In TEMPO 3:4, tolvaptan was initiated at a daily split dose of 45/15 mg, which was increased weekly to 60/30 mg and then to 90/30 mg, based on subject-reported tolerability. Subjects took the highest tolerable dose for the 36-month treatment period. In REPRISE, all subjects received tolvaptan during a single-blind, 5-week titration and run-in phase. Those who tolerated a 60/30-mg or 90/30-mg dose were then randomized to 12 months of double-blind tolvaptan or placebo. Tolvaptan was taken at the highest dose tolerated (with a maximum dose of 90/30 mg). Both studies targeted ADPKD populations with a high likelihood of rapid disease progression. TEMPO 3:4 enrolled subjects with preserved renal function: 18 to 50 years old with estimated creatinine clearance $60 ml/min and TKV $750 m. REPRISE enrolled an older population with more advanced disease: ages 18 to 55 years with eGFR $25 and #65 ml/min per 1.73 m2 , or ages 56 to 65 years with eGFR $25 and #44 ml/min per 1.73 m2 and evidence of ADPKD progression (an eGFR decline of >2.0 ml/min per 1.73 m2 /year based on historical eGFR data). Based on the preceding enrollment criteria, TEMPO 3:4 had a trial population in CKD stages 1 to 3, >80% in stage 1 or 2 CKD. In REPRISE, 75% of subjects were in stage 3 and 20% were in stage 4 CKD. A post hoc analysis of the TEMPO 3:4 trial population indicated a population enriched for high risk of rapid progression, with 89.5% of the population in Mayo risk classes 1C-1E versus 60.5% in an unselected ADPKD population of Mayo Clinic patients.19 Outcomes Evaluated in the Post Hoc Analyses The effect of tolvaptan on rate of change in eGFR in each trial was evaluated for the subgroup of completers, that is, subjects who continued to take the trial drug to the end of the treatment period in TEMPO 3:4 (3 years) or REPRISE (1 year). Similarly, the effect of tolvaptan on annualized rate of TKV growth was calculated for the completer subpopulation in TEMPO 3:4 (TKV was not assessed in REPRISE). To further explore determinants of tolvaptan treatment effects on kidney function in ADPKD, subgroup analyses of change in eGFR over time by baseline demographic and clinical variables were performed. Finally, subject characteristics by completer/noncompleter status were compared to identify variables associated with completion/noncompletion. Statistical Methods Analysis of efficacy endpoints was based on the methods used in each trial and using the full trial datasets. For TEMPO 3:4, comparisons between tolvaptan completers and placebo completers were AJ Mallett et al.: Adherence and Tolvaptan Effect Size in ADPKD CLINICAL RESEARCH Kidney International Reports (2021) 6, 1032–1040 1033 derived by testing the time treatment interaction with a linear mixed model in which both intercept and slope are fixed and random effects. For REPRISE, the comparison was derived from a weighted analysis of covariance with effects of treatment and randomization stratification factors and covariate baseline. In an analysis of the effects of baseline variables, we compared eGFR slope between subjects from TEMPO 3:4 and REPRISE who were matched by propensity score for gender, age, and baseline eGFR. Propensity score-based matching was used to exclude the effects of differences in trial populations (for example, in the proportions of subjects with early versus late-stage CKD) and assess the treatment effects of tolvaptan in subjects with similar clinical profiles. For the propensity analysis, the SAS (SAS Inc., Cary, NC) procedure PROC PSMATCH was utilized in 3 steps with the local optimal algorithm, caliper ¼ 0.03, and the sex as exact match. In Step 1, TEMPO 3:4 placebo subjects were matched to TEMPO 3:4 tolvaptan subjects. The total absolute difference in the logit of the propensity score for all matches was 0.692729. In Step 2, REPRISE tolvaptan subjects were matched to the TEMPO 3:4 tolvaptan subjects found in Step 1. The total absolute difference in the logit of the propensity score for all matches was 1.722285. In Step 3, REPRISE placebo subjects were matched to TEMPO 3:4 placebo subjects found in Step 1. The total absolute difference in the logit of the propensity score for all matches was 0.78467. In a comparison of subject characteristics by completer/noncompleter status, P values were derived by Fisher exact test for binary characteristics and by ttest/Wilcoxon Test for continuous characteristics. RESULTS Subject Disposition In TEMPO 3:4, 740 of 961 (77.0%) subjects randomized to the tolvaptan arm and 417 of 484 (86.2%) randomized to the placebo arm completed the trial on treatment.12 In REPRISE, the number of completers was 578 of 683 (84.6%) for tolvaptan and 637 of 687 (92.7%) for placebo.13 Several completers in each trial had missing or unusable eGFR data, yielding an efficacy analysis population of 713 tolvaptan and 410 placebo completers for TEMPO 3:4 and 576 tolvaptan and 634 placebo completers for REPRISE (Figure 1). Testing of the potential interaction between completer status and treatment found no treatment difference between completers and noncompleters in either TEMPO 3:4 (P ¼ 0.4846) or REPRISE (P ¼ 0.0924). Efficacy in the Completer Subpopulation In both TEMPO 3:4 and REPRISE, rates of change in eGFR with tolvaptan and placebo were very similar between the total