Avacopan cuts steroid side effects in new trial analysis

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Standardised instrument provides more nuanced insights into glucocorticoid toxicity.

A post-hoc data analysis from the ADVOCATE trial has demonstrated “a substantial reduction” in glucocorticoid toxicity among ANCA-associated vasculitis patients taking avacopan compared with those on standard prednisone taper.

The randomised, multi-centre, double-blind, phase III ADVOCATE trial included 331 patients with AAV and compared avacopan with an oral prednisone taper regimen. Patients in both groups who experienced worsening symptoms could be treated with glucocorticoid rescue therapy. 

Overall, patients in the avacopan group received an average of around 1000mg prednisolone equivalent of glucocorticoids compared with around 3000mg in the prednisone taper group.

The study met its primary endpoints of disease remission at 26 weeks and sustained remission at 52 weeks, demonstrating superiority of avacopan over a prednisone-based standard of care with respect to sustained remission at 52 weeks. 

Glucocorticoid toxicity was a key secondary endpoint in the ADVOCATE trial and was assessed using the glucocorticoid toxicity index (GTI), a tool designed to measure change in glucocorticoid toxicity between two timepoints.

“Because ADVOCATE was the first randomised clinical trial to use a standardised instrument for the direct measurement of glucocorticoid toxicity, it offers the opportunity to gain insight into glucocorticoid toxicity in the current era,” wrote the authors.

The GTI encompasses domains that are common, are important to both patients and clinicians, and can change in response to alterations in glucocorticoid use.

The domains covered were: BMI, glucose tolerance, lipid metabolism, blood pressure, glucocorticoid myopathy, skin toxicity, neuropsychiatric effects and infection. A further domain, bone mineral density, was not included as it was not expected to show a detectable level of change over the trial’s duration.

The GTI comprises two overall scores: the cumulative worsening score, which calculates transient and permanent glucocorticoid toxicity from baseline to specific time points, and the aggregate improvement score, which accounts for improvement as well as worsening glucocorticoid toxicity.

The post-hoc analysis drilled down into the different domains of the GTI with the aim of understanding which were most influential in differentiating the avacopan and prednisone groups.

Most patients (over 90%) in both groups experienced glucocorticoid toxicity, often in more than one domain. However, those in the prednisone group were more likely to experience toxicity in three or more domains than those in the avacopan group (41% vs 27% respectively at 26 weeks).

Worsening in the BMI, lipid metabolism and skin toxicity domains differentiated the two groups at week 13 and week 26, in favour of the avacopan group. Glucose tolerance was worse in the prednisone group than the avacopan group at week 13, but not week 26.

“The overall picture of glucocorticoid toxicity within individuals was frequently nuanced, with improvement in some domains often accompanied by worsening in others,” the researchers noted, with 42% of all patients showed mixed toxicity at 26 weeks.

“These results confirm the substantial reduction in glucocorticoid toxicity associated with avacopan in patients with ANCA-associated vasculitis,” the authors concluded.

“The benefits of discontinuing glucocorticoid early were shown in multiple domains of toxicity, reflecting the fact that both the overall GTI scores and many of the component domains favoured avacopan. These findings emphasise the value of a composite measure that directly quantifies improvement and worsening across several domains in each patient.”

Lancet Rheumatol 2023, March

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