trial drug to the end of the treatment period in TEMPO 3:4 (3 years) or REPRISE (1 year). Efficacy (rate of change in eGFR for tolvaptan vs. placebo) was analyzed as in each trial. Subjects from TEMPO 3:4 and REPRISE were also matched by propensity score for age, gender, and baseline eGFR to explore potential additional determinants of treatment effect. Results: The annualized tolvaptan treatment effect in TEMPO 3:4 completers (difference vs. placebo of 0.98 ml/min per 1.73 m2 /y) and REPRISE completers (difference of 1.23) was similar to that of the respective total trial populations (TEMPO 3:4: 0.94; REPRISE: 1.27). The treatment effect of tolvaptan was also similar between matched subjects. Conclusion: Greater treatment completion rate did not drive greater treatment effect in REPRISE. The more advanced CKD of REPRISE subjects may be more relevant. More rapid decline in kidney function in laterstage CKD enabled the effects of tolvaptan to be more easily discerned. Kidney Int Rep (2021) 6, 1032–1040; https://doi.org/10.1016/j.ekir.2021.01.014 KEYWORDS: autosomal dominant polycystic kidney disease; clinical trial; chronic kidney disease; persistence; tolvaptan; treatment effect ª 2021 International Society of Nephrology. Published by Elsevier Inc. This is an open access article under the CC BYNC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney condition and a leading cause of end-stage kidney disease globally.1–4 Tolvaptan, a vasopressin receptor antagonist, is the first drug to be approved for the treatment of ADPKD and has been licensed in a number of regions, including the United States, Europe, Japan, Korea, and Australia.5–7 The drug exerts its therapeutic effects by targeting V2 receptors in renal epithelial cells, resulting in downregulation of the intracellular cyclic adenosine monophosphate signaling pathway. Cystic growth has been linked to upregulation of the cyclic adenosine monophosphate pathway in ADPKD, as reviewed elsewhere.5,8–11 The evidence for tolvaptan effectiveness is based on results from the 3-year TEMPO 3:4 (NCT00428948) and the 1-year REPRISE (NCT02160145) clinical trials. The trials demonstrated that tolvaptan slows eGFR decline and total kidney Correspondence: Andrew J. Mallett, TIHRI - TUH, 100 Angus Smith Drive, Douglas Queensland 4814, Australia. E-mail: andrew.mallett@health.qld.gov.au Received 2 July 2020; revised 7 December 2020; accepted 12 January 2021; published online 2 February 2021 1032 Kidney International Reports (2021) 6, 1032–1040 CLINICAL RESEARCH volume (TKV) growth compared with placebo in subjects with ADPKD at risk of rapid progression.12,13 Inhibition of vasopressin activity also decreases urine concentrating activity and is associated with aquaretic adverse events (e.g., polyuria, thirst, nocturia, pollakiuria), which can negatively impact adherence to treatment.14 In TEMPO 3:4, 23.0% of tolvaptan-treated subjects discontinued from the trial early; the most common reason for discontinuation was adverse events (15.4% of subjects), and those most frequently leading to discontinuation were aquaretic adverse events (8.3% of subjects).12 The double-blind treatment phase of REPRISE included only subjects who tolerated tolvaptan at a split dose of at least 60/30 mg during a preceding single-blind tolvaptan treatment phase. Compared with TEMPO 3:4, discontinuations were, therefore, less frequent during the double-blind phase of REPRISE: 15.0% of subjects in the tolvaptan arm discontinued treatment; 9.5% discontinued due to adverse events, and 2.1% discontinued due to aquaretic adverse events.13 Both trials were analyzed in accordance with the intention-to-treat principle, which mandates that outcome analyses are based on all subjects randomized to a treatment, without regard for noncompliance, protocol deviations, or early withdrawal.15,16 Intention-to-treat is an established feature of interventional clinical trial design intended to minimize bias in the estimation of treatment effect that would arise from the exclusion of subjects nonadherent to study treatment. The approach is mandated by many regulatory bodies, even if studies go on to also include additional per-protocol or as-treated analyses.17,18 However, it is widely recognized that in scenarios in which there are high levels of nonadherence to a trial treatment, intention-to-treat analysis may substantially underestimate the effect of a therapy.16 To evaluate the possibility that subjects who completed their respective trials on treatment would show a larger effect size than those who terminated treatment early, we conducted a post hoc analysis. The primary objective of this analysis was to assess the effects of tolvaptan on eGFR in subgroups of TEMPO 3:4 and REPRISE trial subjects who completed the follow-up period on treatment. A secondary objective was to explore the potential effects of treatment completion on the magnitude of treatment responses observed in TEMPO 3:4 and REPRISE. METHODS TEMPO 3:4 and REPRISE Trial Design and Population TEMPO 3:4 and REPRISE trial design and enrollment criteria have been described previously.12,13 Both were randomized, double-blind, placebo-controlled trials.