trial population and the subgroup of treatment completers (Figure 2). Accordingly, the treatment effect of tolvaptan versus placebo was also similar between the total population and the subgroup of treatment completers. Annualized TKV growth rate was 2.8% for subjects in the tolvaptan group and 5.5% for those in the placebo group in the total TEMPO 3:4 population (P < 0.001).12 Among the subgroup of TEMPO 3:4 completers, annualized TKV growth rate was 2.7% for subjects in the tolvaptan group and 5.5% for those in the placebo group (P < 0.001). As with rates of change in kidney function, rates of TKV Figure 1. Subject flow. CLINICAL RESEARCH AJ Mallett et al.: Adherence and Tolvaptan Effect Size in ADPKD 1034 Kidney International Reports (2021) 6, 1032–1040 growth in the subpopulation of completers were similar to those in the total trial population. Impact of Baseline Characteristics Subgroup analyses of completers by baseline characteristics showed that tolvaptan was efficacious versus placebo in slowing renal function decline regardless of age, sex, or race in both trials (Supplementary Tables S1 and S2). The few nonsignificant differences between tolvaptan and placebo were in subgroups with low subject numbers: non-Caucasian subjects in TEMPO 3:4 and REPRISE and subjects aged >55 years in REPRISE. Propensity score matching for gender, age, and baseline eGFR generated an analysis set of 108 subjects for each trial (54 subjects in each of the tolvaptan and placebo treatment arms). Gender composition was 23 women (43%) and 31 men (57%) in each matched tolvaptan and placebo group, and mean age was 42 to 44 years (Figure 3a). The mean eGFR (w53 ml/min per 1.73 m2 ) in the matched population fell within CKD stage 3a, indicating the area of overlap in the 2 trial populations between subjects with early- to moderatestage CKD (TEMPO 3:4) and subjects with moderate- to late-stage CKD (REPRISE) (Figure 3b). The baseline characteristics of the matched population are provided in Supplementary Table S3 and the age and CKD stage distributions are shown in Supplementary Figure S1. In the matched population, the treatment effect of tolvaptan in TEMPO 3:4 (1.44 ml/min per 1.73 m2 /year) was similar to that in REPRISE (1.89 ml/min per 1.73 m2 /year), with a nonsignificant difference of 0.45 (P ¼ 0.71) (Figure 4). Analyses of baseline demographic and clinical characteristics revealed potential associations of age, body mass index, use of blood pressure lowering drugs, history of hematuria, and history of kidney pain with treatment completion in TEMPO 3:4 but not REPRISE (Table 1). DISCUSSION Tolvaptan has demonstrated statistically and clinically significant efficacy in reducing the rate of kidney function decline in patients with ADPKD with both early-stage and later-stage CKD, with slight differences observed in the tolvaptan effect sizes between the total TEMPO 3:4 and REPRISE populations. In TEMPO 3:4, the annualized mean change in eGFR was reduced by 1.20 ml/min per 1.73 m2 /year with tolvaptan versus Figure 2. Effect of tolvaptan on eGFR change (ml/min per 1.73 m2 /year) in the total trial population and treatment completer subset of TEMPO 3:4 (a) and REPRISE (b). a Comparison of tolvaptan versus placebo within each analysis population. Data are 95% confidence interval for TEMPO 3:4 and standard error for REPRISE. eGFR, estimated glomerular filtration rate; PBO, placebo; TOL, tolvaptan. AJ Mallett et al.: Adherence and Tolvaptan Effect Size in ADPKD CLINICAL RESEARCH Kidney International Reports (2021) 6, 1032–1040 1035 placebo.13 In REPRISE, tolvaptan reduced the annualized mean change in eGFR by 1.27 ml/min per 1.73 m2 / year.13 In TEMPO 3:4, the annualized eGFR slope was 2.72 ml/min per 1.73 m2 /year in the tolvaptan group versus 3.70 ml/min per 1.73 m2 /year in the placebo group (a difference of 0.98 ml/min per 1.73 m2 / year; 95% confidence interval 0.60–1.36; P < 0.001).12 In REPRISE, annualized eGFR slope was 3.16 ml/min per 1.73 m2 /year with tolvaptan and 4.17 ml/min per 1.73 m2 /year with placebo, a significant difference of 1.01 ml/min per 1.73 m2 /year (95% confidence interval 0.62–1.40; P < 0.001).13 The slightly greater tolvaptan treatment effects in REPRISE might plausibly be ascribed to the higher frequency of tolvaptan discontinuation during doubleblind treatment in TEMPO 3:4 (23.0%) compared with REPRISE (15.0%). In this post hoc analysis, we evaluated the hypothesis that subjects completing their respective trials on treatment would show a larger effect size than those who discontinued treatment early. No difference in effect size, however, was found between the total trial population and the subgroup of completers. Tolvaptan was generally effective versus placebo in subgroups of completers defined by baseline age, sex, and race. The treatment difference between tolvaptan and placebo was not significant in nonCaucasian subjects in both trials and in subjects aged >55 years in REPRISE, observations that may have been due to the small sample sizes of these subgroups. Given the lack of impact of treatment completion and demographic characteristics on outcomes, the small differences in tolvaptan treatment effect between TEMPO 3:4 and REPRISE therefore appeared to be due to differences in disease