutional grant funding from MedImmune, Novartis UK, Roche/Genentech, and GSK; and is the academic lead for the Medical Research Council Stratified Medicine UK Consortium in Severe Asthma, which involves industrial partnerships with Amgen, Genetech/Hoffman la Roche, AstraZeneca, MedImmune, GSK, Aerocrine, and Vitalograph. DM reports consultation fees and investigator support from argenx, AstraZeneca, Janssen Pharmaceuticals, Pfizer, Principia Biopharma, and Roche; royalties from UpToDate; and speaker's fees from argenx, Janssen Pharmaceuticals, and Principia Biopharma. MNS is the CEO of Steritas, which holds the licensing rights to the Glucocorticoid Toxicity Index, and owns stock in Steritas (the intellectual property of the GTI is owned by the Massachusetts General Hospital. The intellectual property of the GTI-MD is co-owned by the Massachusetts General Hospital and Steritas. The sole licensing rights to the GTI and GTI-MD worldwide are controlled by Steritas). HY reports employment with and owning stock and stock options in ChemoCentryx (now Amgen). JHS reports consulting fees from ChemoCentryx (now Amgen), Amgen, Roche/Genentech, Sanofi, Bristol-Myers Squibb, AbbVie, InflaRx, Kyverna Therapeutics, Novartis, Q32 Bio, Steritas, Zenas BioPharma, Horizon Therapeutics, argenx, Spruce BioSciences, and PPD; owning stock in Steritas; commercial research grants from Roche/Genentech, Sanofi, Bristol-Myers Squibb; royalties from UpToDate; non-commercial research grants from National Institutes of Health/National Institute of Allergy and Infectious Diseases; and is the co-founder of Steritas and the unpaid chair of its scientific advisory board, with no fiduciary responsibility at the company. All other authors declare no competing interests.
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