Clarifying Crossover Interpretation and Volume-Signal Assessment in ASSIST

We read with interest the Atrasentan and Sodium Glucose Cotransporter-2 Inhibitor Efficacy and Safety Trial (ASSIST) crossover trial by Heerspink et al., published in JASN, which addresses a clinically relevant question: whether atrasentan provides incremental antiproteinuric benefit when added to renin-angiotensin system inhibition and sodium-glucose cotransporter 2 inhibition in IgA nephropathy.1 Two points may further clarify interpretation of the efficacy and safety findings. First, the secondary efficacy result in treatment period 2 merits more granular reporting. At week 24 of period 2, the estimated treatment difference in 24-hour urinary protein-to-creatinine ratio was −26.4% (95% confidence interval, −45.8 to 0.0).1 Because period 2 was longer than period 1 and sequence-specific week 24 estimates were not shown, reporting the nominal P value together with sequence-specific week 12 and week 24 effects would help readers distinguish sustained benefit from period- or sequence-related variability. Second, the safety inference would be strengthened by analyses aligned with the crossover design. Body weight, B-type natriuretic peptide, hemoglobin, and BP were additionally summarized using pooled data from both treatment periods, “not adjusting for sequence and period.”1 The Consolidated Standards of Reporting Trials extension for randomized crossover trials recommends explicit consideration of period and sequence effects in reporting and analysis.2 Reanalyzing these markers with a mixed-model approach paralleling the primary end point would be especially helpful because a key clinical implication of ASSIST is that background sodium-glucose cotransporter 2 inhibition may blunt endothelin antagonist–related fluid retention. Comparative context from A Phase 3, Randomized, Double-blind, Placebo-controlled Study of Atrasentan in Patients with IgA Nephropathy at Risk of Progressive Loss of Renal Function and Zibotentan in combination with dapagliflozin compared with dapagliflozin in patients with CKD highlights why the framework used to assess volume-related signals matters (Table 1).3,4 Table 1 - Selected studies relevant to interpretation of volume-related safety signals in ASSIST Study Population/Context Design Volume-Related Assessment Most Relevant to the Present Letter ASSIST1 IgA nephropathy on maximal RAS inhibition and SGLT2 inhibition Randomized, double-blind crossover; period 1, 12 wk; washout, 12 wk; period 2, 24 wk Body weight, BNP, hemoglobin, and BP were summarized in pooled post hoc comparisons across both periods without adjustment for sequence or period ALIGN3 IgA nephropathy on optimized supportive care Phase 3 randomized parallel-group trial; interim analysis at wk 36 Fluid-retention events were reported as treatment-emergent adverse events, underscoring that volume-related safety remains central when interpreting atrasentan benefit ZENITH-CKD4 Albuminuric CKD; dapagliflozin in all groups Phase 2b randomized active-controlled trial; 12 wk Included body weight plus extracellular fluid, intracellular fluid, and total body water, providing a more direct framework for evaluating fluid retention with ERA+SGLT2 inhibition ALIGN, A Phase 3, Randomized, Double-blind, Placebo-controlled Study of Atrasentan in Patients with IgA Nephropathy at Risk of Progressive Loss of Renal Function; ASSIST, Atrasentan and Sodium Glucose Cotransporter-2 Inhibitor Efficacy and Safety Trial; BNP, B-type natriuretic peptide; ERA, endothelin A receptor antagonist; RAS, renin-angiotensin system; SGLT2, sodium-glucose cotransporter 2; ZENITH-CKD, Zibotentan in combination with dapagliflozin compared with dapagliflozin in patients with CKD. We congratulate the authors on an important and timely trial. Additional sequence-aware efficacy and safety reporting would further strengthen the clinical interpretability of ASSIST.