Given symptoms and impacts of disease or treatments on health-related quality of life (HRQOL) are subjective experiences that only patients can describe, patient-reported outcomes (PROs) have become endpoints of interest in clinical trials. However, the choice of PRO instrument to use can pose a challenge, especially for rare disease studies. PROTECT and DUPLEX are randomized, double-blind, active-control trials evaluating the effect of sparsentan (SPAR; a non-immunosuppressive, dual endothelin and angiotensin receptor antagonist) compared to maximally dosed angiotensin receptor blocker treatment with irbesartan (IRB) in adult patients with the rare kidney diseases - Immunoglobulin A nephropathy (IgAN) and focal segmental glomerulosclerosis (FSGS), respectively. In both studies, the Kidney Disease Quality of Life-36 (KDQOL-36) PRO instrument was chosen to measure more general Physical and Mental components of HRQOL as well as more specific Symptoms and Problems of Kidney Disease (SPKD), Effects of Kidney Disease (EKD) and Burden of Kidney Disease (BKD) domains. The KDQOL-36 was administered at baseline and each visit of the double-blind treatment period of both studies. Here we review the benefits and challenges of exploratory analyses from both trials. Score changes from baseline were analyzed using least-squares means from mixed models for repeated measures with a score change of 5 considered clinically meaningful. In PROTECT, SPAR exhibited consistent within-group improvements in BKD scores at all follow-up visits with a week 110 between-group difference (SPAR-IRB) of 5.1 (P=0.0316) and directional within-group improvement or stability for SPAR in other KDQOL-36 scores. In DUPLEX, within-group improvements were also observed in BKD scores in both SPAR and IRB groups with clinically meaningful within-group change observed for 8 of 10 timepoints through week 108 for SPAR but at week 60 only for IRB; however, no clinically meaningful between-group differences in this or any other KDQOL-36 score were observed. Overall, based on KDQOL-36 information, there was no detrimental impact for patients in either study. Although the KDQOL-36 scales did not discriminate between treatment group differences in most cases, the common impact of treatment on BKD scores provides some evidence of the sensitivity of this component of the KDQOL-36 in these rare kidney diseases. BKD scores may be sensitive to HRQOL changes in rare kidney diseases because this scale covers the impacts of kidney disease generally, while other KDQOL-36 scales are more tailored to the experience of individuals with end-stage kidney disease. With preservation of HRQOL as a recognized therapeutic goal in chronic kidney disease, the overall stable results observed in both studies are reassuring.
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