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Observational Study
. 2023 Jun 22;24(1):182.
doi: 10.1186/s12882-023-03247-6.

Effects of tolvaptan discontinuation in patients with autosomal dominant polycystic kidney disease: a post hoc pooled analysis

Michael Lioudis  1 , Xiaolei Zhou  2 , Eric Davenport  2 , Sasikiran Nunna  3 , Holly B Krasa  4 , Dorothee Oberdhan  5 , Ancilla W Fernandes  5
Affiliations
Observational Study

Effects of tolvaptan discontinuation in patients with autosomal dominant polycystic kidney disease: a post hoc pooled analysis

Michael Lioudis et al. BMC Nephrol. .

Abstract

Background: Tolvaptan slows kidney function decline in patients with autosomal dominant polycystic kidney disease (ADPKD) who are at risk of rapid progression. Given that treatment requires commitment to long-term use, we evaluated the effects of tolvaptan discontinuation on the trajectory of ADPKD progression.

Methods: This was a post hoc analysis of pooled data from two clinical trials of tolvaptan (TEMPO 2:4 [NCT00413777] and TEMPO 3:4 [NCT00428948]), an extension trial (TEMPO 4:4 [NCT01214421]), and an observational study (OVERTURE [NCT01430494]) that enrolled patients from the other trials. Individual subject data were linked longitudinally across trials to construct analysis cohorts of subjects with a tolvaptan treatment duration > 180 days followed by an off-treatment observation period of > 180 days. For inclusion in Cohort 1, subjects were required have ≥ 2 outcome assessments during the tolvaptan treatment period and ≥ 2 assessments during the follow-up period. For Cohort 2, subjects were required to have ≥ 1 assessment during the tolvaptan treatment period and ≥ 1 assessment during the follow-up period. Outcomes were rates of change in estimated glomerular filtration rate (eGFR) and total kidney volume (TKV). Piecewise-mixed models compared changes in eGFR or TKV in the on-treatment and post-treatment periods.

Results: In the Cohort 1 eGFR population (n = 20), the annual rate of eGFR change (in mL/min/1.73 m2) was -3.18 on treatment and -4.33 post-treatment, a difference that was not significant (P = 0.16), whereas in Cohort 2 (n = 82), the difference between on treatment (-1.89) and post-treatment (-4.94) was significant (P < 0.001). In the Cohort 1 TKV population (n = 11), TKV increased annually by 5.18% on treatment and 11.69% post-treatment (P = 0.06). In Cohort 2 (n = 88), the annual TKV growth rates were 5.15% on treatment and 8.16% post-treatment (P = 0.001).

Conclusions: Although limited by small sample sizes, these analyses showed directionally consistent acceleration in measures of ADPKD progression following the discontinuation of tolvaptan.

Keywords: Autosomal dominant polycystic kidney disease (ADPKD); Clinical trial; Glomerular filtration rate; Kidney volume; Tolvaptan; Treatment.

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Conflict of interest statement

ML is a member of a physician advisory board for Otsuka Pharmaceutical.

XZ and ED are employees of RTI Health Solutions (Research Triangle Park, NC), which was contracted by Otsuka to perform the analyses.

SN, DO, and AWF are employees of Otsuka Pharmaceutical Development & Commercialization, Inc (Princeton, NJ, USA).

HBK: employee of Otsuka 2001–2019; consultant for Otsuka 2019–2021.

Figures

Fig. 1
Fig. 1
Source studies for the pooled analysis. Post-treatment follow-up and pre-treatment baseline assessments were available in TEMPO 2:4, 3:4, and 4:4 and were used as off-treatment assessments as appropriate. SOC, standard of care management not including tolvaptan treatment; TOL, tolvaptan
Fig. 2
Fig. 2
Plots of a) eGFR and b) TKV over time for individual patients in Cohort 1. Patients are designated by color as Mayo risk class 1B–1E. a eGFR collected during the first week of treatment and first week posttreatment was removed. b Data points shown in the figure prior to time 0 (last dose of tolvaptan) were on-treatment assessments. Baseline assessments that were prior to the first dose of tolvaptan are not shown in the figure. eGFR, estimated glomerular filtration rate; TKV, total kidney volume
Fig. 3
Fig. 3
Decline in eGFR during the on-treatment and off-treatment periods. a Cohort 1; b Cohort 2. The estimations were calculated from the piecewise-mixed model using the mean baseline eGFR (shown as a blue circle at time 0) in the analysis set. The estimations during the on-treatment period (the green line segment) started at the first postbaseline assessment and ended at the mean duration of the tolvaptan treatment. For the off-treatment period (the red line segment), the estimations were calculated for the mean follow-up (off-treatment) time. The gap between the green and red line segments reflected the estimated reverse of hemodynamic effect following tolvaptan discontinuation. CI, confidence interval; eGFR, estimated glomerular filtration rate
Fig. 4
Fig. 4
Estimated logarithm of TKV during the on-treatment and off-treatment periods. a Cohort 1; b Cohort 2. The estimations were calculated from the piecewise-mixed model using the mean baseline log TKV (shown as a blue circle at time 0) in the analysis set. The estimations during the on-treatment period (the green line segment) started at the first postbaseline assessment and ended at the mean duration of the tolvaptan treatment. For the off-treatment period (the red line segment), the estimations were calculated for the mean follow-up (off-treatment) time. TKV, total kidney volume
See this image and copyright information in PMC

References

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