The TiME Trial: A Fully Embedded, Cluster-Randomized, Pragmatic Trial of Hemodialysis Session Duration

Abstract

Background: Data from clinical trials to inform practice in maintenance hemodialysis are limited. Incorporating randomized trials into dialysis clinical care delivery should help generate practice-guiding evidence, but the feasibility of this approach has not been established.

Methods: To develop approaches for embedding trials into routine delivery of maintenance hemodialysis, we performed a cluster-randomized, pragmatic trial demonstration project, the Time to Reduce Mortality in ESRD (TiME) trial, evaluating effects of session duration on mortality (primary outcome) and hospitalization rate. Dialysis facilities randomized to the intervention adopted a default session duration ≥4.25 hours (255 minutes) for incident patients; those randomized to usual care had no trial-driven approach to session duration. Implementation was highly centralized, with no on-site research personnel and complete reliance on clinically acquired data. We used multiple strategies to engage facility personnel and participating patients.

Results: The trial enrolled 7035 incident patients from 266 dialysis units. We discontinued the trial at a median follow-up of 1.1 years because of an inadequate between-group difference in session duration. For the primary analysis population (participants with estimated body water ≤42.5 L), mean session duration was 216 minutes for the intervention group and 207 minutes for the usual care group. We found no reduction in mortality or hospitalization rate for the intervention versus usual care.

Conclusions: Although a highly pragmatic design allowed efficient enrollment, data acquisition, and monitoring, intervention uptake was insufficient to determine whether longer hemodialysis sessions improve outcomes. More effective strategies for engaging clinical personnel and patients are likely required to evaluate clinical trial interventions that are fully embedded in care delivery.

Keywords: NIH Health Care Systems Research Collaboratory; TiME Trial; consent waiver; dialysis session duration; learning health system; opt-out consent.

Graphical abstract

Figure 1.

Flow for dialysis facilities and patients. HD, hemodialysis; V, volume.

Figure 2.

The difference in hemodialysis session durations between the intervention and usual care groups was less than targeted and decreased over follow-up time. The value shown at each month represents the per-participant mean value and 95% CIs over the preceding 30 days. Estimated session durations and their months were calculated using linear mixed effects models to account for both participants within the same facility and repeated measurements within the same participant. (A) Prescribed session duration for the primary analysis population (patients with Watson volume ≤42.5 L); slope −0.72 for intervention group; slope −0.50 for usual care group (P=0.07 for difference). (B) Prescribed session duration for the full analysis population (all patients); slope −0.41 for intervention group; slope −0.12 for usual care group (P<0.001 for difference). (C) Delivered session duration for the primary analysis population (patients with Watson volume ≤42.5 L); slope −0.87 for intervention group; slope −0.68 for usual care group (P=0.02 for difference). (D) Delivered session duration for the full analysis population (all patients); slope −0.59 for intervention group; slope −0.39 for usual care group (P<0.001 for difference).

Figure 3.

Kaplan-Meier survival curves indicate that mortality did not differ between the intervention and usual care groups. (A) Primary analysis population (patients with Watson volume ≤42.5 L). (B) Full analysis population (all patients).

Figure 4.

The distribution of session durations by patient for the full analysis population (all patients) indicates that the target session duration of ≥ than 4.25 hours was implemented for the majority of sessions by a small proportion of patients. Patients are ordered along the x-axis according to the percentage of sessions ≥4.25 hours throughout follow-up. (A) Prescribed session durations for the intervention group. (B) Prescribed session durations for the usual care group. (C) Delivered session durations for the intervention group. (D) Delivered session durations for the usual care group.